Pyrido-, pyrazo- and pyrimido-pyrimidine derivatives as mTOR inhibitors

Abstract

There is provided a compound of formula I: ##STR00001##
or a pharmaceutically acceptable salt thereof. There are also provided processes for the manufacture of a compound of Formula 1, and the use of a compound of Formula 1 as a medicament and in the treatment of cancer.

Claims

1. A pharmaceutical composition for treating cancer ameliorated by inhibition of mTOR in a warm blooded animal having said cancer comprising a therapeutically-effective amount of a compound of formula 1ap: ##STR00625## or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier, in combination with a cytostatic agent selected from: tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, iodoxyfene, bicalutamide, flutamide, nilutamide cyproterone acetate, goserelin, leuprorelin, buserelin, metestrol acetate, anastrozole, letrozole, vorazole, exemestane, and finasteride.

2. The pharmaceutical composition according to claim 1 wherein the cytostatic agent is fulvestrant.

3. A method of treating cancer ameliorated by inhibition of mTOR in a warm blooded animal having said cancer comprising administering to the animal an effective amount of a compound of formula 1ap: ##STR00626## or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier, in combination with a cytostatic agent selected from: tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, iodoxyfene, bicalutamide, flutamide, nilutamide cyproterone acetate, goserelin, leuprorelin, buserelin, metestrol acetate, anastrozole, letrozole, vorazole, exemestane, and finasteride.

4. The method according to claim 3 wherein the cytostatic agent is fulvestrant.

Description

EXAMPLES

(1) General Experimental Methods

(2) Thin Layer chromatography was carried out using Merck Kieselgel 60 F.sub.254 glass backed plates. The plates were visualized by the use of a UV lamp (254 nm). Silica gel 60 (particle sizes 40-63 m) supplied by E.M. Merck was employed for flash chromatography. .sup.1H NMR spectra were recorded at 300 MHz on a Bruker DPX-300 instrument. Chemical shifts were referenced relative to tetramethylsilane.

(3) Purification of Samples

(4) The samples were purified on Gilson LC units. Mobile phase A—0.1% aqueous TFA, mobile phase B—Acetonitrile; flow rate 6 ml/min; Gradient—typically starting at 90% A/10% B for 1 minute, rising to 97% after 15 minutes, holding for 2 minutes, then back to the starting conditions. Column: Jones Chromatography Genesis 4 μm, C18 column, 10 mm×250 mm. Peak acquisition based on UV detection at 254 nm.

(5) Identification of Samples

(6) QC Method QC2-AQ

(7) Mass spectra were recorded on a Waters ZQ instrument in Electrospray ionisation mode. Mobile phase A—0.1% aqueous formic acid. Mobile phase B—0.1% Formic acid in acetonitrile; Flowrate 2 ml/min; Gradient—starting at 100% A/0% B for 1 minute, rising to 95% B after 7 minutes and holding for 2 minutes before returning to the starting conditions. Column: Varies, currently Genesis AQ 120A 4u 50 mm×4.6 mm, Hichrom Ltd. PDA detection Waters 996, scan range 210-400 nm.

(8) QC Method QC2-Long

(9) Mass spectra were recorded on a Waters ZQ instrument in Electrospray ionisation mode. Mobile phase A—0.1% aqueous formic acid. Mobile phase B—0.1% Formic acid in acetonitrile; Flowrate 2 ml/min; Gradient—starting at 95% A/5% B, rising to 95% B after 20 minutes and holding for 3 minutes before returning to the starting conditions. Column: Varies, but always C18 50 mm×4.6 mm (currently Genesis C18 4u 50 mm×4.6 mm, Hichrom Ltd). PDA detection Waters 996, scan range 210-400 nm.

(10) QC Method QC2-QC

(11) Mass spectra were recorded on a Waters ZQ instrument in Electrospray ionisation mode. Mobile phase A—0.1% aqueous formic acid. Mobile phase B—0.1% Formic acid in acetonitrile; Flowrate 2 ml/min; Gradient—starting at 95% A/5% B, rising to 95% B after 5 minutes and holding for 5 minutes before returning to the starting conditions. Column: Varies, but always C18 50 mm×4.6 mm (currently Genesis C18 4 μm 50×4.6 mm, Hichrom Ltd). PDA detection Waters 996, scan range 210-400 nm.

(12) QC Method QC3-AQ-Long

(13) Mass spectra were recorded on a Waters ZQ instrument in Electrospray ionisation mode. Mobile phase A—0.1% aqueous formic acid. Mobile phase B—0.1% Formic acid in acetonitrile; Flowrate 2 ml/min; Gradient—starting at 100% A/0% B for 1 minute, rising to 95% B after 20 minutes and holding for 5 minutes before returning to the starting conditions. Column: Varies, currently Genesis AQ 4 μm 50 mm×4.6 mm, Hichrom Ltd. PDA detection Waters 996, scan range 210-400 nm.

(14) Examples 1u, 9a, 18bs, 18bv, 18bw, 18bx, 18by, 18bz, 18ca, 18cb, 18cc, 18cd, 18ce, 18cf, 18cg, 18ch, 18ci, 18cj, 18ck, 18cl, 18cm, 18dk, 18dl and 18dm were analysed using the QC Method QC2-AQ.

(15) Examples 12c, 12d, 13c, 13e, 13g, 14b, 15b, 18aa, 18ab, 18ac, 18ad, 18ae, 18af, 18ag, 18ah, 18ai, 18aj, 18ak, 18al, 18am, 18an, 18ao, 18ap, 18aq, 18ar, 18as, 18at, 18au, 18az, 18bc, 18bl, 18bm, 18bt, 18bu, 18cn, 18co, 18cp, 18cq, 18cr, 18cs, 18ct, 18cu, 18cv, 18cw, 18cx, 18cy, 18cz, 18da, 18db, 18dc, 18df, 18dj, 181, 18o, 18q, 18r, 18s, 18t, 18u, 18v, 18w, 18x, 18y, 18z, 19a, 19b, 19c, 19d, 19e, 19f, 19g, 19 h, 19i, 19j, 19k, 19l, 19m, 19n, 19o, 1a, 1aa, 1ab, 1ac, 1ad, 1ae, 1af, 1ag, 1ah, 1ai, 1ak, 1as, 1au, 1az, 1bb, 1cq, 1ct, 1dg, 1ee, 1g, 1i, 1m, 1w, 1x, 1y, 1z, 21a, 3a, 3ac, 3b, 3c, 3d, 3e, 3f, 3g, 3 h, 3i, 3j, 3v, 3w, 3x, 3y, 3z, 4j, 4k, 4l, 4m, 4n, 4o, 4p, 6a, comparative of Example 1c, comparative of Example 1j and comparative of Example 1k were analysed using the QC Method QC2-Long.

(16) Examples 10a, 11a, 12a, 12b, 12e, 13a, 13b, 13d, 13f, 14a, 15a, 15c, 16a, 17a, 18a, 18av, 18aw, 18ax, 18ay, 18b, 18ba, 18bb, 18bd, 18be, 18bf, 18bg, 18bh, 18bi, 18bj, 18bk, 18bn, 18bo, 18 bp, 18bq, 18br, 18c, 18d, 18dd, 18de, 18dg, 18dh, 18di, 18dn, 18do, 18e, 18f, 18g, 18 h, 18i, 18j, 18k, 18m, 18n, 19p, 19q, 19r, 19s, 19t, 19u, 19v, 19w, 19x, 1aj, 1al, 1am, 1an, 1ao, 1ap, 1aq, 1ar, 1at, 1av, 1aw, 1ax, 1ay, 1b, 1ba, 1bc, 1be, 1bf, 1bg, 1bh, 1bi, 1bj, 1bk, 1bl, 1bm, 1bn, 1bo, 1bp, 1bq, 1br, 1bs, 1bt, 1bu, 1bv, 1bw, 1bx, 1by, 1bz, 1c, 1ca, 1cb, 1cc, 1cd, 1ce, 1cf, 1cg, 1ch, 1ci, 1cj, 1ck, 1cl, 1cm, 1cn, 1co, 1cp, 1cr, 1cs, 1cu, 1cyv, 1cw, 1cx, 1cy, 1cz, 1d, 1da, 1db, 1dc, 1dd, 1de, 1df, 1dh, 1di, 1dj, 1dk, 1dl, 1dm, 1dn, 1do, 1dp, 1dq, 1dr, 1ds, 1dt, 1du, 1dv, 1dw, 1dx, 1dy, 1dz, 1e, 1ea, 1eb, 1ed, 1ee, 1f, 1h, 1j, 1k, 1l, 1n, 1o, 1p, 1q, 1r, 1s, 1t, 1v, 20a, 20b, 20c, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2 h, 2i, 2j, 3aa, 3ab, 3ad, 3k, 3l, 3m, 3n, 3o, 3p, 3q, 3r, 3s, 3t, 3u, 4a, 4aa, 4ab, 4ac, 4ad, 4ae, 4af, 4ag, 4ah, 4ai, 4aj, 4ak, 4al, 4am, 4an, 4ao, 4ap, 4aq, 4ar, 4as, 4at, 4au, 4av, 4aw, 4ax, 4ay, 4az, 4b, 4ba, 4bb, 4bc, 4bd, 4be, 4bf, 4c, 4d, 4e, 4f, 4g, 4 h, 4i, 4q, 4r, 4s, 4t, 4u, 4v, 4w, 4x, 4y, 4z, 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5 h, 5i, 5j, 5k, 5l, 5m, 5n, 5o, 5p, 5q, 5r, 5s, 5t, 5u, 5v, 5w, 5x, 5y, 5z, 7a, 7b, 7c, 7d, 7e, 7f, 7g, 7 h, 7i, 7j, 7k, 8a, 8b, 8c, 8d, comparative of Example 1a and comparative of Example 1b were analysed using the QC Method QC2-QC.

(17) Examples 18p and 1bd were analysed using the QC Method QC3-AQ-Long.

(18) Microwave Synthesis

(19) Reactions were carried out using a Personal Chemistry™ Emrys Optimiser microwave synthesis unit with robotic arm. Power range between. 0-300 W at 2.45 GHz. Pressure range between 0-20 bar; temperature increase between 2-5° C./sec; temp range 60-250° C.

(20) General Procedure for the Synthesis of 2,4,7-Substituted Pyridopyrimidine Derivatives:

(21) ##STR00070##

(22) ##STR00071##

(23) To the appropriate amino acid (1 equiv) was added liquid ammonia (sufficient to make a 0.6M solution of substrate in ammonia). The suspension was sealed in a pressure vessel which was then heated slowly to 130° C. It was noted that at this temperature a pressure of 18 bar was observed. This temperature and pressure was maintained for a further 16 hours whereupon the mixture was cooled to room temperature. The pressure vessel was opened and the reaction poured into ice cold water (1 reaction volume). The resulting solution was acidified to pH 1-2 using concentrated HCl which caused a precipitate to form. The acidic mixture was allowed to warm to room temperature and was stirred like this for a further 30 min The suspension was then extracted with diethyl ether (3×400 ml). The combined organic extracts were then filtered and the filtrate concentrated in vacuo to give a white solid which was dried further over P.sub.2O.sub.5 to give the title compound (typically 80-90% yield and 90%+ pure) in suitably pure form to be used without any further purification.

(24) 2-amino-6-chloronicotinic acid—X═N, Y═C, Z═C: (90% yield, 96% purity) m/z (LC-MS, ESP): 173 [M+H].sup.+ R/T=3.63 min

(25) ##STR00072##

(26) To a 0.3 M solution of amino acid (1 equiv) in anhydrous THF, under an inert atmosphere, was added thionyl chloride (3.3 equiv) in a dropwise fashion. The reaction mixture was stirred at room temperature for 2 hours. After this time the reaction was concentrated in vacuo to give a crude yellow solid residue. The crude solid was dissolved in THF (equal to initial reaction volume) and concentrated in vacuo again to give a yellow solid residue. The residue was dissolved once more in THF and concentrated as before to give a solid residue which was then dissolved in THF (to give a solution of 0.3M) and ammonia gas bubbled through the solution for 1 hour. The resultant precipitate was removed by filtration and the filtrate concentrated in vacuo to give a yellow precipitate which was triturated with water at 50° C. then dried to give the title compound (typically 90-95%) yield and suitably clean enough to be used without any further purification.

(27) 2-Amino-6-chloronicotinamide—X═N, Y═C, Z═C: (92% yield, 93% purity) m/z (LC-MS, ESP): 172 [M+H].sup.+ R/T=3.19 min

(28) ##STR00073##

(29) To a stirred solution (0.06 M) of substrate (1 equiv) in anhydrous toluene under an inert atmosphere was added oxalyl chloride (1.2 equiv) in a dropwise manner. The resulting mixture was then heated to reflux (115° C.) for 4 hours whereupon it was cooled and stirred for a further 16 hours. The crude reaction mixture was then concentrated to half its volume in vacuo and filtered to give the desired product in suitably pure form to be used without any further purification.

(30) 7-Chloro-1H-pyrido[2,3-d]pyrimidine-2,4-dione—X═N, Y═C, Z═C: (95% yield, 96% purity) m/z (LC-MS, ESP): 196 [M−H].sup.− R/T=3.22 min

(31) ##STR00074##

(32) To a stirred 0.5 M suspension of the appropriate dione (1 equiv) in anhydrous toluene under an inert atmosphere was slowly added diisopropylethylamine (3 equiv). The reaction mixture was then heated to 70° C. for 30 minutes and then cooled to room temperature prior to the addition of POCl.sub.3 (3 equiv). The reaction was then heated to 100° C. for 2.5 hours before being cooled and concentrated in vacuo to give a crude slurry which was then suspended in EtOAc and filtered through a thin pad of Celite™. The filtrate was concentrated in vacuo to give a brown, oil which was dissolved in CH.sub.2Cl.sub.2 and stirred over silica gel for 30 minutes. After this time the silica was removed by filtration, the filtrate concentrated and the crude residue purified by flash chromatography (SiO.sub.2) to give the title compound in analytically pure form.

(33) 2,4,7-Trichloro-pyrido[2,3-d]pyrimidine—X═N, Y═C, Z═C: (48% yield, 96% purity) m/z (LC-MS, ESP): 234 [M+H].sup.+ R/T=4.21 min

(34) ##STR00075##

(35) To a cooled (0-5° C.) stirred solution (0.1 M) of the appropriate trichloro-substrate (1 equiv) in CH.sub.2Cl.sub.2 was added diisopropylethylamine (1 equiv) in a dropwise fashion. The appropriate amine (1 equiv) was then added to the reaction mixture portionwise over the period of 1 hour. The solution was maintained at room temperature with stirring for a further 1 hour before the mixture was washed with water (2×1 reaction volume). The aqueous extracts were combined and extracted with CH.sub.2Cl.sub.2 (2×1 reaction volume). The organic extracts were then combined, dried (sodium sulphate), filtered and concentrated in vacuo to give an oily residue which solidified upon prolonged drying. The solid was triturated with diethylether and then filtered and the cake washed with cold diethyl ether to leave the title compound in suitable clean form to be used without any further purification.

(36) 2,7-Dichloro-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine—R1=morpholine, X═N, Y═C, Z═C: (92% yield, 90% purity) m/z (LC-MS, ESP): 285 [M+H].sup.+ R/T=3.90 min

(37) 2,7-Dichloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine—R1=(S)-3-Methyl-morpholine, X═N, Y═C, Z═C: (87% yield, 92% purity) m/z (LC-MS, ESP): 301 [M+H].sup.+ R/T=4.13 min

(38) 2,7-Dichloro-4-((R)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine—R1=(R)-3-Methyl-morpholine: (99% yield, 94% purity) m/z (LC-MS, ESP): 301 [M+H].sup.+ R/T=3.49 min

(39) Alternatively, to a stirred 0.47 M suspension of the appropriate dione (1 equiv) in anhydrous anisole under an inert atmosphere was added POCl.sub.3 (2.6 equiv). The mixture was heated to 55° C. and then diisopropylethylamine (2.6 equiv) was slowly added. The reaction mixture was then heated to 85-90° C. for 30 minutes. Water was added in portions (0.15 equiv), and the reaction mixture was held at 85-90° C. for a further 30 minutes. The reaction was cooled to 50° C., and then 15% of the anisole solvent was removed by vacuum distillation. The mixture was then cooled to −5° C. and diisopropylethylamine (1.1 equiv) was added. A 4.9M solution of the appropriate amine (1.05 equiv) in anisole was then added to the reaction mixture continuously over a period of 1 hour. The solution was then warmed to 30° C. and the reaction monitored by HPLC until reaction completion.

(40) One third of the resulting mixture from the above reaction was then added over 10 min to a stirred mixture of 1.95M aqueous potassium hydroxide (3.9 equiv) and i-butanol (6.9 equiv) at 60° C. The stirring was stopped, the phases were allowed to separate, and the aqueous phase was removed. Stirring was resumed, and 1.95M aqueous potassium hydroxide (3.9 equiv) was added to the retained organic phase. The second third of the resulting reaction mixture from the reaction above was then added over 10 min at 60° C. Again, stirring was stopped, the phases were allowed to separate, and the aqueous phase was removed. Stirring was resumed, and 1.95M aqueous potassium hydroxide (3.9 equiv) was added to the retained organic phase. The remaining third of the resulting reaction mixture from the reaction above was then added over 10 min at 60° C. Again, stirring was stopped, the phases were allowed to separate, and the aqueous phase was removed. Water was then added to the organic phase with stirring, and the stirred mixture heated to 75° C. Stirring was stopped, the phases were allowed to separate, and the aqueous phase was removed. The resulting organic phase was stirred and allowed to cool to 30° C., and then as the mixture was heated to 60° C. heptane (11.5 equiv) was added over 20 min when the mixture was around 40° C. After being heated to 60° C., the mixture was cooled over 2.5 h to 10° C. After 30 min, the resulting slurry was filtered off, washed with a 10:1 heptane:anisole mixture (2×1.4 equiv) and then washed with heptane (2×1.4 equiv). The solid was then dried in a vacuum oven at 50° C. to leave the title compound in suitable clean form to be used without any further purification.

(41) ##STR00076##

(42) To a solution (0.2 M) of the appropriate dichloro-substrate (1 equiv) in anhydrous dimethyl acetamide under an inert atmosphere was added diisopropylethylamine (1 equiv) followed by the appropriate amine (1 equiv). The resulting mixture was heated for 48 hours at 70° C. before being cooled to ambient temperature. The reaction was diluted with CH.sub.2Cl.sub.2 (1 reaction volume) and then washed with water (3×1 reaction volumes). The organic extract was concentrated in vacuo to give a syrup which was dissolved in EtOAc (1 reaction volume) and washed with saturated brine solution before being dried (sodium sulphate) and concentrated in vacuo to give an oil. The crude residue was purified by flash chromatography (SiO.sub.2, eluted with EtOAc:Hex (7:3) going to (1:1)) to give the title compound as a yellow solid that was suitably clean to be used without any further purification.

(43) 7-Chloro-2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine—R1=morpholine, R2=cis-dimethylmorpholine, X═N, Y═C, Z═C: (45% yield, 85% purity) m/z (LC-MS, ESP): 348 [M+H].sup.+ R/T=4.16 min

(44) 7-Chloro-4-((S)-3-methyl-morpholin-4-yl)-2-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine—R1=(S)-3-Methyl-morpholine, R2=(S)-3-Methyl-morpholine, X═N, Y═C, Z═C: (71% yield, 90% purity) m/z (LC-MS, ESP): 364 [M+H].sup.+ R/T=3.52 min

(45) 7-Chloro-2-(2-ethyl-piperidin-1-yl)-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine—R1=(S)-3-Methyl-morpholine, R2=2-Ethyl-piperidine, X═N, Y═C, Z═C: (51% yield, 98% purity) m/z (LC-MS, ESP): 376 [M+H].sup.+ R/T=3.88 min

(46) 7-Chloro-4-((S)-3-methyl-morpholin-4-yl)-2-morpholin-4-yl-pyrido[2,3-d]pyrimidine—R1=(S)-3-Methyl-morpholine, R2=morpholine, X═N, Y═C, Z═C: (72% yield, 96% purity) m/z (LC-MS, ESP): 350 [M+H].sup.+ R/T=3.45 min

(47) 7-Chloro-2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-4-((S)-3-methyl-morpholin-4-yl-pyrido[2,3-d]pyrimidine—R1=(S)-3-Methyl-morpholine, R2=cis-dimethylmorpholine: (33% yield) m/z (LC-MS, ESP): 378 [M+H].sup.+ R/T=3.68 min

(48) 7-Chloro-4-((R)-3-methyl-morpholin-4-yl)-2-((R)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine—R1=R2=(R)-3-Methyl-morpholine: (48% yield, 100% purity) m/z (LC-MS, ESP): 364 [M+H].sup.+ R/T=2.80 min

(49) To a 0.33 M solution of 2,7-dichloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine (1 equiv) in N,N-dimethylacetamide was added Hunig's base (1 equiv) followed by the appropriate amine (1.1 equiv). The reaction mixture was heated 40° C. for 1 hour. After this time the reaction was allowed to cool, diluted with EtOAc (1 reaction volume) and then washed with water (1 reaction volume). The aqueous fraction was removed and extracted further with EtOAc (2×1 reaction volume). The combined organic extracts were dried (MgSO.sub.4), filtered and concentrated in vacuo to give a crude oily residue which was purified by flash chromatography (SiO.sub.2) using EtOAc/Hexanes as eluent which furnished the desired products in a suitably clean form.

(50) 7-Chloro-4-((S)-3-methyl-morpholin-4-yl)-2-thiomorpholin-4-yl-pyrido[2,3-d]pyrimidine: (30% yield, 100% purity) m/z (LC-MS, ESP): 366.4[M+H].sup.+ R/T=3.00 min

(51) 7-Chloro-4-((S)-3-methyl-morpholin-4-yl)-2-(4-methyl-piperazin-1-yl)-pyrido[2,3-d]pyrimidine: (32% yield, 95% purity) m/z (LC-MS, ESP): 363.4[M+H].sup.+ R/T=2.37 min

(52) ##STR00077##

(53) The appropriate chloro-substrate (1 equiv) was dissolved in a toluene/ethanol (1:1) solution (0.02 M). Sodium carbonate (2 equiv) and the appropriate pinacolate boron ester or boronic acid (1 equiv) were then added followed by tetrakis(triphenylphosphine)palladium.sup.0 (0.1 equiv). The reaction vessel was sealed and the mixture exposed to microwave radiation (140° C., medium absorption setting) for 30 minutes. Upon completion the samples were filtered through a silica cartridge, washed with EtOAc and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

Example 1

Preparation of 2,4,7-substituted pyridopyrimidine Intermediates

Procedures for the synthesis of 2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-7-aryl-pyrido[2,3-d]pyrimidine derivatives

(54) ##STR00078##

(55) To a (0.1 M) solution of 2,7-dichloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine (1 equiv) in MeCN/H.sub.2O (1:1 mixture) was added the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and potassium carbonate (3 equiv). The mixture was degassed with nitrogen for 20 minutes before the addition of tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction was degassed for a further minutes before being heated to reflux under an inert atmosphere for 3 hours. Whereupon, it was concentrated in vacuo and the crude residue partitioned between CH.sub.2Cl.sub.2/H.sub.2O. The organic fraction was dried (MgSO.sub.4), filtered and concentrated in vacuo to give an oil which was further purified by flash chromatography (SiO.sub.2) using 5% MeOH in CH.sub.2Cl.sub.2 as eluent.

(56) ##STR00079##

(57) 3-[2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-benzamide: (27% yield, 99% purity) m/z (LC-MS, ESP): 384.3 [M+H].sup.+, R/T=3.13 min)

(58) ##STR00080##

(59) 5-[2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-ylamine: (93% yield, 89% purity) m/z (LC-MS, ESP): 357 [M+H].sup.+, R/T=2.53 min)

(60) ##STR00081##

(61) 2-Chloro-7-(4-chloro-phenyl)-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine: (80% yield, 85% purity) m/z (LC-MS, ESP): 357.5 [M+H].sup.+, R/T=4.26 min)

(62) ##STR00082##

(63) {5-[2-Chloro-4-((R)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl}-methanol: (97% yield, 93% purity) m/z (LC-MS, ESP): 401 [M+H].sup.+, R/T=3.42 min)

(64) Procedures for the Synthesis of Boronic Ester:

(65) ##STR00083##

(66) 5-bromo-2-methoxybenzoic acid methyl ester (1 equiv) was dissolved in dioxane (0.1 M). Bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv) were added and the mixture was degassed with nitrogen for 20 minutes. (1,1′-Bis(diphenylphosphino)ferrocene-dichloropalladium (0.05 equiv) was added and the mixture was degassed for a further 5 minutes. The reaction mixture was heated to 120° C. for 2 hours under nitrogen. After cooling to room temperature, the reaction mixture was diluted with CH.sub.2Cl.sub.2 and filtered through Celite™. The filtrate was concentrated in vacuo to give a dark oil. The residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate and the aqueous layer further extracted with EtOAc. The combined organic phases were dried (MgSO.sub.4), filtered and the filtrate was concentrated in vacuo to give a dark residue which was purified by flash column chromatography onto silica gel eluting with 0 to 30% ethyl acetate in hexane.

(67) ##STR00084##

(68) 2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester: (77% yield, 100% purity) m/z (LC-MS, ESP): 293.5 [M+H].sup.+ R/T=4.24 min

(69) Procedures for the Synthesis of Tetrazolyl Boronic Acids:

(70) ##STR00085##

(71) The appropriate cyanophenylpinacolate boron ester or boronic acid (1 equiv) was dissolved in DMF (0.67 M). Sodium azide (6 equiv) and ammonium chloride (6 equiv) were added. The reaction mixture was heated to 120° C. for 2.5 hours. After cooling down, the reaction mixture was poured into a mixture of ice water and EtOAc. Sodium nitrite was added and the aqueous phase was acidified by 6N HCl until pH 2. The mixture was allowed to stir at room temperature for 30 min and then was extracted with EtOAc and n-butanol. Organic fractions were collected, dried over sodium sulphate, filtered off and concentrated in vacuo, to yield a crude residue which was further purified accordingly:

(72) ##STR00086##

(73) The crude residue was recrystallized from CH.sub.2Cl.sub.2/hexane, obtaining the desired product as a white solid.

(74) [3-(1H-tetrazol-5-yl)phenyl]boronic acid: (15% yield, 100% purity) m/z (LC-MS, ESP): 191 [M+H].sup.+ R/T=2.49 min

(75) ##STR00087##

(76) The crude residue was recrystallized from CH.sub.2Cl.sub.2/hexane, to give the desired product as a white solid.

(77) [4-(1H-tetrazol-5-yl)phenyl]boronic acid: (64% yield, 100% purity) m/z (LC-MS, ESP): 191 [M+H].sup.+ R/T=2.49 min

(78) ##STR00088##

(79) The residue was purified by reverse phase column using a gradient from 5% to 20% acetonitrile in 0.1% formic acid/water solution, yielding the desired product. [4-fluoro-3-(1H-tetrazol-5-yl)phenyl]boronic acid: (18% yield, 100% purity) m/z (LC-MS, ESP): 207 [M−H].sup.− R/T=2.51 min

(80) Procedure for the Synthesis of Methanesulfonylamido Boronic Acid:

(81) ##STR00089##

(82) 3-Amino-4-fluorophenylboronic acid (1 equiv) was dissolved in THF (0.1 M). Methane sulphonyl chloride (10 equiv) and pyridine (1 equiv) were added. The reaction mixture was heated to 70° C. for 30 minutes. After cooling down, the reaction mixture was concentrated in vacuo, to yield a crude residue which was used without further purification.

(83) ##STR00090##

(84) 3-(Methanesulfonylamino)-4-fluoro-phenylboronic acid: (51% yield, 90% purity) m/z (LC-MS, ESP): 232 [M−H].sup.− R/T=2.50 min

Procedure for the synthesis of 3-hydroxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ol

(85) ##STR00091##

(86) To a 0.18 M solution of 5-bromo-2-hydroxybenzyl alcohol (1 equiv) in dioxane was added bis(pinacolato)diboron (1.2 equiv) and potassium acetate (3.5 equiv) followed by 1,1′-bis(diphenylphosphino)ferrocene (0.05 equiv). The mixture was degassed with nitrogen for 20 minutes. PdCl.sub.2(dppf) (0.05 equiv) was added and the mixture degassed for a further 5 minutes. The reaction was then heated to reflux under an inert atmosphere for 2 hours. Upon completion, the reaction was cooled, filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO.sub.2) using EtOAc/Hexanes—1:1 as eluent to give the desired product.

(87) 3-Hydroxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ol 6-Bromo-3H-pyrido[2,3-d]pyrimidin-4-one: (67% yield, 94% purity) m/z (LC-MS, ESP): 251 [M−H].sup.− R/T=3.32 minutes)

Procedure for the synthesis of 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one

(88) ##STR00092##

(89) To a 0.05 M solution of 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (1 equiv) in dioxane was added bis(pinacolato)diboron (1.2 equiv) and potassium acetate (1.5 equiv) followed by 1,1′-bis(diphenylphosphino)ferrocene (0.05 equiv). The mixture was degassed with nitrogen for 20 minutes. PdCl.sub.2(dppf) (0.05 equiv) was added and the mixture degassed for a further 5 minutes. The reaction was then heated to 120° C. under an inert atmosphere for 8 hours. Upon completion, the reaction was cooled, filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO.sub.2) using EtOAc/Hexanes—4:1 as eluent to give the desired product.

(90) 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one: (68% yield, 92% purity) m/z (LC-MS, ESP): 260 [M−H].sup.− R/T=3.52 minutes)

Procedure for the synthesis of 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one boronic ester

(91) ##STR00093##

(92) To a 1.2 M solution of 5-bromoanthranilic acid (1 equiv) in N,N-dimethylformamide was added formamidine acetate (1 equiv). The mixture was heated to reflux and stirred at this temperature for 16 hours. After this time, the reaction was cooled and NaHCO.sub.3 solution (5% in H.sub.2O) (3 volumes) were carefully added and the mixture stirred vigorously. The resulting precipitate was collected by filtration and then washed with water (2×1 volume) and then t-butyl methylether (2×1 volume) before being dried in a vacuum oven to give the desired product which required no further purification.

(93) 6-Bromo-3H-pyrido[2,3-d]pyrimidin-4-one: (91% yield, insert) m/z (LC-MS, ESP): 225 [M−H].sup.− R/T=2.31 minutes)

(94) To a (0.35M) solution of 6-bromo-3H-pyrido[2,3-d]pyrimidin-4-one (1 equiv) in dioxane was added bis(pinacolato)diboron (1.2 equiv) and potassium acetate (1.5 equiv) followed by 1,1′-bis(diphenylphosphino)ferrocene (0.05 equiv). The mixture was degassed with nitrogen for 20 minutes. PdCl.sub.2(dppf) (0.05 equiv) was added and the mixture degassed for a further 5 minutes. The reaction was then heated to reflux under an inert atmosphere for 16 hours. After this time, the mixture was cooled, filtered through Celite™ and then partitioned between CH.sub.2Cl.sub.2/NaHCO.sub.3(aq). The organic fraction was removed, dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO.sub.2) 1:1-Hexanes:EtOAc going to neat EtOAc. The purified material was then dissolved in the minimum volume of CH.sub.2Cl.sub.2 and hexane added in order to precipitate the desired product as a whiter crystalline solid

(95) 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one (15% yield, 96% purity) m/z (LC-MS, ESP): Mass ion not observable, R/T=3.30 min)

Procedure for the synthesis of 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrido[2,3-b][1,4]oxazin-2-one

(96) ##STR00094##

(97) To a 0.3 M solution of 7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2-one (1 equiv) were added bis(pinacolato)diboron (1.10 equiv), potassium acetate (3.5 equiv) and 1,1′-bis(diphenylphosphino)ferrocene (0.05 equiv). The mixture was degassed with nitrogen for 20 minutes before the addition of PdCl.sub.2(dppf) (0.05 equiv) and degassing for a further 5 minutes. A condenser was attached to the reaction vessel and the mixture heated to reflux under an inert atmosphere for 16 hours. After this time, the reaction was cooled, filtered through Celite™. The cake was washed CH.sub.2Cl.sub.2 and the filtrate concentrated in vacuo before being re-dissolved in EtOAc and washed with H.sub.2O and then saturated brine. The organic fraction was separated, dried (MgSO.sub.4) and concentrated in vacuo to give a crude residue which was further purified by flash chromatography (SiO.sub.2) using 1:1-EtOAc:Hexanes going to neat EtOAc as eluent to give the desired product.

