Pyrimidines With Tie2 (Tek) Activity

Abstract

The invention relates to a compound of the Formula (I); or salt thereof, wherein R1, R2, R3, R4, R5, R6, A, B, L, n and m are as defined in the description. The invention also relates to pharmaceutical compositions of said compounds, the use of said compounds as medicaments and in the production of an anti-angiogenic effect in a warm blooded animal. The invention also relates to processes for the preparation of said compounds.

Description

EXAMPLE 1

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-phenylurea

5-[(3-Aminophenyl)ethynyl]pyrimidine-4,6-diamine (M875810) (45.0 mg) was stirred in THF and phenyl isocyanate (33.4 mg) was added dropwise. After 30 min, methylethylenediamine-polystyrene (400 mg) was added and stirring continued for 30 min. The reaction mixture was filtered and concentrated to give a yellow solid which was triturated with DCM (7 mL) to give the title compound as a beige solid (38 mg, 56%);

¹H NMR (DMSO-d₆) 6.61 (bs, 4H), 7.01-7.06 (m, 2H), 7.31-7.40 (m, 4H), 7.46-7.54 (m, 3H), 7.77-7.79 (m, 1H), 7.90 (s, 1H), 8.72-8.76 (m, 2H);

MS m/e MH⁺ 345.

Preparation of Intermediate

5-[(3-aminophenyl)ethynyl]pyrimidine-4,6-diamine

4,6-Diamino-5-iodopyrimidine (J. Med. Chem., 2001, 44, 2133-2138) (2.36 g), bis(triphenylphosphine)palladium dichloride (350 mg) and copper(I) iodide (40 mg) were stirred in DMF (100 mL)-trimethylamine (20 mL) and degassed with nitrogen for 10 min. 3-Ethynyl aniline (1.29 g) was added and the mixture heated to 95° C. for 20 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica using 1-10% (7M ammonia in MeOH) in DCM as eluent. Further purification by trituration with DCM (20 mL) gave the title compound as a brown solid (970 mg, 43%);

¹H NMR (DMSO-d₆) 3.72 (bs, 2H), 5.17 (bs, 4H), 6.67-6.71 (m, 1H), 6.80-6.82 (m, 1H), 6.88-6.92 (m, 1H), 7.11-7.17 (m, 1H), 8.08 (s, 1H);

MS m/e MH⁺ 226.

EXAMPLE 2

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-2-phenylacetamide

Phenylacetyl chloride (55.7 mg) and pyridine (47.5 mg) were added to a stirred solution of 5-[(3-aminophenyl)ethynyl]pyrimidine-4,6-diamine (67.6 mg) in THF. After 60 min, the reaction mixture was concentrated to give a yellow solid. Purification by flash chromatography on silica using 1-5% (7M ammonia in MeOH) in DCM as eluent to give the title compound as a yellow solid (23.2 mg, 23%);

¹H NMR (DMSO-d₆) 3.66 (s, 2H), 6.55 (bs, 4H), 7.26-7.42 (m, 8H), 7.52-7.55 (m, 1H), 7.86 (s, 1H), 10.20 (bs, 1H);

MS m/e MH⁺ 344.

EXAMPLE 3

N-{3-[(4,6diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-(3,4-dichlorophenyl)urea

Starting Materials: Intermediate 1 and 3,4-dichlorophenyl isocyanate.

¹H N (DMSO-d₆) 6.57 (bs, 2H), 7.31-7.45 (m, 6H), 7.76-8.84 (m, 4H), 9.50-9.60 (m, 1H), 12.74 (bs, 1H);

MS m/e MH⁺ 414.

EXAMPLE 4

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-[2-(trifluoromethyl)phenyl]urea

Starting Materials: Intermediate 1 and 2-trifluoromethylphenyl isocyanate.

¹H NMR (DMSO-d₆) 6.54 (s, 4H), 7.26-7.72 (m, 6H), 7.83 (s, 1H), 7.93-7.95 (m, 1H), 8.10 (s, 1H), 9.37 (bs, 1H), 11.65 (bs, 1H);

MS m/e MH⁺ 413.

EXAMPLE 5

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

Starting Materials: Intermediate 1,3-trifluoromethylphenyl isocyanate.

¹H NMR (DMSO-d₆) 6.55 (s, 4H), 7.28-7.55 (m, 5H), 7.75 (s, 1H), 7.83 (s, 1H), 8.03 (s, 1H), 8.77 (s, 1H), 9.07 (s, 1H), 11.65 (bs, 1H);

MS m/e MH⁺ 413.

EXAMPLE 6

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-[4-(trifluoromethyl)phenyl]urea

Starting Materials: Intermediate 1 and 4-trifluoromethylphenyl isocyanate.

¹H NMR (DMSO-d₆) 6.55 (s, 4H), 7.268-7.84 (m, 8H), 8.80 (s, 1H), 9.14 (s, 1H), 11.65 (bs, 1H);

MS m/e MH⁺ 413.

EXAMPLE 7

N-{4-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Example 7 was prepared by an analogous method to Example 1, using Intermediate 2 in place of Intermediate 1 and 2-fluoro-5-trifluoromethylphenyl isocyanate in place of phenyl isocyanate.

¹H NMR (DMSO-d₆) 6.54 (s, 4H), 7.38-7.57 (m, 4H), 7.66-7.69 (m, 2H), 7.85 (s, 1H), 8.62-8.65 (m, 1H), 8.95 (bs, 1H), 9.32 (bs, 1H);

MS m/e MH⁺ 431.

EXAMPLE 8

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-(3-methoxyphenyl)urea

A solution of phosgene (20% solution in toluene) (2.3 mL) was added dropwise to a stirred suspension of 5-[(3-aminophenyl)ethynyl]pyrimidine4,6-diamine (Intermediate 1) (50 mg) in EtOAc (1.2 mL) at 60° C. After 1 hr the temperature was increased to reflux overnight. The reaction mixture was concentrated in vacuo and azeotroped with toluene. m-Anisidine (27 mg) and DIPEA (0.08 mL) in THF (1 mL) was added to a stirred suspension of the isocyanate in THF (1 mL). After 10 min water (10 mL) was added, the reaction mixture extracted with EtOAc (2×5 mL), the combined organics dried (MgSO₄), filtered and concentrated in vacuo. Purification by flash chromatography on silica using 1-10% MeOH in DCM as eluent gave the title compound as a white solid (32 mg, 39%);

¹H NMR (DMSO-d₆) 3.72 (s, 3H), 6.48-6.61 (m, 5H), 6.89-6.95 (m, 1H), 7.13-7.21 (m, 2H), 7.23-7.34 (m, 2H), 7.38-7.43 (m, 1H), 7.70 (s, 1H), 7.83 (s, 1H), 8.63 (s, 1H), 8.70 (s, 1H);

MS m/e MH⁺ 375.

