AT 9283

AT9283, AT 9283

N-cyclopropyl-N’-[3-[6-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea

1-cyclopropyl-3-[(3Z)-3-[5-(morpholin-4-ylmethyl)benzimidazol-2-ylidene]-1,2-dihydropyrazol-4-yl]urea

896466-04-9
Molecular Weight	381.43
Molecular Formula	C19H23N7O2

CAS

896466-04-9, 896466-57-2 ((±)-Lactic acid), 896466-61-8 (HCl), 896466-55-0 (methanesulfonate)

MolFormulaC22H29N7O5

MolWeight471.5096

CAS 896466-76-5  L LACTATE

(2S)-2-Hydroxypropanoic acid compd. with N-cyclopropyl-N’-[3-[6-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea

Astex Therapeutics Ltd, INNOVATOR

AT-9283 is a potent AuroraA/AuroraB and multi-kinase inhibitor. AT-9283 has shown to inhibit growth and survival of multiple solid tumor cell lines and is efficacious in mouse xenograft models.

AT 9283 is a substance being studied in the treatment of some types of cancer. It is small molecule a multi-targeted c-ABL, JAK2, Aurora A and B inhibition with 4, 1.2, 1.1 ad approximate 3 nM for Bcr-Abl (T3151), Jak2 and Jak3 aurora A and B, respectively. It blocks enzymes (Aurora kinases) involved in cell division and may kill cancer cells

WO2006070195 to Astex Therapeuitcs discloses pyrazole compounds of the general structure shown below as kinase inhibitors.

The compound AT9283 is in phase II clinical trials for treating advanced or metastatic solid tumors or Non-Hodgkin’s Lymphoma. AT9283 is shown below.

a Reagents and conditions:

(a) SOCl2, THF, DMF; (b) morpholine, THF, Et3N;  ………FORMATION OOF ACID CHLORIDE AND COUPLING WITH MORPHOLINE

(c) NaBH4, BF3.OEt2, THF; …………..KETO TO CH2

(d) 10% Pd-C, H2, EtOH; TWO NITRO GPS TO TWO AMINO , REDN

(e) EDC, HOBt, DMF; (f) AcOH, reflux;COUPLING WITH 4-Nitro-lH-pyrazole-3-carboxylic acid

(g) 10%Pd-C, H2, DMF; NITRO GP TO  AMINO

(h) standard amide and urea coupling methods

WO2006070195

https://www.google.co.in/patents/WO2006070195A1?cl=en

Stage 10: Synthesis of l-cvclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- beiizoimidazol-2-ylV 1 H-pyrazol-4-yli -urea.

To a mixture of 7-morpholin-4-ylmethyl-2,4-dihydro- 1 ,2,4,5a, 10- pentaaza- cyclopenta[a]fluoren-5-one (10.7 g, 32.9 mmol) in NMP (65 mL) was added cyclopropylamine (6.9 mL, 99 mmol). The mixture was heated at 100 0C for 5 h. LC/MS analysis indicated -75% conversion to product, therefore a further portion of cyclopropylamine (2.3 mL, 33 mmol) was added, the mixture heated at 100 0C for 4 h and then cooled to ambient. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 niL). The organic portion was washed with sat. aq. NH4Cl (2 x 50 mL) and brine (50 rnL) and then the aqueous portions re-extracted with EtOAc (3 x 100 mL). The combined organic portions were dried over MgSO4 and reduced in vacuo to give l-cycloρropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea as an orange glassy solid (9.10 g).

Stage 11: Synthesis of l-cvclopropyl-S-P-fS-morpholin^-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yll-urea, L-lactate salt

To a solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea (9.10 g, 24 mmol) in EtOAc-iPrOH (1 :1, 90 mL) was added L-lactic acid (2.25 g, 25 mmol). The mixture was stirred at ambient temperature for 24 h then reduced in vacuo. The residue was given consecutive slurries using toluene (100 mL) and Et2O (100 mL) and the resultant solid collected and dried (8.04 g).

This solid was purified by recrystallisation from boiling iPrOH (200 mL) to give after drying l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-urea, L-lactate salt (5.7 g) as a beige solid.