(98) 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrido[2,3-b][1,4]oxazin-2-one: (97% yield, 90% purity) m/z (LC-MS, ESP): 317 [M+H+MeCN], R/T=3.72 min)

Procedure for the Synthesis of 2-Methoxynicotinonitrile-5-Boronic Acid

(99) ##STR00095##

(100) To a cooled (−78° C.) solution (0.25 M) of 5-bromo-2-methoxybenzonitrile in THF was added n-BuLi (1.10 equiv of a 2.5 M solution in hexanes) dropwise. The mixture was maintained at this temperature with stirring for 45 minutes before the addition of triisopropylborate (1.25 equiv). The reaction was then warmed to −20° C. before the addition of 1N HCl (0.5 reaction volumes). The mixture was allowed to warm to room temperature and stirred like this for a further 20 minutes. After this time the mixture was diluted with H.sub.2O and then extracted with Et.sub.2O (3×4 reaction volumes). The combined organic fractions were then dried (MgSO.sub.4), filtered and concentrated in vacuo to give an off white solid which corresponded to the title compound

(101) 2-Methoxynicotinonitrile-5-boronic acid: (44% yield, 90% purity) m/z (LC-MS, ESP): 177.0 [M+H].sup.+, R/T=2.87 min)

Procedure for the Synthesis of 2-Ethoxynicotinonitrile-5-Boronic Acid

(102) ##STR00096##

(103) To a cooled (−78° C.) solution (0.25 M) of 5-bromo-2-ethoxybenzonitrile in THF was added n-BuLi (1.10 equiv of a 2.5 M solution in hexanes) dropwise. The mixture was maintained at this temperature with stirring for 45 minutes before the addition of triisopropylborate (1.25 equiv). The reaction was then warmed to −20° C. before the addition of 1N HCl (0.5 reaction volumes). The mixture was allowed to warm to room temperature and stirred like this for a further 20 minutes. After this time the mixture was diluted with H.sub.2O and then extracted with Et.sub.2O (3×4 reaction volumes). The combined organic fractions were then dried (MgSO.sub.4), filtered and concentrated in vacuo to give an off white solid which corresponded to the title compound.

(104) 2-Ethoxynicotinonitrile-5-boronic acid: (23% yield, 97% purity) m/z (LC-MS, ESP): 191.0 [M+H].sup.+, R/T=3.09 min)

Procedure for the Synthesis of 2-Isopropoxynicotinonitrile-5-Boronic Acid

(105) ##STR00097##

(106) To a cooled (−78° C.) solution (0.25 M) of 5-bromo-2-isopropoxy-nicotinonitrile in THF was added n-BuLi (1.10 equiv of a 2.5 M solution in hexanes) dropwise. The mixture was maintained at this temperature with stirring for 45 minutes before the addition of triisopropylborate (1.25 equiv). The reaction was then warmed to −20° C. before the addition of 1N HCl (0.5 reaction volumes). The mixture was allowed to warm to room temperature and stirred like this for a further 20 minutes. After this time the mixture was diluted with H.sub.2O and then extracted with Et.sub.2O (3×4 reaction volumes). The combined organic fractions were then dried (MgSO.sub.4), filtered and concentrated in vacuo to give an off white solid which which was triturated with CH.sub.2Cl.sub.2 to give the desired compound.

(107) 2-Isopropoxy-nicotinonitrile-5-boronic acid: (100% yield, 97% purity) m/z (LC-MS, ESP): 204.2 [M+H].sup.−, R/T=3.25 min)

Procedure for the synthesis of 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-phthalazin-1-one

(108) ##STR00098##

(109) To a 3M solution of 5-bromo-2-formyl benzoic acid (1 equiv) in water was added hydrazine hydrate (5 equivs). The reaction was heated to 95° C. for 4 hours whereupon a white precipitate had formed in the mixture. The reaction was cooled, and filtered. The white solid material was washed with cold methanol and dried to give the desired product.

(110) 7-Bromo-2H-phthalazin-1-one: (73% yield, 95% purity) m/z (LC-MS, ESP): 225.2 [M+H].sup.+, R/T=2.99 min)

(111) Bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and 1,1′-bis(diphenylphosphino)ferrocene (0.05 equiv) were dissolved in dioxane. The mixture was degassed with nitrogen for 20 minutes before the addition of PdCl.sub.2(dppf) (0.05 equiv). The mixture was degassed for a further 5 minutes. The mixture was heated to reflux for 16 hours and then allowed to cool to room temperature. Water was added to the mixture before it was extracted with EtOAc (2×2 reaction volumes). The combined organic fractions were dried (MgSO.sub.4), filtered and concentrated in vacuo before being purified by flash chromatography (SiO.sub.2) neat hexanes going to 1:1—Hexanes:EtOAc then neat EtOAc to give the desire product as a white crystalline solid.

(112) 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-phthalazin-1-one: (86% yield, 92% purity) m/z (LC-MS, ESP): 191.3 [M+H].sup.+, R/T=2.29 min)

Procedure for the synthesis of 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one

(113) ##STR00099##

(114) 5-Bromo-2-methylbenzoic acid (1 equiv) was dissolved in a 1:9 MeOH/toluene mixture (0.1 M). The reaction mixture was cooled to 0° C. and a trimethylsilyldiazomethane (1.05 equiv) solution in diethylether (2M) was added slowly until a persistent yellow tinge was observed. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The resulting residue was sonicated in hexane, collected by vacuum filtration over a sintered funnel, dried and used without further purification.

(115) 5-Bromo-2-methyl-benzoic acid methyl ester: (99% yield, 100% purity) m/z (LC-MS, ESP): no ionisation R/T=4.43 min

(116) ##STR00100##

(117) To a solution of 5-Bromo-2-methyl-benzoic acid methyl ester (1 equiv) in chloroform (0.1 M) were added N-bromosuccinimide (1.2 equiv) and benzoyl peroxide (0.05 equiv). The reaction mixture was stirred at reflux for 16 hours. It was then diluted with chloroform and a precipitate was collected by vacuum filtration on a sintered funnel. The filtrate was concentrated in vacuo. The subsequent residue was purified by flash column chromatography onto silica gel eluting with DCM in hexane (0 to 20%) to yield the desired product as a clear colourless oil.

(118) 5-Bromo-2-bromomethyl-benzoic acid methyl ester: 80% yield, 100% purity) m/z (LC-MS, ESP): no ionisation R/T=4.40 min

(119) ##STR00101##

(120) A solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1 equiv) in a 1:1 THF/MeOH mixture was treated by gentle bubbling of ammonia gas for 40 minutes at room temperature. The reaction mixture was concentrated in vacuo. The residue was sonicated in CH.sub.2Cl.sub.2 for 15 minutes then filtered to give the desired product as a white solid.

(121) 6-Bromo-2,3-dihydro-isoindol-1-one: (98% yield, 90% purity) m/z (LC-MS, ESP): 212.3/214.3 [M+H].sup.+ R/T=2.98 min

(122) ##STR00102##

(123) To a solution of 6-bromo-2,3-dihydro-isoindol-1-one (1 equiv) in dry dioxan (0.1 M) were added bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv). The reaction mixture was degassed with nitrogen for 20 minutes. PdCl.sub.2(dppf) (0.05 equiv) was added to the reaction mixture, which was degassed for a further 5 minutes. The reaction mixture was heated to 70° C. for 2 hours under nitrogen then heated to 120° C. for 16 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic phases dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was sonicated in EtOAc, the suspension was filtered onto a sintered funnel and the collected grey solid was dried and used without further purification.

(124) 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one: (82% yield, 29% purity, main impurity being the boronic acid 43%) m/z (LC-MS, ESP): 519.5 [2M+H]R/T=3.38 min

Procedure for the synthesis of 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione

(125) ##STR00103##

(126) ##STR00104##

(127) To a solution of 5-bromoisatoic anhydride (1 equiv) in water (1 M) was added glycine (1.4 equiv) and triethylamine (1 equiv) at room temperature. The reaction mixture was stirred at room temperature for 4 hours to give a cloudy solution. The reaction mixture was concentrated in vacuo. Acetic acid was added and the reaction mixture was stirred at 140° C. for 4.5 hours. The reaction mixture was cooled down slowly to room temperature. A precipitate was formed. The reaction mixture was diluted with diethyl ether then filtered through a sintered funnel to yield the desired product.

(128) 7-Bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione: (75% yield, 100% purity) m/z (LC-MS, ESP): 255.2/257.2 [M+H].sup.+ R/T=2.67 min

(129) ##STR00105##

(130) To a solution of 7-bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (1 equiv) in dry dioxan (0.1 M) were added bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv). The reaction mixture was degassed with nitrogen for 20 minutes. PdCl.sub.2(dppf) (0.05 equiv) was added to the reaction mixture, which was degassed for a further 5 minutes. The reaction was heated to 120° C. for 16 hours under nitrogen. The reaction mixture was partitioned between CH.sub.2Cl.sub.2/MeOH and water. The aqueous phase was further extracted with CH.sub.2Cl.sub.2/MeOH. The combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was sonicated in hexane/CH.sub.2Cl.sub.2, filtered, sonicated in CH.sub.2Cl.sub.2 and filtered to yield the desired product.

(131) 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione: (63% yield, 85% purity main impurity being the boronic acid 15%) m/z (LC-MS, ESP): 303.4 [M+H].sup.+ R/T=3.08 min

(132) ##STR00106##

(133) To a solution of 2-amino-4-bromobenzoic acid (1 equiv) in DMA (0.23 M), were added ammonium chloride (7 equiv), HBTU (1 equiv) and diisopropylethylamine (2 equiv). The reaction mixture was stirred for 24 hours at room temperature. DMA was evaporated and the residue was purified by flash column chromatography onto silica gel eluting with a gradient of TBME/hexane to yield the desired product as a white solid.

(134) 2-Amino-4-bromo-benzamide: 40% yield, 100% purity) m/z (LC-MS, ESP): 215 [M+H]R/T=3.00 min

(135) ##STR00107##

(136) To a solution of 2-amino-4-bromo-benzamide (1 equiv) in DMA (0.14 M) were added triethyl orthoformate (10 equiv) and trifluoroacetic acid (1 equiv). The reaction vessel was sealed and exposed to microwave radiation (160° C., medium absorption setting) for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was filtered through a silica pad with 10% methanol in ethyl acetate yielding the required product as a pale yellow solid. 7-Bromo-3H-quinazolin-4-one: (71% yield, 100% purity) m/z (LC-MS, ESP): 268 [M+H]R/T=2.94 min

(137) ##STR00108##

(138) To a solution of 7-bromo-3H-quinazolin-4-one (1 equiv) in dioxane (0.04 M) were added bispinacolato diboron (2.2 equiv), potassium acetate (1.5 equiv), dppf (0.1 equiv) and PdCl.sub.2(dppf) (0.1 equiv). The reaction mixture was degassed with nitrogen for 5 minutes, sonicated and stirred at 120° C. for 3 hours. The reaction mixture was concentrated in vacuo. The residue was filtered through a Celite™ pad topped with silica with ethyl acetate. The mother liquor was concentrated in vacuo yielding a brown solid which was further purified by flash column chromatography onto silica gel eluting with a gradient of methanol/diethyl ether (0 to 5%) to yield the desired product as a white solid.

(139) 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-quinazolin-4-one: (53% yield, 61% purity main impurity being the boronic acid 39%) m/z (LC-MS, ESP): [M+H].sup.+ R/T=min

(140) ##STR00109##

(141) To a solution of 6-bromo-2-oxindole (1 equiv) in NMP (0.05 M) were added bispinacolato diboron (2.4 equiv), potassium acetate (1.5 equiv), dppf (0.05 equiv) and PdCl.sub.2(dppf) (0.05 equiv). The reaction mixture was stirred at 130° C. for 3 hours and then concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel eluting with EtOAc/hexane (9/1), yielding the desired product as a red solid.

(142) 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one: (22% yield, 51% purity main impurity being the boronic acid 28%) m/z (LC-MS, ESP): 260 [M+H].sup.+ R/T=3.51 min

Procedure for the synthesis of 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one

(143) ##STR00110##

(144) 4-Bromo-2-bromomethyl-benzoic acid methyl ester was prepared according to literature. A solution of 4-bromo-2-bromomethyl-benzoic acid methyl ester (1 equiv) in a 1:1 THF/MeOH mixture was treated by gentle bubbling of ammonia gas for 4 hours at room temperature. The reaction mixture was concentrated in vacuo. The residue was sonicated in water, filtered, then sonicated in diethylether and filtered to give the desired product as a white solid.

(145) 5-Bromo-2,3-dihydro-isoindol-1-one: (81% yield, 100% purity) m/z (LC-MS, ESP): 212.3/214.3 [M+H].sup.+ R/T=3.06 min

(146) ##STR00111##

(147) To a solution of 5-bromo-2,3-dihydro-isoindol-1-one (1 equiv) in dry dioxan (0.1 M) were added bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv). The reaction mixture was degassed with nitrogen for 20 minutes. PdCl.sub.2(dppf) (0.05 equiv) was added to the reaction mixture, which was degassed for a further 5 minutes. The reaction mixture was heated to 70° C. for 2 hours under nitrogen then heated to 120° C. for 16 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic phases dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was dissolved in CH.sub.2Cl.sub.2 and hexane was added. The resulting suspension was filtered and the collected brown powder was dried and used without further purification.

(148) 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one: (94% yield, 76% purity, main impurity being the boronic acid 13%) m/z (LC-MS, ESP): 260.4 [2M+H].sup.+ R/T=3.51 min

Procedures for the Preparation of Examples 1a to 1du

(149) ##STR00112## R.sup.4=(S)-3-methyl-morpholine R.sup.2=(S)-3-methyl-morpholine or cis-dimethylmorpholine or 2-Ethyl-piperidine or morpholine or thiomorpholine or 4-methylpiperazine R.sup.7=aryl or heteroaryl
Procedures for the Suzuki Coupling:

(150) The synthesis of the appropriate chloro-substrate has been described in the present document as intermediates. The appropriate pinacolate boron ester or boronic acids were prepared according to synthesis described in the present document (as intermediates) or commercially available, typically from the following suppliers:

(151) Sigma-Aldrich, Lancaster, Frontier Scientific, Boron Molecular, Interchim, Asymchem, Combi-blocks, Apollo Scientific, Fluorochem, ABCR, Digital Speciality Chemicals.

(152) Conditions A:

(153) The appropriate chloro-substrate (1 equiv) was dissolved in a toluene/ethanol (1:1) solution (0.02 M). Sodium carbonate (2 equiv) and the appropriate pinacolate boron ester or boronic acid (1 equiv) were then added followed by tetrakis(triphenylphosphine)palladium.sup.0 (0.1 equiv). The reaction vessel was sealed and the mixture exposed to microwave radiation (140° C., medium absorption setting) for 30 minutes. Upon completion the samples were filtered through a silica cartridge, washed with EtOAc and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(154) Conditions B:

(155) A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.4 equiv), the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) in n-butanol (0.03 M of chloro-substrate) was stirred at 120° C. for 2 hours. Upon completion the samples were filtered through a silica cartridge, washed through with CH.sub.2Cl.sub.2 and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(156) Conditions C:

(157) To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.4 equiv), and the appropriate pinacolate boron ester or boronic acid (1.1 equiv) in acetonitrile/water (1:1) (0.041 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (150° C., medium absorption setting) for 30 minutes under nitrogen atmosphere. Upon completion the samples were filtered through a silica cartridge, washed with CH.sub.2Cl.sub.2 and methanol and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(158) Conditions D:

(159) To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (1.2 equiv), and the appropriate pinacolate boron ester or boronic acid (1.2 equiv) in acetonitrile/water (1:1) (0.083 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 25 minutes under nitrogen atmosphere. Upon completion the sample was purified by column chromatography on silica gel using a gradient MeOH/CH.sub.2Cl.sub.2 to afford the desired product which was recrystallised from diethyl ether.

(160) Conditions E:

(161) To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.4 equiv), and the appropriate pinacolate boron ester or boronic acid (1.3 equiv) in acetonitrile/water (1:1) (0.041 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction vessel was sealed and heated at 95° C. for 16 hours. Upon completion the reaction mixture was partitioned between aqueous HCl and CH.sub.2Cl.sub.2 and washed with aqueous HCl. Combined aqueous phase were extracted with CH.sub.2Cl.sub.2 (2×), neutralised with aqueous NaOH (2N) to give a cloudy solution that was extracted with CH.sub.2Cl.sub.2. Combined organic phases were washed with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 4% MeOH in CH.sub.2Cl.sub.2 to give the desired product.

(162) Conditions F:

(163) To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.0 equiv), and the appropriate pinacolate boron ester or boronic acid (1.5 equiv) in acetonitrile/water (1:1) (0.028 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction vessel was sealed and heated at 120° C. for 2 hours under nitrogen atmosphere. Upon completion the reaction mixture was partitioned between water and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 4% MeOH in CH.sub.2Cl.sub.2 to give the desired product which was recrystallised from hexane/diethyl ether.

(164) Conditions G:

(165) To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), and the appropriate pinacolate boron ester or boronic acid (1.05 equiv) in acetonitrile/water (1:1) (0.068 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction vessel was sealed and heated at 100° C. for 5 hours under nitrogen atmosphere. Upon completion the reaction mixture was partitioned between brine and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 4% MeOH in CH.sub.2Cl.sub.2 to give the desired products which were recrystallised from hexane/CH.sub.2Cl.sub.2.

(166) Conditions H:

(167) A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 100° C. for 8 hours. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

(168) Conditions I:

(169) Conditions I were similar to conditions H apart form the heating method: 100° C. for 2 hours.

(170) Conditions J:

(171) A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (1.2 equiv), the appropriate pinacolate boron ester or boronic acid (1.2 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) in acetonitrile/water (0.03 M of chloro-substrate) was stirred at 100° C. for 2 hours. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

(172) Conditions K:

(173) Conditions K were similar to conditions G apart form the heating method: 100° C. for 16 hours.

(174) Conditions L:

(175) To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), and the appropriate pinacolate boron ester or boronic acid (1.10 equiv) in acetonitrile/water (1:1) (0.041 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (100° C., medium absorption setting) for 90 minutes. Upon completion the reaction mixture was partly concentrated. The residue was partitioned between water and ethyl acetate and extracted with ethyl acetate and n-butanol. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 30 to 10% hexane in ethyl acetate to give the desired product which was recrystallised from hexane/CH.sub.2Cl.sub.2.

(176) Conditions M:

(177) A mixture of the appropriate chloro-substrate (1 equiv), cesium fluoride (3.0 equiv), the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) in acetonitrile/water (0.09 M of chloro-substrate) was stirred at 115° C. for 48 hours. Upon completion the sample was concentrated in vacuo to half original volume. The residue was partitioned between water and CH.sub.2Cl.sub.2. Organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 100% ethyl acetate in hexane to give the desired product.

(178) Conditions N:

(179) A mixture of the appropriate chloro-substrate (1 equiv), tripotassium phosphate (1.5 equiv), the appropriate pinacolate boron ester or boronic acid (1.05 equiv) and bis(tri-t-butylphosphine)palladium (0.05 equiv) was suspended in dioxane (0.16 M of chloro-substrate). The reaction vessel was sealed and exposed to microwave radiation (170° C., medium absorption setting) for 45 minutes. Upon completion the sample was concentrated in vacuo. The residue was partitioned between water and CH.sub.2Cl.sub.2. The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 40 to 100% ethyl acetate in hexane to give the desired product.

(180) Conditions O:

(181) A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) in n-butanol (0.068 M of chloro-substrate) was stirred at 95° C. for 15 minutes. Upon completion, the residue was partitioned between ethyl acetate and brine. Organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 30 to 100% ethyl acetate in hexane to give the desired product which was recrystallised from ethyl acetate/hexane.

(182) Conditions P:

(183) To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.0 equiv), and the appropriate pinacolate boron ester or boronic acid (2.0 equiv) in acetonitrile/water (1:1) (0.041 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (120° C., medium absorption setting) for 10 minutes under nitrogen atmosphere. Upon completion the samples were filtered through a silica cartridge, washed through with CH.sub.2Cl.sub.2 and the concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

(184) Conditions Q:

(185) A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), the appropriate pinacolate boron ester or boronic acid (1.1 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) were dissolved in n-butanol (0.056 M of chloro-substrate). The reaction vessel was sealed and exposed to microwave radiation (150° C., medium absorption setting) for 30 minutes. Upon completion the samples were filtered through a silica cartridge, washed with CH.sub.2Cl.sub.2 and methanol and then concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with ethyl acetate and then 5% MeOH in CH.sub.2Cl.sub.2 to give the desired product.

(186) Conditions R:

(187) A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), the appropriate pinacolate boron ester or boronic acid (1.2 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) in acetonitrile/water (0.05 M of chloro-substrate) was stirred at 115° C. for 1.5 hours. Upon completion the crude reaction was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 5 to 20% MeOH in CH.sub.2Cl.sub.2 to give the desired product.

(188) Conditions S:

(189) A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (10.0 equiv), the appropriate pinacolate boron ester or boronic acid (1.2 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 100° C. for 2 hours. Upon completion the reaction mixture was partitioned between water and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% MeOH in CH.sub.2Cl.sub.2 to give the desired product which was recrystallised from hexane/CH.sub.2Cl.sub.2.

(190) Conditions T:

(191) A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.0 equiv), the appropriate pinacolate boron ester or boronic acid (2.0 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) was dissolved in acetonitrile/water (0.02 M of chloro-substrate). The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 30 minutes. Upon completion the sample was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% MeOH in CH.sub.2Cl.sub.2 to give the desired product.

(192) Conditions U:

(193) A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), the appropriate pinacolate boron ester or boronic acid (1.0 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 110° C. for 8 hours. Upon completion the reaction mixture was partitioned between water and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. Combined organic phases were washed with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 2% MeOH in CH.sub.2Cl.sub.2 to give the desired product which was recrystallised from hexane/CH.sub.2Cl.sub.2.

(194) Conditions V:

(195) A mixture of the appropriate chloro-substrate (1 equiv), cesium fluoride (3.0 equiv), the appropriate pinacolate boron ester or boronic acid (1 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 100° C. for 16 hours. The reaction mixture was partitioned between water and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% MeOH in CH.sub.2Cl.sub.2 to give the desired product which was recrystallised from hexane/CH.sub.2Cl.sub.2.

(196) Conditions W:

(197) A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), the appropriate pinacolate boron ester or boronic acid (1 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) was dissolved in acetonitrile/water (0.04 M of chloro-substrate). The reaction vessel was sealed and exposed to microwave radiation (110° C., medium absorption setting) for 10 minutes. The crude residue was purified by column chromatography on silica gel eluting with 0 to 2% MeOH in TBME to give the desired product.

(198) TABLE-US-00001 TABLE 1 Retention Purity time m/z (%) (min) [M + H].sup.+ Conditions Example Structure 1a 96 7.66 466.6 A 1b 99 4.31 480.4 A 1c 98 4.67 478.4 A 1d 99 4.13 406.2 A 1e 99 3.94 422.3 A 1f 99 4.32 420.3 A 1g 99 3.83 436.3 A 1h 89 3.99 422.2 A 0 1i 96 3.85 436.3 A 1j 99 4.5 420.3 A 1k 98 4.49 426.3 A 1l 100 3.91 452.3 A 1m 99 3.99 437.4 B 1n 99 4.2 437.4 B 1o 99 4.23 437.4 B 1p 99 4.16 425.4 B 1q 98 4.1 492.5 B 1r 98 1.09 438.4 B 0 1s 99 3.98 410.4 B 1t 100 4.04 468.5 B 1u 100 4.95 422.3 B 1v 98 4.32 441.4 B 1w 91 6.46 441.3 B 1x 98 7.16 439.3 B 1y 97 6.54 441.4 B 1z 95 5.92 425.5 B 1aa 100 8.28 424.4 B 1ab 99 6.67 467.4 B 0 1ac 100 8.01 509.5 B 1ad 100 7.23 468.4 B 1ae 100 6.99 481.4 B 1af 99 7.55 495.4 B 1ag 100 6.51 511.4 B 1ah 99 6.95 425.2 B 1ai 89 7.52 465.2 B 1aj 80 4.5 459.3 B 1ak 97 6.79 463.2 C 1al 99 4.07 491.4 C 0 1am 99 3.94 484.3 C 1an 99 3.95 484.3 C 1ao 97 3.75 449.3 C 1ap 99 3.86 463.3 C 1aq 99 3.87 529.4 D 1ar 99 3.41 407.3 E 1as 98 6.59 449.4 F 1at 97 4.05 499.3 G 1au 96 7 425.3 G 1av 99 4.28 449.4 H 0 1aw 97 4.33 431.3 I 1ax 99 3.99 450.5 J 1ay 98 4.19 443.3 K 1az 100 8.94 421.2 L 1ba 100 4.28 464.5 M 1bb 98 8.16 450.3 N 1bc 99 3.99 454.4 O 1bd 90 8.4 485.3 P 1be 99 3.91 507.4 C 1bf 99 3.39 532.4 C 0 1bg 97 4.19 494.4 M 1bh 98 4.15 474.3 Q 1bi 96 4.13 474.4 R 1bj 94 3.99 492.3 R 1bk 98 4.04 517.4 S 1bl 98 4.13 431.2 B 1bm 98 4.27 445.3 B 1bn 97 4.27 451.2 B 1bo 99 4.21 436.3 B 1bp 99 4.40 440.2 B 0 1bq 87 4.22 420.3 B 1br 93 4.40 420.3 B 1bs 94 4.30 454.2 B 1bt 95 4.32 436.3 B 1bu 99 3.53 407.3 B 1bv 99 3.94 396.3 B 1bw 85 4.49 445.3 B 1bx 99 4.59 450.3 B 1by 98 4.20 450.3 B 1bz 87 4.30 436.3 B 0 1ca 99 4.62 434.4 B 1cb 99 4.74 434.4 B 1cc 92 4.67 463.0 B 1cd 99 4.63 450.4 B 1ce 85 3.71 421.3 B 1cf 98 4.35 410.3 B 1cg 97 4.34 436.3 B 1ch 98 4.48 459.3 B 1ci 87 4.49 465.3 B 1cj 100 4.50 450.3 B 00 1ck 99 4.14 466.5 T 01 1cl 100 3.8 474.4 P 02 1cm 99 4.01 477.3 T 03 1cn 99 4.73 474.3 E 04 1co 99 4.08 477.3 D 05 1cp 87 4.48 461.3 D 06 1cq 84 7.44 493.4 L 07 1cr 97 3.85 475.3 T 08 1cs 100 4.63 450.4 D 09 1ct 99 464.3 S 0 1cu 100 3.89 436.2 B 1cv 100 3.89 J Note: The following examples were synthesized from the corresponding boronic acids: 1aa, 1ab, 1ac, 1ad, 1ae, 1af, 1ag, 1ah, 1ai, 1aj, 1ak, 1al, 1am, 1an, 1ao, 1ap, 1aq, 1as, 1at, 1au, 1av, 1aw, 1ax, 1ay, 1az, 1ba, 1bb, 1bd, 1be, 1bk, 1bl, 1bm, 1bn, 1bo, 1bp, 1bq, 1br, 1bs, 1bt, 1bu, 1bv, 1bw, 1bx, 1by, 1bz, 1ca, 1cb, 1cc, 1cd, 1cf, 1cg, 1ch, 1ci, 1cj, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1n, 1o, 1p, 1r, 1t, 1w, 1x, 1y 1cn, 1co, 1cp, 1cs, 1cy and 1z. The following Examples were synthesized from the corresponding pinacolate boron esters: 1a-c, 1ck, 1cl, 1cm, 1cq, 1cr, 1ct, 1cu, 1ar, 1bf, 1ce, 1m, 1q, 1s, 1u and 1y.
NMR Data for Example 1n

(199) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.88 (ArH, d, J=2.20 Hz, 1H), 8.55 (ArH, dd, J=8.70, 2.45 Hz, 1H), 8.04 (ArH, d, J=8.43 Hz, 1H), 7.42 (ArH, d, J=8.44 Hz, 1H), 6.88 (ArH, d, J=8.70 Hz, 1H), 5.01-4.90 (CH, m, 1H), 4.65 (CH, d, J=13.12 Hz, 1H), 4.40 (CH, d, J=6.68 Hz, 1H), 4.04 (OCH.sub.3+CH.sub.2, s, 5H), 3.96-3.69 (CH.sub.2, m, 7H), 3.60 (CH, dt, J=11.86, 11.60, 2.67 Hz, 1H), 3.40 (CH, dt, J=13.01, 12.73, 3.60 Hz, 1H), 1.50 (CH.sub.3, d, J=6.78 Hz, 3H), 1.39 (CH.sub.3, d, J=6.81 Hz, 3H)

(200) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.41, 165.29, 162.98, 160.10, 160.01, 146.58, 138.51, 134.81, 128.05, 112.42, 110.84, 104.75, 71.29, 70.92, 67.26, 66.92, 53.75, 52.87, 46.94, 44.43, 39.33, 14.73 and 14.36.

(201) NMR Data for Example 1u

(202) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.80 (ArH, d, J=1.91 Hz, 1H), 8.39 (ArH, dd, J=8.66, 2.39 Hz, 1H), 7.96 (ArH, d, J=8.48 Hz, 1H), 7.35 (ArH, d, J=8.49 Hz, 1H), 6.59 (ArH, d, J=8.66 Hz, 1H), 4.91 (CH, dd, J=4.15, 1.62 Hz, 1H), 4.78 (NH.sub.2, s, 2H), 4.67-4.55 (CH, m, 1H), 4.34 (CH, d, J=6.88 Hz, 1H), 4.04-3.91 (CH.sub.2, m, 2H), 3.90-3.64 (CH.sub.2, m, 7H), 3.62-3.49 (CH.sub.2, m, 1H), 3.44-3.29 (CH.sub.2, m, 1H), 1.45 (CH.sub.3, d, J=6.77 Hz, 3H), 1.34 (CH.sub.3, d, J=6.82 Hz, 3H)

(203) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.54, 163.10, 160.45, 160.13, 159.45, 148.10, 137.82, 134.76, 125.17, 112.16, 108.45, 104.59, 71.44, 71.06, 67.41, 67.07, 52.98, 47.05, 44.56, 36.46, 14.84 and 14.75.

(204) NMR Data for Example 1ag

(205) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.59 (ArH, dd, J=7.33, 2.43 Hz, 1H), 8.40 (ArH, ddd, J=8.53, 5.03, 2.47 Hz, 1H), 7.97 (ArH, d, J=8.42 Hz, 1H), 7.42 (ArH, d, J=8.46 Hz, 1H), 7.20-7.10 (ArH, m, 1H), 4.84 (CH, dd, J=3.67, 2.96 Hz, 1H), 4.53 (CH, d, J=12.77 Hz, 1H), 4.33 (CH.sub.2, d, J=6.83 Hz, 1H), 3.99-3.89 (CH.sub.2, m, 2H), 3.86-3.77 (CH.sub.2, m, 4H), 3.75-3.65 (CH.sub.2, m, 5H), 3.67-3.32 (CH.sub.2, m, 3H), 3.57-3.45 (CH.sub.2, m, 1H), 3.36-3.26 (CH.sub.2, m, 1H), 1.42 (CH.sub.3, d, J=6.78 Hz, 3H), 1.30 (CH.sub.3, d, J=6.82 Hz, 3H)

(206) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.26, 164.26, 162.74, 160.29, 159.93, 135.52, 135.11, 133.47, 133.34, 130.89, 116.84, 116.51, 113.11, 105.11, 71.26, 70.91, 67.11, 66.91, 62.20, 52.79, 47.02, 44.46, 43.02, 39.36, 14.77 and 14.37.