EXAMPLE 9

Phenyl {4-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}carbamate

Phenylchloroformate (0.84 mL) was added dropwise to a stirred solution of 5-[(4-aminophenyl)ethynyl]pyrimidine-4,6-diamine (Intermediate 2) (1.0 g) and pyridine (0.72 mL) in THF (75 mL) at 0° C. After 2 hr water (10 mL) was added, the reaction mixture stirred for 10 min then concentrated in vacuo. The solid obtained was triturated with water followed by ether, then dried under vacuum at 60° C. to give the title compound as a brown solid (1.21 g, 79%);

¹H N (DMSO-d₆) 6.47-6.61 (bs, 4H), 7.18-7.29 (m, 3H), 7.38-7.54 (m, 4H), 7.62-7.69 (d, 2H), 7.83 (s, 1H), 10.35 (s, 1H);

MS m/e MH⁺ 346.

EXAMPLE 10

Phenyl {3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}carbamate

Example 10 was prepared by an analogous method to Example 9 and purification was carried out by trituration with ether then by flash chromatography on silica using 1-10% MeOH in DCM as eluent, followed by trituration with methanol.

Starting Materials: Intermediate 1 and phenylchloroformate.

¹H NMR DMSO-d₆) 6.53 (s, 4H), 7.17-7.46 (m, 8H), 7.77 (s, 1H), 7.83 (s, 1H), 10.24 (bs, 1H);

MS m/e MH⁺ 346.

EXAMPLE 11

N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-N′-{4-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}urea

5-[(4-Aminophenyl)ethynyl]pyrimidine4,6-diamine (Intermediate 2) (30.0 mg), triethylamine (0.022 mL) and phenyl(5-tert-butyl-1,3,4-thiadiazol-2-yl)carbamate (Intermediate 3) (44.0 mg) in THF (2 mL) were irradiated under microwave conditions (CEM explorer, 80° C., 50W) for 20 min. The reaction mixture was concentrated in vacuo, purification by flash chromatography on silica using 1-10% MeOH in DCM as eluent gave the title compound as a yellow solid (11 mg, 21%);

¹H NMR (DMSO-d₆) 1.38 (s, 9H), 6.52 (bs, 4H), 7.49-7.52 (d, 2H), 7.63-7.66 (d, 2H), 7.82 (s, 1H), 9.18 (bs, 1H);

MS m/e MH⁺ 409.

Intermediate 3

Phenyl (5-tert-butyl-1,3,4-thiadiazol-2-yl)carbamate

Phenylchloroformate (0.6 mL) was added dropwise to 2-amino-5-tert-butyl-1,3,4-thiadiazole (0.5 g) and pyridine (0.51 mL) in THF (40 mL) at 0° C. After 2 hour, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organics were dried (MgSO₄), filtered and concentrated in vacuo. Purification by flash chromatography on silica using 20-50% EtOAc in isohexane gave the title compound as a yellow solid (0.819 mg, 93%)

¹H NMR (DMSO-d₆) 1.38 (s, 9H), 7.22-7.28 (m, 3H), 7.41-7.44 (m, 2H);

MS m/e MH⁺ 278.

Intermediates 4 to 8 were prepared by an analogous method to Intermediate 3 by using the appropriate aminoheterocycle.

Intermediate 4

Phenyl (3-methylisoxazol-5-yl)carbamate

Starting Materials: Phenylchloroformate and 5-amino-3-methylisoxazole.

¹H NMR (DMSO-d₆) 2.17 (s, 3H), 5.93 (s, 1H), 7.21-7.30 (m, 3H), 7.41-7.46 (m, 2H), 11.79 (bs, 1H);

MS m/e MH⁺ 219.

Intermediate 5

Phenyl (5-tert-butylisoxazol-3-yl)carbamate

Starting Materials: Phenylchloroformate and 3-amino-5-tert-butylisoxazole.

¹H NMR (DMSO-d₆) 1.28 (s, 9H), 6.42 (s, 1H), 7.18-7.26 (m, 3H), 7.39-7.45 (m, 2H), 11.13 (bs, 1H);

MS m/e MH⁺ 261.

Intermediate 6

phenyl [4-(trifluoromethyl)pyridin-2-yl]carbamate

Starting Materials: Phenylchloroformate and 2-amino-4-trifluoromethylpyridine.

¹H NMR (DMSO-d₆) 7.22-7.30 (m, 3H), 7.41-7.46 (m, 3H), 8.11 (s, 1H), 8.59-8.61 (d, 1H), 11.23 (bs, 1H);

MS m/e MH⁺ 283.

Intermediate 7

Phenyl [3-(acetylamino)phenyl]carbamate

Starting Materials: Phenylchloroformate and 3-amino-acetanilide.

¹H NMR (DMSO-d₆) 2.01 (s, 3H), 7.17-7.30 (m, 6H), 7.38-7.44 (m, 2H), 7.77 (s, 1H), 9.90 (bs, 1H), 10.16 (bs, 1H);

MS m/e MH⁺ 271.

Intermediate 8

Phenyl (3-methylisothiazol-5-yl)carbamate

Starting Materials: Phenylchloroformate and 5-amino-3-methylisothiazole.

¹H NMR (DMSO-d₆) 2.30 (s, 3H), 6.68 (s, 1H), 7.25-7.31 (m, 3H), 7.41-7.46 (m, 2H), 11.90 (bs, 1H);

MS m/e MH⁺ 235.

Examples 12 to 15 were prepared by an analogous method to Example 11 by reacting Intermediate 2 with the appropriate phenyl carbamate:

Example 12

N-{4-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-(3-methylisothiazol-5-yl)urea

Starting Materials: Intermediate 2 and Intermediate 8.

¹H NMR (DMSO-d₆) 2.28 (s, 3H), 6.65 (s, 1H), 6.68 (bs, 4H), 7.46-7.49 (d, 2H), 7.64-7.66 (d, 2H), 7.86 (s, 1H), 9.28 (s, 1H), 10.44 (bs, 1H);

MS m/e MH⁺ 366.

EXAMPLE 13

N-{4-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-(3-methylisoxazol-5-yl)urea

Starting Materials: Intermediate 2 and Intermediate 4.

¹H NMR (DMSO-d₆) 2.16 (s, 3H), 5.95 (s, 1H), 6.66 (bs, 4H), 7.44-7.47 (d, 2H), 7.62-7.65 (d, 2H), 7.85 (s, 1H), 9.12 (s, 1H), 10.20 (bs, 1H);

MS m/e MH⁺ 350.

EXAMPLE 14

N-{4-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Starting Materials: Intermediate 2 and Intermediate 6.

¹H NMR (DMSO-d₆) 7.37 (d, 1H), 7.54-7.57 (d, 2H), 7.70-7.73 (d, 2H), 7.88 (bs, 4H), 8.06 (s, 1H), 8.16 (s, 1H), 8.53-8.55 (d, 1H), 9.77 (s, 1H), 9.91 (s, 1H);

MS m/e MH⁺ 414.

EXAMPLE 15

N-(3-{[({4-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}amino)carbonyl]amino}phenyl)acetamide

Starting Materials: Intermediate 2 and Intermediate 7.