EXAMPLE 66

Stage 1: Preparation of (3,4-dinitrophenyl)-morpholin-4-yl-methanone

3,4-Dinitrobenzoic acid (1.000Kg, 4.71mol, l.Owt), tetiuhydrofuran (10.00L5 lO.Ovol), and dimethylformamide (0.010L, O.Olvol) were charged to a flask under nitrogen. Thionyl chloride (0.450L, 6.16mol, 0.45vol) was added at 20 to 3O0C and the reaction mixture was heated to 65 to 7O0C. Reaction completion was determined by 1H NMR analysis (d6-DMSO), typically in 3 hours. The reaction mixture was cooled to 0 to 50C and triethylamine (1.25L, 8.97mol, 1.25vol) was added at 0 to 100C. Morpholine (0.62L, 7.07mol, 0.62vol) was charged to the reaction mixture at 0 to 1O0C and the slurry was stirred for 30 minutes at 0 to 1O0C. Reaction completion was determined by H NMR analysis (d6-DMSO). The reaction mixture was warmed to 15 to 2O0C and water (4.00L, 4.0vol) was added. This mixture was then charged to a 4OL flange flask containing water (21.0OL, 21.0vol) at 15 to 250C to precipitate the product. The flask contents were cooled to and aged at 0 to 50C for 1 hour and the solids were collected by filtration. The filter-cake was washed with water (4x 5.00L, 4x 5.0vol) and the pH of the final wash was found to be pH 7. The wet filter-cake was analysed by H NMR for the presence of triethylamine hydrochloride. The filter-cake was dried at 40 to 450C under vacuum until the water content by KF <0.2%w/w, to yield (3,4-dinitrophenyl)-morpholin-4-yl-methanone (1.286Kg, 97.0%, KF 0.069%w/w) as a yellow solid.

Stage 2: Preparation of 4-(3,4-dinitro-benzyl)-morpholine

C11H11N3O6 C11H13N3O5

FW:281.22 FW:267.24

(3,4-DinitiOphenyl)-morpholin-4-yl-methanone (0.750Kg, 2.67mol, l.Owt) and tetrahydrofuran (7.50L, lO.Ovol) were charged to a flask under nitrogen and cooled to 0 to 50C. Borontrifluoride etherate (0.713L, 5.63mol, 0.95vol) was added at 0 to 50C and the suspension was stirred at this temperature for 15 to 30 minutes. Sodium borohydride (0.212Kg, 5.60mol, 0.282wt) was added in 6 equal portions over 90 to 120 minutes. (A delayed exotherm was noted 10 to 15 minutes after addition of the first portion. Once this had started and the reaction mixture had been re-cooled, further portions were added at 10 to 15 minute intervals, allowing the reaction to cool between additions). The reaction mixture was stirred at 0 to 50C for 30 minutes. Reaction completion was determined by 1H NMR analysis (d6-DMSO). Methanol (6.30L, 8.4vol) was added drop wise at 0 to 1O0C to quench the reaction mixture (rapid gas evolution, some foaming). The quenched reaction mixture was stirred at 0 to 1O0C for 25 to 35 minutes then warmed to and stirred at 20 to 3O0C (exotherm, gas/ether evolution on dissolution of solid) until gas evolution had slowed. The mixture was heated to and stirred at 65 to 7O0C for 1 hour. The mixture was cooled to 30 to 4O0C and concentrated under vacuum at 40 to 450C to give crude 4-(3,4-dinitro-benzyl)-morpholine (0.702Kg, 98.4%) as a yellow/orange solid.

4-(3,4-Dinitro-benzyl)-niorpholme (2.815kg, 10.53mol, l.Owt) and methanol (12.00L, 4.3vol) were charged to a flask under nitrogen and heated to 65 to 7O0C. The temperature was maintained until complete dissolution. The mixture was then cooled to and aged at 0 to 50C for 1 hour. The solids were isolated by filtration. The filter-cake was washed with methanol (2x 1.50L, 2x 0.5vol) and dried under vacuum at 35 to 45°C to give 4-(3,4-dinitro-benzyl)-morpholine (2.353Kg, 83.5% based on input Stage 2, 82.5% overall yield based on total input Stage 1 material,) as a yellow solid.