(207) NMR Data for Example 1aq

(208) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.61 (ArH, t, J=1.46, 1.46 Hz, 1H), 8.33 (ArH, d, J=7.84 Hz, 1H), 8.06 (ArH, d, J=8.37 Hz, 1H), 7.90 (ArH, s, 1H), 7.62 (ArH, d, J=7.84 Hz, 1H), 7.44 (ArH, d, J=8.38 Hz, 1H), 5.30 (CH.sub.2, s, 1H), 4.97-4.84 (CH.sub.2, m, 1H), 4.64-4.52 (CH.sub.2, m, 1H), 4.45-4.34 (CH.sub.2, m, 1H), 4.06-3.94 (CH.sub.2, m, 2H), 3.93-3.64 (CH.sub.2, m, 8H), 3.61-3.51 (CH.sub.2, m, 1H), 3.45-3.30 (CH.sub.2, m, 1H), 3.19 (CH.sub.2, d, J=4.84 Hz, 2H), 1.49 (CH.sub.3, d, J=6.78 Hz, 3H), 1.36 (CH.sub.3, d, J=6.82 Hz, 3H).

(209) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 160.22, 140.70, 140.01, 134.25, 131.82, 129.24, 128.02, 126.34, 113.12, 105.41, 104.65, 71.23, 70.87, 66.88, 61.03, 52.85, 47.04, 45.34, 44.42, 39.35, 14.78 and 14.38.

(210) NMR Data for Example 1ar

(211) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.81-8.73 (ArH, m, 2H), 8.14-7.99 (ArH, m, 3H), 7.48 (ArH, d, J=8.35 Hz, 1H), 5.02-4.89 (CH, m, 1H), 4.69-4.59 (CH.sub.2, m, 1H), 4.41 (CH, d, J=6.84 Hz, 1H), 4.08-3.96 (CH.sub.2, m, 2H), 3.82 (H2, dddd, J=19.69, 14.05, 6.26, 3.77 Hz, 7H), 3.65-3.53 (CH.sub.2, m, 1H), 3.48-3.31 (CH.sub.2, m, 1H), 1.51 (CH.sub.3, d, J=6.78 Hz, 3H), 1.38 (CH.sub.3, d, J=6.83 Hz, 3H)

(212) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.29, 162.96, 160.03, 159.82, 150.36, 145.80, 135.20, 121.83, 113.02, 105.93, 71.24, 70.87, 67.21, 66.87, 52.88, 46.99, 44.45, 39.35, 14.76 and 14.41.

(213) NMR Data for Example 1as

(214) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.67 (ArH, t, J=1.54, 1.54 Hz, 1H), 8.29 (ArH, dd, J=6.60, 1.28 Hz, 1H), 8.07 (ArH, d, J=8.41 Hz, 1H), 8.03-7.98 (ArH, m, 2H), 7.62-7.49 (ArH, m, 2H), 4.98-4.89 (CH, m, br, 1H), 4.67-4.59 (CH, m, br, 1H), 4.41 (CH, d, J=6.78 Hz, 1H), 4.05-3.66 (CH.sub.2, m, 10H), 3.64-3.34 (CH.sub.2, m, 3H), 1.75 (s, 1.5H), 1.50 (CH.sub.3, d, J=6.78 Hz, 3H), 1.38 (CH.sub.3, d, J=6.82 Hz, 3H).

(215) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 168.86, 165.34, 162.90, 161.21, 160.01, 138 97, 135.00, 133.74, 131.09, 129.23, 128.98, 126.52, 113.20, 105.20, 100.00, 71.23, 70.89, 67.22, 66.90, 52.82, 46.97, 44.45, 39.34, 14.75 and 14.36

(216) NMR Data for Example 1at

(217) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.06 (ArH, d, J=2.05 Hz, 1H), 7.98 (ArH, d, J=8.41 Hz, 1H), 7.86-7.79 (ArH, m, 1H), 7.46-7.33 (ArH, m, 3H), 7.23 (NH, s, 1H), 4.83 (CH, dd, J=3.58, 2.50 Hz, 1H), 4.56-4.46 (CH, m, 1H), 4.32 (CH, d, J=6.74 Hz, 1H), 3.93-3.89 (CH.sub.2, m, 2H), 3.88-3.77 (CH.sub.2, m, 2H), 3.76-3.58 (CH.sub.2, m, 5H), 3.49 (CH.sub.2, dt, J=11.76, 11.38, 2.76 Hz, 1H), 3.35-3.20 (CH.sub.2, m, 1H), 2.89 (SCH.sub.3, s, 3H), 1.42 (CH.sub.3, d, J=6.78 Hz, 3H), 1.27 (CH.sub.3, d, J=5.25, Hz, 3H)

(218) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.32, 162.87, 161.30, 159.96, 140.41, 137.57, 135.01, 129.92, 124.55, 122.25, 120.57, 113.32, 105.24, 71.25, 70.90, 67.22, 66.91, 52.86, 46.99, 44.42, 39.40, 31.60, 22.66, 14.77 and 14.12.

(219) NMR Data for Example 1ax

(220) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.88 (ArH, t, J=1.52, 1.52 Hz, 1H), 8.32-8.25 (ArH, m, 1H), 8.13-8.06 (ArH, m, 1H), 7.99 (ArH, d, J=8.42 Hz, 1H), 7.53-7.39 (ArH, m, 2H), 4.90-4.80 (CH, m, 1H), 4.58-4.48 (CH, m, 1H), 4.33 (CH, d, J=6.90 Hz, 1H), 3.95-3.65 (CH.sub.2, +OH m, 8H), 3.64 (CH.sub.2, d, J=2.85 Hz, 2H), 3.56-3.45 (CH, m, 1H), 3.31 (CH, d, J=3.67 Hz, 1H), 1.42 (CH.sub.3, d, J=6.79 Hz, 3H), 1.29 (CH.sub.3, d, J=6.81 Hz, 3H)

(221) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 169.20, 165.22, 161.32, 159.85, 139.91, 135.01, 131.39, 129.70, 128.71, 113.31, 70.90, 67.10, 52.80, 47.07, 44.42, 39.36, 14.77 and 14.37.

(222) NMR Data for Example 1az

(223) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.04-7.95 (ArH, m, 2H), 7.87 (ArH, d, J=8.54 Hz, 1H), 7.32 (ArH, d, J=8.55 Hz, 1H), 6.71-6.64 (ArH, m, 2H), 4.92-4.81 (CH, m, 1H), 4.57 (CH, d, br, 1H), 4.29 (CH.sub.2, d, J=7.10 Hz, 1H), 3.91 (CH.sub.2, m, 2H), 3.82-3.58 (CH.sub.2+NH.sub.2, m, 9H), 3.48 (CH.sub.2, dd, J=11.36, 2.76 Hz, 1H), 3.33 (CH.sub.2, dd, J=13.48, 3.61 Hz, 1H), 1.39 (CH.sub.3, d, J=6.78 Hz, 3H), 1.28 (CH.sub.3, d, J=6.82 Hz, 3H)

(224) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.28, 162.18, 148.68, 135.36, 129.54, 119.67, 114.75, 112.63, 104.43, 104.00, 71.29, 70.94, 67.27, 67.12, 66.95, 52.78, 44.45, 39.15, 14.74 and 14.37.

(225) NMR Data for Example 1ba

(226) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.69 (ArH, t, J=1.58, 1.58 Hz, 1H), 8.44-8.33 (ArH, m, 1H), 8.11-8.03 (ArH, m, 1H), 7.99 (ArH, d, J=8.42 Hz, 1H), 7.57-7.38 (ArH, m, 2H), 4.87 (CH.sub.2, dd, J=4.84, 0.43 Hz, 1H), 4.57 (CH, d, J=12.80 Hz, 1H), 4.31 (CH.sub.2, t, J=6.72, 6.72 Hz, 1H), 3.94 (CH.sub.2, dd, J=11.15, 3.26 Hz, 2H), 3.90 (OCH.sub.3, d, J=6.23 Hz, 3H), 3.83-3.62 (CH.sub.2, m, 7H), 3.57-3.45 (CH.sub.2, m, 1H), 3.39-3.24 (CH.sub.2, m, 1H), 1.42 (CH.sub.3, d, J=6.78 Hz, 3H), 1.30 (CH.sub.3, d, J=6.81 Hz, 3H)

(227) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 166.92, 165.41, 162.93, 161.43, 161.01, 139.13, 134.91, 132.51, 130.87, 130.57, 128.87, 113.26, 105.16, 71.29, 70.91, 67.25, 66.91, 52.86, 52.18, 46.96, 44.45, 14.77 and 14.37.

(228) NMR Data for Example 1bc

(229) .sup.1H NMR (300 MHz, DMSO) δ ppm 8.37 (ArH, dd, J=7.40, 2.26 Hz, 1H), 8.20 (ArH, d, J=8.50 Hz, 1H), 8.14-8.05 (ArH, m, 1H), 7.62 (ArH, d, J=8.51 Hz, 1H), 7.29 (ArH, dd, J=9.77, 8.71 Hz, 1H), 5.42 (CH, t, J=5.76, 5.76 Hz, 1H), 4.77 (CH, dd, J=6.57, 1.98 Hz, 1H), 4.65 (CH.sub.2OH, d, J=5.67 Hz, 2H), 4.51-4.37 (CH.sub.2, m, 2H), 3.98-3.83 (CH.sub.2, m, 3H), 3.80-3.70 (CH.sub.2, m, 2H), 3.69-3.56 (CH.sub.2, m, 4H), 3.45 (CH.sub.2, dt, J=11.86, 11.77, 2.75 Hz, 1H), 3.30-3.16 (CH.sub.2, m, 3H), 1.38 (CH.sub.3, d, J=6.75 Hz, 3H), 1.25 (CH.sub.3, d, J=6.75 Hz, 3H)

(230) .sup.13C NMR (75 MHz, DMSO) δ ppm 164.91, 162.60, 160.18, 159.82, 136.10, 134.86, 130.19, 129.99, 128.61, 128.27, 128.15, 115.85, 115.57, 113.00, 104.80, 70.89, 70.66, 66.84, 66.67, 52.29, 46.76, 44.34, 14.84 and 14.34.

(231) NMR Data for Example 1bd

(232) .sup.1H NMR (300 MHz, DMSO) δ ppm 8.63 (ArH, t, J=1.49, 1.49 Hz, 1H), 8.26 (ArH, d, J=7.95 Hz, 1H), 8.17 (ArH, d, J=8.46 Hz, 1H), 7.91-7.80 (ArH, m, 1H), 7.62 (ArH, dd, J=14.96, 8.10 Hz, 2H), 7.37 (NH.sub.2, s, 2H), 4.69 (CH, dd, J=6.21, 1.34 Hz, 1H), 4.35 (CH.sub.2, d, J=13.74 Hz, 2H), 3.91-3.74 (CH.sub.2, m, 3H), 3.73-3.46 (CH.sub.2, m, 6H), 3.36 (CH.sub.2, dt, J=11.82, 11.71, 2.49 Hz, 1H), 2.41 (CH.sub.2, td, J=3.46, 1.69, 1.69 Hz, 1H), 1.30 (CH.sub.3, d, J=6.74 Hz, 3H), 1.17 (CH.sub.3, d, J=6.75 Hz, 3H)

(233) .sup.13C NMR (75 MHz) δ ppm 164.85, 162.63, 159.86, 159.49, 145.34, 139.35, 136.44, 130.73, 129.98, 127.34, 124.96, 113.18, 105.38, 79.87, 79.43, 78.99, 70.89, 70.67, 66.85, 66.67, 52.29, 46.79, 44.37, 14.88 and 14.41.

(234) NMR Data for Example 1bk

(235) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.19 (ArH, dd, J=7.62, 2.22 Hz, 1H), 8.12 (ArH, ddd, J=8.54, 5.03, 2.25 Hz, 1H), 8.01 (ArH, d, J=8.41 Hz, 1H), 7.38 (ArH, d, J=8.43 Hz, 1H), 7.24-7.19 (ArH, m, 1H), 6.83 (NH, s, br, 1H), 4.98-4.85 (CH, m, 1H), 4.67-4.55 (CH, m, 1H), 4.36 (CH.sub.2, d, J=6.95 Hz, 1H), 4.06-3.93 (CH.sub.2, m, 2H), 3.91-3.65 (CH.sub.2, m, 1H), 3.53 (CH.sub.2, dd, J=11.40, 2.69 Hz, 1H), 3.44-3.28 (CH.sub.2, m, 1H), 3.07 (SCH3, s, 3H), 1.47 (CH.sub.3, d, J=6.77 Hz, 3H), 1.34 (CH.sub.3, d, J=6.81 Hz, 3H)

(236) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.45, 162.93, 160.61, 160.12, 157.28, 153.99, 136.32, 135.15, 123.51, 116.31, 116.05, 113.26, 105.18, 71.39, 71.01, 67.36, 67.01, 53.00, 47.07, 44.51, 39.44, 31.71, 22.77 14.86, and 14.95.

(237) Compounds were also synthesized according to the following procedures:

Procedure for the synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-isopropoxy-benzamide (Example 1cw)

(238) ##STR00213##

(239) 5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-isopropoxy-benzonitrile (1 equiv) was added portionwise to concentrated H.sub.2SO.sub.4 (0.1 M substrate in acid). The reaction was heated to 90° C. and maintained at this temperature until all starting material had dissolved to give a bright red solution. The mixture was cooled and water (2 reaction volumes) added dropwise, then the solution was neutralized by careful addition of solid NaOH until pH 4-5 was attained. The mixture was cooled and neutralised by addition of 2N NaOH and then extracted using EtOAc (2×10 reaction volumes). The combined extracts were dried (MgSO.sub.4), filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO.sub.2) using MeOH/DCM—0:100 going to 5:95 as eluent to give the desire product as a yellow powder.

(240) 5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-isopropoxy-benzamide: (53% yield, 100% purity) m/z (LC-MS, ESP): 507.5 [M+H].sup.−, R/T=3.01 min)

Procedure for the synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-hydroxy-benzamide (Example 1cx)

(241) ##STR00214##

(242) 5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-isopropoxy-benzonitrile (1 equiv) was added portionwise to concentrated H.sub.2SO.sub.4 (0.1 M substrate in acid). The reaction was heated to 90° C. and maintained at this temperature until all starting material had dissolved to give a bright red solution. The mixture was cooled and water (2 reaction volumes) added dropwise, then the solution was neutralized by careful addition of solid NaOH until pH 4-5 was attained. The mixture was cooled and neutralised by addition of 2N NaOH and then extracted using EtOAc (2×10 reaction volumes). The combined extracts were dried (MgSO.sub.4), filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO.sub.2) using MeOH/DCM—0:100 going to 5:95 as eluent to give the desire product as a yellow powder.

(243) 5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-hydroxy-benzamide: (44% yield, 100% purity) m/z (LC-MS, ESP): 465.4 [M+H].sup.−, R/T=2.70 min)

Procedure for the synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridine-2-carboxylic acid amide (Example 1cy)

(244) ##STR00215##

(245) Synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridine-2-carbonitrile was carried out as follows:—

(246) To the appropriate chloro-substrate (1 equiv), potassium carbonate (3 equiv) and the appropriate boronic acid or pinacolate boron ester (1.1 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) which were dissolved in N,N-dimethylacetamide (0.17 M of chloro-substrate). The mixture was degassed with nitrogen, sealed and exposed to microwave radiation (130° C., medium absorption setting) for 15 minutes. The mixture was concentrated in vacuo and then suspended in t-butylmethyl ether, filtered and dried to give the desired product.

(247) 5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridine-2-carbonitrile: (84% yield, 93% purity) m/z (LC-MS, ESP): 191.3 [M+H].sup.+, R/T=2.29 min)

(248) To a suspension of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridine-2-carbonitrile (1 equiv) in concentrated H.sub.2SO.sub.4. The mixture was heated to 90° C. until a pale brown solution formed. The mixture was allowed to cool and then basified with 50% w/w NaOH solution. The aqueous mixture was extracted using EtOAc (3×2 reaction volumes). The combined organic fractions were dried (MgSO.sub.4), filtered and concentrated in vacuo to give a pale yellow solid which was triturated with EtOAc to give the desire product.

(249) 5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridine-2-carboxylic acid amide: 93% yield, 96% purity) m/z (LC-MS, ESP): 450.4 [M+H].sup.+, R/T=3.72 min)

Procedure for the synthesis of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-ylamine (Example 1cz)

(250) ##STR00216##

(251) To a 1.2 M solution of compound 1au (1 equiv) in THF was added hydrazine hydrate (9 reaction volumes). The reaction vessel was sealed and exposed to microwave radiation (115° C., medium absorption setting) for 2 hours. Upon completion, the reaction mixture was extracted with EtOAc (2×1 reaction volume). The organic fractions were combined, dried (MgSO.sub.4), filtered and concentrated in vacuo to give the desired product in suitably clean form for use in subsequent reactions.

(252) {4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-hydrazine 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-phthalazin-1-one: (77% yield, 84% purity) m/z (LC-MS, ESP): 437.4 [M+H].sup.+, R/T=2.23 min)

(253) A 0.12 M solution of {4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-hydrazine 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-phthalazin-1-one (1 equiv) in EtOH was added to a glass lined autoclave which contained activated Ra—Ni. The reaction was maintained under 5 bar H.sub.2 for 30 hours. Upon completion, the mixture was filtered through a pad of Celite™ and the filtrate concentrated in vacuo. The resulting crude residue was purified by reverse phase flash chromatography using 5:95-0.1% TFA/MeCN:0.1% TFA/H.sub.2O as eluent to give the desire product as a yellow powder.

(254) 4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-ylamine: (70% yield, 100% purity) m/z (LC-MS, ESP): 422 [M+H].sup.+, R/T=2.25 min)

Procedure for the synthesis of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzamide (Example 1da)

(255) ##STR00217##

(256) To the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv) and the appropriate boronic acid or pinacolate boron ester (1.1 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) which were dissolved in MeCN/H.sub.2O (0.03 M of chloro-substrate). The mixture was degassed with nitrogen, sealed and exposed to microwave radiation (110° C., medium absorption setting) for 25 minutes. The mixture filtered and the precipitate collected, and recrystallised from MeCN/H.sub.2O to give the desired product.

(257) 4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzonitrile: (49% yield, 87% purity) m/z (LC-MS, ESP): 449 [M+H].sup.+, R/T=2.93 min)

(258) 4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzonitrile (1 equiv) was dissolved concentrated sulfuric acid (0.15 M substrate in acid). The reaction was heated rapidly to 90° C. for 5 minutes before cooling the mixture and quenched, carefully, with solid NaOH until the solution was basic. The mixture was extracted with EtOAc/nBuOH (2×1 reaction volume—1:1 ratio). The organic extracts were combined, dried (MgSO.sub.4), filtered and concentrated in vacuo to give a residue which was further purified using flash chromatography (SiO.sub.2) with TBME going to TBME/MeOH (95:5) as eluent, the give the title compound as a yellow solid.

(259) 4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzamide Synthesis: (71% yield, 99% purity) m/z (LC-MS, ESP): 467 [M+H].sup.+, R/T=2.60 min)

Procedure for the synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1H-pyridin-2-one (Example 1db)

(260) ##STR00218##

(261) To a 0.2 M solution of compound 1ah (1 equiv) in DMA was added a 1.6 M aqueous solution of sodium hydroxide (5 equiv). The reaction vessel was sealed and exposed to microwave radiation (110° C., medium absorption setting) for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was suspended in water and sonicated to give a turbid solution, washed with TBME then cooled and neutralised with 2M HCl, forming a yellow precipitate. The precipitate was filtered and washed with water and TBME and dried to give the desired product.

(262) 5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1H-pyridin-2-one: (69% yield, 96% purity) m/z (LC-MS, ESP): 423 [M+H].sup.+, R/T=3.60 min)

Procedure for the synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1H-pyridin-2-one (Example 1dc)

(263) ##STR00219##

(264) To the compound 1ah (1 equiv) was added a solution of 40% methylamine in methanol (100 equiv). The reaction vessel was sealed and exposed to microwave radiation (115° C., medium absorption setting) for 30 minutes. The solution was concentrated in vacuo to yield a yellow solid. The crude residue was then purified by preparative HPLC to give the desired product. {5-[2,4-Bis-(3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-methyl-amine: (61% yield, 99% purity) m/z (LC-MS, ESP): 436 [M+H].sup.+, R/T=3.34 min)

(265) NMR Data for Example 1dc

(266) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.69 (ArH, d, J=2.06 Hz, 1H), 8.56 (ArH, dd, J=9.02, 2.32 Hz, 1H), 7.97 (ArH, d, J=8.47 Hz, 1H), 7.33 (ArH, d, J=8.48 Hz, 1H), 6.59 (ArH, d, J=9.03 Hz, 1H), 5.92 (NH, s, br, 1H), 4.90 (CH.sub.2, dd, J=5.85, 0.41 Hz, 1H), 4.59 (CH.sub.2, d, J=12.53 Hz, 1H), 4.41-4.29 (CH.sub.2, m, 1H), 4.05-3.93 (CH.sub.2, m, 2H), 3.90-3.62 (CH.sub.2, m, 8H), 3.62-3.50 (CH.sub.2, m, 1H), 3.43-3.31 (CH.sub.2, m, 1H), 3.00 (NCH.sub.3, s, 3H), 1.47 (CH.sub.3, d, J=6.78 Hz, 3H), 1.35 (CH.sub.3, d, J=6.82 Hz, 3H)

(267) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 167.59, 165.30, 162.90, 159.99, 158.84, 144.22, 139.19, 134.85, 123.35, 111.65, 106.51, 104.57, 71.28, 70.91, 67.24, 66.92, 52.83, 46.96, 44.42, 39.34, 29.05, 14.73 and 14.34.

Procedure for the synthesis of {5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-dimethyl-amine (Example 1dd)

(268) ##STR00220##

(269) To a solution of compound 1ah (1 equiv) in THF (0.05 M) was added a solution of 33% dimethylamine in ethanol (200 equiv). The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 40 minutes. The solution was concentrated in vacuo to yield a yellow solid. The crude residue was then purified by preparative HPLC to give the desired product.

(270) {5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-dimethyl-amine: (54% yield, 97% purity) m/z (LC-MS, ESP): 450 [M+H].sup.+, R/T=3.52 min)

Procedure for the synthesis of 8-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (Example 1de)

(271) ##STR00221##

(272) The appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), 3-methoxy-4-methoxycarbonylphenylboronic acid, pinacol ester (1.1 equiv) were suspended in (1:1) acetonitrile/water (0.1 M of chloro-substrate). The mixture was sonicated and degassed for 15 minutes with nitrogen. Tetrakistriphenylphosphine (0.05 equiv) was then added and the mixture was sonicated for a further 5 minutes with nitrogen. The mixture was heated to 100° C. for 3 hours under nitrogen. The reaction was cooled and the insoluble residue was filtered off. The filtrate was concentrated to half the original volume and the remaining water mixture was extracted with CH.sub.2Cl.sub.2. The organic layers were washed with water and brine, combined and dried with magnesium sulphate, filtered and concentrated in vacuo to yield an oil which was purified by flash column chromatography eluting with 50% to 100% EtOAc/Hexane.

(273) 4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid methyl ester: (67% yield, 100% purity) m/z (LC-MS, ESP): 494 [M+H].sup.+, R/T=2.86 min)

(274) A solution of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid methyl ester (1 equiv) in ethylenediamine (0.35 M) was stirred at room temperature for 24 hours. DMA was added to the solution (ethylenediamine/DMA 1:1.25). The reaction vessel was sealed and exposed to microwave radiation (180° C., medium absorption setting) for 1 hour. The reaction mixture was diluted with CH.sub.2Cl.sub.2 and extracted with water and washed with brine. The organic layer was dried with magnesium sulphate, filtered and concentrated in vacuo to yield a yellow solid which was then purified by preparative HPLC to give the desired product.

(275) 8-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one: (49% yield, 99% purity) m/z (LC-MS, ESP): 490 [M+H].sup.+, R/T=3.52 min)

(276) NMR Data for Example 1de

(277) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.65 (NH, s, br, 1H), 8.01 (ArH, d, J=8.38 Hz, 1H), 7.78 (ArH, s, 1H), 7.68 (ArH, s, 1H), 7.44 (ArH, dd, J=18.50, 8.20 Hz, 2H), 4.93-4.77 (CH.sub.2, m, 1H), 4.50 (CH.sub.2, s, 1H), 4.46-4.32 (CH.sub.2, m, 1H), 4.05-3.61 (CH.sub.2, m, 14H), 3.53 (CH.sub.2, d, J=2.04 Hz, 1H), 3.41-3.26 (CH.sub.2, m, 1H), 1.47 (CH.sub.3, d, J=6.76 Hz, 3H), 1.33 (CH.sub.3, d, J=6.78 Hz, 3H).

(278) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.11, 165.07, 165.00, 163.41, 162.64, 161.07, 159.90, 144.87, 135.18, 129.50, 118.02, 116.80, 113.87, 109.20, 105.45, 71.20, 70.89, 67.14, 66.89, 52.77, 47.04, 44.76, 44.40, 39.33, 14.78 and 13.32.

Procedure for the synthesis of 7-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (Example 1df)

(279) ##STR00222##

(280) A solution of the compound 1bg (1 equiv) in ethylenediamine (0.35 M) was stirred at room temperature for 24 hours. DMA was added to the solution (ethylenediamine/DMA 1:1.25). The reaction vessel was sealed and exposed to microwave radiation (180° C., medium absorption setting) for 1 hour. The reaction mixture was diluted with ethyl acetate and extracted with water. The organic layer was dried with magnesium sulphate, filtered and concentrated in vacuo to yield a residue which was then purified by flash column chromatography eluting with 0% to 20% MeOH/CH.sub.2Cl.sub.2.

(281) 8-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one: (40% yield, 100% purity) m/z (LC-MS, ESP): 490 [M+H].sup.+, R/T=3.49 min)

(282) NMR Data for Example 1df

(283) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.60 (ArH, d, J=2.23 Hz, 1H), 7.93-7.83 (ArH, m, 2H), 7.34 (ArH, d, J=8.56 Hz, 1H), 6.89 (ArH, d, J=8.97 Hz, 1H), 4.82-4.71 (CH.sub.2, m, 1H), 4.47 (CH.sub.2, dd, J=7.28, 6.58 Hz, 1H), 4.30 (CH.sub.2, d, J=6.93 Hz, 1H), 3.95-3.55 (CH.sub.2, m, 13H), 3.55-3.42 (CH.sub.2, m, 1H), 3.35-3.21 (CH.sub.2, m, 1H), 1.40 (CH.sub.3, d, J=6.77 Hz, 3H), 1.26 (CH.sub.3, d, J=6.80 Hz, 3H).

Procedure for the synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-difluoromethoxy-benzamide (Example 1dg)

(284) ##STR00223##

(285) To a solution of 5-bromo-2-difluoromethoxy-benzoic acid (1 equiv) in THF (0.1 M) was added dropwise thionyl chloride (5 equiv) at room temperature. The reaction mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was suspended in dry THF (0.04 M) and ammonia gas was slowly bubbled into the reaction mixture for 45 minutes. The reaction mixture was concentrated in vacuo. The residue was dissolved in minimum CH.sub.2Cl.sub.2 and hexane was added to give a white precipitate that was collected by vacuum filtration in suitably clean form for use in subsequent reactions.

(286) 5-Bromo-2-difluoromethoxy-benzamide: (45% yield, 73% purity) m/z (LC-MS, ESP): 266/268 [M+H].sup.+, R/T=3.42 min)

(287) To a solution of 5-bromo-2-difluoromethoxy-benzamide (1 equiv) in dioxan (0.1 M) were added bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv). The reaction mixture was degassed with nitrogen for 15 minutes. PdCl.sub.2(dppf) (0.05 equiv) was added to the reaction mixture, which was degassed for a further 5 minutes. The reaction mixture was stirred at 110° C. for 12 hours under nitrogen. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic phases were washed with water, dried with magnesium sulphate, filtered and concentrated in vacuo to give the desired product for use in subsequent reactions 2-Difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide: (71% yield, crude taken forward without further analysis)

(288) A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), 2-difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (1.1 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 100° C. for 4 hours. Upon completion the reaction mixture was partitioned between water and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. Combined organic phases were washed with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.

(289) 5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-difluoromethoxy-benzamide: (14% yield, 100% purity) m/z (LC-MS, ESP): 515 [M+H].sup.+, R/T=7.40 min

Procedure for the synthesis of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-difluoromethoxy-N-methyl-benzamide (Example 1dh)

(290) ##STR00224##

(291) To a solution of 5-bromo-2-difluoromethoxy-benzoic acid (1 equiv) in DMF (0.1 M) was added triethylamine (4 equiv). The reaction mixture was cooled to 0° C. and HBTU (1.2 equiv) was added. The reaction mixture was allowed to reach room temperature over 1 hour and methylamine hydrochloride (2 equiv) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between EtOAc and water and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with water, dried with magnesium sulphate, filtered and concentrated under in vacuo to give the desired product in suitably clean form for use in subsequent reactions.

(292) 5-Bromo-2-difluoromethoxy-N-methyl-benzamide: (100% yield, 75% purity) m/z (LC-MS, ESP): 280/282 [M+H].sup.+, R/T=3.55 min)

(293) 2-Difluoromethoxy-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide was prepared in a similar way as 2-Difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide using 5-bromo-2-difluoromethoxy-N-methyl-benzamide as the starting material.

(294) 2-Difluoromethoxy-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide: (100% yield, crude taken forward without further analysis)

(295) A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), 2-difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (1.1 equiv) and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 100° C. for 2 hours. Upon completion the reaction mixture was partitioned between water and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. Combined organic phases were washed with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.

(296) 5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-difluoromethoxy-N-methyl-benzamide: (53% yield, 87% purity) m/z (LC-MS, ESP): 421 [M+H].sup.+, R/T=4.06 min)

Procedure for the synthesis of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzamide (Example 1di)

(297) ##STR00225##

(298) 4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid methyl ester (1 equiv) was dissolved in methanol (0.2 M). 1M Sodium hydroxide aqueous solution (5.0 equiv) was added. The reaction mixture was stirred at room temperature for 3 hours. Upon completion the reaction mixture was neutralised with 1M aqueous HCl and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 10% MeOH in CH.sub.2Cl.sub.2 to give the desired product.

(299) 4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid: (100% yield, 100% purity) m/z (LC-MS, ESP): 480 [M+H].sup.+, R/T=2.69 min)

(300) 4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid (1 equiv) was suspended in THF (0.05 M). Thionyl chloride was added dropwise at 40° C. The reaction mixture was then heated for an hour at 40° C. Ammonia gas was then slowly bubbled into the reaction mixture. THF was then added for further dilution (0.025 M) and the reaction mixture was heated for an hour at 40° C. Upon completion the reaction mixture was cooled down and concentrated in vacuo. The residue was partitioned between water and CH.sub.2Cl.sub.2. The aqueous phase was extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% MeOH in CH.sub.2Cl.sub.2 to give the desired product.

(301) 4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzamide: (88% yield, 99% purity) m/z (LC-MS, ESP): 479 [M+H].sup.+, R/T=3.92 min)

(302) NMR Data for Example 1di

(303) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.30 (ArH, d, J=8.17 Hz, 1H), 8.04 (ArH, dd, J=6.21, 4.98 Hz, 2H), 7.80 (NH, br, s, 1H), 7.67 (ArH, dd, J=8.21, 1.49 Hz, 1H), 7.49 (ArH, d, J=8.44 Hz, 1H), 5.96 (NH, s, br, 1H), 4.98-4.85 (CH.sub.2, m, 1H), 4.61 (CH.sub.2, d, J=12.90 Hz, 1H), 4.39 (CH.sub.2, d, J=6.89 Hz, 1H), 4.13 (OCH.sub.3, s, 3H), 4.05-3.64 (CH.sub.2, m, 9H), 3.64-3.51 (CH.sub.2, m, 1H), 3.41 (CH.sub.2, dd, J=13.34, 3.62 Hz, 1H), 1.49 (CH.sub.3, d, J=6.79 Hz, 3H), 1.36 (CH.sub.3, d, J=6.82 Hz, 3H).