¹H NMR (DMSO-d₆) 2.05 (s, 3H), 6.85-7.05 (m, 1H), 7.08-7.10 (m, 1H), 7.15 (bs, 4H), 7.48-7.50 (d, 2H), 7.64-7.68 (d, 2H), 7.79 (s, 1H), 8.18 (s, 1H), 8.78-8.82 (d, 1H), 9.88 (s, 1H);

MS m/e MH⁺ 402.

Examples 16 to 18 were prepared by an analogous method to Example 11 but using Intermediate 1 in place of Intermediate 2 with the appropriate phenyl carbamate.

Example 16

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-(3-methylisothiazol-5-yl)urea

Starting Materials: Intermediate 1 and Intermediate 8.

¹H NMR (DMSO-d₆) 2.27 (s, 3H), 6.56 (bs, 4H), 6.65 (s, 1H), 7.27-7.33 (m, 1H), 7.36-7.44 (m, 2H), 7.74 (m, 1H), 7.83 (s, 1H), 9.08 (s, 1H), 10.35 (bs, 1H);

MS m/e MH⁺ 366.

EXAMPLE 17

N-(3-{[({3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}amino)carbonyl]amino}phenyl)acetamide

Starting Materials: Intermediate 1 and Intermediate 7.

¹H NMR (DMSO-d₆) 2.03 (s, 3H), 6.54 (bs, 4H), 7.14-7.19 (m, 3H), 7.23-7.34 (m, 2H), 7.39-7.44 (m, 1H), 7.69 (s, 1H), 7.77 (s, 1E), 7.83 (s, 1H), 8.57 (s, 1H), 8.74 (s, 1H), 9.88 (s, 1H);

MS m/e MH⁺ 402.

EXAMPLE 18

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Starting Materials: Intermediate 1 and Intermediate 6.

¹H NMR (DMSO-d₆) 6.57 (bs, 4H), 7.28-7.41 (m, 3H), 7.47-7.52 (m, 1H), 7.79 (s, 1H), 7.84 (s, 1H), 8.04 (s, 1H), 8.52-8.55 (d, 1E), 9.76 (s, 1H), 9.78 (s, 1H);

MS m/e MH⁺ 414.

Examples 19 and 20 were prepared by an analogous method to Example 16, except purification was carried out by trituration with ether.

EXAMPLE 19

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-(3-methylsoxazol-5-yl)urea

Starting Materials: Intermediate 1 and Intermediate 4.

¹H NMR (DMSO-d₆) 2.16 (s, 3H), 5.95 (s, 1H), 6.56 (bs, 4H), 7.27-7.33 (m, 1H), 7.37-7.45 (m, 2H), 7.71 (s, 1H), 7.83 (s, 1H), 8.80 (s, 1H), 10.11 (bs, 1H);

MS m/e MH⁺ 350.

EXAMPLE 20

N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-N′-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}urea

Starting Materials: Intermediate 1 and Intermediate 3.

¹H NMR (DMSO-d₆) 1.38 (s, 9H), 6.56 (bs, 4H), 7.27-7.33 (m, 1H), 7.36-7.41 (m, 1H), 7.43-7.49 (m, 1H), 7.78 (s, 1H), 7.83 (s, 1H), 9.06 (s, 1H);

MS m/e MH⁺ 409.

EXAMPLE 21

N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}urea

5-[(3-Aminophenyl)ethynyl]pyrimidine-4,6-diamine (Intermediate 1) (0.494 g), triethylamine (0.4 mL) and phenyl (5-tert-butylisoxazol-3-yl)carbamate (Intermediate 5) (0.69 g) in THF (20 mL) were refluxed for 4 hr. The reaction mixture was concentrated in vacuo, purification by flash chromatography on silica using 1-10% MeOH in DCM as eluent to give the title compound as a beige solid (558 mg, 65%);

¹H NMR (DMSO-d₆) 1.29 (s, 9H), 6.49 (s, 1H), 6.57 (bs, 4H), 7.25-7.32 (m, 1H), 7.34-7.39 (m, 1H), 7.40-7.45 (m, 1H), 7.72 (s, 1H), 7.83 (s, 1H), 8.79 (s, 1H), 9.56 (s, 1H);

MS m/e MH⁺ 409.

EXAMPLE 22

N-{3-[(4,6-diamiopyrimidin-5-yl)ethynyl]phenyl}-N′-(2,3-dihydro-1,4-benzodioxin-6-yl)urea

5-[(3-Aminophenyl)ethynyl]pyrimidine-4,6-diamine (Intermediate 1) (50 mg), sodium carbonate (141 mg), N-(trichloroacetyl)-3,4 ethylenedioxyaniline (Intermediate 9) (79 mg) in DMF (2 mL) were heated at 100° C. for 5 days. Purification by RPHPLC (H2O:MeCN 0-70%) gave the title compound as a beige solid (8 mg, 9%);

¹H NMR (DMSO-d₆) 4.14-4.24 (m, 4H), 6.75-6.79 (m, 2H), 7.07-7.10 (d, 1H), 7.26-7.39 (m, 3H), 7.82 (s, 1H), 7.86 (bs, 4H), 8.16 (s, 1H), 8.56 (s, 1H), 8.66 (s, 1H);

MS m/e MH⁺ 403.

Intermediate 9

2,2,2-Trichloro-N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide

Trichloroacetyl chloride (12.3 mL) was added dropwise over 10 min to a cooled (ice bath), stirred, solution of 3,4-ethylenedioxyaniline (15.12 g) in EtOAc (150 mL) under an inert atmosphere. A purple precipitate was observed which redissolved on further stirring at ambient temperature. After 4 hours, the reaction mixture was concentrated in vacuo and recrystallised from ethanol to give the title compound as a solid (25.79 g, 87%);

¹H NMR (DMSO-d₆) 4.22 (s, 4H), 6.83-6.87 (m, 1H), 7.07-7.13 (m, 1H), 7.19 (s, 1H), 10.59 (bs, 1H);

MS m/e MH⁺ 296.

Intermediate 10

2,2,2-Trichloro-N-(2-morpholin-4-ylphenyl)acetamide

Intermediate 10 was prepared by an analogous method to intermediate 9 by using N-(2-aminophenyl)morpholine in place of 3,4-ethylenedioxyaniline:

¹H NMR (DMSO-d₆) 2.81-2.89 (m, 4H), 3.70-3.78 (m, 4H), 7.18-7.25 (m, 2H), 7.27-7.40 (m, 1H), 7.85-7.92 (m, 1H), 10.21 (bs, 1H);

MS m/e MH⁺ 323.

EXAMPLE 23

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-(2-morpholin-4-ylphenyl)urea

Example 23 was prepared by an analogous method to Example 22 but using Intermediate 10 in place of Intermediate 9.

¹H NMR (DMSO-d₆) 2.76-2.83 (m, 4H), 3.80-3.88 (m, 4H), 6.95-7.02 (m, 1H), 7.03-7.10 (m, 1H), 7.16-7.21 (m, 1H), 7.31-7.49 (m, 3H), 7.87-7.90 (s, 1H), 7.99-8.10 (m, 4H), 8.17 (s, 1H), 8.20 (s, 1H), 9.59 (s, 1H);

MS m/e MH⁺ 430.