Stage 3: Preparation of 4-morpholin-4-yl-methyl-benzene-L2-diamine

C11H13N3O5 C11H17N3O

FW:267.24 FW:207.27

4-(3,4-Dinitro-benzyl)-morρholine (0.800Kg, 2.99mol, l.Owt), and ethanol (11.20L, 14.0vol) were charged to a suitable flask and stirred at 15 to 250C and a vacuum / nitrogen purge cycle was performed three times. 10% Palladium on carbon (10%Pd/C, 50%wet paste, 0.040Kg, 0.05wt wet weight) was slurried in ethanol (0.80L, l.Ovol) and added to the reaction. The mixture was cooled to 10 to 2O0C and a vacuum / nitrogen purge cycle was performed three times. A vacuum / hydrogen purge cycle was performed three times and the reaction was stirred under a hydrogen atmosphere at 10 to 2O0C. Reaction completion was determined by 1H NMR analysis (d6-DMSO), typically 14 to 20 hours. A vacuum / nitrogen purge cycle was performed three times and the reaction mixture was filtered through glass microfibre paper under nitrogen. The filter-cake was washed with ethanol (3x 0.80L, 3x l.Ovol) and the combined filtrate and washes were concentrated to dryness under vacuum at 35 to 450C to give 4-morpholin-4-yl-methyl-benzene-l,2- diamine (0.61 IKg 98.6%) as a brown solid.

Stage 4: Preparation of 4-nitiO-lH-pyrazole-3-carboxγlic acid methyl ester

C4H3N3O4 C5H5N3O4

FW: 157.09 FW: 171.11

4-Nitro-lH-pyrazole-3-carboxylic acid (1.00kg, 6.37mol, l.Owt) and methanol (8.00L, 8.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5°C under nitrogen and thionyl chloride (0.52L, 7.12mol, 0.52vol) was added at this temperature. The mixture was warmed to 15 to 25°C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (d6-DMSO). The mixture was concentrated under vacuum at 35 to 45°C. Toluene (2.00L, 2.0vol) was charged to the residue and removed under vacuum at 35 to 450C. The azeotrope was repeated twice using toluene (2.00L, 2.0vol) to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.071Kg, 98.3%) as an off white solid.

Stage 5: Preparation of 4-amino-lH-pyrazole-3-carboxylic acid methyl ester. O2Me

C5H 5N3O4 C5H7N3O2 FW: 171.11 FW: 141.13

A suspension of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.084Kg, 6.33mol, l.Owt) and ethanol (10.84L, lO.Ovol) was heated to and maintained at 30 to 35°C until complete dissolution occurred. 10% Palladium on carbon (10% Pd/C wet paste, 0.152Kg, 0.14wt) was charged to a separate flask under nitrogen and a vacuum / nitrogen purge cycle was performed three times. The solution of 4-nitro- lH-pyrazole-3-carboxylic acid methyl ester in ethanol was charged to the catalyst and a vacuum / nitrogen purge cycle was performed three times. A vacuum / hydrogen purge cycle was performed three times and the reaction was placed under an atmosphere of hydrogen. The reaction mixture was stirred at 28 to 30°C until deemed complete by 1H NMR analysis (d6-DMSO). The mixture was filtered under nitrogen and concentrated under vacuum at 35 to 450C to give 4-amino-lH- pyrazole-3-carboxylic acid methyl ester (0.883Kg, 98.9%) as a purple solid.

Stage 6: Preparation of 4-fert-butoxycarbonylamino-lH-pyrazole-3-carboxylic acid

C5H7N3O2 C9H13N3O4

FW: 141.13 FW:227.22

4-Amino-lH-pyrazole-3-carboxylic acid methyl ester (1.024Kg, 7.16mol, l.Owt) and dioxane (10.24L, lO.Ovol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. 2M aq. Sodium hydroxide solution (4.36L, 8.72mol, 4.26vol) was charged at 15 to 250C and the mixture was heated to 45 to 550C. The temperature was maintained at 45 to 550C until reaction completion, as determined by 1H NMR analysis (d6-DMSO). Di-te/Y-butyl dicarbonate (Boc anhydride, 1.667Kg, 7.64mol, 1.628wt) was added at 45 to 55°C and the mixture was stirred for 55 to 65 minutes. 1H NMR IPC analysis (d6-DMSO) indicated the presence of 9% unreacted intermediate. Additional di-fert-butyl dicarbonate (Boc anhydride, 0.141Kg, 0.64mol, 0.14wt) was added at 55°C and the mixture was stirred for 55 to 65 minutes. Reaction completion was determined by 1H NMR analysis (d6-DMSO). The dioxane was removed under vacuum at 35 to 450C and water (17.60L, 20.0vol) was added to the residue. The pH was adjusted to pH 2 with 2M aq. hydrochloric acid (4.30L, 4.20vol) and the mixture was filtered. The filter-cake was slurried with water (10.00L3 9.7vol) for 20 to 30 minutes and the mixture was filtered. The filter-cake was washed with heptanes (4.10L, 4.0vol) and pulled dry on the pad for 16 to 20 hours. The solid was azeodried with toluene (5x 4.00L, 5x 4.6vol) then dried under vacuum at 35 to 45°C to give 4-tert- butoxycarbonylamino-lH-pyrazole-3-carboxylic acid (1.389Kg, 85.4%) as a purple solid.