(304) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 166.78, 165.32, 162.81, 160.99, 160.02, 158.15, 143.57, 134.98, 132.76, 121.80, 120.15, 113.62, 111.30, 105.44, 71.27, 70.89, 67.23, 66.90, 56.42, 52.88, 47.01, 44.41, 39.36, 14.77 and 14.40.

Procedure for the synthesis of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-N-methyl-benzamide (Example 1dj)

(305) ##STR00226##

(306) 4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid (1 equiv) was dissolved in THF (0.1 M) and HBTU (1.5 equiv) was added. Methylamine in THF (15 equiv) was added dropwise followed by triethylamine (1.5 equiv) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and CH.sub.2Cl.sub.2. The aqueous phase was extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.

(307) 4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-N-methyl-benzamide: (56% yield, 96% purity) m/z (LC-MS, ESP): 493 [M+H].sup.+, R/T=4.00 min)

(308) NMR Data for Example 1dj

(309) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.26 (ArH, d, J=8.16 Hz, 1H), 7.98 (ArH, dd, J=8.74, 4.91 Hz, 2H), 7.91-7.81 (NH, m, br, 1H), 7.60 (ArH, dd, J=8.21, 1.52 Hz, 1H), 7.43 (ArH, d, J=8.45 Hz, 1H), 4.93-4.81 (CH.sub.2, m, 1H), 4.62-4.51 (CH.sub.2, m, 1H), 4.39-4.28 (CH.sub.2, m, 1H), 4.07 (OCH.sub.3, s, 3H), 4.00-3.58 (CH.sub.2, m, 9H), 3.57-3.45 (CH.sub.2, m, 1H), 3.40-3.27 (CH.sub.2, m, 1H), 2.99 (NHCH.sub.3, d, J=4.82 Hz, 3H), 1.43 (CH.sub.3, d, J=6.78 Hz, 3H), 1.31 (CH.sub.3, d, J=6.81 Hz, 3H).

Procedure for the synthesis of 2-methoxy-N-methyl-5-[4-((S)-3-methyl-morpholin-4-yl)-2-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzamide (Example 1 dk)

(310) ##STR00227##

(311) To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), and 2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (1.05 equiv) in acetonitrile/water (1:1) (0.028 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 20 minutes. Upon completion the reaction mixture was partitioned between water and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 20% MeOH in CH.sub.2Cl.sub.2 to give the desired product.

(312) 2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid: (91% yield, 100% purity) m/z (LC-MS, ESP): 466.4 [M+H].sup.+, R/T=2.68 min)

(313) 2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid (1 equiv) was dissolved in DMF (0.1 M) and DIPEA (8 equiv) was added. HBTU (1.2 equiv) was added at 0° C. and the reaction mixture was stirred for 30 minutes. Methylamine hydrochloride (5 equiv) was added and the reaction mixture was stirred 0° C. for 30 minutes and at room temperature for 1 hour. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. Combined organic phases were washed with water and brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography to give the desired product.

(314) 4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-N-methyl-benzamide: (73% yield, 97% purity) m/z (LC-MS, ESP): 479.2 [M+H].sup.+, R/T=3.97 min)

(315) NMR Data for Example 1dk

(316) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.71 (ArH, d, J=2.45 Hz, 1H), 8.45 (ArH, dd, J=8.75, 2.48 Hz, 1H), 7.97 (ArH, d, J=8.52 Hz, 1H), 7.78 (NH, s, br, 1H), 7.51 (ArH, d, J=8.56 Hz, 1H), 7.01 (ArH, d, J=8.84 Hz, 1H), 4.39 (CH.sub.2, d, J=6.69 Hz, 1H), 3.96 (OCH.sub.3, s, 3H), 3.95-3.77 (CH.sub.2, m, 7H), 3.76-3.58 (CH.sub.2, m, 7H), 2.98 (NCH.sub.3, d, J=4.81 Hz, 3H), 1.42 (CH.sub.3, d, J=6.78 Hz, 3H).

(317) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.74, 164.71, 161.22, 160.99, 159.11, 159.04, 135.09, 132.93, 131.23, 131.16, 121.32, 119.02, 113.63, 111.84, 104.61, 70.90, 66.90, 56.27, 52.70, 44.70, 44.48, 26.70 and 14.85.

Procedure for the synthesis of 6-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1H-indazol-3-ylamine (Example 1dl)

(318) ##STR00228##

(319) To a mixture of 7-chloro-4-((S)-3-methyl-morpholin-4-yl)-2-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine (1 equiv), potassium carbonate (2.5 equiv), and 4-cyano-3-fluorophenylboronic acid (1.2 equiv) in acetonitrile/water (1:1) (0.03 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (110° C., medium absorption setting) for 25 minutes under nitrogen atmosphere. Upon completion the precipitate was collected by vacuum filtration, which was in suitably pure form to be used with no further purification.

(320) ##STR00229##

(321) 4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzonitrile: (49% yield, 96% purity) m/z (LC-MS, ESP): 449.2 [M+H].sup.+ R/T=2.93 min

(322) To a 0.2 M solution of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzonitrile (1 equiv) in n-BuOH was added 0.2 reaction volumes of hydrazine hydrate. A reflux condenser was attached to the mixture which was then heated to 140° C. for 2 hours whereupon it was cooled, and concentrated in vacuo to give an orange residue which was purified by flash chromatography (SiO.sub.2) using Et.sub.2O:MeOH—94:6 as eluent which allowed a yellow solid which was then recrystallised from CH.sub.2Cl.sub.2/Hexanes to furnish the title compound as a yellow solid.

(323) ##STR00230##

(324) 6-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1H-indazol-3-ylamine: (90% yield, 97% purity) m/z (LC-MS, ESP): 461.2 [M+H].sup.+ R/T=3.77 min

(325) NMR Data for Example 1dl

(326) (.sup.1H NMR (300 MHz, CD.sub.3SOCD.sub.3) δ ppm 11.6 (1H, s, formate), 8.31-8.01 (ArH, m, 2H), 7.74 (ArH, ddd, J=18.90, 15.23, 8.49 Hz, 3H), 5.42 (NH.sub.2, s, 2H), 4.88-4.70 (NH, m, 1H), 4.44 (CH.sub.2, d, J=10.93 Hz, 2H), 3.91 (CH.sub.2, m, 3H), 3.81-3.54 (CH.sub.2, m, 6H), 3.46 (CH.sub.2, dt, J=11.82, 11.67, 2.52 Hz, 1H), 3.38-3.13 (CH.sub.2, m, 1H), 2.51 (CH, td, J=3.52, 1.73, 1.73 Hz, 1H), 1.38 (CH.sub.3, d, J=6.75 Hz, 3H), 1.26 (CH.sub.3, d, J=6.79 Hz, 3H).

(327) 13C NMR (75 MHz, CD.sub.3SOCD.sub.3) δ ppm 164.43, 162.05, 161.20, 159.29, 149.19, 141.79, 136.12, 135.32, 120.42, 116.81, 114.78, 113.13, 108.47, 104.30, 70.39, 70.15, 66.34, 66.15, 51.81, 46.24, 43.81, 30.89, 22.0, 14.31 and 13.89.

Procedure for the synthesis of N-{4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-acetamide (Example 1dm)

(328) ##STR00231##

(329) To a 0.1 M solution of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-ylamine (example 1cz) (1 equiv) in pyridine was added acetic anhydride (3 equiv). A reflux condenser was attached to the reaction vessel which was then heated to 70° C. for 2 days. Upon completion, the reaction was purified, in its crude for by preparative HPLC to give the title compound as a white solid.

(330) N-{4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-yl}-acetamide: (95% yield, 99% purity) m/z (LC-MS, ESP): 464.1 [M+H].sup.+ R/T=3.77 min

(331) NMR Data for Example 1dm

(332) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.70 (NH, s, 1H), 8.37-8.29 (ArH, m, 2H), 8.01 (ArH, d, J=8.36 Hz, 1H), 7.94 (ArH, dd, J=5.26, 1.54 Hz, 1H), 7.49 (ArH, d, J=8.39 Hz, 1H), 4.87 (CH.sub.2, ddd, J=2.90, 1.56, 0.64 Hz, 1H), 4.56 (CH.sub.2, d, J=13.43 Hz, 1H), 4.33 (CH.sub.2, d, J=6.86 Hz, 1H), 3.99-3.58 (CH.sub.2, m, 10H), 3.57-3.45 (CH.sub.2, m, 1H), 3.39-3.25 (CH.sub.2, m, 1H), 2.19 (CH.sub.3, s, 3H), 1.43 (CH.sub.3, d, J=6.78 Hz, 3H), 1.31 (CH.sub.3, d, J=6.82 Hz, 3H)

(333) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 168.79, 165.32, 162.82, 160.00, 159.87, 151.94, 148.64, 148.15, 135.18, 118.86, 113.66, 111.94, 106.03, 71.27, 70.89, 67.23, 66.89, 52.89, 46.98, 44.46, 39.35, 24.81, 14.77 and 14.41.

Procedure for the Synthesis of Examples 1dn to 1dp

(334) ##STR00232##

(335) The appropriate 7-chloropyridopyrimidine was reacted with 2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester according to conditions E to give 2-methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-thiomorpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid methyl ester as the desired product (1 equiv) which was then diluted in MeOH to give a 0.03M solution. NaOH (5 equiv of 1 M solution) was then added and the resultant mixture stirred at room temperature for 5 days. After this time the reaction was filtered and neutralized with 1M HCl before being concentrated in vacuo to give a crude yellow residue which was diluted in CH.sub.2Cl.sub.2. The mixture was filtered and the resulting filtrate concentrated to give the desired product as an oil.

(336) ##STR00233##

(337) 2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-thiomorpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid: (99% yield, 95% purity) m/z (LC-MS, ESP): 482.2[M+H]+R/T=2.78 min

(338) ##STR00234##

(339) 2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-(4-methyl-piperazin-1-yl)-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid: (88% yield, 96% purity) m/z (LC-MS, ESP): 479.5[M+H].sup.+ R/T=2.26 min

(340) ##STR00235##

(341) 2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzoic acid: (91% yield, 100% purity) m/z (LC-MS, ESP): 466.4 [M+H].sup.+ R/T=2.68 min

(342) To a warmed (40° C.) 0.06 M solution of the appropriate benzoic acid derivative (1 equiv) in anhydrous THF was added thionyl chloride (2.5 equiv) in a dropwise fashion. The reaction was maintained at this temperature and stirred for a further 1 hour. After this time the mixture was evaporated to give a brown oil, which was diluted in dry THF (sufficient to make 0.06 M solution) before ammonia gas was bubble through the mixture, which was accompanied by an exotherm. Upon completion, addition of ammonia was stopped and the mixture concentrated in vacuo to give a yellow oily residue which was dissolved in CH.sub.2Cl.sub.2 (1 reaction volume) and washed with water (2×1 reaction volume). The organic extract was removed, dried (MgSO.sub.4), filtered and concentrated in vacuo to give the title compound.

(343) ##STR00236##

(344) 2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-thiomorpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzamide: (30% yield, 97% purity) m/z (LC-MS, ESP): 481.1[M+H]R/T=4.02 min

(345) NMR Data for Example 1dn

(346) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.83 (ArH, d, J=2.46 Hz, 1H), 8.61 (ArH, dd, J=8.75, 2.48 Hz, 1H), 8.00 (ArH, d, J=8.47 Hz, 1H), 7.72 (NH, d, J=0.76 Hz, 1H), 7.56 (ArH, d, J=8.50 Hz, 1H), 7.13 (ArH, d, J=8.82 Hz, 1H), 5.88 (NH, d, J=0.98 Hz, 1H), 4.42-4.23 (CH.sub.2, m, 4), 4.05 (CH.sub.3O, s, 3H), 4.03-3.94 (CH.sub.2, m, 1H), 3.85 (CH.sub.2, ddd, J=14.51, 8.58, 5.82 Hz, 2H), 3.78-3.62 (CH.sub.2, m, 3H), 2.75-2.65 (CH.sub.2, m, 3H), 1.46 (CH.sub.3, d, J=6.76 Hz, 3H).

(347) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 166.60, 165.41, 162.87, 161.09, 159.89, 159.23, 134.73, 133.71, 131.82, 131.68, 120.56, 113.16, 111.89, 104.63, 70.95, 66.91, 56.29, 52.81, 46.70, 44.54, 27.45 and 14.70.

(348) ##STR00237##

(349) 2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-(4-methyl-piperazin-1-yl)-pyrido[2,3-d]pyrimidin-7-yl]-benzamide: (12% yield, 98% purity) m/z (LC-MS, ESP): 481.1[M+H]+R/T=43.28 min

(350) NMR Data for Example 1do

(351) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.78 (ArH, d, J=2.48 Hz, 1H), 8.57 (ArH, dd, J=8.76, 2.52 Hz, 1H), 8.28 (NH, s, br, 1H), 7.96 (ArH, d, J=8.50 Hz, 1H), 7.68 (NH, s, br, 1H), 7.54 (ArH, d, J=8.55 Hz, 1H), 7.08 (ArH, d, J=8.84 Hz, 1H), 4.42-4.28 (CH.sub.2, m, 1H), 4.09 (CH.sub.2, s, br, 2H), 4.01 (OCH.sub.3, s, 3H), 3.77 (CH.sub.2, ddd, J=36.04, 19.80, 10.87 Hz, 9H), 2.76 (CH.sub.2, t, J=5.05, 5.05 Hz, 4H), 2.47 (NCH.sub.3, s, 3H), 1.42 (CH.sub.3, d, J=6.77 Hz, 3H).

(352) ##STR00238##

(353) 2-Methoxy-5-[4-((S)-3-methyl-morpholin-4-yl)-2-morpholin-4-yl-pyrido[2,3-d]pyrimidin-7-yl]-benzamide: (61% yield, 97% purity) m/z (LC-MS, ESP): 465.4 [M+H].sup.+ R/T=2.69 min

(354) NMR Data for Example 1dp

(355) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.77 (ArH, d, J=2.44 Hz, 1H), 8.58 (ArH, dd, J=8.76, 2.47 Hz, 1H), 7.94 (ArH, d, J=8.48 Hz, 1H), 7.65 (NH, s, br, 1H), 7.51 (ArH, d, J=8.53 Hz, 1H), 7.06 (ArH, d, J=8.84 Hz, 1H), 5.91 (NH, s, br, 1H), 4.32 (CH.sub.2, d, J=6.79 Hz, 1H), 3.98 (OCH.sub.3, s, 3H), 3.95-3.86 (CH.sub.2, m, 5H), 3.84-3.55 (CH.sub.2, m, 9H), 1.40 (CH.sub.3, d, J=6.77 Hz, 3H)

(356) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 166.63, 165.31, 162.78, 160.96, 160.31, 159.29, 134.76, 133.68, 131.69, 131.60, 120.56, 113.09, 111.88, 104.76, 70.94, 67.04, 66.91, 56.28, 52.76, 44.58, 44.45 and 14.75.

Procedure for the Synthesis of Example 1dq

(357) ##STR00239##

(358) To a (0.1 M) solution of example 1at (1 equiv) in CHCl.sub.3 was added m-CPBA (5.5 equiv). A reflux condenser was added to the apparatus and the mixture heated to 60° C. for 17 hours. After this time the reaction was concentrated in vacuo and purified by flash chromatography (SIO.sub.2) using CH.sub.2Cl.sub.2:MeOH—95:5 as eluent to furnish the desired product.

(359) ##STR00240##

(360) N-{3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-8-oxy-pyrido[2,3-d]pyrimidin-7-yl]-phenyl}-methanesulfonamide: (39% yield, 100% purity) m/z (LC-MS, ESP): 515.5[M+H].sup.+ R/T=2.95 min.

(361) NMR Data for Example 1dq

(362) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 10.04 (NH, s, br, 1H), 8.42 (ArH, s, 1H), 7.55-7.25 (ArH, m, 4H), 6.96 (ArH, d, J=8.67 Hz, 1H), 4.80 (CH.sub.2, s, br, 1H), 4.51 (CH.sub.2, s, br, 1H), 4.31 (CH.sub.2, d, J=6.71 Hz, 1H), 4.00-3.51 (CH.sub.2, m, 9H), 3.49-3.34 (CH.sub.2, m, 1H), 3.24 (CH.sub.2, dd, J=13.22, 3.30 Hz, 1H), 2.80 (SCH.sub.3, s, 3H), 1.42 (CH.sub.3, d, J=6.78 Hz, 1H), 1.19 (CH.sub.3, d, J=6.69 Hz, 3H).

(363) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.58, 159.69, 158.28, 149.96, 138.59, 134.47, 129.53, 125.86, 123.35, 123.30, 116.17, 107.52, 71.33, 71.11, 67.32, 67.10, 53.39, 47.62, 44.87, 39.79, 38.68, 31.90, 22.97 and 15.16.

Procedure for the Synthesis of Example 1dr

(364) ##STR00241##

(365) 7-Chloro-2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine was couple with 3-nitrobenzoic acid using Suzuki conditions D to give the desire product as a yellow powder.

(366) ##STR00242##

(367) 2,4-Bis-((S)-3-methyl-morpholin-4-yl)-7-(3-nitro-phenyl)-pyrido[2,3-d]pyrimidine: (90% yield, 100% purity) m/z (LC-MS, ESP): 451.6[M+H].sup.+ R/T=3.41 min

(368) To a 0.1M solution of 2,4-bis-((S)-3-methyl-morpholin-4-yl)-7-(3-nitro-phenyl)-pyrido[2,3-d]pyrimidine (1 equiv) in EtOH/H.sub.2O-1:1 was added ammonium chloride (8 equiv) and iron powder (8 equiv). The reaction mixture was heated to 100° C. for 1 hour before cooling and filtering through a thin Celite™ pad. The cake was washed with EtOH (1 reaction volume). The filtrate was concentrated in vacuo and then partitioned between water and CH.sub.2Cl.sub.2 (1 reaction volume of each). The organic phase was removed, dried (MgSO.sub.4), filtered and concentrated in vacuo and then purified by flash chromatography (SiO.sub.2) using MeOH:CH.sub.2Cl.sub.2 (0:100-5:95-10-90) as eluent to give the title compound as a yellow solid.

(369) ##STR00243##

(370) 3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-phenylamine: (88% yield, 98% purity) m/z (LC-MS, ESP): 421.1[M+H].sup.+ R/T=3.76 min

(371) NMR Data for Example 1dr

(372) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 7.93 (ArH, d, J=8.45 Hz, 1H), 7.62-7.55 (ArH, m, 1H), 7.41-7.32 (m, 1H), 7.20 (ArH, d, J=7.32 Hz, 2H), 6.71 (ArH, ddd, J=7.88, 2.40, 0.86 Hz, 1H), 4.87 (ArH, dd, J=3.54, 1.66 Hz, 1H), 4.57 (NH, d, J=13.25 Hz, 1H), 4.30 (NH, s, br, 1H), 3.98-3.56 (CH.sub.2, m, 11H), 3.56-3.44 (CH.sub.2, m, 1H), 3.37-3.24 (CH.sub.2, m, 1H), 1.40 (CH.sub.3, d, J=6.77 Hz, 3H), 1.29 (CH.sub.3, d, J=6.81 Hz, 3H)

(373) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.46, 162.87, 162.60, 159.96, 146.80, 139.75, 134.48, 129.35, 117.99, 116.69, 114.74, 113.48, 104.92, 71.32, 70.93, 67.28, 66.94, 52.80, 46.90, 44.49, 39.33, 14.71 and 14.33.

Procedure for the Synthesis of Example 1ds

(374) ##STR00244##

(375) To a 0.3M solution of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzonitrile (example 1av) (1 equiv) in EtOH was added hydrazine hydrate (5 equiv). The mixture was refluxed for 90 minutes whereupon it was cooled and partitioned between CH.sub.2Cl.sub.2 and water (1 reaction volume of each). The organic extract was removed. The aqueous phase was further extracted with CH.sub.2Cl.sub.2 (2×1 reaction volume). The combined organic extracts were then dried (MgSO.sub.4), filtered and concentrated in vacuo to give a yellow slurry which was further purified by flash chromatography (SiO.sub.2) using EtOAC/Hexanes as eluent to give the title compound as a yellow powder.

(376) ##STR00245##

(377) 5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-1H-indazol-3-ylamine: (52% yield, 100% purity) m/z (LC-MS, ESP): 461.6[M+H].sup.+ R/T=2.85 min

(378) NMR Data for Example 1ds

(379) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.52 (ArH, s, 1H), 8.06 (ArH, dd, J=8.84, 1.50 Hz, 1H), 7.94 (ArH, d, J=8.49 Hz, 1H), 7.42 (ArH, d, J=8.50 Hz, 1H), 7.29 (ArH, d, J=8.79 Hz, 2H), 4.87 (CH.sub.2, dd, J=3.99, 1.99 Hz, 1H), 4.60 (CH.sub.2, s, br, 1H), 4.32 (CH.sub.2, d, J=6.78 Hz, 1H), 3.98-3.58 (CH.sub.2, m, 9H), 3.51 (CH.sub.2, dt, J=11.78, 11.46, 2.71 Hz, 1H), 3.39-3.25 (CH.sub.2, m, 1H), 1.42 (CH.sub.3, d, J=6.77 Hz, 3H), 1.29 (CH.sub.3, d, J=6.81 Hz, 3H) (NH's not clearly seen)

(380) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.43, 162.97, 162.33, 160.01, 142.86, 134.62, 130.11, 127.06, 120.17, 115.21, 112.98, 109.71, 104.51, 71.32, 70.94, 67.28, 66.95, 52.80, 46.95, 44.48, 39.36, 27.01, 14.79 and 14.33.

(381) TABLE-US-00002 Retention Purity time m/z (%) (min) [M+H].sup.+ Conditions Example Structure 1dt 96 3.96 461.2 U 1du 97 4.10 513.1 I 1dv 99 4.04 495.0 J 1dw 98 3.70 504.1 V 1dx 99 3.79 474.1 I 0 1dy 99 3.79 474.1 W 1dz 99 4.06 499.2 D 1ea 99 4.16 451.2 D 1eb 98 3.96 446.2 P 1ec 99 7.55 466.2 J 1ed 98 3.86 461.2 D 1ee 98 4.04 485.2 D Note: The following examples were synthesized from the corresponding boronic acids: 1du, 1dv, 1dz and 1ee. The following examples were synthesized from the corresponding pinacolate boron esters: 1dw, 1dx, 1ea, 1eb and 1ec. The following Examples were synthesized from a mixture of the corresponding boronic acids and pinacolate boron esters: 1dt, 1dy, and 1ed.
NMR Data for Example 1ec

(382) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.15 (ArH, d, J=7.5 Hz, 2H), 7.97 (ArH, d, J=8.46 Hz, 1H), 7.42 (ArH, d, J=8.46 Hz, 1H), 6.98 (ArH, d, J=9.24 Hz, 1H), 4.91 (CH.sub.2, d, J=5.55 Hz, 1H), 4.77 (CH.sub.2OH, s, 2H), 4.61 (CH.sub.2, d, J=12.42 Hz, 1H), 4.36-4.34 (CH.sub.2, m, 1H), 4.00-3.70 (OCH.sub.3+CH.sub.2, m, 9H), 3.69-3.51 (CH.sub.2, m, 1H), 3.41-3.31 (CH.sub.2, m, 1H), 1.46 (CH.sub.3, d, J=6.69 Hz, 3H), 1.35 (CH.sub.3, d, J=6.87 Hz, 3H).

(383) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.42, 162.88, 161.87, 159.95, 159.16, 134.54, 131.13, 129.25, 128.89, 128.44, 112.85, 110.27, 104.49, 71.30, 70.92, 67.26, 66.93, 61.98, 55.56, 52.78, 46.91, 44.45, 39.32, 14.69 and 14.31.

(384) NMR Data for Example 1ed

(385) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.34 (ArH, s, 1H), 8.11 (ArH, d, J=8.02 Hz, 1H), 8.00 (ArH, d, J=8.41 Hz, 1H), 7.90 (ArH, d, J=7.98 Hz, 1H), 7.43 (ArH, d, J=8.42 Hz, 1H), 7.10 (NH, br, s, 1H), 4.95-4.81 (CH.sub.2, m, 1H), 4.57 (CH.sub.2, d, J=13.37 Hz, 1H), 4.47 (NHCH.sub.2, s, 2H), 4.33 (CH.sub.2, d, J=6.68 Hz, 1H), 3.99-3.58 (CH.sub.2, m, 9H), 3.51 (CH.sub.2, dt, J=11.81, 11.45, 2.72 Hz, 1H), 3.31 (CH.sub.2, dt, J=12.91, 12.52, 3.57 Hz, 1H), 1.42 (CH.sub.3, d, J=6.78 Hz, 3H), 1.30 (CH.sub.3, d, J=6.81 Hz, 3H).

(386) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 171.32, 165.36, 162.94, 161.42, 160.04, 144.06, 142.31, 135.01, 133.20, 127.63, 123.83, 123.08, 113.49, 105.35, 71.27, 70.91, 67.24, 66.91, 52.85, 46.96, 45.70, 44.48, 39.35, 14.76 and 14.39.

(387) NMR Data for Example 1ef

(388) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.08 (ArH, d, J=1.95 Hz, 1H), 8.01-7.94 (ArH, m, 1H), 7.82 (ArH, td, J=6.63, 1.80, 1.80 Hz, 1H), 7.48 (NH, br, s, 1H), 7.39 (ArH, dd, J=12.99, 5.20 Hz, 3H), 4.34 (CH.sub.2, q, J=6.63, 6.56, 6.56 Hz, 1H), 3.97-3.76 (CH.sub.2, m, 7H), 3.75-3.57 (CH.sub.2, m, 7H), 2.87 (SO.sub.2CH.sub.3, s, 3H), 1.42 (CH.sub.3, d, J=6.78 Hz, 3H).

(389) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.21, 162.77, 161.34, 160.28, 140.30, 137.69, 135.07, 129.91, 124.53, 122.37, 120.57, 113.44, 105.22, 70.91, 66.97, 66.89, 52.84, 44.58, 44.39, 39.32 and 14.79.

(390) NMR Data for Example 1dz

(391) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.11-8.03 (ArH, m, 2H), 7.96 (ArH, d, J=8.44 Hz, 1H), 7.38-7.31 (ArH, m, 1H), 7.32-7.24 (ArH, m, 2H), 4.85 (CH.sub.2, d, J=5.45 Hz, 1H), 4.54 (CH.sub.2, d, J=12.83 Hz, 1H), 4.32 (CH.sub.2, d, J=6.78 Hz, 1H), 3.97-3.57 (CH.sub.2, m, 9H), 3.50 (CH.sub.2, dt, J=11.75, 11.35, 2.73 Hz, 1H), 3.37-3.24 (CH.sub.2, m, 1H), 2.95 (SO.sub.2CH.sub.3, s, 3H), 1.42 (CH.sub.3, d, J=6.78 Hz, 1H), 1.29 (CH.sub.3, d, J=6.81 Hz, 3H) (NH not seen).

(392) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.36, 162.93, 161.33, 160.00, 138.73, 135.29, 134.86, 129.34, 119.66, 112.95, 104.90, 71.27, 70.92, 67.24, 66.93, 52.82, 46.97, 44.45, 39.58, 33.35, 14.75 and 14.36.

(393) NMR Data for Example 1ea

(394) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 7.87 (ArH, d, J=8.55 Hz, 1H), 7.81 (ArH, d, J=1.80 Hz, 1H), 7.47 (ArH, dd, J=8.17, 1.85 Hz, 1H), 7.35 (ArH, d, J=8.57 Hz, 1H), 6.69 (ArH, d, J=8.14 Hz, 1H), 4.85 (CH.sub.2, d, J=5.96 Hz, 1H), 4.62-4.52 (CH.sub.2, m, 1H), 4.28 (CH.sub.2, d, J=6.77 Hz, 1H), 4.02 (NH.sub.2, s, br, 2H), 3.95 (d, J=6.54 Hz, 1H), 3.93 (CH.sub.3, s, 3H), 3.92-3.57 (CH.sub.2, m, 9H), 3.55-3.45 (CH.sub.2, m, 1H), 3.38-3.25 (CH.sub.2, m, 1H), 1.39 (CH.sub.3, d, J=6.77 Hz, 3H), 1.29 (CH.sub.3, d, J=6.81 Hz, 3H).

(395) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.48, 162.91, 162.45, 159.98, 147.22, 138.70, 134.14, 128.92, 121.24, 113.97, 112.74, 110.15, 104.11, 71.35, 70.95, 67.32, 66.96, 55.83, 52.79, 46.89, 44.44, 39.31, 31.60, 22.66 and 14.30.

(396) NMR Data for Example 1eb

(397) .sup.1H NMR (300 MHz, CD.sub.3COCD.sub.3) δ ppm 11.83 (ArH, s, 1H), 9.06 (ArH, d, J=2.07 Hz, 1H), 8.75 (ArH, d, J=2.09 Hz, 1H), 8.30-8.10 (ArH, m, 1H), 7.72 (ArH, d, J=8.55 Hz, 1H), 7.54 (ArH, s, 1H), 6.59 (NH, s, 1H), 4.77 (CH.sub.2, dd, J=6.66, 1.89 Hz, 1H), 4.49-4.34 (CH.sub.2, m, 2H), 4.03-3.83 (CH.sub.2, m, 3H), 3.81-3.55 (CH.sub.2, m, 6H), 3.54-3.38 (CH.sub.2, m, 1H), 3.23 (CH.sub.2, dd, J=13.19, 3.46 Hz, 1H), 1.37 (CH.sub.3, d, J=6.74 Hz, 3H), 1.25 (CH.sub.3, d, J=6.75 Hz, 3H).

(398) .sup.13C NMR (75 MHz, CD.sub.3COCD.sub.3) δ ppm 165.41, 163.09, 161.32, 160.22, 150.21, 143.45, 136.25, 128.14, 128.09, 126.99, 120.44, 113.54, 104.90, 101.82, 71.32, 71.09, 67.27, 67.09, 52.78, 47.17, 44.79 and 15.25.

(399) NMR Data for Example 1dy

(400) 1H NMR (300 MHz, CD.sub.3SOCD.sub.3) δ ppm 8.40 (ArH, d, J=1.37 Hz, 1H), 8.33 (ArH, dd, J=8.38, 1.63 Hz, 1H), 8.25 (ArH, d, J=8.45 Hz, 2H), 8.17 (ArH, s, 1H), 7.79 (ArH, d, J=8.48 Hz, 1H), 4.84-4.73 (CH, m, 1H), 4.45 (CH.sub.2, d, J=13.67 Hz, 2H), 4.00-3.84 (CH.sub.2, m, 3H), 3.81-3.57 (CH.sub.2, m, 6H), 3.46 (CH.sub.2, dt, J=11.84, 11.73, 2.61 Hz, 1H), 3.23 (CH.sub.2, dt, J=13.16, 12.92, 3.65 Hz, 1H), 1.39 (CH.sub.3, d, J=6.75 Hz, 3H), 1.26 (CH.sub.3, d, J=6.75 Hz, 3H)

(401) 13C NMR (75 MHz, CD.sub.3SOCD.sub.3) δ ppm 164.30, 162.06, 160.45, 159.32, 159.03, 149.10, 145.91, 143.53, 135.86, 126.40, 125.73, 125.30, 123.33, 113.30, 105.06, 70.35, 70.14, 66.31, 66.14, 51.79, 46.27, 43.81, 30.38, 14.35 and 13.89.