EXAMPLE 24

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-(1-methylpiperidin-4-yl)urea

Phenyl {3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}carbamate (Example 10) (50 mg), 1-methylpiperidin-4-amine (34 mg) and triethylamine (44 mg) in THF (2 mL) were heated at reflux under an inert atmosphere for 18 hours. The solvent was evaporated and the residue was diluted with diethyl ether (10 mL). The product was filtered and dried in vacuo to afford the title compound as a beige solid (41 mg, 77%);

¹H NMR (DMSO-d₆) 1.36-1.46 (m, 2H), 1.79-1.83 (m, 2H), 1.98-2.06 (m, 2H), 2.17 (s, 3H), 2.63-2.67 (m, 2H), 3.44-3.48 (m, 1H), 6.18 (m, 1H), 6.53 (s, 4H), 7.20-7.27 (m, 2H), 7.34-7.38 (m, 1H), 7.63 (s, 1H), 7.86 (s, 1H), 8.32 (s, 1H);

MS m/e MH⁺ 366.

EXAMPLE 25

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-(1-propylpiperidin-4-yl)urea

Example 25 was prepared by an analogous method to Example 24 by using 1-propylpiperidin-4-amine in place of 1-methylpiperidin-4-amine.

¹H NMR (DMSO-d₆) 0.87 (t, 3H), 1.37-1.48 (m, 4H), 1.76-1.83 (m, 2H), 1.99-2.06 (m, 2H), 2.23 (t, 2H), 2.71-2.75 (m, 2H), 3.41-3.52 (m, 1H), 6.17 (d, 1H), 6.52 (s, 4H), 7.19-7.26 (m, 2H), 7.34-7.38 (m, 1H), 7.63 (s, 1H), 7.85 (s, 1H), 8.34 (s, 1H);

MS m/e MH⁺ 394.

EXAMPLE 26

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-2-phenylacetamide

Phenylacetyl chloride (55.7 mg) and pyridine (47.5 mg) were added to a stirred solution of 5-[(3-aminophenyl)ethynyl]pyrimidine-4,6-diamine (intermediate 1)(67.6 mg) in THF. After 60 min, the reaction mixture was concentrated to give a yellow solid. Purification by flash chromatography on silica using 1-5% (7M ammonia in MeOH) in DCM as eluent to give the title compound as a yellow solid (23 mg, 23%);

¹H NMR (DMSO-d₆) 3.66 (s, 2H), 6.55 (bs, 4H), 7.26-7.42 (m, 8H), 7.52-7.55 (m, 1H), 7.86 (s, 1H), 10.20 (bs, 1H);

MS m/e MH⁺ 344.

EXAMPLE 27

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-2-(2-methoxyphenyl)acetamide

A solution of 2-methoxyphenylacetic acid (50 mg) in DMF (1 mL) was added to HATU (120 mg) and polymer supported DIPEA (Argonaut Technologies, 3.9 mmolg⁻¹, 300 mg). The mixture was shaken for 5 min. A solution of 5-[(3-aminophenyl)ethynyl]pyrimidine-4,6-diamine (intermediate 1) (68 mg) in DMF (1 mL) was added, and agitation continued overnight. The resin was removed by filtration and washed with DCM (15 mL). The filtrate was evaporated and the residue partitioned between EtOAc (15 mL) and water (10 mL). The organics were washed with further water (10 mL) and brine (4×10 mL), dried over anhydrous MgSO₄ and evaporated in vacuo. Trituration with DCM gave the title compound as a solid (63 mg, 56%);

¹H NMR (DMSO-d₆) 3.63 (s, 2H), 3.77 (s, 3H), 6.51 (bs, 4H) 6.89 (t, 1H), 6.97 (d, 2H), 7.21 (d, 2H), 7.28 (t, 1H), 7.37 (d, 1H), 7.51 (s, 1H), 7.81-7.86 (m, 2H), 10.04, s, 1H);

MS m/e MH⁺ 374.

Examples 28 to 30 were prepared by an analogous method to Example 27 by using the appropriate acid in place of 2-methoxyphenylacetic acid.

EXAMPLE 28

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-2-[3-(trifluoromethyl)phenyl]acetamide

Starting Materials: Intermediate 1 and 3-trifluoromethylphenylacetic acid.

¹H NMR (DMSO-d₆) 3.78 (s, 2H), 6.52 (bs, 4H), 7.29 (t, 1H), 7.40 (d, 1H), 7.49 (d, 1H), 7.53-7.66 (m, 4H), 7.69 (s, 1H), 7.81-7.87 (m, 2H), 10.25 (s, 1H);

MS m/e MH⁺ 412.

EXAMPLE 29

N-{3- [(4,6-diaminopyrimidin-5yl)ethynyl]phenyl}-2-[4-(trifluoromethyl)phenyl]acetamide

Starting Materials: Intermediate 1 and 4-trifluoromethylphenylacetic acid.

¹H NMR (DMSO-d₆) 3.77 (s, 2H), 6.44-6.63 (bs, 4H), 7.29 (t, 1H), 7.39 (d, 1H), 7.50 (d, 1H), 7.55 (d, 2H), 7.70 (d, 2H), 7.83 (s, 2H), 10.25 (s, 1H);

MS m/e MH⁺ 412.

EXAMPLE 30

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-2-(3-methoxyphenyl)acetamide

Starting Materials: Intermediate 1 and 3-methoxyphenylacetic acid.

¹H NMR (DMSO-d₆) 3.61 (s, 2H), 3.73 (s, 3H), 6.78-6.95 (m, 6H), 7.19-7-33 (m, 2H), 7.38 (d, 1H), 7.87 (s, 1H), 7.90 (s, 1H), 10.30 (s, 1H);

MS m/e MH⁺ 374.

EXAMPLE 31

N-(S-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea

A solution of N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12) (195 mg), HCl in ether (1.0M, 0.1 mL), liquid ammonia (3 mL) and THF (10 mL) was irradiated in a microwave (130° C., 600 W) for 4 hours. The reaction mixture was concentrated in vacuo then purified by RPHPLC (H₂O: MeCN, 10-90%) to give the title compound as a colourless solid (11 mg);

¹H NMR (DMSO-d₆) 9.61 (s, 1H), 8.95 (s, 1H), 8.57 (s, 1H), 8.50 (s, 1H), 7.86 (s, 1H), 7.26-7.44 (m, 3H), 6.48 (s, 1H), 1.29 (s, 9H);

MS m/e MH⁺ 377.

Intermediate 11

N-(5-tert-butylisoxazol-3-yl)-N′-(3-ethynylphenyl)urea

A solution of 5-tert-butylisoxazol-3-amine (1.4 g) and di-succinimidyl carbonate (2.56 g) in MeCN (30 mL) was heated to 80° C. for 4 hours. The solution was cooled to ambient temperature, 3-ethynylaniline (1.17 g) added and the mixture heated for a further 16 hours at 80° C. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between ether and water, the organic phase washed with water and then concentrated in vacuo. Trituration from isohexane gave the title compound as a colourless solid (1.57 g);

¹H NMR (DMSO-d₆) 9.53 (s, 1H), 8.87 (s, 1H), 7.65 (d, 1H), 7.29 (t, 1H), 7.11 (d, 1H), 6.49 (s, 1H), 4.14 (s, 1H), 1.28 (s, 9H);

MS m/e MH⁺ 284.