Stage 7: Preparation of [3-(2-amino-4-moipholin-4-ylmetliyl-phenylcarbamoviy lH-pyrazol-4-yl]-carbamic acid tert-butyl ester

C9H13N3O4 C11H17N3O C20H28N6O4

FW: 227.22 FW: 207.27 FW: 416.48

+ regioisomer

4-førf-Butoxycarbonylamino-lH-pyrazole-3-carboxylic acid (0.750Kg, 3.30 mol, l.Owt), 4-morpholin-4yl-methyl-benzene-l,2-diamine (0.752Kg, 3.63mol, l.Owt) and N,N’-dimethylformamide (11.25L, 15.0vol) were charged under nitrogen to a flange flask equipped with a mechanical stirrer and thermometer. 1- Hydroxybenzotriazole (HOBT, 0.540Kg, 3.96mol, 0.72wt) was added at 15 to 250C. N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide (EDC, 0.759Kg, 3.96mol, 1.01 wt) was added at 15 to 250C and the mixture was stirred at this temperature for 16 to 24 hours. Reaction completion was determined by 1H NMR analysis. The reaction mixture was concentrated under vacuum at 35 to 45°C. The residue was partitioned between ethyl acetate (7.50L, lO.Ovol) and sat. aq. sodium hydrogen carbonate solution (8.03L, 10.7vol) and the layers were separated. The organic phase was washed with brine (3.75L, 5.0vol), dried over magnesium sulfate (1.00Kg, 1.33wt) and filtered. The filter-cake was washed with ethyl acetate (1.50L, 2.0vol). The combined filtrate and wash were concentrated under vacuum at 35 to 450C to give [3-(2-amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-lH-pyrazol- 4-yl]-carbamic acid tert-butyl ester (1.217Kg, 88.6%) as a dark brown solid.

Stage 8 : Preparation of 3 -f 5-morpholin-4-ylmethyl- 1 H-benzoimidazol-2-ylV 1 H- pyrazol-4-ylamme

C15H19N6O

FW: 298.35

As a mixture of two regioisomers

[3-(2-Amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-lH-pyrazol-4-yl]- carbamic acid tert-butyl ester (1.350Kg, 3.24 mol, l.Owt) and ethanol (6.75L, 5.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cone. aq. hydrochloric acid (1.10L, 13.2 mol, 0.80vol) was added at 15 to 3O0C under nitrogen and the contents were then heated to 70 to 8O0C and maintained at this temperature for 16 to 24 hours. A second portion of hydrochloric acid (0.1 IL, 1.32 mol, O.OSOvol) was added at 70 to 8O0C and the reaction was heated for a further 4 hours. Reaction completion was determined by HPLC analysis. The reaction mixture was cooled to 10 to 200C and potassium carbonate (1.355Kg, 9.08mol, l.Owt) was charged portionwise at this temperature. The suspension was stirred until gas evolution ceased and was then filtered. The filter-cake was washed with ethanol (1.35L, l.Ovol) and the filtrates retained. The filter-cake was slurried with ethanol (4.00L, 3.0vol) at 15 to 250C for 20 to 40 minutes and the mixture was filtered. The filter-cake was washed with ethanol (1.35L3 1.Ovol) and the total combined filtrates were concentrated under vacuum at 35 to 450C. Ethanol (4.00L, 3. Ovol) was charged to the residue and removed under vacuum at 35 to 450C. Tetrahydrofuran (5.90L, 4.4vol) was added to the residue and stirred for 10 to 20 minutes at 15 to 25°C. The resulting solution was filtered, the filter-cake was washed with tetrahydrofuran (1.35L, l.Ovol) and the combined filtrates were concentrated under vacuum at 35 to 450C. Tetrahydrofuran (5.40L, 4. Ovol) was charged to the concentrate and removed under vacuum at 35 to 450C. Tetrahydrofuran (5.40L, 4. Ovol) was charged to the concentrate and removed under vacuum at 35 to 45°C to give the desired product, 3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-ylamine (0.924Kg, 95.5%, 82.84% by HPLC area) as a purple foam.