(402) NMR Data for Example 1dv

(403) .sup.1H NMR (300 MHz, CD.sub.3SOCD.sub.3) δ ppm 8.39 (ArH, dd, J=5.45, 3.65 Hz, 1H), 8.23 (ArH, d, J=8.47 Hz, 1H), 8.14-8.03 (ArH, m, 2H), 7.81-7.69 (ArH+NH, m, 2H), 4.77 (CH.sub.2, dd, J=6.52, 2.00 Hz, 1H), 4.43 (CH.sub.2, d, J=13.75 Hz, 2H), 3.99-3.83 (CH.sub.2, m, 2H), 3.80-3.56 (CH.sub.2, m, 6H), 3.52-3.15 (CH.sub.2, m, 5H), 2.50 (CH.sub.2, td, J=3.67, 1.83, 1.83 Hz, 2H), 1.38 (CH.sub.3, d, J=6.75 Hz, 3H), 1.25 (CH.sub.3, d, J=6.75 Hz, 3H), 1.19-1.10 (CH.sub.3, m, 3H).

(404) .sup.13C NMR (75 MHz, CD.sub.3SOCD.sub.3) δ ppm 164.80, 163.51, 162.52, 159.84, 158.73, 158.27, 142.53, 142.43, 136.38, 131.02, 125.84, 123.52, 123.48, 115.08, 114.76, 113.45, 105.57, 70.87, 70.64, 66.83, 66.65, 52.32, 46.79, 44.32, 34.59, 15.10, 14.87 and 14.42.

(405) NMR Data for Example 1dy

(406) .sup.1H NMR (300 MHz, CD.sub.3SOCD.sub.3) δ ppm 10.52 (NH, s, 1H), 8.19 (ArH, d, J=8.50 Hz, 1H), 7.79-7.68 (ArH, m, 2H), 7.61 (ArH, d, J=8.52 Hz, 1H), 7.35 (ArH, d, J=7.66 Hz, 1H), 4.84-4.69 (CH.sub.2, m, 1H), 4.42 (CH.sub.2, dd, J=7.38, 5.30 Hz, 2H), 3.91 (CH.sub.2, dd, J=14.30, 7.97 Hz, 3H), 3.82-3.52 (CH.sub.2, m, 8H), 3.45 (CH.sub.2, d, J=2.42 Hz, 1H), 3.26-3.15 (CH.sub.2, m, 1H), 1.37 (CH.sub.3, d, J=6.74 Hz, 3H), 1.25 (CH.sub.3, d, J=6.76 Hz, 3H).

(407) .sup.13C NMR (75 MHz, CD.sub.3SOCD.sub.3) δ ppm 176.84, 164.89, 162.55, 160.83, 159.82, 144.90, 138.19, 135.98, 128.66, 125.02, 120.94, 113.09, 108.05, 104.92, 70.90, 70.67, 66.84, 66.67, 52.32, 46.76, 44.30, 36.29, 14.85 and 14.35.

(408) NMR Data for Example 1dt

(409) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.58 (ArH, d, J=7.97 Hz, 1H), 8.49 (ArH, d, J=45.95 Hz, 1H), 7.99 (ArH, d, J=8.42 Hz, 1H), 7.50 (ArH, dd, J=17.31, 8.21 Hz, 1H), 7.24 (ArH, d, J=17.82 Hz, 1H), 5.01-4.86 (CH.sub.2, s, br, 1H), 4.65-4.39 (CH.sub.2, m, 3H), 4.33 (CH.sub.2, d, J=6.25 Hz, 1H), 4.04-3.58 (CH.sub.2, m, 8H), 3.49 (CH.sub.2, d, J=11.36 Hz, 1H), 3.31 (CH.sub.2, d, J=2.99 Hz, 1H), 1.41 (CH.sub.3, d, J=6.72 Hz, 3H), 1.29 (CH.sub.3, d, J=6.76 Hz, 3H) (1 proton missing, lots of overlap seen, NH not seen either)

(410) .sup.13C NMR (75 MHz, CDCl.sub.3) δ 171.52, 165.39, 162.90, 161.33, 160.01, 145.14, 139.06, 135.02, 132.17, 123.57, 122.56, 113.20, 105.21, 71.29, 70.92, 67.25, 66.93, 52.78, 46.95, 45.68, 44.51, 39.34, 27.00, 14.74 and 14.35.

(411) NMR Data for Example 1du

(412) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.12 (ArH, d, J=8.32 Hz, 2H), 8.03 (ArH, d, J=8.43 Hz, 1H), 7.51-7.39 (ArH, m, 3H), 5.08 (CH.sub.2, br, s, 1H), 4.89 (CH.sub.2, d, J=4.91 Hz, 1H), 4.58 (CH.sub.2, d, J=12.59 Hz, 1H), 4.40 (CH.sub.2NH, br, s, 2H), 4.22 (NH, br, s, 1H), 4.04-3.64 (CH.sub.2, m, 9H), 3.56 (CH.sub.2, dt, J=11.80, 11.45, 2.75 Hz, 1H), 3.44-3.30 (CH.sub.2, m, 1H), 2.87 (SO.sub.2CH.sub.3s, 3H), 1.48 (CH.sub.3, d, J=6.78 Hz, 3H), 1.35 (CH.sub.3, d, J=6.81 Hz, 3H)

(413) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.16, 163.70, 162.51, 159.71, 138.71, 138.33, 134.99, 128.40, 128.15, 113.45, 105.20, 71.23, 70.89, 67.18, 66.90, 52.82, 47.07, 46.90, 44.21, 41.25, 39.41, 14.78 and 14.38.

(414) Tested in the Biological Assay: Ex. (1b) 0.00185 μM; Ex. (1c) 0.00184 μM Ex. (1d) 0.00245 μM; Ex. (1az) 0.006865 μM.

(415) Tested in Alternative Enzyme Assay: Ex. (1a) 0.0089 μM; Ex. (1e) 0.0044 μM; Ex. (1f) 0.005 μM; Ex. (1g) 0.011 μM; Ex. (1h) 0.0021 μM; Ex. (1i) 0.0056 μM; Ex. (1j) 0.035 μM; Ex. (1k) 0.015 μM; Ex. (1l) 0.0057 μM; Ex. (1m) 0.31 μM; Ex. (1n) 0.085 μM; Ex. (1o) 0.14 μM; Ex. (1p) 0.038 μM; Ex. (1q) 0.39 μM; Ex. (1r) 0.23 μM; Ex. (1s) 0.028 μM; Ex. (1t) 0.34 μM; Ex. (1u) 0.015 μM; Ex. (1v) 0.18 μM; Ex. (1w) 0.26 μM; Ex. (1x) 0.53 μM; Ex. (1y) 0.33 μM; Ex. (1z) 0.37 μM; Ex. (1aa) 0.025 μM; Ex. (1ab) 0.029 μM; Ex. (1ac) 0.14 μM; Ex. (1ad) 0.0069 μM; Ex. (1ae) 0.38 μM; Ex. (1af) 0.054 μM; Ex. (1ag) 0.029 μM; Ex. (1ah) 0.012 μM; Ex. (1ai) 1.1 M; Ex. (1aj) 0.49 μM; Ex. (1ak) 0.017 μM; Ex. (1al) 0.23 μM; Ex. (1am) 0.21 μM; Ex. (1an) 0.14 μM; Ex. (1ao) 0.0083 μM; Ex. (1ap) 0.02 μM; Ex. (1aq) 0.084 μM; Ex. (1ar) 0.006 μM; Ex. (1as) 0.013 μM; Ex. (1at) 0.031 μM; Ex. (1au) 0.09 μM; Ex. (1av) 0.29 μM; Ex. (1aw) 0.062 μM; Ex. (1ax) 0.0092 μM; Ex. (1ay) 0.15 μM; Ex. (1ba) 0.44 μM; Ex. (1bb) 0.14 μM; Ex. (1bc) 0.083 μM; Ex. (1bd) 0.011 μM; Ex. (1be) 0.18 μM; Ex. (1bf) 0.06 μM; Ex. (1bg) 0.17 μM; Ex. (1bh) 0.014 μM; Ex. (1bi) 0.032 μM; Ex. (1bj) 0.035 μM; Ex. (1bk) 0.039 μM; Ex. (1bl) 0.0027 μM; Ex. (1bm) 0.055 μM; Ex. (1bn) 0.04 μM; Ex. (1bo) 0.018 μM; Ex. (1bp) 0.11 μM; Ex. (1bq) 0.14 μM; Ex. (1br) 0.056 μM; Ex. (1bs) 0.039 μM; Ex. (1bt) 0.11 μM; Ex. (1bu) 0.016 μM; Ex. (1bv) 0.0051 μM; Ex. (1bw) 0.036 μM; Ex. (1bx) 0.038 μM; Ex. (1by) 0.0046 μM; Ex. (1bz) 0.018 μM; Ex. (1ca) 0.35 μM; Ex. (1cb) 0.5 μM; Ex. (1cc) 0.0064 μM; Ex. (1cd) 0.46 μM; Ex. (1ce) 0.091 μM; Ex. (1cf) 0.073 μM; Ex. (1cg) 0.00026 μM; Ex. (1ch) 0.22 μM; Ex. (1ci) 0.15 μM; Ex. (1cj) 0.091 μM; Ex. (1ck) 0.065 μM; Ex. (1cl) 0.2 μM; Ex. (1cm) 0.16 μM; Ex. (1cn) 0.31 μM; Ex. (1co) 2.5 μM; Ex. (1cp) 1 μM; Ex. (1cq) 0.25 μM; Ex. (1cr) 0.69 μM; Ex. (1cs) 7.5 μM; Ex. (1et) 0.024 μM; Ex. (1cu) 0.042 μM; Ex. (1cv) 0.3 μM; Ex. (1cw) 0.49 μM; Ex. (1cx) 0.12 μM; Ex. (1cy) 0.72 μM; Ex. (1cz) 0.066 μM; Ex. (1da) 1.8 μM; Ex. (1db) 0.031 μM; Ex. (1dc) 0.02 μM; Ex. (1dd) 0.073 μM; Ex. (1de) 0.0049 μM; Ex. (1dg) 0.014 μM; Ex. (1dh) 0.041 μM; Ex. (1di) 0.23 μM; Ex. (1dj) 0.25 μM; Ex. (1dk) 0.02 μM; Ex. (1dl) 0.018 μM; Ex. (1dm) 0.0075 μM; Ex. (1dn) 0.0055 μM; Ex. (1do) 0.03 μM; Ex. (1dp) 0.0067 μM; Ex. (1dq) 0.037 μM; Ex. (1dt) 0.0026 μM; Ex. (1du) 0.00039 μM; Ex. (1dv) 0.72 μM; Ex. (1dw) 0.021 μM; Ex. (1dx) 0.035 μM; Ex. (1dy) 0.0035 μM; Ex. (1dz) 0.099 μM; Ex. (1ea) 0.057 μM; Ex. (1eb) 0.17 μM; Ex. (1ec) 0.013 μM; Ex. (1ed) 0.016 μM; Ex. (1ee) 0.0048 μM.

(416) Tested in phospho-Ser473 Akt assay: Ex. (1df) 0.3813 μM; Ex. (1dr) 0.01415 μM; Ex. (1ds) 0.06066 μM.

Example 2

(417) ##STR00258##

(418) To a solution (0.2 M) of the appropriate chloro-substrate (1 equiv) in dioxane was added diisopropylethylamine (2 equiv). To this mixture was then added the appropriate amine (2 equiv). The reaction was then heated under the influence of microwave radiation (120° C., medium absorption setting) for 10 minutes. Upon completion the sample was concentrated in vacuo and the resulting residue dissolved in CH.sub.2Cl.sub.2 and washed with H.sub.2O. The organic fraction was removed, dried (MgSO.sub.4). The crude residue was purified by flash chromatography (SiO.sub.2) to give the desired products.

(419) TABLE-US-00003 Retention Purity time M/z (%) (min) [M+H}.sup.+ Example Structure 2a 97 3.28 448.3 2b 99 3.78 439.3 0 2c 99 3.31 462.4 2d 100 3.76 463.3 2e 99 3.11 483.3 2f 99 3.82 463.4 2g 100 3.39 436.5 2h 100 3.68 463.4 2i 98 3.26 448.4 2j 100 3.38 450.3

(420) Tested in Alternative Enzyme Assay: Ex. (2a) 0.7 μM; Ex. (2b) 0.56 μM; Ex. (2c) 0.6 μM; Ex. (2d) 0.27 μM; Ex. (2e) 0.35 μM; Ex. (2f) 0.17 μM; Ex. (2g) 0.064 μM; Ex. (2h) 0.29 μM; Ex. (2i) 0.64 μM; Ex. (2j) 0.2 μM.

Example 3

(421) (Compounds 3a to 3ab)

(422) R.sup.4=(S)-3-methyl-morpholine

(423) R.sup.2=(S)-3-methyl-morpholine

(424) Ar=aryl

(425) ##STR00269##

(426) Carboxy-substrates are reported in Example 1.

(427) Method: Amide Formation

(428) Conditions A:

(429) The appropriate carboxy-substrate (1 equiv) was dissolved in DMF (0.067 M). HBTU (1.2 equiv) and appropriate amines (1.05 equiv) were added along with 3 drops of triethylamine at 0° C. The reaction vessels were sealed and the mixtures were stirred between 1 and 12 hours at room temperature. Upon completion the samples were concentrated in vacuo. The crude residues were then purified by preparative HPLC to give the desired products.

(430) TABLE-US-00004 TABLE 3 Retention Purity time m/z (%) (min) [M+H].sup.+ Conditions Example Structure 3a 98 7.36 515.3 A 0 3b 82 5.31 518.4 A 3c 96 7.2 477.3 A 3d 96 6.95 533.4 A 3e 95 7.33 495.3 A 3f 95 8.34 531.3 A 3g 98 6.61 519.4 A 3h 98 6.64 519.4 A 3i 99 7.32 533.4 A 3j 99 8.19 505.4 A 3k 98 4.15 521.5 A 0 3l 99 4.27 513.4 A 3m 90 4.22 491.3 A 3n 98 4.35 505.5 A 3o 95 4.2 493.4 A 3p 98 4.36 503.4 A 3q 98 4.31 501.4 A 3r 95 4.62 519.5 A 3s 99 4.19 517.3 A 3t 99 3.97 507.4 A 3u 99 4.07 521.4 A 0 3v 96 7.38 495.4 A 3w 91 8.42 523.3 A 3x 97 8.44 523.4 A 3y 97 7.69 511.3 A 3z 92 8.33 521.3 A 3aa 86 4.12 509.3 A 3ab 83 4.19 519.3 A 3ac 100 7.13 477.4 A 3ad 100 4.00 493.4 A

(431) Tested in Alternative Enzyme Assay: Ex. (3a) 0.048 μM; Ex. (3b) 0.32 μM; Ex. (3c) 0.09 μM; Ex. (3d) 0.28 μM; Ex. (3e) 0.0047 μM; Ex. (3f) 0.28 μM; Ex. (3g) 0.0052 μM; Ex. (3h) 0.18 μM; Ex. (3i) 0.14 μM; Ex. (3j) 0.17 μM; Ex. (3k) 0.23 μM; Ex. (3l) 0.044 μM; Ex. (3m) 0.32 μM; Ex. (3n) 0.23 μM; Ex. (30) 0.37 μM; Ex. (3p) 0.56 μM; Ex. (3q) 0.12 μM; Ex. (3r) 0.5 μM; Ex. (3s) 0.38 μM; Ex. (3t) 0.042 μM; Ex. (3u) 0.13 μM; Ex. (3v) 0.16 μM; Ex. (3w) 0.5 μM; Ex. (3x) 0.24 μM; Ex. (3y) 0.74 μM; Ex. (3z) 0.34 μM; Ex. (3aa) 0.026 μM; Ex. (3ab) 0.14 μM; Ex. (3ac) 1.6 μM; Ex. (3ad) 0.066 μM.

Example 4

(432) ##STR00300##

(433) Benzyl alcohol substrates are reported in Example 1.

(434) The appropriate benzyl alcohol (1 equiv) was dissolved in CH.sub.2Cl.sub.2 (0.08 M). Triethylamine (1 equiv) was added at room temperature, followed by the addition of thionyl chloride (2 equiv). The reaction mixture was stirred at 30° C. for 45 minutes. Upon completion the reaction mixture was partitioned between brine and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 10 to 70% ethyl acetate in hexane.

(435) ##STR00301##

(436) 7-(3-Chloromethyl-phenyl)-2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine: (72% yield, 90% purity) m/z (LC-MS, ESP): 454 [M+H].sup.+ R/T=3.15 min

(437) ##STR00302##

(438) The appropriate benzyl alcohol (1 equiv) was dissolved in CH.sub.2Cl.sub.2 (0.052 M). Thionyl chloride (3.3 equiv) was added. The reaction mixture was heated up to 55° C. and a solution of triethylamine (1.7 equiv) in CH.sub.2Cl.sub.2 (0.044 M) was added dropwise over 10 minutes. The reaction mixture was allowed to stir at 30° C. for 10 minutes. Upon completion the reaction mixture was partitioned between brine and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 10 to 50% ethyl acetate in hexane.

(439) 7-(4-Chloromethyl-phenyl)-2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine: (65% yield, 90% purity) m/z (LC-MS, ESP): 454 [M+H].sup.+ R/T=3.15 min

(440) ##STR00303##

(441) The appropriate benzyl alcohol (1 equiv) was dissolved in CH.sub.2Cl.sub.2 (0.044 M). Thionyl chloride (3.3 equiv) was added. The reaction mixture was heated up to 55° C. and a solution of triethylamine (1.7 equiv) in CH.sub.2Cl.sub.2 (0.044 M) was added dropwise over 10 minutes. The reaction mixture was allowed to stir at 30° C. for 30 minutes. Upon completion the reaction mixture was partitioned between brine and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was used without further purification.

(442) 7-(3-Chloromethyl-4-fluoro-phenyl)-2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine: (96% yield, 90% purity) m/z (LC-MS, ESP): 472 [M+H].sup.+ R/T=3.96 min

(443) ##STR00304##

(444) The appropriate benzyl alcohol (1 equiv) was dissolved in CH.sub.2Cl.sub.2 (0.086 M). Triethylamine (2.5 equiv) and thionyl chloride (2.5 equiv) were added. The reaction mixture was heated up to 45° C. a for 3 hours. Upon completion the reaction mixture was partitioned between water and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 10 to 50% ethyl acetate in hexane.

(445) 7-(3-Chloromethyl-4-methoxy-phenyl)-2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine: (37% yield, 90% purity) m/z (LC-MS, ESP): 484 [M+H].sup.+ R/T=3.21 min

(446) (Compounds 4a to 4ak)

(447) R.sup.4=(S)-3-methyl-morpholine

(448) R.sup.2=(S)-3-methyl-morpholine

(449) Ar=aryl

(450) ##STR00305##
Method: Benzylamines, Benzylethers and Benzylsulfones Formation
Conditions A:

(451) The appropriate chlorobenzyl-substrate (1 equiv) was dissolved in THF (0.067 M). The appropriate amine (80 equiv) as well as triethylamine (1 equiv) was added. The reaction vessels were sealed and the mixtures were stirred for 3 to 5 hours at 95° C. Upon completion the samples were concentrated in vacuo. The crude residues were then purified by preparative HPLC to give the desired products.

(452) Conditions B:

(453) The appropriate chlorobenzyl-substrate (1 equiv) was dissolved in an aqueous ammonia/n-butanol (1.5:1) solution (0.011 M). The reaction vessel was sealed and the mixture was stirred for 10 minutes at 140° C. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(454) Conditions C:

(455) The appropriate chlorobenzyl-substrate (1 equiv) and sodium hydroxide (1 equiv) were dissolved in ethanol (0.011 M). The reaction vessel was sealed and the mixture was stirred for 3 hours at 50° C. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(456) Conditions D:

(457) The appropriate chlorobenzyl-substrate (1 equiv) was dissolved in DMF (0.022 M). Imidazole (3 equiv) and potassium tert-butoxide (3 equiv) were added. The reaction vessel was sealed and the mixture was stirred for 2 hours at room temperature. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

(458) Conditions E:

(459) The appropriate chlorobenzyl-substrate (1 equiv) was dissolved in DMF (0.066 M). Sodium sulfinate (1.3 equiv) was added. The mixture was stirred for 2 hours at 125° C. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

(460) Conditions F:

(461) The appropriate chlorobenzyl-substrate (1 equiv), potassium carbonate (2.6 equiv) triethylamine (1 equiv) and the appropriate amine (1.1 equiv) were suspended in DMF (0.028 M). The reaction vessel was sealed and the mixture was stirred for 16 hours at 40° C. Upon completion the sample was filtered through a silica cartridge, washed with CH.sub.2Cl.sub.2 and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(462) TABLE-US-00005 TABLE 4 Retention Purity time m/z (%) (min) [M+H].sup.+ Conditions Example Structure 4a  87 3.61 449.3 A 06 4b  95 3.41 435.2 B 07 4c  99 3.4  505.5 A 08 4d 100 3.42 505.5 A 09 4e 100 3.44 519.5 A 0 4f 100 3.39 479.4 A 4g  95 4.36 464.4 C 4h  96 3.4  479.4 A 4i  95 3.4  435.4 B 4j  92 5.6  475.4 A 4k  94 5.65 477.4 A 4l  97 5.39 449.4 A 4m  90 5.6  519.5 A 4n  96 5.83 489.5 A 4o  95 5.56 493.4 A 0 4p   26,  69 6.63, 6.78  501.4 A 4q  99 3.43 486.4 D 4r  94 3.44 505.5 A 4s  97 3.44 505.3 A 4t  94 6.06 498.7 E 4u  98 3.42 453.4 B 4v  99 3.63 493.4 A 4w  99 3.62 495.4 A 4x  96 3.55 467.4 A 4y  99 3.6  537.4 A 0 4z  99 3.67 507.4 A 4aa  97 3.59 511.4 A 4ab  91 3.58 499.4 A 4ac  99 3.55 497.4 A 4ad  99 3.4  523.4 A 4ae  99 3.47 522.4 A 4af  99 3.42 481.4 A 4ag  99 3.49 536.4 A 4ah 98 3.43 537.5 A 4ai  99 3.48 509.4 A 0 4aj  99 3.46 525.5 A 4ak  99 3.42 523.5 A 4al  99 3.55 505.4 F 4am  99 3.60 507.4 F 4an  99 3.66 533.4 F 4ao  99 3.77 547.5 F 4ap  99 3.70 561.4 F 4aq  99 3.52 549.5 F 4ar  99 3.85 571.5 F 4as  99 3.85 549.5 F 0 4at  99 3.76 535.5 F 4au  99 3.83 549.5 F 4av  96 3.32 578.5 F 4aw  99 3.82 561.5 F 4ax  99 3.59 519.4 F 4ay  99 3.66 521.4 F 4az  99 3.65 521.4 F 4ba  99 3.46 509.4 F 4bb  99 3.52 523.4 F 4bc  99 3.84 561.5 F 0 4bd  99 3.81 599.5 F 4be  93 3.29 559.4 F 4bf  99 3.91 575.5 F
NMR Data for Example 4h

(463) .sup.1H NMR (300 MHz, DMSO) δ ppm 8.21 (ArH, d, J=8.39 Hz, 2H), 8.08-8.01 (ArH, m, 1H), 7.65 (ArH, d, J=8.49 Hz, 1H), 7.49 (ArH, d, J=4.85 Hz, 2H), 4.82-4.72 (CH.sub.2, m, 1H), 4.45 (CH.sub.2, +NH m, 3H), 3.99-3.82 (CH.sub.2, m, 7H), 3.69 (CH.sub.2, ddd, J=19.97, 8.86, 5.32 Hz, 8H), 3.53 (CH.sub.2, t, J=5.65, 5.65 Hz, 2H), 3.29-3.15 (CH.sub.2, m, 2H), 1.38 (CH.sub.3, d, J=6.75 Hz, 3H), 1.25 (CH.sub.3, d, J=6.75 Hz, 3H)

(464) NMR Data for Example 4r

(465) .sup.1H NMR (300 MHz, CDCl.sub.3 δ ppm 8.19 (ArH, s, 1H), 8.03 (ArH, ddd, J=8.43, 5.31, 3.28 Hz, 2H), 7.54-7.37 (ArH, m, 3H), 5.00-4.85 (CH, m, 1H), 4.68-4.56 (CH.sub.2, m, 1H), 4.36 (CH.sub.2, ddd, J=6.83, 4.79, 2.16 Hz, 2H), 4.07-3.92 (CH.sub.2, m, 2H), 3.91-3.66 (CH.sub.2, m, 11H), 3.63-3.49 (CH.sub.2, m, 1H), 3.39 (CH.sub.2, dd, J=13.37, 3.58 Hz, 1H), 3.04-2.92 (CH.sub.2, m, 1H), 2.80 (CH.sub.2, d, J=10.30 Hz, 1H), 2.65 (CH.sub.2, dd, J=10.23, 4.92 Hz, 1H), 2.52-2.39 (CH.sub.2, m, 1H), 2.21 (CH.sub.2, d, J=7.02 Hz, 1H), 1.89-1.73 (CH.sub.2, m, 1H), 1.46 (CH.sub.3, d, J=6.77 Hz, 3H), 1.35 (CH.sub.3, d, J=6.81 Hz, 3H)

(466) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.57, 163.03, 162.50, 160.11, 139.06, 134.83, 130.62, 128.81, 127.10, 113.70, 105.06, 71.44, 71.06, 67.41, 67.25, 67.07, 62.87, 60.08, 52.98, 52.49, 47.07, 44.58, 39.47, 35.02, 14.86 and 14.90.

(467) NMR Data for Example 4s

(468) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.22 (ArH, s, 1H), 8.11-7.96 (ArH, m, 2H), 7.48 (ArH, dd, J=10.85, 7.98 Hz, 3H), 4.99-4.86 (CH, m, 1H), 4.68-4.55 (CH, m, 1H), 4.44-4.30 (CH.sub.2, m, 2H), 4.06-3.92 (CH.sub.2, m, 2H), 3.93-3.65 (CH.sub.2, m, 10H), 3.62-3.50 (CH.sub.2, m, 1H), 3.39 (CH.sub.2, dd, J=13.39, 3.57 Hz, 1H), 3.14-3.01 (CH.sub.2, m, 1H), 2.88 (CH.sub.2, d, J=10.59 Hz, 1H), 2.77-2.67 (CH.sub.2, m, 1H), 2.63-2.43 (CH.sub.2, m, 1H), 2.31-2.14 (CH.sub.2, m, 1H), 1.92-1.79 (CH.sub.2, m, 1H), 1.47 (CH.sub.3, d, J=6.77 Hz, 3H), 1.35 (CH.sub.3, d, J=6.81 Hz, 3H)

(469) .sup.13C NMR (75 MHz, CDCl.sub.3)) δ ppm 165.56, 163.03, 162.34, 160.12, 139.16, 134.89, 130.80, 128.94, 128.91, 127.39, 113.69, 105.11, 71.44, 71.21, 71.06, 67.40, 67.06, 62.61, 59.93, 52.98, 52.42, 47.08, 44.58, 39.47, 34.88, 31.73, 22.80, 14.86 and 14.91.

(470) Tested in the Biological Assay: Ex. (4f) 0.001967 μM.

(471) Tested in Alternative Enzyme Assay: Ex. (4a) 0.0016 μM; Ex. (4b) 0.025 μM; Ex. (4c) 0.093 μM; Ex. (4d) 0.013 μM; Ex. (4e) 0.0019 μM; Ex. (4f)<0.0027 μM; Ex. (4g) 0.13 μM; Ex. (4h) 0.031 μM; Ex. (4i) 0.027 μM; Ex. (4j) 0.054 μM; Ex. (4k) 0.016 μM; Ex. (4l) 0.0091 μM; Ex. (4m) 0.015 μM; Ex. (4n) 0.0071 μM; Ex. (40) 0.021 μM; Ex. (4p) 0.17 μM; Ex. (4q) 0.13 μM; Ex. (4r) 0.04 μM; Ex. (4s) 0.029 μM; Ex. (4t) 0.09 μM; Ex. (4u) 0.027 μM; Ex. (4v) 0.14 μM; Ex. (4w) 0.028 μM; Ex. (4x) 0.12 μM; Ex. (4y) 0.13 μM; Ex. (4z) 0.13 μM; Ex. (4aa) 0.21 μM; Ex. (4ab) 1.1 μM; Ex. (4ac) 0.087 μM; Ex. (4ad) 0.081 μM; Ex. (4ae) 0.16 μM; Ex. (4af) 0.58 μM; Ex. (4ag) 0.54 μM; Ex. (4ah) 0.2 μM; Ex. (4ai) 0.22 μM; Ex. (4aj) 0.46 μM; Ex. (4ak) 0.015 μM; Ex. (4al) 0.064 μM; Ex. (4am) 0.024 μM; Ex. (4an) 0.095 μM; Ex. (4ao) 0.064 μM; Ex. (4ap) 0.11 μM; Ex. (4aq) 0.012 μM; Ex. (4ar) 0.06 μM; Ex. (4as) 0.091 μM; Ex. (4at) 0.12 μM; Ex. (4au) 0.096 μM; Ex. (4av) 0.0038 μM; Ex. (4aw) 0.11 μM; Ex. (4ax) 0.1 μM; Ex. (4ay) 0.14 μM; Ex. (4az) 0.038 μM; Ex. (4ba) 0.013 μM; Ex. (4bb) 0.032 μM; Ex. (4bc) 0.076 μM; Ex. (4bd) 0.12 μM; Ex. (4be) 0.049 μM; Ex. (4bf) 0.059 μM.

Example 5

(472) ##STR00364##

(473) Benzyl chloride substrates are reported in Example 4.

(474) The appropriate benzyl chloride (1 equiv) was dissolved in an ammonium hydroxide and n-butanol (1.5:1) solution (0.01 M). The reaction vessel was sealed and the mixture exposed to microwave radiation (140° C., medium absorption setting) for 10 minutes. Upon completion the reaction mixture was partitioned between brine and ethyl acetate and extracted with ethyl acetate. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% methanol in CH.sub.2Cl.sub.2.

(475) ##STR00365##

(476) 3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-benzylamine: (81% yield, 100% purity) m/z (LC-MS, ESP): 435 [M+H].sup.+ R/T=2.44 min

(477) ##STR00366##

(478) 5-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzylamine: (85% yield, 98% purity) m/z (LC-MS, ESP): 453 [M+H]R/T=3.21 min

(479) ##STR00367##

(480) 4-[2,4-Bis-(3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-benzylamine: (95% yield, 97% purity) m/z (LC-MS, ESP): 435 [M+H].sup.+ R/T=2.36 min

(481) ##STR00368##

(482) The appropriate benzyl chloride (1 equiv) was dissolved in a 2 M solution of methylamine in THF (80 equiv). Triethylamine (1 equiv) was added. The reaction mixture was stirred at 95° C. for 2.5 hours. Upon completion the reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and n-butanol and the organic phase was washed with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 7% methanol in CH.sub.2Cl.sub.2.

(483) ##STR00369##

(484) {3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-benzyl}-methyl-amine: (77% yield, 94% purity) m/z (LC-MS, ESP): 449 [M+H].sup.+ R/T=2.44 min

(485) ##STR00370##

(486) {4-[2,4-Bis-(3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-benzyl}-methyl-amine: (93% yield, 87% purity) m/z (LC-MS, ESP): 449 [M+H].sup.+ R/T=2.40 min

(487) Procedures for the Synthesis of Examples 5a to 5z

(488) R.sup.4=(S)-3-methyl-morpholine

(489) R.sup.2=(S)-3-methyl-morpholine

(490) ##STR00371##
Conditions A:

(491) The appropriate aminobenzyl-substrate (1 equiv) was dissolved in CH.sub.2Cl.sub.2 (0.035 M). The appropriate acyl chloride or acid anhydride (2 equiv) as well as triethylamine (1 equiv) was then added. The mixtures were stirred for 2 hours at room temperature. Upon completion the samples were concentrated in vacuo. The crude residues were then purified by preparative HPLC to give the desired products.