Intermediate 12

N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea

Bis(triphenylphosphine)palladium dichloride (170 mg), copper(I) iodide (12.5 mg) and triethylamine (10 mL) were added to a degassed solution of 4-chloro-5-iodopyrimidine (Chem. Pharm. Bull. 1986, 34(7), 2719-2724) (2.40 g) and N-(5-tert-butylisoxazol-3-yl)-N′-(3-ethynylphenyl)urea (Intermediate 11) (3.1 g) in DMF (50 mL) and then heated at 50° C. for 1.5 hours. The reaction mixture was concentrated, water added and then extracted into DCM. The organic layer was washed with water then brine and concentrated in vacuo to give the title compound as a brown foam (4.50 g) which was used without further purification.

MS m/e MH⁺ 396 (³⁵CI), 398 (³⁷CI).

EXAMPLE 32

N-(S-tert-butylisoxazol-3-yl)-N′-(3-{[4-(methylamino)pyrimidin-5-yl]ethynyl}phenyl)urea

Example 32 was prepared using an analogous method to Example 31 by using methylamino in place of ammonia.

¹H NMR (DMSO-d₆) 9.61 (s, 1H), 8.97 (s, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.25 (s, br, 1H), 7.86 (s, 1H), 7.31-7.61 (m, 3H), 6.48 (s, 1H), 2.98 (d, 3H), 1.28 (s, 9H);

MS m/e MH⁺ 391.

EXAMPLE 33

N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-{[3-(isopropylamino)propyl]amino}pyrimidin-5-yl)ethynyl]phenyl}urea

A solution of N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12) (200 mg), HCl (1.0 M in ether) (0.1 mL) and N-isopropylpropane-1,3-diamine (0.14 mL) were heated in MeCN (5.0 mL) at 50° C. for 3 hours. The reaction mixture was concentrated in vacuo, NaHCO₃ (50% saturated aq.) added and the mixture extracted into DCM, washed with water and concentrated in vacuo. Purification by flash chromatography on silica (0-10% (7N NH₃ in MeOH) in DCM) gave the title compound as a yellow solid (72 mg);

¹H NMR (DMSO-d₆) 9.41 (s, br, 1H), 8.52 (s, 1H), 8.29 (s, 1H), 7.79 (s, 1H), 7.50 (d, 1H), 7.31 (t, 1H), 7.23 (d, 1H), 6.38 (t, 1H), 5.89 (s, 1H), 3.63 (q, 1H), 2.71-2.81 (m, 3H), 1.82 (p, 2H), 1.35 (s, 9H), 1.00 (d, 6H);

MS m/e MH⁺ 476.

Examples 34 and 35 were prepared by an analogous method to Example 33 by using the appropriate amine in place of N-isopropylpropane-1,3-diamine and with further purification by RPHPLC.

EXAMPLE 34

N-(5-tert-butylisoxazol-3-yl)-N′-[3-({4-[(2-pyrrolidin-1-ylethyl)amino]pyrimidin-5-yl}ethynyl)phenyl]urea

Starting Materials: Intermediate 12 and 1-(2-aminoethyl)pyrrolidine.

¹H NMR (DMSO-d₆) 9.68 (s, 1H), 9.51 (s, br, 1H), 9.06 (s, 1H), 8.62 (s, 1H), 8.58 (s, 1H), 7.87 (s, 1H), 7.71 (s, br, 1H), 7.28-7.40 (m, 3H), 6.47 (s, 1H), 3.80 (q, 1H), 3.60-3.70 (m, 2H), 3.39 (dd, 2H), 3.00-3.15 (m, 2H), 1.94-2.06 (m, 2H), 1.80-1.92 (m, 2H), 1.28 (s, 9H);

MS m/e MH⁺ 474.

EXAMPLE 35

N-(5-tert-butylisoxazol-3-yl)-N′-[3-({4-[(5-tert-butylisoxazol-3-yl)amino]pyrimidin-5-yl}ethynyl)phenyl]urea

Starting Materials: Intermediate 12 and 3-amino-5-tert-butylisoxazole.

¹H NMR (DMSO-d₆) 10.01 (s, 1H), 9.57 (s, 1H), 8.91 (s, 1H), 8.69 (s, 1H), 8.64 (s, 1H), 7.86 (s, 1H), 7.33-1.45 (m, 3H), 6.73 (s, 1H), 6.50 (s, 1H), 1.32 (s, 9H), 1.29 (s, 9H);

MS m/e MH⁺ 500.

The following Examples were made in a similar way to Example 31 by using the appropriate amine in place of ammonia.

EXAMPLE 36

N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-{[3-(dimethylamino)propyl]amino}pyrimidin-5-yl)ethynyl]phenyl}urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12), N,N-dimethylpropylamine. Purification by silica gel chromatography using 0-10% (10% aq NH₃ in MeOH) in DCM as eluent, followed by RPHPLC (H2O:MeCN 0-70%).

¹H NMR (DMSO-d₆) 1.28 (s, 9H), 1.88-2.03 (m, 2H), 2.49 (s, 6H), 3.02-3.18 (m, 2H), 3.48-3.62 (m, 2H), 6.47 (s, 1H), 7.27-7.46 (m, 3H), 7.89 (s, 1H), 8.23 (t, 1H), 8.50 (s, 1H), 8.64 (s, 1H), 9.30 (s, 1H), 9.62 (br, 1H), 9.89 (s, 1H);

MS m/e MH⁺ 462.

EXAMPLE 37

N-(5-tert-butylsoxazol-3-yl)-N′-[3-({4-[(2-hydroxyethyl)amino]pyrimidin-5-yl}ethynyl)phenyl]urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12), ethanolamine. Purification by silica gel chromatography using 0-10% (10% aq NH₃ in MeOH) in DCM as eluent, followed by RPHPLC (H₂O:MeCN 0-70%).

¹H NMR (DMSO-d₆) 1.29 (s, 9H), 3.55-3.61 (m, 4H), 6.48 (s, 1H), 7.29-7.48 (m, 3H), 7.85 (s, 1H), 8.19 (s, br, 1H), 8.45 (s, 1H), 8.64 (s, 1H), 8.98 (s, 1H), 9.61 (s, 1H);

MS m/e MH⁺ 421.

EXAMPLE 38

N-(5-tert-butylisoxazol-3-yl)-N′-[3-({4-[(2-morpholin-4-ylethyl)amino]pyrimidin-5-yl}ethynyl)phenyl]urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12), 2-morpholin-4-ylethanamine. Purification by silica gel chromatography using 0-10% (10% aq NH₃ in MeOH) in DCM as eluent.

¹H NMR (DMSO-d₆) 1.29 (s, 9H), 2.40-2.57 (m, 6H), 3.50-3.59 (m, 6H), 6.50 (s, 1H), 7.08 (t, 1H), 7.24-7.42 (m, 3H), 7.83 (s, 1H), 8.32 (s, 1H), 8.46 (s, 1H), 8.90 (s, 1H), 9.56 (s, 1H);

MS m/e MH⁺ 490.