Stage 9: Preparation of 7-morpholin-4-ylmethyl-2,4-dihydro- 1,2,4,5a ,10-pentaaza- cyclopentaFal fluoren-5 -one

C15H18N6O C16H16N6O2 FW: 298.35 FW: 324.34

As a mixture of two regioisomers

3-(5-Morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-ylamine (0.993Kg, 3.33 mol, l.Owt) and tetrahydrofuran (14.0L, 15.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The contents were stirred under nitrogen at 15 to 25°C and l,l ‘-carbonyldiimidazole (0.596Kg, 3.67 mol, O.όOwt) was added. The contents were then heated to 60 to 700C and stirred at this temperature for 16 to 24 hours. Reaction completion was determined by TLC analysis. The mixture was cooled to 15 to 200C and filtered. The filter-cake was washed with tetrahydrofuran (4.00L, 4. Ovol) and pulled dry for 15 to 30 minutes. The solid was dried under vacuum at 35 to 450C to yield 7- morpholin-4-ylmethyl-2,4-dihydro- 1 ,2,4,5a, 10-pentaaza-cyclopenta[a]fluoren-5- one (0.810Kg, 75.0%th, 92.19% by HPLC area) as a purple solid. Stage 10: Preparation of l-cvclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-vD- 1 H-pyrazol-4-yll -urea

C16H16N6O2 C19H23N7O2

FW: 324.34 FW: 381.44

As a mixture of two regioisomers

7-Morpholin-4-ylmethyl-254-dihydro-l,2,4,5a,10-pentaaza-cyclopenta[a]fluoren-5- one (0.797Kg, 2.46mol, l.Owt) and l-methyl-2-pyrrolidinone (2.40L, 3.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.279Kg, 4.88mol, 0.35 lwt) was added at 15 to 30°C under nitrogen. The contents were heated to 95 to 105°C and stirred at this temperature for 16 to 24 hours. Reaction completion was determined by1H NMR analysis. The reaction mixture was cooled to 10 to 200C and ethyl acetate (8.00L, lO.Ovol) and sat. aq. sodium chloride (2.50L, 3.0vol) were charged, the mixture was stirred for 2 to 5 minutes and the layers separated. The organic phase was stirred with sat. aq. sodium chloride (5.00L, ό.Ovol) for 25 to 35 minutes, the mixture filtered and the filter-cake washed with ethyl acetate (0.40L, 0.5vol). The filter-cake was retained and the filtrates were transferred to a separating funnel and the layers separated. The procedure was repeated a further 3 times and the retained solids were combined with the organic phase and the mixture concentrated to dryness under vacuum at 35 to 450C. The concentrate was dissolved in propan-2-ol (8.00L, lO.Ovol) at 45 to 55°C and activated carbon (0.080Kg5 O.lwt) was charged. The mixture was stirred at 45 to 550C for 30 to 40 minutes and then hot filtered at 45 to 55°C. The filter-cake was washed with propan-2-ol (0.40L, 0.5vol). Activated carbon (0.080L, O.lwt) was charged to the combined filtrates and wash and the mixture stirred at 45 to 550C for 30 to 40 minutes. The mixture was hot filtered at 45 to 550C and the filter-cake washed with propan-2-ol (0.40L, 0.5vol). The filtrates and wash were concentrated under vacuum at 35 to 450C. Ethyl acetate (8.00, lO.Ovol) and water (2.20L, 3.0vol) were charged to the concentrate at 25 to 350C and the mixture stirred for 1 to 2 minutes. The layers were separated and the organic phase was concentrated under vacuum at 35 to 45°C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and concentrated under vacuum at 35 to 450C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and the mixture was stirred for 2 to 20 hours at 15 to 250C. The mixture was cooled to and aged at 0 to 5°C for 90 to 120 minutes and then filtered. The filter-cake was washed with ethyl acetate (0.80L, l.Ovol) and pulled dry for 15 to 30 minutes. The solid was dried under vacuum at 35 to 450C to yield l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea (0.533Kg, 56.8%, 93.20% by HPLC area) as a brown solid.