(492) Conditions B:

(493) The appropriate methylaminobenzyl-substrate (1 equiv) was dissolved in CH.sub.2Cl.sub.2 (0.035 M). The appropriate acyl chloride or acid anhydride (2 equiv) as well as triethylamine (1 equiv) were added. The mixtures were stirred for 12 hours at 95° C. Upon completion the samples were concentrated in vacuo. The crude residues were then purified by preparative HPLC to give the desired products.

(494) TABLE-US-00006 TABLE 5 Retention Purity time m/z (%) (min) [M+H].sup.+ Conditions Example Structure 5a 98 4.02 477.4 A 5b 99 4.12 507.4 A 5c 99 4.22 503.4 A 5d 99 4.27 505.4 A 5e 99 4.34 517.4 A 5f 99 4.41 519.4 A 5g 99 4.51 531.3 A 5h 98 4.17 491.4 B 5i 99 4.17 521.5 B 0 5j 98 4.39 517.4 B 5k 98 4.48 519.5 B 5l 99 4.58 531.5 B 5m 99 4.64 533.5 B 5n 98 4.73 545.4 B 5o 100 4.38 527.4 C 5p 99 4.51 541.4 C 5q 99 3.8 477.4 A 5r 98 3.93 491.4 B 5s 99 3.93 521.4 B 0 5t 100 3.94 495.4 A 5u 100 4.02 525.4 A 5v 100 4.16 521.4 A 5w 100 4.19 523.4 A 5x 100 4.27 535.4 A 5y 100 4.32 537.5 A 5z 98 4.38 549.5 A

(495) Tested in Alternative Enzyme Assay: Ex. (5a) 0.023 μM; Ex. (5b) 0.054 μM; Ex. (5c) 0.12 μM; Ex. (5d) 0.12 μM; Ex. (5e) 0.12 μM; Ex. (5f) 0.37 μM; Ex. (5g) 0.12 μM; Ex. (5h) 0.19 μM; Ex. (5i) 0.2 μM; Ex. (5j) 0.31 μM; Ex. (5k) 0.89 μM; Ex. (5l) 0.049 μM; Ex. (5m) 1.4 μM; Ex. (5n) 0.64 μM; Ex. (5o) 0.12 μM; Ex. (5p) 0.5 μM; Ex. (5q) 0.091 μM; Ex. (5r) 0.56 μM; Ex. (5s) 0.67 μM; Ex. (5t) 0.057 μM; Ex. (5u) 0.16 μM; Ex. (5v) 0.14 μM; Ex. (5w) 0.16 μM; Ex. (5x) 0.29 μM; Ex. (5y) 0.44 μM; Ex. (5z) 1.4 μM.

Example 6

(496) ##STR00398##

(497) The chloro-substrate was reported in Example 1.

(498) The appropriate chloro-substrate (1 equiv) was dissolved in n-butanol (0.055 M). 2-formylfuran-3-boronic acid (1.0 equiv), potassium carbonate (1.2 equiv), and tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv) were added. The reaction vessel was sealed and exposed to microwave radiation (110° C., medium absorption setting) for 15 minutes. Upon completion the reaction mixture was filtered through a silica cartridge and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 40% ethyl acetate in hexane to give the desired product.

(499) ##STR00399##

(500) 3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-furan-2-carbaldehyde: (26% yield, 90% purity) m/z (LC-MS, ESP): 424 [M+H].sup.+ R/T=2.81 min

(501) (Compound 6a)

(502) ##STR00400##

(503) The above product was dissolved in THF (0.018 M) and sodium borohydride (2 equiv) was added. This mixture was allowed to stir at room temperature for 5 minutes. Upon completion the reaction mixture was filtered through a silica cartridge and the filtrate was concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.

(504) TABLE-US-00007 TABLE 6 Retention Purity time m/z (%) (min) [M + H].sup.+ Example Structure 6a 96 6.89 426.3 01

(505) Tested in Alternative Enzyme Assay: Ex. (6a) 0.013 μM.

Example 7

(506) ##STR00402##

(507) The chloro-substrate was reported in Example 1.

(508) The appropriate chloro-substrate (1 equiv) was dissolved in dioxane (0.16 M). 5-formyl-2-furylboronic acid (1.05 equiv), tripotassium phosphate (1.5 equiv) and bis(tri-t-butylphosphine)palladium (0.05 equiv) were added. The reaction vessel was sealed and exposed to microwave radiation (170° C., medium absorption setting) for 45 minutes. Upon completion the reaction mixture was partitioned between water and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 40 to 100% ethyl acetate in hexane to give the desired product.

(509) ##STR00403##

(510) 5-[2,4-Bis-(3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-furan-2-carboxaldehyde: (100% yield, 100% purity) m/z (LC-MS, ESP): 424 [M+H].sup.+ R/T=2.75 min

(511) (Compounds 7a to 7k)

(512) ##STR00404##

(513) The appropriate formylfuran-substrate (1 equiv) was dissolved in a THF/CH.sub.2Cl.sub.2 (1:1) solution (0.036 M). The appropriate amines (2.2 equiv) sodium borohydride (2.4 equiv) and acetic acid (0.03 equiv) were added. The reaction mixture was stirred at room temperature for 24 hours. Upon completion the samples were filtered through a silica cartridge, washed with methanol and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(514) TABLE-US-00008 TABLE 7 Retention Purity time m/z (%) (min) [M + H].sup.+ Example Structure 7a 97 3.2  496.4 05 7b 99 3.32 469.4 06 7c 99 3.49 439.4 07 7d 99 3.51 453.4 08 7e 99 3.58 465.4 09 7f 97 3.53 509.4 0 7g 98 3.61 479.4 7h 99 3.56 483.4 7i 95 3.86 491.4 7j 98 3.46 482.4 7k 99 3.54 467.4

(515) Tested in Alternative Enzyme Assay: Ex. (7a) 0.59 μM; Ex. (7b) 0.13 μM; Ex. (7c) 0.091 μM; Ex. (7d) 0.097 μM; Ex. (7e) 0.15 μM; Ex. (7f) 0.12 μM; Ex. (7g) 0.17 μM; Ex. (7h) 0.33 μM; Ex. (7i) 0.079 μM; Ex. (7j) 0.12 μM; Ex. (7k) 0.14 μM.

Example 8

(516) (Compounds 8a to 8b)

(517) ##STR00416##

(518) The methylbenzoic ester substrates were reported in Example 1.

(519) Conditions A:

(520) Example 1ba (1 equiv) was dissolved in dioxane (0.16 M). Ethanolamine (51.0 equiv) was added. The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 50 minutes. Upon completion the reaction mixture was concentrated in vacuo. The crude residue was then purified by column chromatography on silica gel using a gradient 0 to 5% MeOH in CH.sub.2Cl.sub.2 to afford the desired product.

(521) Conditions B:

(522) Example 1bg (1 equiv) was dissolved in dioxane (0.05 M). Ethanolamine (2.0 equiv) was added. The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 2×20 minutes. Upon completion the reaction mixture was concentrated in vacuo. The reaction mixture was partitioned between water and CH.sub.2Cl.sub.2 and extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was then purified by column chromatography on silica gel using a gradient 0 to 5% MeOH in CH.sub.2Cl.sub.2 to afford the desired product.

(523) ##STR00417##
Conditions C:

(524) To a solution of the appropriate carboxylic acid derivative (1 equiv) suspended in CH.sub.2Cl.sub.2 was added HBTU (1.3 equiv) followed by diisopropylethylamine (3 equiv). The mixture was cooled (−78° C.) and the appropriate amine added (1.1 equiv). The mixture was stirred for 3 hrs before being concentrated to dryness and purified by preparative HPLC to give the desire products.

(525) TABLE-US-00009 TABLE 8 Retention Purity time m/z (%) (min) [M + H].sup.+ Conditions Example Structure 8a 100 3.75 493.5 A 8b  99 3.86 523.5 B 8c  97 3.79 465.3 C 0 8d  98 3.70 507.4 C
NMR Data for Example 8a

(526) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.55 (ArH, s, 1H), 8.09 (ArH, d, J=7.85 Hz, 1H), 7.95 (ArH, d, J=8.42 Hz, 1H), 7.86 (ArH, d, J=7.86 Hz, 1H), 7.49-7.33 (ArH, m, 2H), 4.89-4.75 (CH, m, 1H), 4.56-4.46 (CH, m, 1H), 4.38-4.26 (CH.sub.2, m, 1H), 3.97-3.87 (CH.sub.2, m, 2H), 3.85-3.75 (CH.sub.2, m, 4H), 3.72-3.55 (CH.sub.2, m, 7H), 3.53-3.44 (CH.sub.2, m, 1H), 3.34-3.24 (CH2, m, 1H), 1.41 (CH.sub.3, d, J=6.77 Hz, 3H), 1.28 (CH.sub.3, d, J=6.82 Hz, 3H).

(527) Tested in Alternative Enzyme Assay: Ex. (8a) 0.028 μM; Ex. (8b) 0.079 μM; Ex. (8c) 0.13 μM; Ex. (8d) 2 μM.

Example 9

(528) (Compound 9a)

(529) ##STR00422##

(530) The benzyl alcohol substrate was reported in Example 1.

(531) Example 1bc (1 equiv) was dissolved in THF (0.022 M). Sodium tert-butoxide (3.0 equiv) and iodomethane (10.0 equiv) were added. The reaction vessel was stirred at room temperature for 48 hours. Upon completion the sample was filtered through a silica cartridge, washed with EtOAc and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

(532) TABLE-US-00010 TABLE 9 Retention Purity time m/z (%) (min) [M + H].sup.+ Example Structure 9a 100 2.87 468.4

(533) Tested in Alternative Enzyme Assay: Ex. (9a) 0.088 μM.

Example 10

(534) (Compound 10a)

(535) ##STR00424##

(536) The pyridinone substrate was reported in Example 13.

(537) Example 13c (1 equiv) was dissolved in DMF (0.1 M). Potassium carbonate (1.1 equiv) and iodomethane (1.1 equiv) were added. The reaction vessel was stirred at 100° C. for 2 hours. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

(538) TABLE-US-00011 TABLE 10 Retention Purity time m/z (%) (min) [M + H].sup.+ Example Structure 10a 100 3.67 437.2

(539) Tested in Alternative Enzyme Assay: Ex. (10a) 0.11 μM.

Example 11

(540) (Compound 11a)

(541) ##STR00426##

(542) The sulfonamide substrate was reported in Example 1.

(543) Example 1at (1 equiv) was dissolved in DMF (0.1 M). Potassium carbonate (2.0 equiv) and iodomethane (1.5 equiv) were added. The reaction vessel was heated at 100° C. for 2 hours. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

(544) TABLE-US-00012 TABLE 11 Retention Purity time m/z (%) (min) [M + H].sup.+ Example Structure 11a 87 4.11 513.3

(545) Tested in Alternative Enzyme Assay: Ex. (11a) 0.37 μM.

Example 12

(546) ##STR00428##

(547) To a solution of the appropriate 7-substituted-1H-pteridine-2,4-dione (1 equiv) in anhydrous toluene (sufficient to make a 0.1 M solution) was added Hunig's base (3 equiv). A reflux condenser was attached to the reaction vessel and the mixture heated, under an inert atmosphere) to 70° C. for 30 minutes. After this time, the reaction was cooled to 40° C. whereupon POCl.sub.3 (3 equiv) was added. The mixture was then heated, with stirring, to 110° C. for 3 hrs. Upon completion, the reaction was cooled and concentrated in vacuo to give a tarry residue which was dissolved in the minimum volume of CH.sub.2Cl.sub.2 and filtered through a thick silica pad. The resulting filtrate was concentrated in vacuo to give the desired 2,4-dichloro-7-substituted-pteridine product (typically 65-99% yield) in suitably pure form to be used without any further purification.

(548) 2,4-Dichloro-7-p-tolyl-pteridine; R7=toluyl, R2=Cl, R4=Cl, X═N, Y═C, Z═N: (61% yield, 99% purity) m/z (LC-MS, ESP): Did not ionize, R/T=3.27 min

(549) 2,4-Dichloro-7-phenyl-pteridine; R7=phenyl, R2=Cl, R4=Cl, X═N, Y═C, Z═N: (66% yield, 99% purity) m/z (LC-MS, ESP): Did not ionize, R/T=3.10 min

(550) ##STR00429##

(551) To a cooled (−5° C.) solution of the appropriate amine (1 equiv=R4) in N,N-dimethylacetamide (sufficient to make 0.2 M solution) was added the appropriate 2,4-dichloro-7-substituted-pteridine (1 equiv added as a 0.04 M solution in N,N-dimethylacetamide). After approx 10 minutes Hunig's base was added (1 equiv) and the resultant mixture stirred at −5° C. for 30 minutes. After this time, the reaction was allowed to warm to room temperature, whereupon the appropriate amine (1 equiv=R2) and Hunig's base (1 equiv) were then added. The resultant mixture was heated to 60° C. and maintained at this temperature, with stirring, for 16 hours. Upon completion, the mixture was allowed to cool to room temperature before being purified by preparative HPLC to give the desired product.

(552) TABLE-US-00013 TABLE 12 Purity Retention time m/z (%) (min) [M + H].sup.+ Example Structure 12a 99  5.33 421.5 0 12b 96  5.55 435.4 12c 95 10.29 421.3 12d 94  9.48 407.2 12e 94  9.48 356.2

(553) Tested in Alternative Enzyme Assay: Ex. (12a) 0.02669 μM; Ex. (12b) 0.2147 μM; Ex. (12c) 0.04872 μM; Ex. (12d) 0.0263 μM; Ex. (12e) 0.5414 μM.

Example 13

(554) (Compounds 13a to 13f)

(555) ##STR00435##

(556) The pyridine substrates were reported in Example 1.

(557) Conditions A:

(558) Example 1w (1 equiv) was dissolved in a dry THF/methanol (1:1) solution (0.057 M). Sodium hydride (4.5 equiv) was added. The reaction mixture was stirred at room temperature for 15 minutes under nitrogen. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 40 minutes. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

(559) Conditions B:

(560) Example 1w (1 equiv) was dissolved in dry THF (0.057 M). Dimethylethanolamine (10.0 equiv) and sodium hydride (5.0 equiv) were added. The reaction mixture was stirred at room temperature for 15 minutes under nitrogen. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 20 minutes. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

(561) Conditions C:

(562) Example 1au (1 equiv) was dissolved in DMSO (0.59 M). 8N aqueous sodium hydroxide solution (50.0 equiv) was added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 20 minutes. Upon completion concentrated aqueous HCl was added carefully. The mixture was neutralized with 2N aqueous sodium hydroxide solution. The suspension was diluted with methanol then filtered through a sintered funnel. The filtrate was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(563) Conditions D:

(564) Example 1au (1 equiv) was dissolved in NMP (0.1 M). Potassium cyanide (20.0 equiv) was added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 46 hours. Upon completion the reaction mixture was partitioned between water and CH.sub.2Cl.sub.2. The aqueous phase was extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 50 to 100% ethyl acetate in hexane to give the desired product.

(565) Conditions E:

(566) Example 1au (1 equiv) was dissolved in NMP (0.1 M). Potassium cyanide (20.0 equiv) was added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 46 hours. Upon completion the reaction mixture was partitioned between water and CH.sub.2Cl.sub.2. The aqueous phase was extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 50 to 100% ethyl acetate in hexane first, then eluting with 10% methanol in CH.sub.2Cl.sub.2. The crude fractions were then further purified by preparative HPLC to give the desired product.

(567) Conditions F:

(568) Example 1ah (1 equiv) was dissolved in NMP (0.1 M). Potassium cyanide (8.0 equiv) was added. The reaction vessel was sealed and the mixture exposed to microwave radiation (180° C., medium absorption setting) for 40 minutes. Upon completion the sample was filtered through a silica cartridge, washed with EtOAc and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(569) TABLE-US-00014 TABLE 13 Retention Purity time m/z (%) (min) [M + H].sup.+ Conditions Example Structure 13a 99 4   437.3 A 13b 99 3.42 494.4 B 13c 97 5.77 423.4 C 13d 97 3.96 432.4 D 13e 98 6.62 450.2 E 0 13f 99 3.93 432.3 F 13g 89 5.03 478.4

(570) Tested in Alternative Enzyme Assay: Ex. (13a) 0.2 μM; Ex. (13b) 0.33 μM; Ex. (13c) 0.14 μM; Ex. (13d) 0.48 μM; Ex. (13e) 0.19 μM; Ex. (13f) 0.16 μM; Ex. (13g) 0.11 μM.

Example 14

(571) (Compounds 14a-14b)

(572) ##STR00443##

(573) The ester substrate was reported in Example 1.

(574) Ester Hydrolysis:

(575) Conditions A

(576) Example 1bg (1 equiv) was dissolved in methanol (0.2 M). 1M Sodium hydroxide aqueous solution (5.0 equiv) was added. The reaction mixture was stirred at room temperature for 3 hours. Upon completion the reaction mixture was neutralised with 1M aqueous HCl and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 10% MeOH in CH.sub.2Cl.sub.2 to give the desired product.

(577) Amide Formation:

(578) Conditions B

(579) Example 1bg (1 equiv) was suspended in THF (0.05 M). Thionyl chloride (2.5 equiv) was added dropwise at 40° C. The reaction mixture was then heated for an hour at 40° C. Ammonia gas was then slowly bubbled into the reaction mixture. THF was then added for further dilution (0.025 M) and the reaction mixture was heated for an hour at 40° C. Upon completion the reaction mixture was cooled down and concentrated in vacuo. The residue was partitioned between water and CH.sub.2Cl.sub.2. The aqueous phase was extracted with CH.sub.2Cl.sub.2. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% MeOH in CH.sub.2Cl.sub.2 to give the desired product.

(580) TABLE-US-00015 TABLE 14 Retention Purity time m/z (%) (min) [M + H].sup.+ Conditions Example Structure 14a 98 3.95 480.5 A 14b 98 7.09 479.4 B
NMR Data for Example 14a

(581) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.82-8.69 (ArH, m, 1H), 8.68-8.56 (ArH, m, 1H), 8.03-7.90 (ArH, m, 1H), 7.52-7.39 (ArH, m, 1H), 7.18-7.05 (ArH, m, 1H), 4.92-4.80 (CH, m, 1H), 4.61-4.47 (CH, m, 1H), 4.37-4.27 (CH.sub.2, m, 1H), 4.07 (OCH.sub.3, s, 3H), 4.00-3.87 (CH.sub.2, m, 2H), 3.85-3.60 (CH.sub.2, m, 6H), 3.57-3.24 (CH.sub.2, m, 3H), 1.41 (CH.sub.3, d, J=6.65 Hz, 3H), 1.30 (CH.sub.3, d, J=6.74 Hz, 3H)

(582) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.33, 134.98, 134.96, 132.64, 132.61, 132.58, 119.77, 112.83, 112.11, 100.01, 71.29, 70.90, 67.24, 66.91, 52.80, 46.96, 44.44, 39.34 and 14.74.

(583) NMR Data for Example 14b

(584) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.83 (ArH, d, J=2.46 Hz, 1H), 8.64 (ArH, dd, J=8.76, 2.49 Hz, 1H), 8.01 (ArH, d, J=8.47 Hz, 1H), 7.71 (NH, s, br, 1H), 7.57 (ArH, d, J=8.50 Hz, 1H), 7.13 (ArH, d, J=8.83 Hz, 1H), 5.79 (NH, s, br, 1H), 5.00-4.84 (CH, m, 1H), 4.62 (CH, dd, J=13.82, 0.70 Hz, 1H), 4.37 (CH.sub.2, d, J=6.77 Hz, 1H), 4.05 (OCH.sub.3, s, 3H), 4.03-3.94 (CH.sub.2, m, 2H), 3.91-3.79 (CH.sub.2, m, 3H), 3.79-3.63 (CH.sub.2, m, 4H), 3.64-3.51 (CH.sub.2, m, 1H), 3.44-3.30 (CH.sub.2, m, 1H), 1.47 (CH.sub.3, d, J=6.78 Hz, 3H), 1.35 (CH.sub.3, d, J=6.81 Hz, 3H)

(585) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 166.58, 165.45, 162.87, 159.99, 159.22, 134.71, 133.75, 131.84, 131.65, 120.52, 113.07, 111.87, 104.80, 102.94, 71.33, 70.94, 67.29, 66.94, 56.28, 52.80, 46.93, 44.49, 39.33, 14.72 and 14.34.

(586) Tested in Alternative Enzyme Assay: Ex. (14a) 0.00015 μM; Ex. (14b) 0.0032 μM.

Example 15

(587) ##STR00446##

(588) The chloro-substrate was reported in Example 1.

(589) To a mixture of 7-chloro-4-((S)-3-methyl-morpholin-4-yl)-2-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine (1 equiv), potassium carbonate (1.2 equiv), and 3-BOC-aminophenylboronic acid (1.2 equiv) in acetonitrile/water (1:1) (0.08 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 10 minutes under nitrogen atmosphere. Upon completion the samples were filtered through a silica cartridge, washed with ethyl acetate and then concentrated in vacuo. The crude residue was used as such in the next reaction.

(590) ##STR00447##

(591) {3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-phenyl}-carbamic acid tert-butyl ester: (95% yield, 100% purity) m/z (LC-MS, ESP): 520.9 [M+H].sup.+ R/T=3.23 min

(592) The above product (1 equiv) was dissolved in a TFA/CH.sub.2Cl.sub.2 solution (1:20) (0.018 M). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was then concentrated in vacuo. The residue was partitioned between water and CH.sub.2Cl.sub.2. The aqueous phase was neutralized with 1N aqueous sodium hydroxide. Combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was used as such in the next reaction.

(593) ##STR00448##

(594) 3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-phenylamine: (100% yield, 100% purity) m/z (LC-MS, ESP): 520.9 [M+H].sup.+ R/T=2.72 min

(595) (Compound 15a)

(596) ##STR00449##

(597) The above product (1 equiv) was dissolved in THF (0.013 M). Chloroethanesulfonyl chloride (3.5 equiv) was gently added to the reaction mixture at 0° C. and the reaction mixture was stirred at room temperature for 15 hours. 8N Aqueous sodium hydroxide (50 equiv) was then added and the reaction mixture was heated at 40° C. for 12 hours. The reaction mixture was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 5% MeOH in CH.sub.2Cl.sub.2 to give the desired product.

(598) ##STR00450##

(599) 3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-phenylamine (1 equiv) was dissolved in THF (0.1 M). Pyridine (10 equiv) and isopropylsulfonyl chloride (10 equiv) were added to the reaction mixture at room temperature. The reaction mixture was then stirred at 90° C. for 4 hours. The reaction mixture was partitioned between CH.sub.2Cl.sub.2 and water.

(600) Organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 60% EtOAc in hexane to give the desired product.

(601) ##STR00451##

(602) 3-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-phenylamine (1 equiv) was dissolved in CH.sub.2Cl.sub.2 (0.24 M). Tetrahydro-2-furoic acid (1.1 equiv), HBTU (2.0 equiv) and triethylamine (2 equiv) were added and the reaction mixture was then stirred at room temperature for 3 hours. The reaction mixture was partitioned between CH.sub.2Cl.sub.2 and water. Organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 4% MeOH in TBME to give the desired product.

(603) TABLE-US-00016 TABLE 15 Retention Purity time m/z (%) (min) [M + H].sup.+ Example Structure 15a 98 3.99 529.4 15b 96 8.28 527.3 15c 99 4.19 519.3
NMR Data for Example 15b

(604) .sup.1H NMR (300 MHz), CDCl.sub.3) δ ppm 8.00-7.94 (ArH, m, 2H), 7.81 (ArH, td, J=7.12, 1.52, 1.52 Hz, 1H), 7.45-7.32 (ArH, m, 3H), 6.84 (NH, s, br, 1H), 4.93-4.80 (CH.sub.2, m, 1H), 4.55 (CH.sub.2, d, J=12.97 Hz, 1H), 4.38-4.25 (CH.sub.2, m, 1H), 4.01-3.57 (CH.sub.2, m, 9H), 3.57-3.45 (CH.sub.2, m, 1H), 3.36-3.32 (CH.sub.2, m, 2H), 1.42 (CH.sub.3, d, J=6.78 Hz, 3H), 1.37-1.26 (3×CH.sub.3, m, 9H)

(605) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.36, 162.85, 161.36, 159.98, 140.27, 137.89, 134.92, 129.80, 124.03, 121.31, 119.64, 113.30, 105.19, 71.28, 70.91, 67.25, 66.91, 52.89, 52.87, 44.42, 39.33, 31.60, 22.66, 16.60, 14.75 and 14.36.

(606) NMR Data for Example 15c

(607) .sup.1H NMR (300 MHz, CD.sub.3COCD.sub.3) δ ppm 8.52 (ArH, s, 1H), 8.24 (ArH, d, J=8.48 Hz, 1H), 7.91-7.80 (ArH, m, 2H), 7.62 (ArH, d, J=8.47 Hz, 1H), 7.46 (ArH, t, J=7.94, 7.94 Hz, 1H), 6.48 (NH, br, s, 1H), 4.84-4.70 (CH.sub.2, m, 1H), 4.53-4.33 (CH.sub.2, m, 3H), 4.09-3.79 (CH.sub.2, m, 5H), 3.80-3.56 (CH.sub.2, m, 5H), 3.49-3.40 (CH.sub.2, m, 1H), 3.23-3.28 (CH.sub.2, m, 1H), 2.20 (CH.sub.2, d, J=6.66 Hz, 1H), 2.11-1.81 (CH.sub.2, m, 4H), 1.39 (CH.sub.3, d, J=6.75 Hz, 3H), 1.26 (CH.sub.3, d, J=6.75 Hz, 3H).

(608) .sup.13C NMR (75 MHz, CD.sub.3COCD.sub.3) δ ppm 171.66, 160.37, 147.37, 145.71, 138.93, 138.46, 135.69, 128.98, 126.26, 126.11, 122.52, 121.58, 118.91, 118.37, 104.46, 77.93, 70.31, 70.13, 68.81, 66.28, 66.15, 51.77, 46.41, 43.85, 29.98, 25.06, 14.39 and 13.92.

(609) Tested in Alternative Enzyme Assay: Ex. (15a) 0.0043 μM; Ex. (15c) 0.33 μM.

(610) Tested in phospho-Ser473 Akt assay: Ex. (15b) 0.5051 μM.

Example 16

(611) (Compound 16a)

(612) ##STR00455##

(613) The aminopyridine substrate was reported in Example 1.

(614) Example 1u (1 equiv) was dissolved in pyridine (0.11 M). Acetic anhydride (5.0 equiv) was added and the reaction mixture was heated at 70° C. for 6 hours. Upon completion the sample was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

(615) TABLE-US-00017 TABLE 16 Retention Purity time m/z (%) (min) [M + H].sup.+ Example Structure 16a 100 3.8 464.4
NMR Data for Example 16a

(616) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.18-8.12 (ArH, m, 2H), 8.05 (ArH, d, J=8.42 Hz, 1H), 7.52-7.40 (ArH, m, 3H), 4.96 (CH, d, br, J=4.93 Hz, 1H), 4.66 (CH, d, br, J=12.90 Hz, 1H), 4.40 (d, br, J=6.71 Hz, 1H), 4.07-3.54 (CH.sub.2, m, 11H), 3.47-3.35 (CH, m, 1H), 1.51 (CH.sub.3, d, J=6.79 Hz, 3H), 1.39 (CH.sub.3, d, J=6.82 Hz, 3H)

(617) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.41, 162.93, 161.83, 160.02, 137.14, 136.13, 134.84, 129.19, 128.77, 112.99, 105.03, 71.29, 70.91, 67.26, 66.91, 52.85, 46.95, 44.46, 39.34, 14.73 and 14.37.

(618) Tested in Alternative Enzyme Assay: Ex. (16a) 0.034 μM.

Example 17

(619) (Compound 17a)

(620) ##STR00457##

(621) The chloro-substrate was reported in Example 1.

(622) The appropriate chloro-substrate (1 equiv) was dissolved in toluene (0.07 M). Phenol (1.0 equiv), palladium acetate (0.05 equiv), BINAP (0.05 equiv) and tripotassium phosphate (1.0 equiv) were added. The reaction vessel was sealed and exposed to microwave radiation (140° C., medium absorption setting) for 10 minutes. Upon completion the samples was concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired product.

(623) TABLE-US-00018 TABLE 17 Retention Purity time m/z (%) (min) [M + H].sup.+ Example Structure 17a 93 4.70 436.4

(624) Tested in Alternative Enzyme Assay: Ex. (17a) 0.52 μM.

Example 18

(625) ##STR00459##

(626) The chloro-substrate was reported in Example 1.

(627) To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), and the appropriate boronic acid (1.1 equiv) in acetonitrile/water (1:1) (0.033 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The suspension was sonicated while degassed with nitrogen for 5 minutes then heated to 95° C. for 2 hours. Upon completion the reaction mixture was allowed to cool down to room temperature. The reaction mixture was concentrated in vacuo to half original volume. The crude residue was extracted with CH.sub.2Cl.sub.2 and the combined organic phases were washed with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo to give a yellow solid. The residue was sonicated in diethyl ether, collected by vacuum filtration to give the desired product as a yellow powder.

(628) ##STR00460##

(629) {5-[2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl}-methanol: (78% yield, 100% purity) m/z (LC-MS, ESP): 401 [M+H].sup.+ R/T=3.47 min

(630) ##STR00461##

(631) {3-[2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-phenyl}-methanol: (90% yield, 90% purity) m/z (LC-MS, ESP): 371 [M+H]R/T=4.06 min

(632) Alternatively, to a stirred mixture of bis(pinacolato)diboron (1.05 equiv) and potassium acetate (3 equiv) in N-methylpyrrolidine (13.5 equiv), purged with nitrogen, was added the corresponding bromobenzylalcohol (1 equiv) followed by PdCl.sub.2(dppf) (0.02 equiv). The mixture was then heated to 60° C. and held for 10 min, then heated to 70° C. and held for 15 min and finally heated to 80° C. and held for 1 h. The appropriate chloro-substrate (1 equiv) was then added followed by PdCl.sub.2(dppf) (0.02 equiv) and N-methylpyrrolidine (4.5 equiv). The temperature was then held at 75° C., then 4.3M aqueous potassium carbonate (3.5 equiv) was added over 13 min, then water (12 equiv) was added and the reaction was stirred at 75° C. for 90 min. Water (144 equiv) was then added slowly over 70 min with stirring while the temperature was reduced to 66° C. The temperature of the stirred mixture was then kept at 64° C. for 30 min, then cooled to 20° C. over 2.5 h, and held at 20° C. overnight. The resulting slurry was filtered, and the solid washed first with a 3:1 water:N-methylpyrrolidone mixture (18 equiv of water), then washed with water (24 equiv) and then washed with ethyl acetate (4×4.4 equiv). The solid was then dried in a vacuum oven at 50° C. to leave the title compound in suitable clean form to be used without any further purification. For example, {5-[2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl}-methanol: (73% yield)

(633) (Compounds 18a to 18do)

(634) ##STR00462##
Conditions A:

(635) The appropriate chloro-substrate (1 equiv) was dissolved in DMA (0.04 M). Tripotassium phosphate (1.5 equiv) and the appropriate nucleophile (secondary amine) (1.5 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (200° C., medium absorption setting) for 30 minutes. Upon completion the samples were filtered through a silica cartridge, washed with EtOAc and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(636) Conditions B:

(637) The appropriate chloro-substrate (1 equiv) was suspended in a propan-2-ol and aqueous ammonia (1:3) solution (0.02 M). The reaction vessel was sealed and the mixture exposed to microwave radiation (140° C., medium absorption setting) for 20 minutes. The crude residue was then purified by preparative HPLC to give the desired products.