EXAMPLE 39

N-[3-({4-[(4-aminobutyl)amino]pyrimidin-5-yl}ethynyl)phenyl]-N′-(5-tert-butylisoxazol-3-yl)urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12), 1,4-butanediamine. Purification by silica gel chromatography using 0-10% (10% aq NH₃ in MeOH) in DCM as eluent.

¹H NMR (CDCl₃) 1.29 (s, 9H), 1.33-1.45 (m, 2H), 1.53-1.66 (m, 2H), 2.57 (t, 2H), 3.37-3.49 (m, 2H), 6.49 (s, 1H), 7.30 (d, 1H), 7.35 (d, 1H), 7.38-7.46 (m, 2H), 7.78 (s, 1H), 8.29 (s, 1H), 8.43 (s, 1H);

MS m/e MH⁺ 448.

EXAMPLE 40

N-(5-tert-butylsoxazol-3-yl)-N′-[3-({4-[(3-pyrrolidin-1-ylpropyl)amino]pyrimidin-5-yl}ethynyl)phenyl]urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl} urea (Intermediate 12), 3-pyrrolidin-1-ylpropan-1-amine. Purification by silica gel chromatography twice using 0-10% (1% aq NH₃, 10% MeOH in DCM) in DCM and then 20% EtOH in EtOAc as eluent.

¹H NMR (DMSO-d₆) 1.29 (s, 9H), 1.57-1.64 (m, 4H), 1.68-1.79 (m, 2H), 2.37-2.57 (m, 6H), 3.49 (q, 2H), 6.49 (s, 1H), 7.25-7.44 (m, 4H), 7.78 (s, 1H), 8.29 (s, 1H), 8.44 (s, 1H), 8.90 (s, 1H), 9.56 (s, 1H);

MS m/e MH⁺ 488.

EXAMPLE 41

N-(S-tert-butylisoxazol-3-yl)-N′-[3-({4-[(2,4-dimethoxybenzyl)amino]pyrimidin-5-yl}ethynyl)phenyl]urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl} urea (Intermediate 12), 2,4-dimethoxybenzylamine. Purification by silica gel chromatography twice using 0-10% (10% aq NH₃ in MeOH) in DCM and then 20% EtOAc in isohexane as eluent.

¹H NMR (DMSO-d₆) 1.29 (s, 9H), 3.71 (s, 3H), 3.81 (s, 3H), 4.57 (d, 2H), 6.45 (d, 1H), 6.49 (s, 1H), 6.57 (d, 1H), 7.00 (d, 1H), 7.30 (d, 1H), 7.36 (t, 1H), 7.41 (d, 1H), 7.54 (t, 1H), 7.60 (s, 1H), 8.35 (s, 1H), 8.41 (s, 1H), 8.90 (s, 1H), 9.56 (s, 1H);

MS m/e MH⁺ 527.

EXAMPLE 42

N-[-3-({4-[(2-aminoethyl)amino]pyrimidin-5-yl}ethynyl)phenyl]-N′-(5-tert-butylisoxazol-3-yl)urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12), 1,2-diaminoethane. Purification by silica gel chromatography using 0-10% (10% aq NH₃ in MeOH) in DCM as eluent, followed by trituration from ether and DCM.

¹H NMR (DMSO-d₆) 1.29 (s, 9H), 2.75 (t, 2H), 3.36-3.49 (m, 2H), 6.49 (d, 1H), 6.49 (s, 1H), 7.21-7.46 (m, 3H), 7.77 (s, 1H), 8.30 (s, 1H), 8.43 (s, 1H), 8.94 (s, 1H), 9.56 (s, 1H);

MS m/e MH⁺ 420.

EXAMPLE 43

N-(S-tert-butylisoxazol-3-yl)-N′-{3-[(4-{[2-(dimethylamino)ethyl]amino}pyrimidin-5-yl)ethynyl]phenyl}urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12), N,N-dimethyl-1,2-diaminoethane. Purification as for Example 42.

¹H NMR (DMSO-d₆) 1.29 (s, 9H), 2.12-2.37 (m, 8H), 3.41-3.57 (m, 2H), 6.48 (s, 1H), 7.17 (t, 1H), 7.26-7.46 (m, 3H), 7.79 (s, 1H), 8.31 (s, 1H), 8.45 (s, 1H), 8.91 (s, 1H), 9.57 (s, 1H);

MS m/e MH⁺ 448.

EXAMPLE 44

N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-{[4-(dimethylamino)butyl]amino}pyrimidin-5-yl)ethynyl]phenyl}urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12), N,N-dimethyl-1,4-diaminobutane. Purification as for Example 42.

¹H NMR (DMSO-d₆) 1.29 (s, 9H), 1.44-1.64 (m, 4H), 2.38 (s, 6H), 2.50-2.61 (m, 2H), 3.36-3.54 (m, 2H), 6.48 (s, 1H), 7.24-7.42 (m, 4H), 7.80 (s, 1H), 8.30 (s, 1H), 8.44 (s, 1H), 8.92 (s, 1H), 9.58 (s, 1H);

MS m/e MH⁺ 476.

EXAMPLE 45

N-(5-tert-butylisoxazol-3-yl)-N′-[3-({4-[N-{2-(dimethylamino)ethyl}-N-methyl-amino]pyrimidin-5-yl}ethynyl)phenyl]urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12), 1,1,2-trimethyl-1,2-diaminoethane. Purification as for Example 42.

¹H NMR (DMSO-d₆) 1.29 (s, 9H), 2.48 (s, 6H), 2.57-2.70 (m, 2H), 3.28 (s, 3H), 4.00 (t, 2H), 6.48 (s, 1H), 7.18 (d, 1H), 7.33-7.42 (m, 2H), 7.73 (s, 1H), 8.44 (s, 1H), 8.50 (s, 1H), 9.04 (s, 1H), 9.59 (s, 1H);

MS m/e MH⁺ 462.

EXAMPLE 46

N-(S-tert-butylisoxazol-3-yl)-N′-[3-({4-[(2-piperidin-1-ylethyl)amino]pyrimidin-5-yl)}ethynyl)phenyl]urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12), 2-piperidin-1-ylethanamine. Purification as for Example 42.

¹H NMR (DMSO-d₆) 1.29 (s, 9H), 1.30-1.80 (m, 6H), 2.39-2.60 (m, 2H), 2.82-3.03 (m, 2H), 3.46-3.85 (m, 4H), 6.47 (s, 1H), 7.25-7.51 (m, 4H), 7.85 (s, 1H), 8.39 (s, 1H), 8.51 (s, 1H), 8.92 (s, 1H), 9.58 (s, 1H);

MS m/e MH⁺ 488.

EXAMPLE 47

N-(5-tert-butylisoxazol-3-yl)-N′-[3-({4-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}ethynyl)phenyl]urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12), 3-morpholin-4-ylpropan-1-amine. Purification as for Example 42.