Several batches of Stage 9 product were processed in this way and the details of the quantities of starting material and product for each batch are set out in Table IA.

Table IA – Yields from urea formation step – Stage 10

Stage 11 : Preparation of l-cyclopiOpyl-3-r3-(5-moipholin-4-ylmethyl-lH- benzoimidazol-2-yls)-lH-pyrazol-4-yll-urea £-lactic acid salt L-Lactic acid

acid

C19H23N7O2 C22H29N7O5

FW: 381.44 FW: 471.52 l-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-ρyrazol- 4-yl]-urea (1.859Kg, 4.872mol, l.Owt), propan-2-ol (9.00L5 5.0vol) and ethyl acetate (8.0OL, 4.5vol) were charged to a flange flask equipped with a mechanical stirrer and thermometer. The contents were stirred under nitrogen and L-lactic acid (0.504Kg, 5.59mol, 0.269wt) was added at 15 to 25°C followed by a line rinse of ethyl acetate (0.90L, 0.5vol). The mixture was stirred at 15 to 25°C for 120 to 140 minutes. The solid was isolated by filtration, the filter-cake washed with ethyl acetate (2x 2.00L, 2x l.Ovol) and pulled dry for 20 to 40 minutes. The filter-cake was dissolved in ethanol (33.00L, 17.7vol) at 75 to 850C, cooled to 65 to 700C and the solution clarified through glass microfibre paper. The filtrates were cooled to and aged at 15 to 250C for 2 to 3 hours. The crystallised solid was isolated by filtration, the filter-cake washed with ethanol (2x 1.00L, 2x 0.5vol) and pulled dry for at least 30 minutes. The solid was dried under vacuum at 35 to 45°C to yield 1- cyclopropyl-3 – [3-(5 -morpholin-4-ylmethyl- 1 H-benzoimidazol-2-yl)- 1 H-pyrazol-4- yl]-urea l-lactic acid salt (1.386Kg, 58.7%th, 99.47% by HPLC area,) as a dark pink uniform solid.

The infra-red spectrum of the lactate salt (KBr disc method) included characteristic peaks at 3229, 2972 and 1660 cm“1.

Without wishing to be bound by any theory, it is believed that the infra red peaks can be assigned to structural components of the salt as follow:

Peak: Due to:

3229 cm“1 N-H

2972 cm“1 aliphatic C-H

1660 cm“1 urea C=O EXAMPLE 67

Synthesis of Crystalline Free Base And Crystalline Salt Forms Of l-Cyclopropyl-3-

[3-(5-Morpholin-4-ylmethyl-lH-Benzoimidazol-2-vπ-lH-Pyrazol-4-yll-Urea

A. Preparation of l-Cvclopropyl-3-[3-f5-Moφholm-4-ylmethyl-lH- Benzoimidazol-2-yl)-lH-Pyrazol-4-yll-Urea free base

A sample of crude l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol- 2-yl)-lH-pyrazol-4-yl]-urea free base was prepared as outlined in Example 60 and initially purified by column chromatography on silica gel, eluting with EtOAc- MeOH (98:2 – 80:20). A sample of the free base obtained was then recrystallised from hot methanol to give crystalline material of l-cyclopropyl-3-[3-(5-morpholin- 4-ylmethyl- 1 H-benzoimidazol-2-yl)- 1 H-pyrazol-4-yl] -urea free base.

B. Preparation of l-Cyclopropyl-S-rS-fS-Morpholin^-ylmethyl-lH-Benzoimidazol- 2-yl)-lH-Pyrazol-4-yl]-Urea free base dihydrate

A sample of crude l-cyclopropyl-3-[3-(5-moφholm-4-ylmethyl-lH-benzoimidazol- 2-yl)-l H-pyrazol-4-yl] -urea free base was dissolved in THF and then concentrated in vacuo to a minimum volume (~4 volumes). To the solution was added water dropwise (2 – 4 volumes) until the solution became turbid. A small amount of THF was added to re-establish solution clarity and the mixture left to stand overnight to give a crystalline material which was air-dried to give l-cyclopropyl-3-[3-(5- morpholin-4-ylmethyl- 1 H-benzoimidazol-2-yl)- 1 H-pyrazol-4-yl] -urea free base dihydrate.