(638) Conditions C:

(639) The appropriate chloro-substrate (1 equiv) was dissolved in dioxane (0.04 M). Diisopropylethylamine (5.0 equiv) and the appropriate nucleophile (secondary amine) (1.5 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 20 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(640) Conditions D:

(641) The appropriate chloro-substrate (1 equiv) was dissolved in dioxane (0.04 M). Tripotassium phosphate (3.0 equiv), xantphos (0.05 equiv), palladium acetate (0.05 equiv) and the appropriate nucleophile (amine) (1.5 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (150° C., medium absorption setting) for 20 minutes. Upon completion the samples were filtered through a silica cartridge, washed with EtOAc and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(642) Conditions E:

(643) The appropriate chloro-substrate (1.0 equiv) was dissolved in dioxane (0.04 M). Diisopropylethylamine (5.0 equiv) and the appropriate nucleophile (secondary amine, with BOC-protected amino side chain) (1.5 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 20 minutes. Upon completion the samples were concentrated in vacuo. To the crude residue was then added a 4 M solution of HCl in dioxane (0.15 M). The reaction mixtures were stirred at room temperature for 3 hours. Upon completion the samples were basified with a 2 N sodium hydroxide solution. The crude residue was then purified by preparative HPLC to give the desired products.

(644) Conditions F:

(645) The appropriate nucleophile (substituted imidazole) (10.0 equiv) was dissolved in DMF (0.4 M). Sodium hydride (5.0 equiv) was then added. The reaction mixture was stirred at room temperature for 10 minutes under nitrogen and a solution of the appropriate chloro-substrate (1.0 equiv) in DMF (0.075 M) was added. The reaction vessel was sealed and the mixture exposed to microwave radiation (150° C., medium absorption setting) for 30 minutes. Upon completion the samples were filtered through a silica cartridge, eluted with CH.sub.2Cl.sub.2 and then concentrated in vacuo. The crude residue were then purified by preparative HPLC to give the desired products.

(646) Conditions G:

(647) The appropriate chloro-substrate (1 equiv) was dissolved in dioxane (0.04 M). Diisopropylethylamine (5.0 equiv) and the appropriate nucleophile (secondary amine) (4.5 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 40 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(648) Conditions H:

(649) The appropriate chloro-substrate (1 equiv) was dissolved in dioxane (0.04 M). Diisopropylethylamine (5.0 equiv) and the appropriate nucleophile (secondary amine) (10.0 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 60 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(650) Conditions I:

(651) The appropriate chloro-substrate (1 equiv) was dissolved in a solution of 1% DMA in dioxane (0.04 M). Diisopropylethylamine (5.0 equiv) and the appropriate nucleophile (secondary amine) (10.0 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (180° C., medium absorption setting) for 60 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(652) Conditions J:

(653) The appropriate chloro-substrate (1 equiv) was dissolved in a solution of 1% DMA in dioxane (0.04 M). Diisopropylethylamine (7.0 equiv) and the appropriate nucleophile (secondary amine) (3.0 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (150° C., medium absorption setting) for 60 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(654) Conditions K:

(655) The appropriate chloro-substrate (1 equiv) was dissolved in DMF (0.075 M). Potassium carbonate (5.0 equiv) and the appropriate nucleophile (alcohol) (10.0 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (120° C., medium absorption setting) for 20 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(656) Conditions L:

(657) The appropriate chloro-substrate (1 equiv) was dissolved in DMF (0.075 M). Potassium carbonate (5.0 equiv) and the appropriate nucleophile (alcohol) (20.0 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (150° C., medium absorption setting) for 40 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(658) Conditions M:

(659) The appropriate chloro-substrate (1 equiv) was dissolved in DMA (0.13 M). Diisopropylethylamine (2.0 equiv) and the appropriate nucleophile (amine) (2.0 equiv) were then added. The reaction vessel was heated to 100° C. for 3 hours. Upon completion, the reaction mixture was partitioned between dichloromethane and water and the aqueous layer further extracted with dichloromethane. The combined organic phases were dried (MgSO.sub.4), filtered and the filtrate was concentrated in vacuo to give a yellow residue which was purified by recrystallisation from diethyl ether.

(660) Conditions N:

(661) 5-[2-Chloro-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-ylamine (1 equiv) was dissolved in DMA (0.21 M). Diisopropylethylamine (1.0 equiv) and the appropriate nucleophile (amine) (1.1 equiv) were then added. The reaction vessel was sealed and the mixture exposed to microwave radiation (130° C., medium absorption setting) for 10 minutes. Upon completion, the reaction mixture was partitioned between dichloromethane and water and the aqueous layer further extracted with CH.sub.2Cl.sub.2. The combined organic phases were dried (MgSO.sub.4), filtered and the filtrate was concentrated in vacuo to give a yellow residue which was purified by column chromatography on silica gel eluting with 0% to 10% MeOH in CH.sub.2Cl.sub.2 to give the desired product.

(662) Conditions O:

(663) The appropriate chloro-substrate (1 equiv) was dissolved in DMA (0.16 M). Diisopropylethylamine (1.0 equiv) and the appropriate nucleophile (amine) (1.2 equiv) were then added. The reaction vessel was heated to 80° C. for 48 hours. Upon completion, the reaction mixture was partitioned between ethyl acetate and water and the organic layer washed with brine. The combined organic phases were dried (MgSO.sub.4), filtered and the filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC to give the desired product.

(664) Conditions P:

(665) The appropriate chloro-substrate (1 equiv) was dissolved in anisole (0.25 M) (10 vol). Diisopropylethylamine (1.3 equiv) and the appropriate nucleophile (amine) (1.3 equiv) were then added. The reaction vessel was heated to 125° C. and stirred for 11 h. Upon completion, the reaction mixture was allowed to cool to 50° C. Aqueous 20% citric acid solution (7 vol) was added, stirred for 5 min and then allowed to separate partitioned. The aqueous layer was removed and retained. The organic layer was then extracted with a further aliquot of aqueous 20% citric acid solution (3 vol). The organic layer discarded, and the aqueous layers combined. The combined aqueous layers were washed first with anisole (5 vol), then 50% aqueous sodium hydroxide solution (1.23 vol) was added slowly. The resulting aqueous phase was extracted with ethyl acetate (10 vol). The aqueous layer was discarded and the organic layer was washed first with 10% aqueous sodium hydroxide solution (5 vol) and then water (5 vol). The organic layer was then slurried with silicycle Si-thiourea scavenger at 50° C. for 2 h, then the scavenger was filtered off and washed with ethyl acetate (2×1 vol). The organic phase was cooled to 20° C., seeded to start crystallization and stirred until a slurry obtained. The slurry was heated to 50° C. under vacuum and ethyl acetate (3 vol) was removed by vacuum distillation. 2-Methylpentane (3.4 vol) was added and the mixture heated to 60° C. and then slowly cooled to 20° C. over 2 h. The resulting slurry was filtered, and the solid washed with 1:1 ethyl acetate:pentane (2×0.5 vol). The solid was then dried in a vacuum oven at 50° C. to leave the desired product. For example, compound 1a was obtained (50.4% yield). The crude product (1 equiv) was dissolved in DMSO (5 vol based on product weight) at 50° C. Water (2 vol) was added and the mixture stirred at 50° C. until product crystallizes. The slurry was heated to 60° C. and then water (3 vol) was added slowly over 30 min so that the temperature was maintained at 60° C. The mixture was slowly cooled to 20° C. over 2 h, and then held at 20° C. for 30 min. The resulting slurry was filtered, and the solid washed with 2:1 water:DMSO (0.5:1 vol), and then water (3×2 vol). The solid was then dried in a vacuum oven at 50° C. to leave the desired product.

(666) TABLE-US-00019 TABLE 18 Purity Retention m/z (%) time (min) [M + H].sup.+ Conditions Example Structure 18a 91 4.43 464.5 A 18b 98 3.89 382.4 B 18c 96 4.36 450.4 C 18d 97 4.48 464.4 C 18e 93 3.56 479.4 C 18f 97 4.45 542.4 C 18g 97 4.11 494.4 C 18h 98 4.60 518.4 C 0 18i 96 4.54 464.4 C 18j 98 4.83 526.4 C 18k 93 3.96 466.4 C 18l 79 8.73 559.5 D 18m 94 4.28 458.5 D 18n 99 3.86 460.5 D 18o 92 6.48 459.3 D 18p 91 9.79 459.3 D 18q 91 8.03 436.3 C 18r 86 8.77 522.4 C 0 18s 81 5.59 479.4 C 18t 88 9.14 464.4 C 18u 91 8.76 522.4 C 18v 92 6.73 493.4 C 18w 87 9.69 584.5 C 18x 80 7.26 480.4 C 18y 85 7.41 480.4 C 18z 95 5.67 533.4 C 18aa 88 6.79 510.3 C 18ab 93 6.81 452.3 C 0 18ac 93 5.44 535.4 C 18ad 99 5.40 465.5 E 18ae 94 9.86 478.4 C 18af 94 9.11 518.3 C 18ag 72, 25 10.37, 10.81 504.4 C 18ah 94 7.56 494.3 C 18ai 96 5.55 519.4 C 18aj 99 7.82 480.4 C 18ak 96 10.49 588.4 C 18al 96 10.92 540.4 C 00 18am 97 8.84 542.4 C 01 18an 95 9.74 551.4 C 02 18ao 96 6.18 479.3 C 03 18ap 92 8.46 450.3 C 04 18aq 97 10.99 560.4 C 05 18ar 89 8.12 532.4 C 06 18as 91 5.71 507.4 C 07 18at 99 10.88 679.4 C 08 18au 85 5.37 465.4 E 09 18av 98 4.54 466.6 C 0 18aw 98 4.30 450.5 C 18ax 99 4.02 454.5 C 18ay 100 3.83 433.4 F 18az 92 9.32 491.4 F 18ba 93 4.54 475.4 F 18bb 100 5.06 511.4 F 18bc 97 10.48 525.3 F 18bd 10, 89 4.70, 4.77 492.5, 492.5 C 18be 99 4.67 526.6 C 18bf 99 4.48 528.5 C 0 18bg 98 4.38 464.5 C 18bh 98 4.37 464.5 C 18bi 100 3.56 527.5 C 18bj 99 3.84 466.4 C 18bk 99 3.83 466.4 C 18bl 95 9.06 500.5 C 18bm 98 7.65 480.5 C 18bn 97 3.78 452.5 C 18bo 95 4.03 454.4 C 18bp 98 4.01 396.4 H 0 18bq 99 4.14 410.4 G 18br 99 4.30 424.4 H 18bs 93 5.27 426.4 C 18bt 94 7.18 428.3 H 18bu 84 5.95 439.3 I 18bv 91 4.91 439.4 C 18bw 94 5.38 440.4 G 18bx 94 5.40 440.4 G 18by 92 5.44 440.4 C 18bz 97 5.52 446.3 H 0 18ca 90 4.92 451.4 C 18cb 93 4.95 453.4 C 18cc 96 5.50 454.4 H 18cd 92 5.18 456.4 H 18ce 96 5.37 463.4 G 18cf 91 5.31 465.4 G 18cg 92 4.95 465.4 C 18ch 93 5.73 468.3 C 18ci 99 4.95 495.4 C 18cj 97 5.79 498.4 G 0 18ck 91 5.28 470.3 G 18cl 93 5.57 466.3 C 18cm 92 5.58 466.3 C 18cn 97 6.87 447.3 F 18co 93 6.70 479.2 C 18cp 92 6.18 453.2 J 18cq 92 6.18 453.1 J 18cr 92 6.72 440.2 C 18cs 97 7.84 468.3 I 18ct 98 5.38 467.3 I 0 18cu 98 6.63 397.2 K 18cv 88 7.17 411.2 L 18cw 100 6.24 427.2 K 18cx 83 6.87 441.2 L 18cy 93 5.45 454.2 K 18cz 97 5.72 468.3 K 18da 98 7.96 489.3 K 18db 98 6.73 440.3 K 18dc 96 8.26 436.2 K 18dd 95 4.05 452.4 J 0 18de 93 5.36 438.2 A 18df 93 11.22 452.3 A 18dg 96 4.86 438.4 A 18dh 100 4.66 454.4 A 18di 100 4.37 426.4 A 18dj 98 7.86 467.4 M 18dk 97 4.77 463.2 N 18dl 99 4.78 408.1 N 18dm 97 4.89 477.3 N 18dn 97 4.03 466.2 O 0 18do 99 3.99 466.2 O
NMR Data for Example 18b

(667) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.85 (ArH, d, J=2.46 Hz, 1H), 8.64 (ArH, dd, J=8.75, 2.48 Hz, 1H), 8.30 (OH, s, br, 1H), 8.04 (ArH, d, J=8.47 Hz, 1H), 7.59 (ArH, d, J=8.54 Hz, 1H), 7.14 (ArH, d, J=8.83 Hz, 1H), 5.03-4.91 (CH.sub.2, m, 1H), 4.66 (CH.sub.2, dd, J=13.05, 0.77 Hz, 1H), 4.41 (CH.sub.2, d, J=6.75 Hz, 1H), 4.07 (OCH.sub.3, s, 3H), 4.04-3.98 (CH.sub.2, m, 1H), 3.97-3.68 (CH.sub.2, m, 11H), 3.60 (CH.sub.2, d, J=2.75 Hz, 1H), 3.41 (CH.sub.2, s, 1H), 1.50 (CH.sub.3, d, J=6.77 Hz, 3H), 1.39 (CH.sub.3, d, J=6.81 Hz, 3H)

(668) NMR Data for Example 18k

(669) .sup.1H NMR (300 MHz, CHCl.sub.3) δ ppm 10.59-10.51 (OH, m, 1H), 8.18 (ArH, dd, J=4.42, 2.17 Hz, 2H), 7.99 (ArH, d, J=8.45 Hz, 1H), 7.44 (ArH, d, J=8.48 Hz, 1H), 7.01 (ArH, d, J=9.22 Hz, 1H), 4.81 (CH.sub.2OH, s, 2H), 4.37-4.11 (CH.sub.2, m, 3H), 4.09-3.65 (OCH.sub.3+CH.sub.2, m, 13H), 2.02-1.94 (CH.sub.2, m, 1H), 1.73-1.38 (CH.sub.2, m, 1H), 1.50 (CH.sub.3, d, J=6.77 Hz, 3H)

(670) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 162.05, 161.84, 161.81, 159.16, 150.47, 134.52, 129.29, 128.68, 128.43, 127.47, 117.04, 112.75, 110.28, 104.93, 104.30, 70.96, 67.12, 66.95, 66.77, 61.97, 55.57, 52.75, 50.99, 44.48 and 14.72.

(671) NMR Data for Example 18v

(672) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.07 (ArH, dd, J=7.09, 2.14 Hz, 2H), 7.89 (ArH, d, J=8.47 Hz, 1H), 7.33 (ArH, d, J=8.49 Hz, 1H), 6.91 (ArH, d, J=9.31 Hz, 1H), 6.88 (NH, S, Br, 1H), 5.34 (NH, s, Br, 1H), 4.95 (CH.sub.2, dd, J=12.22, 0.66 Hz, 2H), 4.70 (CH.sub.2OH, s, 2H), 4.34-4.20 (CH, m, 1H), 3.93-3.53 (OCH.sub.3, +CH.sub.2, m, 10H), 2.91 (CH.sub.2, d, J=12.29 Hz, 2H), 2.38 (CH.sub.2, s, 2H), 1.89 (CH.sub.2, dd, J=6.92, 6.38 Hz, 2H), 1.76-1.54 (CH.sub.2, m, 3H), 1.38 (CH.sub.3, d, J=6.76 Hz, 3H)

(673) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 176.91, 165.39, 162.98, 161.80, 160.14, 159.13, 134.52, 131.20, 129.28, 128.84, 128.44, 119.99, 112.70, 110.26, 104.34, 70.97, 67.10, 66.94, 61.97, 55.57, 52.76, 44.52, 43.73, 43.69, 43.16, 26.88, and 14.70.

(674) NMR Data for Example 18ab

(675) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.19 (ArH, d, J=7.14 Hz, 2H), 8.00 (ArH, d, J=8.47 Hz, 1H), 7.43 (ArH, d, J=8.42 Hz, 1H), 7.01 (ArH, d, J=9.13 Hz, 1H), 4.82 (CH.sub.2OH, s, 2H), 4.71-4.59 (CH.sub.2, m, 1H), 4.47-4.35 (CH.sub.2, m, 1H), 3.97 (OCH.sub.3, s, 3H), 3.85 (CH.sub.2, ddd, J=17.63, 13.74, 9.24 Hz, 8H), 2.12 (CH.sub.2, s, Br, 5H), 1.50 (CH.sub.3 d, J=6.75 Hz, 3H).

(676) .sup.13C NMR (75 MHz, CDCl.sub.3) ppm 159.35, 159.10, 134.61, 131.26, 129.22, 128.89, 128.54, 112.41, 110.21, 104.39, 71.06, 66.95, 61.99, 55.56, 52.80, 44.51, 27.01 and 14.78.

(677) NMR Data for Example 18ax

(678) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.27-8.17 (ArH, m, 2H), 8.00 (ArH, d, J=8.50 Hz, 1H), 7.45 (ArH, d, J=8.51 Hz, 1H), 7.01 (ArH, d, J=8.65 Hz, 1H), 5.40 (NH, br, s, 1H), 4.81 (CH.sub.2OH, s, 2H), 4.49-4.35 (CH.sub.2, m, 1H), 3.97 (OCH.sub.3, s, 3H), 3.93-3.64 (CH.sub.2, m, 6H), 3.58-3.48 (CH.sub.2, m, 2H), 3.43 (OCH.sub.3, s, 3H), 1.49 (CH.sub.3, d, J=6.71 Hz, 3H), 1.34 (CH.sub.3, d, J=6.68 Hz, 3H)

(679) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.67, 161.56, 160.64, 159.19, 134.53, 129.27, 128.83, 128.39, 112.53, 110.30, 76.23, 70.98, 67.00, 62.02, 59.18, 55.57, 52.73, 44.31, 18.23, 18.20 and 14.85.

(680) NMR Data for Example 18bn

(681) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.23-8.15 (ArH, m, 2H), 7.99 (ArH, d, J=8.45 Hz, 1H), 7.42 (ArH, d, J=8.46 Hz, 1H), 7.00 (ArH, d, J=8.35 Hz, 1H), 4.81 (CH.sub.2OH, s, 2H), 4.65 (CH, s, br, 1H), 4.05-3.64 (OCH.sub.3+CH.sub.2, m, 13H), 3.24 (OH, s, 1H), 1.50 (CH.sub.3, d, J=6.73 Hz, 3H).

(682) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.18, 162.87, 159.34, 159.06, 134.57, 131.25, 129.26, 128.84, 128.47, 112.36, 110.20, 104.35, 71.00, 70.97, 66.94, 61.91, 55.55, 52.82, 44.43, 27.01 and 14.87.

(683) NMR Data for Example 18bo

(684) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.28-8.17 (ArH, m, 2H), 8.00 (ArH, d, J=8.49 Hz, 1H), 7.45 (ArH, d, J=8.50 Hz, 1H), 7.02 (ArH, d, J=8.60 Hz, 1H), 5.51-5.34 (CH, m, 1H), 4.81 (CH.sub.2OH, s, 2H), 4.47-4.34 (CH, m, 1H), 4.00 (CH.sub.2, d, J=1.94 Hz, 1H), 3.97 (OCH.sub.3, s, 3H), 3.93-3.89 (CH2, m, 2H), 3.83-3.63 (CH.sub.2, m, 4H), 3.53 (CH.sub.2, d, br, J=4.02 Hz, 2H), 3.43 (OCH.sub.3, s, 3H), 1.50 (CH.sub.3, d, J=6.73 Hz, 3H), 1.34 (CH.sub.3, d, J=6.69 Hz, 3H)

(685) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.69, 161.55, 160.67, 159.19, 134.52, 131.15, 129.26, 128.84, 128.41, 119.72, 112.58, 110.30, 70.98, 67.12, 67.00, 62.05, 59.18, 55.58, 52.73, 44.32, 18.20 and 14.84.

(686) NMR Data for Example 18dj

(687) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.10-8.03 (ArH, m, 2H), 7.95 (ArH, d, J=8.41 Hz, 1H), 7.42-7.30 (ArH, m, 3H), 5.52-5.27 (NH.sub.2, m, br, 2H), 4.98 (CH.sub.2, dd, J=12.74, 0.96 Hz, 2H), 4.31-4.29 (CH, m, 1H), 3.97-3.55 (CH.sub.2, m, 8H), 3.07-2.86 (CH.sub.2, m, 2H), 2.45-2.35 (CH.sub.2, m, 1H), 1.99-1.88 (CH.sub.2, m, br, 2H), 1.70 (CH.sub.2, m, 2H), 1.41 (CH.sub.3, d, J=6.76 Hz, 3H)

(688) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 176.75, 170.03, 165.35, 162.99, 161.12, 160.17, 137.17, 136.10, 134.83, 129.19, 128.76, 112.81, 104.86, 100.00, 70.95, 67.12, 66.91, 52.83, 44.50, 43.72, 43.68, 43.10, 28.88 and 14.73.

(689) NMR Data for Example 18dk

(690) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.67 (ArH, d, J=1.86 Hz, 1H), 8.38 (ArH, dd, J=8.76, 2.36 Hz, 1H), 8.29 (NH, s, weak signal, 1H), 7.91 (ArH, d, J=8.45 Hz, 1H), 7.27 (ArH, d, J=8.46 Hz, 1H), 6.58 (ArH, d, J=8.75 Hz, 1H), 5.54-5.45 (CH.sub.2, m, 1H), 4.97 (NH.sub.2, br, s, 2H), 4.37-4.24 (CH.sub.2, m, 1H), 3.97-3.54 (CH.sub.2, m, 6H), 3.09-2.87 (CH.sub.2, m, 2H), 2.77 (NHCH.sub.3, d, J=4.82 Hz, 3H), 2.42-2.24 (CH.sub.2, m, 1H), 1.87 (CH.sub.2, d, J=0.84 Hz, 2H), 1.79-1.59 (CH.sub.2, m, 2H), 1.40 (CH.sub.3, d, J=6.76 Hz, 3H).

(691) NMR Data for Example 18dl

(692) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.68 (ArH, d, J=1.98 Hz, 1H), 8.49 (ArH, dd, J=8.87, 2.32 Hz, 1H), 8.38 (NH, s, br, weak signal 1H), 7.99 (ArH, d, J=8.47 Hz, 1H), 7.34 (ArH, d, J=8.49 Hz, 1H), 6.67 (ArH, d, J=8.85 Hz, 1H), 4.38 (CH.sub.2, d, J=6.77 Hz, 1H), 4.05-3.82 (CH.sub.2, m, 7H), 3.81-3.62 (CH.sub.2, m, 7H), 1.47 (CH.sub.3, d, J=6.77 Hz, 3H).

(693) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 165.16, 162.79, 160.31, 159.09, 158.45, 143.98, 139.12, 135.00, 124.48, 111.80, 110.03, 104.70, 70.92, 67.00, 66.90, 52.81, 44.57, 44.40 and 14.78.

(694) NMR Data for Example 18dm

(695) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.67 (ArH, d, J=2.05 Hz, 1H), 8.36 (ArH, dd, J=8.76, 2.27 Hz, 1H), 7.90 (ArH, dd, J=8.45, 2.12 Hz, 1H), 7.26 (ArH, dd, J=8.47, 0.73 Hz, 1H), 6.57 (ArH, d, J=8.76 Hz, 1H), 5.10-4.87 (NH.sub.2, m, 2H), 4.37-4.22 (CH.sub.2, m, 1H), 3.96-3.51 (CH.sub.2, m, 6H), 3.08 (NCH.sub.3+CH.sub.2, s, 4H), 2.95-2.91 (NCH.sub.3, s, 3H), 2.80-2.59 (CH.sub.2, m, 1H), 1.76 (CH.sub.2, d, J=2.61 Hz, 3H), 1.64-1.44 (CH, m, 1H), 1.38 (CH.sub.3, t, J=6.34, 6.34 Hz, 3H).

(696) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 173.59, 165.46, 165.31, 163.03, 160.17, 158.89, 145.99, 138.35, 134.76, 124.89, 111.71, 109.15, 104.41, 70.96, 66.96, 52.81, 46.85, 44.38, 39.43, 37.26, 35.56, 28.06, 24.95 and 14.71.

(697) NMR Data for Example 18dn

(698) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.10 (ArH, d, J=7.89 Hz, 2H), 7.97 (ArH, d, J=8.49 Hz, 1H), 7.42 (ArH, d, J=8.46 Hz, 1H), 6.98 (ArH, d, J=8.55 Hz, 1H), 4.88 (CH.sub.2, d, J=5.25 Hz, 1H), 4.77 (CH.sub.2OH, s, 2H), 4.56 (CH.sub.2, d, J=13.38 Hz, 1H), 4.38-4.36 (CH.sub.2, m, 1H), 4.02-3.51 (OCH.sub.3+CH.sub.2, m, 11H), 3.43-3.33 (CH.sub.2, m, 1H), 1.47 (CH.sub.3, d, J=6.77 Hz, 3H), 1.35 (CH.sub.3, d, J=6.78 Hz, 3H).

(699) .sup.13C NMR (75 MHz, CD.sub.3COCD.sub.3) δ ppm 165.11, 162.27, 161.87, 159.54, 159.23, 134.74, 130.76, 129.41, 128.86, 128.39, 113.09, 110.32, 104.45, 71.20, 70.95, 67.17, 66.91, 61.80, 55.57, 52.82, 47.05, 44.44, 39.45, 14.74 and 14.44.

(700) NMR Data for Example 18do

(701) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 8.10 (ArH, d, J=8.76 Hz, 2H), 7.98 (ArH, d, J=8.49 Hz, 1H), 7.42 (ArH, d, J=8.46 Hz, 1H), 6.97 (ArH, d, J=8.37 Hz, 1H), 4.88 (CH.sub.2, d, J=5.46 Hz, 1H), 4.77 (CH.sub.2OH, s, 2H), 4.58-4.49 (CH.sub.2, m, 1H), 4.39-4.36 (CH.sub.2, d J=7.41 Hz, 1H), 4.02-3.51 (OCH.sub.3+CH.sub.2, m, 11H), 3.43-3.33 (CH.sub.2, m, 1H), 1.48 (CH.sub.3, d, J=6.78 Hz, 3H), 1.35 (CH.sub.3, d, J=6.78 Hz, 3H).

(702) .sup.13C NMR (75 MHz, CD.sub.3COCD.sub.3) δ ppm 165.05, 161.87, 159.45, 159.24, 134.78, 130.70, 129.44, 128.86, 128.38, 113.14, 110.33, 104.43, 71.19, 70.95, 67.16, 66.90, 61.77, 55.57, 52.82, 47.08, 44.44, 39.47, 14.76 and 14.44.

(703) Tested in Alternative Enzyme Assay: Ex. (18a) 0.03 μM; Ex. (18b) 0.1 μM; Ex. (18c) 0.066 μM; Ex. (18d) 0.15 μM; Ex. (18e) 0.039 μM; Ex. (18f) 0.038 μM; Ex. (18g) 0.031 μM; Ex. (18h) 0.23 μM; Ex. (18i) 0.03 μM; Ex. (18j) 0.088 μM; Ex. (18k) 0.019 μM; Ex. (18l) 0.097 μM; Ex. (18m) 0.042 μM; Ex. (18n) 0.31 μM; Ex. (18o) 0.51 μM; Ex. (18p) 0.25 μM; Ex. (18q) 0.11 μM; Ex. (18r) 0.18 μM; Ex. (18s) 0.037 μM; Ex. (18t) 0.054 μM; Ex. (18u) 0.073 μM; Ex. (18v) 0.014 μM; Ex. (18w) 0.25 μM; Ex. (18x) 0.014 μM; Ex. (18y) 0.023 μM; Ex. (18z) 0.088 μM; Ex. (18aa) 0.019 μM; Ex. (18ab) 0.012 μM; Ex. (18ac) 0.014 μM; Ex. (18ad) 0.078 μM; Ex. (18ae) 0.034 μM; Ex. (18af) 0.23 μM; Ex. (18ag) 0.25 μM; Ex. (18ah) 0.03 μM; Ex. (18ai) 0.063 μM; Ex. (18aj) 0.022 μM; Ex. (18ak) 0.42 μM; Ex. (18al) 0.36 μM; Ex. (18am) 0.077 μM; Ex. (18an) 0.14 μM; Ex. (18ao) 0.073 μM; Ex. (18ap) 0.013 μM; Ex. (18aq) 0.19 μM; Ex. (18ar) 0.079 μM; Ex. (18as) 0.08 μM; Ex. (18at) 0.78 μM; Ex. (18au) 0.11 μM; Ex. (18av) 0.27 μM; Ex. (18aw) 0.058 μM; Ex. (18ax) 0.026 μM; Ex. (18ay) 0.087 μM; Ex. (18az) 0.092 μM; Ex. (18ba) 0.16 μM; Ex. (18bb) 0.65 μM; Ex. (18bc) 0.043 μM; Ex. (18bd) 0.19 μM; Ex. (18be) 0.79 μM; Ex. (18bf) 0.077 μM; Ex. (18bg) 0.047 μM; Ex. (18bh) 0.04 μM; Ex. (18bi) 0.32 μM; Ex. (18bj) 0.024 μM; Ex. (18bk) 0.022 μM; Ex. (18bl) 0.61 μM; Ex. (18bm) 0.025 μM; Ex. (18bn) 0.01 μM; Ex. (18bo) 0.058 μM; Ex. (18 bp) 0.049 μM; Ex. (18bq) 0.072 μM; Ex. (18br) 0.03 μM; Ex. (18bs) 0.042 μM; Ex. (18bt) 0.062 μM; Ex. (18bu) 0.047 μM; Ex. (18bv) 0.11 μM; Ex. (18bw) 0.031 μM; Ex. (18bx) 0.035 μM; Ex. (18by) 0.039 μM; Ex. (18bz) 0.01 μM; Ex. (18ca) 0.0026 μM; Ex. (18cb) 0.25 μM; Ex. (18cc) 0.018 μM; Ex. (18cd) 0.025 μM; Ex. (18ce) 0.37 μM; Ex. (18cf) 0.013 μM; Ex. (18cg) 0.067 μM; Ex. (18ch) 0.078 μM; Ex. (18ci) 0.068 μM; Ex. (18cj) 0.055 μM; Ex. (18ck) 0.0095 μM; Ex. (18cl) 0.023 μM; Ex. (18 cm) 0.029 μM; Ex. (18cn) 0.013 μM; Ex. (18co) 0.0052 μM; Ex. (18cp) 0.0057 μM; Ex. (18cq) 0.027 μM; Ex. (18cr) 0.0063 μM; Ex. (18cs) 0.0047 μM; Ex. (18ct) 0.097 μM; Ex. (18cu) 0.08 μM; Ex. (18cv) 0.043 μM; Ex. (18cw) 0.034 μM; Ex. (18cx) 0.024 μM; Ex. (18cy) 0.12 μM; Ex. (18cz) 0.079 μM; Ex. (18da) 0.71 μM; Ex. (18db) 0.0031 μM; Ex. (18dc) 0.21 μM; Ex. (18dd) 0.028 μM; Ex. (18de) 0.26 μM; Ex. (18df) 0.4 μM; Ex. (18dg) 0.3 μM; Ex. (18dh) 0.15 μM; Ex. (18di) 0.15 μM; Ex. (18dj) 0.052 μM; Ex. (18dm) 0.061 μM; Ex. (18dn) 0.0094 μM; Ex. (18do) 0.026 μM. Tested in phospho-Ser473 Akt assay: Ex. (18dk) 0.6821 μM; Ex. (18dl) 0.2951 μM.

Example 19

(704) ##STR00582##

(705) The chloro-substrates were reported in Example 18.