¹H NMR (DMSO-d₆) 1.29 (s, 9H), 1.85-2.04 (m, 2H), 2.45-2.52 (m, 4H), 3.00-3.15 (m, 2H), 3.22-3.70 (m, 6H), 6.47 (s, 1H), 7.27-7.51 (m, 4H), 7.63 (s, 1H), 8.35 (s, 1H), 8.47 (s, 1H), 8.92 (s, 1H), 9.57 (s, 1H);

MS m/e MH⁺ 504.

Example 48

N-(5-tert-butylisoxazol-3-yl)-N′-[3-({4-[(3-piperidin-1-ylpropyl)amino]pyrimidin-5-yl}ethynyl)phenyl]urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12), 3-piperidin-1-ylpropan-1-amine. Purification as for Example 42.

¹H NMR (DMSO-d₆) 1.29 (s, 9H), 1.48-2.05 (m, 8H), 2.67-3.62 (m, 8H), 6.47 (s, 1H), 7.25-7.48 (m, 4H), 7.83 (s, 1H), 8.35 (s, 1H), 8.47 (s, 1H), 8.92 (s, 1H), 9.57 (s, 1H);

MS m/e MH⁺ 502.

EXAMPLE 49

N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}pyrimidin-5-yl)ethynyl]phenyl}urea

SM: N-(5-tert-butylisoxazol-3-yl)-N′-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea (Intermediate 12), 3-(4-methylpiperazin-1-yl)propan-1-amine. Purification as for Example 42.

¹H NMR (DMSO-d₆) 1.29 (s, 9H), 1.68-1.84 (m, 2H), 2.22-2.78 (m, 13H), 3.41-3.56 (m, 2H), 6.49 (s, 1H), 7.26-7.46 (m, 4H), 7.79 (s, 1H), 8.31 (s, 1H), 8.44 (s, 1H), 8.94 (s, 1H), 9.58 (s, 1H);

MS m/e MH⁺ 516

EXAMPLE 50

N-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-N′-[3-({4-[(2-morpholin-4-ylethyl)amino]pyrimidin-5-yl}ethynyl)phenyl]urea

The solution of N-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-N′-[3-({4-[(2-morpholin-4-ylethyl)amino]pyrimidin-5-yl}ethynyl)phenyl]urea (Intermediate 15) in THF (6 mL), 2-morpholin-4-ylethanamine (0.18 mL) and 2.0 M HCl in ether (1 drop) were heated together at 45° C. for 16 hours. After cooling to ambient temperature silica gel was added and the solvent removed in vacuo. Purification by silica gel chromatography using 0-10% (10% aq NH₃ in MeOH) in DCM as eluent, followed by RPHPLC (H2O:MeCN 0-70%), then treatment with aqueous Na₂CO₃ and collection by filtration gave the title compound as a colourless solid (35 mg);

¹H NMR (DMSO-d₆) 1.20 (s, 9H), 2.42 (t, 4H), 2.53 (t, 2H), 3.50-3.58 (m, 6H), 3.59 (s, 3H), 6.05 (s, 1H), 7.08 (t, 1H), 7.25 (d, 1H), 7.31-7.40 (m, 2H), 7.84 (s, 1H), 8.31 (s, 1H), 8.45 (s, 1H), 8.53 (s, 1H), 8.98 (s, 1H);

MS m/e MH⁺ 503.

Intermediate 13

phenyl 3-ethynylphenylcarbamate

Phenyl chloroformate was added dropwise to a solution of 3-ethynylaniline (20.0 mL) and pyridine (24.1 mL) in THF (300 mL) at 0° C. The resultant solution was stirred at 0° C. for 3.5 hours. Pyridine (7.5 mL) was added, followed by additional phenyl chloroformate (6 mL) dropwise. Water (50 mL) was added and the THF removed in vacuo. The resultant aqueous suspension was extracted into ether, washed with 1M HCl, water and brine and concentrated in vacuo to give the title compound as a pale brown solid (27.5 g, 78%).

¹H NMR (CDCl₃) 3.06 (s, 1H), 7.00 (s, br, 1H), 7.14-7.31 (m, 5H), 7.35-7.51 (m, 3H), 7.56 (s, 1H);

MS m/e (M−H)⁻ 236.

Intermediate 14

N-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-N′-(3-ethynylphenyl)urea.

A solution of 3-tert-butyl-1-methyl-1H-pyrazol-5-amine (792 mg), phenyl 3-ethynylphenylcarbamate (Intermediate 13) (1.19 g) and triethylamine (1.4 mL) in THF (30 mL) was heated to 60° C. for 24 hours. Additional triethylamine (0.5 mL) and 3-tert-butyl-1-methyl-1H-pyrazol-5-amine (200 mg) were added and the mixture heated for a further 4 hours and concentrated in vacuo. The residue was partitioned between DCM and 50% saturated aqueous Na₂CO₃ solution. The aqueous phase was extracted with DCM and the combined organics washed with 50% saturated aqueous Na₂CO₃ solution, water and brine and concentrated in vacuo. Purification by flash chromatography on silica using 0-5% MeOH in DCM as eluent, followed by 20-50% EtOAc in DCM gave the title compound as a white solid (725 mg, 49%).

¹H NMR (CDCl₃) 1.30 (s, 9H), 3.08 (s, 1H), 3.75 (s, 3H), 6.11 (s, 1H), 6.63 (s, 1H), 6.84 (s, 1H), 7.19-7.30 (m, 2H), 7.40 (dt, 1H), 7.46 (s, 1H);

MS m/e MH⁺ 297.

Intermediate 15

N-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-N′-[3-({4-chloropyrimidin-5-yl}ethynyl)phenyl]urea

Triethylamine (5.0 mL) was added to a degassed solution of 4-chloro-5-iodopyrimidine (Chem. Pharm. Bull. 1986, 34(7), 2719-2724) (590 mg), N-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-N′-(3-prop-1-ynylphenyl)urea (Intermediate 14) (725 mg) PdCl₂(PPh₃)₂ (40 mg) and cuprous iodide (3 mg) in DMF (12.5 mL). The mixture was heated to 60° C. for 6.5 hours and concentrated in vacuo. The residue was dissolved in THF (18 mL) and used without further purification.

MS m/e MH⁺ 409,411.

The following Example was made in a similar way to Example 21:

EXAMPLE 51

N-{3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}-N′-(2,3-dihydro-1H-inden-1-yl)urea

SM: Phenyl {3-[(4,6-diaminopyrimidin-5-yl)ethynyl]phenyl}carbamate (Example 10), 1-Indanamine

¹H NMR (DMSO-d₆) 1.74-1.86 (m, 1H), 2.43-2.53 (m, 1H), 2.75-3.01 (m, 2H), 5.19 (q, 1H), 6.54 (s, 4H), 6.59 (d, 1H), 7.22-7.32 (m, 6H), 7.40-7.44 (m, 1H), 7.69 (s, 1H), 7.86 (s, 1H), 8.40 (s, 1H);

MS m/e MH⁺ 385.