C. Preparation of l-Cyclopl^pyl-3-[3-(5-Morpholm-4-ylmethyl-lH-Benzoimidazol- 2-ylVlH-Pyrazol-4-yl]-Urea hydrochloride salt

A sample of crude l-cyclopropyl-3-[3-(5-moφholin-4-ylmethyl-lH-benzoimidazol- 2-yl)-l H-pyrazol-4-yl] -urea free base was dissolved in the minimum amount of MeOH and then diluted with EtOAc. To the solution at 0 °C was slowly added 1.1 equivalents of HCl (4M solution in dioxane). Following addition, solid precipitated from solution which was collected by filtration. To the solid was added MeOH and the mixture reduced in vacuo. To remove traces of residual MeOH the residue was evaporated from water and then dried at 60 0C/ 0.1 mbar to give the hydrochloride salt.

D. Preparation of l-Cyclopropyl-3-[3-(‘5-Morpholm-4-ylmethyl-lH- Benzoimidazol-2-yiyiH-Pyrazol-4-yl1-Urea ethanesulfonate salt

To a solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea free base in MeOH-EtOAc was added 1 equivalent of ethanesulfonic acid. The mixture was stirred at ambient temperature and then reduced in vacuo. The residue was taken up in MeOH and to the solution was added Et2O. Mixture left to stand for 72 h and the solid formed collected by filtration and dried to give l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea ethanesulfonate salt.

E. Preparation of l-Cvclopropyl-3-[3-(‘5-Morpholm-4-ylmethyl-lH-Benzoimidazol- 2-yl)-lH-Pyrazol-4-yl]-Urea methanesulfonate salt

To a solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea free base (394 mg) in MeOH-EtOAc was added 1 equivalent of methanesulfonic acid (67 μl). A solid was formed which was collected by filtration, washing with EtOAc. The solid was dissolved in the minimum amount of hot MeOH, allowed to cool and then triturated with Et2O. The solid was left to stand for 72 h and then collected by filtration, washing with MeOH, to give l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea methanesulfonate salt.

EXAMPLE 68

Characterisation of l-Cvclopropyl-3-[3-(5-Morpholin-4-ylmethyl-lH-

Benzoimidazol-2-yl)-lH-Pyrazol-4-yll-Urea Free Base and Salts

Various forms of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol- 2-yl)-lH-pyrazol-4-yl]-urea were characterised. The forms selected for characterisation were identified from studies which primarily investigated extent of polymorphism and salt stability. The salts selected for further characterisation were the L-lactate salt, Free base dihydrate, Esylate salt, Free base and Hydrochloride salt.

Paper

Fragment-Based Discovery of the Pyrazol-4-yl Urea (AT9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity†

Steven Howard*, Valerio Berdini, John A. Boulstridge, Maria G. Carr, David M. Cross, Jayne Curry, Lindsay A. Devine, Theresa R. Early, Lynsey Fazal, Adrian L. Gill, Michelle Heathcote,Sarita Maman, Julia E. Matthews,Rachel L. McMenamin, Eva F. Navarro, Michael A. O’Brien,Marc O’Reilly, David C. Rees, Matthias Reule, Dominic Tisi, Glyn Williams, Mladen Vinković andPaul G. Wyatt

Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, U.K.

J. Med. Chem., 2009, 52 (2), pp 379–388

DOI: 10.1021/jm800984v

Publication Date (Web): December 30, 2008

Copyright © 2008 American Chemical Society

†

Coordinates of the protein complexes with compounds 5, 7, 9, 10, and 16 have been deposited in the Protein Data Bank under accession codes 2w1d, 2w1f, 2w1c, 2w1e, 2w1g (Aurora A),2w1h (CDK2), and 2w1i (JAK2).