(706) (Compounds 19a to 19x)

(707) Conditions A:

(708) To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.5 equiv), and the appropriate boronic acid (1.0 equiv) in acetonitrile/water (1:1) (0.026 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction vessel was sealed and heated at 95° C. for 2 hours. Upon completion the samples were filtered through a silica cartridge, washed with CH.sub.2Cl.sub.2 and methanol and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(709) Conditions B:

(710) To a mixture of the appropriate chloro-substrate (1 equiv), cesium fluoride (3.5 equiv), and the appropriate boronic acid (1.0 equiv) in acetonitrile (0.026 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction vessel was sealed and heated at 95° C. for 2 hours. Upon completion the samples were filtered through a silica cartridge, washed with CH.sub.2Cl.sub.2 and methanol and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(711) Conditions C:

(712) To a mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (2.5 equiv), and the appropriate pinacolate boron ester or boronic acid (1.1 equiv) in acetonitrile/water (1:1) (0.041 M of chloro-substrate) was added tetrakis(triphenylphosphine)palladium.sup.0 (0.05 equiv). The reaction vessel was sealed and exposed to microwave radiation (150° C., medium absorption setting) for 30 minutes under nitrogen atmosphere. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(713) TABLE-US-00020 TABLE 19 Purity Retention m/z (%) time (min) [M + H].sup.+ Conditions Example Structure 19a 93 7.66 433.2 A 19b 88 8.95 471.3 A 19c 79 7.54 473.3 A 19d 92 11.14 519.3 A 19e 99 6.14 472.3 A 19f 90 7.43 458.3 A 19g 84 10.52 532.3 A 19h 75 9.58 501.3 B 0 19i 94 11.13 488.3 A 19j 84 7.36 444.3 A 19k 88 7.33 486.3 A 19l 88 8.75 487.3 A 19m 93 11.64 511.3 A 19n 87 9.26 457.3 A 19o 89 9.05 473.3 A 19p 97 4.31 444.3 C 19q 95 4.13 414.2 C 19r 94 4.14 414.2 C 00 19s 97 4.43 444.2 C 01 19t 98 4.28 444.2 C 02 19u 87 4.41 432.2 C 03 19v 98 4.07 417.2 C 04 19w 96 4.12 445.3 C 05 19x 99 5.66 418.2 A 06
NMR Data for Example 19j

(714) .sup.1H NMR (300 MHz, DMSO) δ ppm 9.63 (ArH, d, J=1.49 Hz, 1H), 8.84-8.69 (ArH, m, 2H), 8.49-8.37 (ArH, m, 1H), 8.19 (ArH, dd, J=8.61, 2.35 Hz, 1H), 8.00 (ArH, d, J=8.76 Hz, 1H), 7.57 (ArH, ddd, J=7.99, 4.81, 0.71 Hz, 1H), 7.15 (ArH, d, J=8.71 Hz, 1H), 5.23 (ArH, dd, J=2.03, 1.13 Hz, 1H), 5.23 (CH, m, 1H), 4.78 (CH, d, J=6.83 Hz, 1H), 4.61 (CH.sub.2OH, s, 2H), 4.22 (CH.sub.2, d, J=13.08 Hz, 1H), 4.03-3.92 (CH.sub.2, m, 1H), 3.98 (OCH.sub.3, s, 3H), 3.88-3.61 (CH.sub.2, m, 3H), 2.50 1.49 (CH.sub.3, d, J=6.79 Hz, 3H)

(715) .sup.13C NMR (75 MHz, DMSO) δ ppm 164.91, 161.77, 161.25, 160.36, 158.71, 151.75, 149.97, 136.10, 133.86, 131.45, 129.97, 127.92, 126.79, 124.08, 117.24, 110.92, 108.15, 70.77, 66.83, 66.80, 58.39, 56.04, 52.15, 44.39 and 15.24.

(716) NMR Data for Example 19x

(717) .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 9.86-9.80 (ArH, m, 1H), 9.00-8.91 (ArH, m, 1H), 8.77 (ArH, dd, J=4.80, 1.71 Hz, 3H), 8.28 (ArH, ddd, J=9.24, 8.03, 5.57 Hz, 1H), 7.83 (ArH, d, J=8.64 Hz, 2H), 7.60-7.53 (ArH, m, 2H), 7.53-7.43 (CH, m, 1H), 4.72 (CH.sub.2, d, J=6.93 Hz, 1H), 4.33-4.23 (CH.sub.2, m, 1H), 4.00-3.80 (CH.sub.2, m, 4H), 1.65 (CH.sub.3, d, J=6.81 Hz, 3H)

(718) .sup.13C NMR (75 MHz, CDCl.sub.3) δ ppm 164.55, 161.73, 161.53, 151.52, 150.66, 136.99, 136.34, 134.91, 133.42, 129.34, 129.12, 123.19, 119.66, 117.15, 108.64, 106.49, 70.98, 67.02, 52.92, 44.49 and 15.16.

(719) Tested in Alternative Enzyme Assay: Ex. (19a) 0.048 μM; Ex. (19b) 0.018 μM; Ex. (19c) 0.052 μM; Ex. (19d) 0.25 μM; Ex. (19e) 0.11 μM; Ex. (19f) 0.096 μM; Ex. (19g) 0.0087 μM; Ex. (19h) 0.77 μM; Ex. (19i) 0.28 μM; Ex. (19j) 0.057 μM; Ex. (19k) 0.077 μM; Ex. (19l) 0.12 μM; Ex. (19m) 0.41 μM; Ex. (19n) 0.22 μM; Ex. (19) 0.19 μM; Ex. (19p) 0.24 μM; Ex. (19q) 0.14 μM; Ex. (19r) 0.012 μM; Ex. (19s) 2 μM; Ex. (19t) 0.097 μM; Ex. (19u) 0.055 μM; Ex. (19v) 0.07 μM; Ex. (19w) 0.086 μM; Ex. (19x) 0.81 μM.

Example 20

(720) ##STR00607##

(721) The amino substrate was reported in Example 18.

(722) (Compounds 20a to 20c)

(723) Conditions A:

(724) The appropriate amino-substrate (1 equiv) was suspended in THF (0.04 M). The appropriate sulfonyl chloride (2.0 equiv) was added. The reaction vessel was sealed and exposed to microwave radiation (140° C., medium absorption setting) for 10 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(725) Conditions B:

(726) The appropriate amino-substrate (1 equiv) was suspended in DMF (0.04 M). The appropriate acyl chloride (1.2 equiv) and potassium carbonate (2.4 equiv) were added. The reaction vessel was sealed and exposed to microwave radiation (140° C., medium absorption setting) for 10 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(727) Conditions C:

(728) The appropriate amino-substrate (1 equiv) was suspended in DMF (0.09 M). The appropriate acyl chloride (3.0 equiv) was added. The reaction vessel was sealed and exposed to microwave radiation (130° C., medium absorption setting) for 15 minutes. Upon completion the samples were concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired products.

(729) TABLE-US-00021 TABLE 20 Retention Purity time m/z (%) (min) [M + H].sup.+ Conditions Example Structure 20a 93 4.67 536.5 A 08 20b 97 4.58 486.4 B 09 20c 85 4.56 436.3 C 0

(730) Tested in Alternative Enzyme Assay: Ex. (20a) 1.4 μM; Ex. (20b) 0.67 μM; Ex. (20c) 0.024 μM.

Example 21

(731) ##STR00611##

(732) The chloro-substrate was reported in Example 18.

(733) (Compound 21a)

(734) The appropriate chloro-substrate (1 equiv) was dissolved in ethanol (0.025 M). Sodium formate (11.0 equiv) and palladium on carbon (0.5 equiv) were added. The reaction vessel was sealed and heated at 100° C. for 12 hours. Upon completion the sample was filtered through Celite™, and the filtrate was concentrated in vacuo. The crude residue was then purified by reverse phase chromatography eluting with a gradient of 5 to 95% acetonitrile in 0.1% formic acid/water, to give the desired product.

(735) TABLE-US-00022 TABLE 21 Retention Purity time m/z (%) (min) [M + H].sup.+ Example Structure 21a 97 5.94 367.3
NMR Data for Example 21a

(736) .sup.1H NMR (300 MHz, DMSO) δ ppm 8.70 (ArH, s, 1H), 8.42-8.37 (ArH, m, 2H), 8.16 (ArH, dd, J=8.59, 2.34 Hz, 1H), 8.01 (ArH, d, J=8.79 Hz, 1H), 7.14 (ArH, d, J=8.69 Hz, 1H), 5.20 (CH, t, J=5.67, 5.67 Hz, 1H), 4.59 (CH.sub.2, d, J=5.61 Hz, 2H), 4.05-3.93 (CH.sub.2, m, 2H), 3.89 (OCH.sub.3, s, 3H), 3.80-3.59 (CH.sub.2, m, 4H), 3.57 (s, 1H), 3.31 (s, 1H), 2.50 (td, J=3.64, 1.80, 1.80 Hz, 1H), 1.42 (CH.sub.3, d, J=6.79 Hz, 3H)

(737) .sup.13C NMR (75 MHz, DMSO) δ ppm 164.04, 161.48, 160.52, 158.69, 157.38, 136.11, 131.43, 129.96, 127.87, 126.77, 117.33, 110.93, 109.11, 70.71, 66.83, 58.37, 56.03, 52.14, 44.28 and 15.17.

(738) Tested in Alternative Enzyme Assay: Ex. (21a) 0.2 μM.

Comparative Example 1

(739) ##STR00613##

(740) Using the method of Example 1, to a cooled (0-5° C.) stirred solution (0.1 M) of the appropriate trichloro substrate (1 equiv) in CH.sub.2Cl.sub.2 was added diisopropylethylamine (1 equiv) in a dropwise fashion. The appropriate amine (1 equiv) was then added to the reaction mixture portionwise over the period of 1 hour. The solution was maintained at room temperature with stirring for a further 1 hour before the mixture was washed with water (2×1 reaction volume). The aqueous extracts were combined and extracted with CH.sub.2Cl.sub.2 (2×1 reaction volume). The organic extracts were then combined, dried (sodium sulphate), filtered and concentrated in vacuo to give an oily residue which solidified upon prolonged drying. The solid was triturated with diethylether and then filtered and the cake washed with cold diethyl ether to leave the title compound in a suitably clean form to be used without any further purification.

(741) ##STR00614##

(742) 2,7-Dichloro-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine—R1=morpholine: (92% yield, 90% purity) m/z (LC-MS, ESP): 285 [M+H].sup.+ R/T=3.90 min

(743) ##STR00615##

(744) To a solution (0.2 M) of the appropriate dichloro-substrate (1 equiv) in anhydrous dimethyl acetamide under an inert atmosphere was added diisopropylethylamine (1 equiv) followed by the appropriate amine (1 equiv). The resulting mixture was heated for 48 hours at 70° C. before being cooled to ambient temperature. The reaction was diluted with CH.sub.2Cl.sub.2 (1 reaction volume) and then washed with water (3×1 reaction volumes). The organic extract was concentrated in vacuo to give a syrup which was dissolved in EtOAC (1 reaction volume) and washed with saturated brine solution before being dried, filtered (sodium sulphate) and concentrated in vacuo to give an oil. The crude residue was purified by flash chromatography (SiO.sub.2, eluted with EtOAc:Hex (7:3) going to (1:1)) to give the title compound as a yellow solid that was suitably clean to be used without any further purification.

(745) ##STR00616##

(746) 7-Chloro-2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine—R1=morpholine, R2=cis-dimethylmorpholine: (42% yield, 100% purity) m/z (LC-MS, ESP): 364 [M+H].sup.+ R/T=2.96 min

(747) ##STR00617##

(748) 7-Chloro-2-((S)-3-methyl-morpholin-4-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine R1=morpholine, R2=(S)-3-Methyl-morpholine: (70% yield, 97% purity) m/z (LC-MS, ESP): 350 [M+H].sup.+ R/T=3.44 min

(749) ##STR00618##

(750) 7-Chloro-2-(2-ethyl-piperidin-1-yl)-4-morpholin-4-yl-pyrido[2,3-d]pyrimidine R1=morpholine, R2=2-Ethyl-piperidine: (56% yield, 95% purity) m/z (LC-MS, ESP): 362 [M+H].sup.+ R/T=3.78 min

Comparative Examples 1a, 1b, 1c, 1j, and 1k

(751) R.sup.4=morpholine

(752) R.sup.2=(S)-3-methyl-morpholine or cis-dimethylmorpholine or 2-Ethyl-piperidine

(753) R.sup.7=aryl or heteroaryl

(754) ##STR00619##

(755) The appropriate chloro-substrate (1 equiv) was dissolved in a toluene/ethanol (1:1) solution (0.02 M). Sodium carbonate (2 equiv) and the appropriate pinacolate boron ester or boronic acid (1 equiv) were then added followed by tetrakis(triphenylphosphine)palladium.sup.0 (0.1 equiv). The reaction vessel was sealed and the mixture exposed to microwave radiation (140° C., medium absorption setting) for 30 minutes. Upon completion the samples were filtered through a silica cartridge, washed with EtOAc and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the desired comparative examples.

(756) The following Comparative Examples were prepared

(757) TABLE-US-00023 Retention Purity time m/z Comparative Example (%) (min) [M + H].sup.+ Structure 1a 99 4.13 452.3 0 1b 95 3.95 452.3 1c 99 9.01 464.4 1j 88 8.57 406.5 1k 93 8.12 412.3

Example 22

(758) Biological Assay

(759) For mTOR enzyme activity assays, mTOR protein was isolated from HeLa cell cytoplasmic extract by immunoprecipitation, and activity determined essentially as described previously using recombinant PHAS-1 as a substrate (ref. 21).

(760) Examples 1a-1l, 1ak, 1al, 1ap, 1at, 1az, 3l, 4a, 4c, 4d, 4f, 4i, 4w, 4x, 5q were tested and exhibited IC.sub.50 values against mTOR of less than 200 nM. For example 5q was measured to have an IC50 of 46 nm.

(761) The comparative Examples were also tested and when compared to the corresponding Examples, the exhibited IC.sub.50 values for the Comparative Examples were higher than those of the corresponding Examples (ie IC50 Comparative Example 1a>IC50 Example 1a). For example Example 1k was measured to have an IC50 of 5 nm whereas Comparative Example 1k was measured to have an IC50 of 33 nm. Therefore, compounds of the present invention are more active in the mTOR assay.

Example 23

(762) Alternative Enzyme Assay

(763) The assay used AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant mTOR.

(764) A C-terminal truncation of mTOR encompassing amino acid residues 1362 to 2549 of mTOR (EMBL Accession No. L34075) was stably expressed as a FLAG-tagged fusion in HEK293 cells as described by Vilella-Bach et al., Journal of Biochemistry, 1999, 274, 4266-4272. The HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely maintained at 37° C. with 5% CO.sub.2 up to a confluency of 70-90% in Dulbecco's modified Eagle's growth medium (DMEM; Invitrogen Limited, Paisley, UK Catalogue No. 41966-029) containing 10% heat-inactivated foetal calf serum (FCS; Sigma, Poole, Dorset, UK, Catalogue No. F0392), 1% L-glutamine (Gibco, Catalogue No. 25030-024) and 2 mg/ml Geneticin (G418 sulphate; Invitrogen Limited, UK Catalogue No. 10131-027). Following expression in the mammalian HEK293 cell line, expressed protein was purified using the FLAG epitope tag using standard purification techniques.

(765) Test compounds were prepared as 10 mM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 μl) of each compound dilution were placed into a well of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one). A 10 μl mixture of recombinant purified mTOR enzyme, 1 μM biotinylated peptide substrate (Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-Tyr-Val-Ala-Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH.sub.2; Bachem UK Ltd), ATP (20 μM) in a buffer solution [comprising Tris-HCl pH 7.4 buffer (50 mM), EGTA (0.1 mM), bovine serum albumin (0.5 mg/ml), DTT (1.25 mM) and manganese chloride (10 mM)] were added to the assay plates and incubated with compound for 2 hours at room temperature.

(766) Each reaction was stopped by the addition of 5 μl of a mixture of EDTA (50 mM), bovine serum albumin (BSA; 0.5 mg/ml) and Tris-HCl pH 7.4 buffer (50 mM) containing p70 S6 Kinase (T389) 1A5 Monoclonal Antibody (Cell Signalling Technology, Catalogue No. 9206B) and AlphaScreen Streptavidin donor and Protein A acceptor beads (200 ng/well Perkin Elmer, Catalogue No. 6760002B and 6760137R respectively). Assay plates were left for approx 16 hours at room temperature before measurement. The resultant signals arising from laser light excitation at 680 nm were measured using a Packard Envision instrument. Phosphorylated biotinylated peptide is formed in situ as a result of mTOR mediated phosphorylation. The phosphorylated biotinylated peptide that is associated with AlphaScreen Streptavidin donor beads forms a complex with the p70 S6 Kinase (T389) 1A5 Monoclonal Antibody that is associated with Alphascreen Protein A acceptor beads. Upon laser light excitation at 680 nm, the donor bead:acceptor bead complex produces a signal that can be measured. Accordingly, the presence of mTOR kinase activity results in an assay signal. In the presence of an mTOR kinase inhibitor, signal strength is reduced.

(767) Control wells that produced a maximum signal corresponding to maximum enzyme activity were created by using 5% DMSO instead of test compound. Control wells that produced a minimum signal corresponding to fully inhibited enzyme were created by adding EDTA (83 mM) instead of test compound.

(768) mTOR enzyme inhibition for a given test compound was expressed as an IC.sub.50 value.

(769) The compounds tested in this assay exhibited IC.sub.50 values against mTOR of less than 40 μm.

(770) The following compounds exhibited IC.sub.50 values against mTOR of less than 1 μm: 1bp, 1ca, 1cb, 1cd, 12e, 18df, 1m, 1q, 1r, 17, 19 h, 19m, 18n, 18o, 18ak, 18al, 18at, 1t, 18bb, 18be, 18bi, 18bl, 1x, 1y, 1ba, 1z, 20b, 1ae, 7a, 7 h, 18ce, 5f, 4af, 4ag, 4aj, 5y, 3b, 5j, 5k, 5p, 3w, 3y, 3z, 11a, 18da, 3m, 3o, 3p, 3r, 3s, 1aj, 5r, 5s, 1cn, 2a, 2b, 1cq, 1cr, 2d, 3ad, 2 h, 1cw and 1dd, with the following compounds exhibiting IC.sub.50 values against mTOR of less than 300 nM: 1c, 1bq, 1bt, 1ch, 1ci, 4ap, 4at, 4aw, 4ax, 4ay, 4bd, 12b, 18de, 18dh, 18di, 18dg, 21a, 1o, 18b, 18d, 18 h, 19d, 19e, 19i, 19l, 19n, 19o, 18p, 18q, 18r, 18w, 18af, 18ag, 18an, 18aq, 18au, 18av, 1v, 18ay, 18ba, 18bd, 1bg, 1w, 1ac, 4p, 9a, 1bb, 1av, 7b, 7e, 7f, 7g, 7k, 7j, 5c, 5d, 5e, 5g, 4v, 4x, 4y, 4z, 4aa, 4ae, 4ah, 4ai, 5u, 5v, 5w, 5x, 3d, 3f, 18bv, 18cb, 3 h, 5 h, 5i, 51, 50o, 3i, 3j, 3v, 3x, 3u, 3ab, 1al, 1am, 1an, 1be, 18cy, 18dc, 13a, 19p, 19q, 3k, 3n, 3q, 13f, 13b, 4g, 1au, 5q, 1ay, 18dj, 13c, 13e, 10a, 1cl, 2c, 2e, 1cs, 2i, 8d, 13g and 1cu, with the following compounds exhibiting IC.sub.50 values against mTOR of less than 100 nM: 1b, 1a, 1d, 1bl, 1bm, 1bn, 1f, 1bo, 1i, 1g, 1h, 1br, 1bs, 1bu, 1bv, 1e, 1j, 1bw, 1bx, 1by, 1bz, 1ce, 1ce, 1k, 1cf, 1cg, 1l, 1cj, 4al, 4am, 4an, 4ao, 4aq, 4ar, 4as, 4au, 4av, 4az, 4ba, 4bb, 4bc, 4be, 4bf, 12c, 12d, 12a, 18a, 6a, 1as, 1ax, 1n, 1p, 1s, 1ck, 18c, 18e, 18f, 18g, 18i, 18j, 18k, 1ar, 19a, 19b, 19c, 19f, 19g, 19j, 19k, 181, 18m, 1bd, 1aq, 18s, 18t, 18u, 18v, 18x, 18y, 18z, 18aa, 18ab, 18ac, 18ad, 18ae, 18ah, 18ai, 18aj, 18am, 18ao, 18ap, 18ar, 18as, 18aw, 18ax, 18az, 18bc, 18bf, 18bg, 18bk, 18bh, 18bj, 15a, 18bm, 8b, 4 h, 14a, 8a, 1aa, 1ab, 1ad, 1af, 1ag, 14b, 1bc, 4i, 1ah, 4j, 41, 4m, 4n, 4o, 18bn, 18bo, 4u, 1bh, 16a, 1at, 7c, 7d, 7i, 3a, 3c, 5a, 5b, 4w, 4ac, 4ad, 5t, 3e, 3g, 18 bp, 18bq, 18br, 18bs, 18bt, 18bu, 18bw, 18by, 18bz, 18ca, 18cc, 18cd, 18cf, 18cg, 18ch, 18ci, 18cj, 18ck, 18cl, 4ak, 18bx, 18cm, 18cv, 1bi, 1bj, 4a, 1aw, 3t, 3aa, 1ap, 1bf, 18cn, 18co, 18cp, 18cs, 18ct, 18cu, 18cw, 18cx, 18cz, 18cq, 19r, 19t, 31, 19u, 19v, 19w, 20c, 1u, 4b, 4q, 4t, 4c, 4e, 4f, 18dd, 4d, 1az, 4r, 4s, 2f, 2g, 2j and 1cyv. For example, Compound 4aa has an IC.sub.50 of 151 nM.

(771) The Comparative Examples were also tested and when compared to the corresponding Examples, the exhibited IC.sub.50 values for the Comparative Examples were higher than those of the corresponding Examples. For example Example 1k was measured to have an IC50 of 15 nm whereas Comparative Example 1k was measured to have an IC50 of 225 nm. Therefore, compounds of the present invention are more active in reducing cell growth.

Example 24

(772) Cell Proliferation Assay (GI.sub.50)

(773) Cell growth was assessed using the sulforhodamine B (SRB) assay (A). T47D (ECACC, 85102201) cells were routinely passaged in RPMI (Invitrogen, 42401018) plus 10% foetal calf serum (FCS), 1% L-glutamine (Gibco BRL, 25030) to a confluence not greater than 80%. To undertake the assay, T47D cells were seeded at 2.5×10.sup.3 cells/well in 90 μl RPMI plus 10% foetal calf serum, 1% L-glutamine in 96 well plates (Costar, 3904) and incubated at 37° C. (+5% CO.sub.2) in a humidified incubator. Once the cells had fully adhered (typically following 4-5 hours incubation) the plate was removed from the incubator and 10 μL of the diluent added to the control wells (A1-12 and B1-12). Compound was prepared in a six point semi-log dilution at 10× the final concentration required e.g. for a 6 point range of 30 μM to 100 nM in semi-log steps dilution started at 300 μM in stock plate. Dosing was completed by addition of 10 μL of compound at highest concentration to C1-12 through to the lowest concentration in H1-12. The plates were then incubated for 120 hours prior to SRB analysis.

(774) Upon completion of incubation, media was removed and the cells fixed with 100 μl of ice cold 10% (w/v) trichloroacetic acid. The plates were incubated at 4° C. for 20 minutes and then washed four times with water. Each well of cells was then stained with 100 μl of 0.4% (w/v) SRB (Sulforhodamine B, Sigma, Poole, Dorset, UK, Catalogue number S-9012) in 1% acetic acid for 20 minutes before washing four times with 1% acetic acid. Plates were then dried for 2 hours at room temperature. The dye from the stained cells was solubilized by the addition of 100 μl of 10 mM Tris Base into each well. Plates were gently shaken and left at room temperature for 30 minutes before measuring the optical density at 564 nM on a Microquant microtiter plate reader. The concentration of inhibitor eliciting a 50% reduction in growth (GI.sub.50) was determined by analysis of staining intensity of the treated cells as a percentage of the vehicle control wells using Excelfit software. (A) Skehan, P., Storung, R., Scudiero, R., Monks, A., McMahon, J., Vistica, D., Warren, J. T., Bokesch, H., Kenny, S. and Boyd, M. R. (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst. 82, 1107-1112.

(775) Examples 1a-11 were tested and exhibited GI.sub.50 values of less than 300 nM.

(776) The Comparative Examples were also tested and when compared to the corresponding Examples, the exhibited GI.sub.50 values for the Comparative Examples were higher than those of the corresponding Examples (ie GI.sub.50 Comparative Example 1a>GI.sub.50 Example 1a). For example Example 1k was measured to have an GI50 of 32 nm whereas Comparative Example 1k was measured to have an GI50 of 268 nm. Therefore, compounds of the present invention are more active in reducing cell growth.

Example 25

(777) In Vitro Phospho-Ser473 Akt Assay

(778) This assay determines the ability of test compounds to inhibit phosphorylation of Serine 473 in Akt as assessed using Acumen Explorer technology (Acumen Bioscience Limited), a plate reader that can be used to rapidly quantitate features of images generated by laser-scanning.

(779) A MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem, Teddington, Middlesex, UK, Catalogue No. HTB-132) was routinely maintained at 37° C. with 5% CO.sub.2 up to a confluency of 70-90% in DMEM containing 10% heat-inactivated FCS and 1% L-glutamine.

(780) For the assay, the cells were detached from the culture flask using ‘Accutase’ (Innovative Cell Technologies Inc., San Diego, Calif., USA; Catalogue No. AT 104) using standard tissue culture methods and resuspended in media to give 1.7×10.sup.5 cells per ml. Aliquots (90 μl) were seeded into each of the inner 60 wells of a black Packard 96 well plate (PerkinElmer, Boston, Mass., USA; Catalogue No. 6005182) to give a density of ˜15000 cells per well. Aliquots (90 μl) of culture media were placed in the outer wells to prevent edge effects. The cells were incubated overnight at 37° C. with 5% CO.sub.2 to allow them to adhere.

(781) On day 2, the cells were treated with test compounds and incubated for 2 hours at 37° C. with 5% CO.sub.2. Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required with growth media to give a range of concentrations that were 10-fold the required final test concentrations. Aliquots (10 μl) of each compound dilution were placed in a well (in triplicate) to give the final required concentrations. As a minimum response control, each plate contained wells having a final concentration of 100 μM LY294002 (Calbiochem, Beeston, UK, Catalogue No. 440202). As a maximum response control, wells contained 1% DMSO instead of test compound. Following incubation, the contents of the plates were fixed by treatment with a 1.6% aqueous formaldehyde solution (Sigma, Poole, Dorset, UK, Catalogue No. F1635) at room temperature for 1 hour.

(782) All subsequent aspiration and wash steps were carried out using a Tecan 96 well plate washer (aspiration speed 10 mm/sec). The fixing solution was removed and the contents of the plates were washed with phosphate-buffered saline (PBS; 50 μl; Gibco, Catalogue No. 10010015). The contents of the plates were treated for 10 minutes at room temperature with an aliquot (50 μl) of a cell permeabilisation buffer consisting of a mixture of PBS and 0.5% Tween-20. The ‘permeabilisation’ buffer was removed and non-specific binding sites were blocked by treatment for 1 hour at room temperature of an aliquot (50 μl) of a blocking buffer consisting of 5% dried skimmed milk [‘Marvel’ (registered trade mark); Premier Beverages, Stafford, GB] in a mixture of PBS and 0.05% Tween-20. The ‘blocking’ buffer was removed and the cells were incubated for 1 hour at room temperature with rabbit anti phospho-Akt (Ser473) antibody solution (50 μl per well; Cell Signalling, Hitchin, Herts, U.K., Catalogue No 9277) that had been diluted 1:500 in ‘blocking’ buffer. Cells were washed

(783) three times in a mixture of PBS and 0.05% Tween-20. Subsequently, cells were incubated for 1 hour at room temperature with Alexafluor488 labelled goat anti-rabbit IgG (50 μl per well; Molecular Probes, Invitrogen Limited, Paisley, UK, Catalogue No. A11008) that had been diluted 1:500 in ‘blocking’ buffer. Cells were washed 3 times with a mixture of PBS and 0.05% Tween-20. An aliquot of PBS (50 μl) was added to each well and the plates were sealed with black plate sealers and the fluorescence signal was detected and analysed.

(784) Fluorescence dose response data obtained with each compound were analysed and the degree of inhibition of Serine 473 in Akt was expressed as an IC.sub.50 value.

(785) The compounds tested in this assay exhibited IC.sub.50 values against mTOR of less than 10 μm.

(786) The following compounds exhibited IC.sub.50 values against mTOR of less than 1 μm: 1bu, 1ce, 12b, 18de, 18dg, 18j, 1ar, 19e, 19 h, 19i, 19l, 19m, 19n, 19o, 18n, 18o, 18z, 18aa, 18ag, 18ai, 18al, 1v, 18az, 1ah, 7e, 7i, 7j, 5d, 5f, 4v, 4ab, 4aj, 5t, 5u, 5w, 5x, 5y, 5z, 3f, 3g, 18 bp, 18bs, 18bv, 18by, 18cb, 18cv, 1aw, 3u, 1bf, 18ct, 19q, 19s, 19u, 19v, 19w, 1au, 5r, 4t, 18dj, 1cl, 2d, 2e, 1cs, 2 h, 2j and 1cw, with the following compounds exhibiting IC.sub.50 values against mTOR of less than 300 nM: 1bo, 1bp, 1j, 1bx, 1by, 1cf, 1ci, 1cj, 4an, 4ap, 4av, 12d, 18dh, 18di, 6a, 1n, 1p, 1q, 18e, 18 h, 19b, 19c, 19f, 19k, 18p, 1bd, 18w, 18ab, 18af, 18aj, 18aq, 18as, 18av, 18ay, 18bb, 18bc, 18bf, 18bl, 1ab, 4p, 9a, 1av, 3a, 5b, 5c, 5e, 5g, 4aa, 4ad, 4ah, 5v, 3e, 18bq, 18bt, 18bz, 18ca, 18cd, 18cg, 18ci, 18bx, 5n, 1am, 1ao, 18cn, 18cx, 1bk, 13b, 4g, 5s, 4q, 18dd, 1cp, 1cq, 2f, 2g, 13g, 1cyv and 1ct, with the following compounds exhibiting IC.sub.50 values against mTOR of less than 100 nM: 1b, 1a, 1c, 1d, 1bl, 1bm, 1f, 1i, 1g, 1h, 1br, 1bs, 1bv, 1e, 1bz, 1ce, 1k, 1cg, 11, 4al, 4am, 4ao, 4aq, 4as, 4at, 4au, 4aw, 4ax, 4ay, 4az, 4ba, 4bb, 4bc, 4bd, 4be, 4bf, 12c, 12a, 18a, 1as, 1s, 18c, 18d, 18f, 18g, 18i, 18k, 19j, 18m, 18q, 18r, 18s, 18t, 18u, 18v, 18x, 18y, 18ac, 18ad, 18ae, 18ah, 18ak, 18am, 18an, 18ap, 18ar, 18au, 18aw, 18ax, 18ba, 18bd, 18be, 18bg, 18bi, 18bk, 18bh, 18bj, 18bm, 1bg, 8b, 4 h, 1ba, 8a, 1aa, 1ac, 1ae, 1af, 1ag, 14b, 1bc, 4i, 4j, 4k, 4l, 4m, 4n, 4o, 18bn, 18bo, 4u, 1bb, 1at, 7b, 7c, 7d, 7f, 7g, 7k, 5a, 4w, 4x, 4y, 4z, 4ac, 4af, 4ai, 18br, 18bw, 18cc, 18cf, 18ch, 18cj, 18ck, 18cl, 4ak, 18cm, 4a, 3i, 3y, 1ak, 1al, 1ap, 1be, 18co, 18cr, 18cs, 18db, 19p, 3l, 1u, 4b, 5q, 4c, 4e, 4f, 4d, 1az, 4r, 4s, 1cn, 1co and 3ad. For example, Compound 18di has an IC.sub.50 of 151 nM

(787) The Comparative Examples were also tested and when compared to the corresponding Examples, the exhibited IC.sub.50 values for the Comparative Examples were higher than those of the corresponding Examples. For example Example 1k was measured to have an IC50 of 83 nm whereas Comparative Example 1k was measured to have an IC50 of 412 nm. Therefore, compounds of the present invention are more active in reducing cell growth.

REFERENCE LIST

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