Claims

1. A compound of the Formula I:

2. A compound of Formula I according to claim 1, wherein: R6 is selected from halo, cyano, a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or an alkanoylamino group —N(Rc)C(O)(1-6C)alkyl in which Rc is hydrogen or (1-6C)alkyl; or R6 is selected from (1-6C)alkyl or (1-6C)alkoxy, wherein the (1-6C)alkyl and the (1-6C)alkoxy groups are optionally substituted by one or more groups independently selected from cyano, fluoro, hydroxy, (1-6C)alkoxy, amino, mono(1-6C)alkylamino, di-[(1-6C)alkyl]amino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring;and salts thereof.

3. A compound of the Formula I according to claim 1, wherein R1 and R2 are independently selected from hydrogen, (1-6C)alkylsulfonyl, phenyl(CH2)u— wherein u is 0, 1, 2, 3, 4, 5 or 6, (1-6C)alkanoyl, (1-6C)alkyl, (1-6C)alkoxycarbonyl, or (3-6C)cycloalkyl(CH2)x— in which x is 0, 1, 2, 3, 4, 5 or 6, or R1 and R2 together with the nitrogen atom to which they are attached represent a saturated or partially saturated 3 to 7 membered heterocyclic ring optionally containing another heteroatom selected from N or O; wherein the alkyl and the cycloalkyl groups are optionally substituted by one or more groups selected from fluoro, hydroxy, (1-6C)alkyl, (1-6C)alkoxy, amino, mono(1-6C)alkylamino or di-[(1-6C)alkyl]amino, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more of the following: (1-4C)alkyl, hydroxy, amino, mono(1-6C)alkylamino or di-[(1-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring;and wherein the phenyl is optionally substituted by one or more groups selected from halo, (1-6C)alkyl, (1-6C)alkoxy, amino, mono(1-6C)alkylamino or di-[(1-6C)alkyl]amino, wherein the (1-6C)alkyl or (1-6C)alkoxy are optionally substituted by hydroxy, amino, mono(1-6C)alkylamino or di-[(1-6C)alkyl]amino;R3 is selected from hydrogen, (1-6C)alkyl or (1-6C)alkoxy, wherein the alkyl and the alkoxy groups are optionally substituted by one or more groups selected from fluoro, hydroxy, (1-6C)alkyl, (1-6C)alkoxy, amino, mono(1-6C)alkylamino or di-[(1-6C)alkyl]amino, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more of the following: (1-4C)alkyl, hydroxy, amino, mono(1-6C)alkylamino or di-[(1-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring;or R3 represents a group —NR1R2 as defined above;R4 is selected from hydrogen, (1-6C)alkyl or (1-6C)alkoxy;A represents an aryl group or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;R5 is selected from cyano, halo, (1-6C)alkoxy or (1-6C)alkyl optionally substituted by cyano or by one or more fluoro;n is 0, 1, 2 or 3;L is attached meta or para on ring A with respect to the point of attachment of the ethynyl group and represents —C(RaRb)C(O)N(R9)—, —N(R8)C(O)C(RaRb)—, —N(R8)C(O)N(R9)—, —N(R8)C(O)O—, or —OC(O)N(R9)—, wherein R8 and R9 independently represent hydrogen or (1-6C)alkyl and wherein Ra and Rb independently represent hydrogen or (1-6C)alkyl or Ra and Rb together with the carbon atom to which they are attached represent (3-6C)cycloalkyl;B represents a (3-7C)cycloalkyl ring, an aryl group or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;R6 is selected from halo, cyano, a saturated or partially saturated 3 to 7 membered heterocyclic ring or an alkanoylamino group —N(Ra)C(O)(1-6C)alkyl in which Ra is hydrogen or (1-6C)alkyl; or R6 is selected from (1-6C)alkyl or (1-6C)alkoxy, wherein the alkyl and the alkoxy groups are optionally substituted by one or more groups selected from cyano, fluoro, hydroxy, (1-6C)alkoxy, amino, mono(1-6C)alkylamino, di-[(1-6C)alkyl]amino, or a saturated or partially saturated 3 to 7 membered heterocyclic ring; andm is 0, 1, 2 or 3;and when m is at least 2 then two substituents on adjacent carbon atoms in ring B may together represent a methylenedioxy group;and salts thereof.

4. A compound according to claim 1 wherein A is selected from phenyl, pyridyl, thiazolyl, thiadiazolyl or pyrimidinyl.

5. A compound according to claim 1 wherein B is selected from phenyl, 2,3-di-hydro-indenyl, piperidinyl, pyridyl, pyrazolyl, isothiazolyl, thiadiazolyl, isoxazolyl, benzodioxinyl, benzodioxolyl or tetrahydropyranyl

6. A compound according to claim 1 wherein L is selected from —N(R8)C(O)N(R9)—, —N(R8)C(O)O— or —N(R8)C(O)CH2— wherein R8 and R9 independently represent hydrogen or (1-6C)alkyl.

7. A compound according to claim 1 wherein R1 and R2 are both hydrogen or R1 is hydrogen or (1-6C)alkyl and R2 is (1-6C)alkyl wherein (1-6C)alkyl) is optionally substituted by hydroxy, amino, mono(1-6C)alkylamino or di(1-6C)alkylamino, carbamoyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, —N(Rd)C(O)(1-6C)alkyl in which Rd is hydrogen or (1-6C)alkyl, aryl (particularily phenyl), a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring;wherein the (1-6C)alkoxy, mono(1-6C)alkylamino and —N(Rd)C(O)(1-6C)alkyl groups are optionally substituted by hydroxy; andwherein an aryl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring is optionally substituted by (1-4C)alkyl, (1-4C)alkoxy or —C(O)CH2Y wherein Y is selected from hydroxy or di(1-6C)alkylamino.

8. A compound according to claim 1 wherein R3 and R4 are both hydrogen.

9. A compound according to claim 1 wherein R6 is independently selected from halo, cyano, oxo, (3-7C)cycloalkyl, a saturated 3 to 7 membered heterocyclic ring (optionally substituted by (1-4C)alkyl), —N(Rc)C(O)(1-6C)alkyl wherein Rc is hydrogen or (1-6C)alkyl (particularily (1-4C)alkyl), (1-6C)alkyl (optionally substituted by halo) or (1-6C)alkoxy and m is selected from 1 or 2.

10. A compound according to claim 1 which is any one or more of examples 1 to 51 or a salt thereof.

11. A pharmaceutical composition which comprises a compound of the Formula I, or a pharmaceutically acceptable salt thereof, as defined in claim 1 in association with a pharmaceutically acceptable diluent or carrier.

12. (canceled)

13. (canceled)

14. (canceled)

15. A process for preparing a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof (wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 L, ring A and ring B, n and m are, unless otherwise specified, as defined in claim 1) comprising: (a) For compounds of the formula I wherein L is —N(R8)C(O)N(H)—, the reaction of a compound of the formula II:

16. A compound selected from Formulae II, XIV, XVI, XIX and -XX as defined in claim 15 or a compound of Formula VIc:

17. A method of inhibiting Tie2 receptor tyrosine kinase in a warm-blooded animal in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1.

18. A method for producing an anti-angiogenic effect in a warm-blooded animal in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1.