, * To whom correspondence should be addressed. Phone: +44 (0)1223 226209. Fax: +44 (0)1223 226201. E-mail: s.howard@astex-therapeutics.com.

http://pubs.acs.org/doi/abs/10.1021/jm800984v

http://pubs.acs.org/doi/suppl/10.1021/jm800984v/suppl_file/jm800984v_si_001.pdf

Abstract

Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC50 ≈ 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound16(AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.

1-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]urea (16)

 16 as a pale-yellow solid (8.19 g, 87%). 1H NMR (400 MHz, Me-d3-OD): 8.07 (s, 1H), 7.58 (s, 2H), 7.26 (d, J = 8 Hz, 1H), 3.74−3.69 (m, 4H), 3.67 (s, 2H), 2.74−2.69 (m, 1H), 2.55−2.50 (m, 4H), 1.02−0.93 (m, 2H), 0.72−0.65 (m, 2H). LC/MS: tR = 1.08 min, m/z = 382 [M + H]+.

1-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]urea (16),Hydrochloride Salt

 1H NMR (400 MHz, DMSO-d6): 13.26−13.07 (m, 2H), 11.05−10.80 (m, 1H), 9.64 (s, 1H), 8.08 (s, 1H), 7.98−7.19 (4H, m), 4.44 (s, 2H), 3.94 (d, J = 12.4 Hz, 2H), 3.77 (t, J = 12.3 Hz, 2H), 3.28−3.20 (m, 2H), 3.17−3.05 (m, 2H), 2.65−2.57 (m, 1H), 0.96−0.79 (m, 2H), 0.63−0.51 (m, 2H).

Reference:

[1] J Med. Chem. 2009, 52, 379-388………http://pubs.acs.org/doi/pdf/10.1021/jm800984v

[2] Cell Cycle 2009, 8, 1921-1929.

[US2014336073]

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SB1578, ONX 0805

SB1578

ONX 0805

(9E)-15-(2-(Pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26), 15,17,20,22-nonaene

7,​12,​26-​Trioxa-​19,​21,​24-​triazatetracyclo[18.​3.1.12,​5.114,​18]​hexacosa-​1(24)​,​2,​4,​9,​14,​16,​18(25)​,​20,​22-​nonaene, 15-​[2-​(1-​pyrrolidinyl)​ethoxy]​-​, (9E)​-

Phase 1 clinical trials

C26 H30 N4 O4

CAS 937273-04-6

CITRATE 1262279-15-1

HCL 1262279-16-2

S*Bio Pte Ltd INNOVATOR

US8153632

SB1578 (disclosed in WO2007058627 and in WO2011008172 as the citrate salt) is in ongoing phase I studies for the treatment of rheumatoid arthritis. SB 1578 is shown below.

SB1578, also known as ONX-0805, is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases. ( J Immunol. 2012 Oct 15;189(8):4123-34)

Synonym: ONX 0805; ONX0805; ONX0805; SB1578; SB1578; SB 1578.

PATENT

WO 2011008172

http://www.google.im/patents/WO2011008172A1?cl=en

The compound 9E-15-(2-pyrrolidin-1-yl-ethoxy)-7,12,25-trioxa-19,21 ,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1 (24),2,4,9,14,16l18(26)l20,22-nonaene (Compound I) was first described in PCT/SG2006/000352 and shows significant promise as a pharmaceutically active agent for the treatment of a number of medical conditions. Pharmaceutical development of this compound is underway based on the activity profiles demonstrated by the compound.

Compound I

In the development of a drug suitable for mass production and ultimately commercial use acceptable levels of drug activity against the target of interest is only one of the important variables that must be considered. For example, in the formulation of pharmaceutical compositions it is imperative that the pharmaceutically active substance be in a form that can be reliably reproduced in a commercial

manufacturing process and which is robust enough to withstand the conditions to which the pharmaceutically active substance is exposed.

From a manufacturing perspective, it is important that the commercial manufacturing process of a pharmaceutically active substance is such that the same material is produced when the same manufacturing conditions are used. In addition, it is desirable that the pharmaceutically active substance exists in a solid form where minor changes to the manufacturing conditions do not lead to major changes in the solid form of the pharmaceutically active substance produced. For example, it is important that the manufacturing process produces material having the same crystalline properties on a reliable basis, and also that the process produces material having the same level of hydration.

In addition, it is important that the pharmaceutically active substance be stable to degradation, hygroscopicity and subsequent changes to its solid form. This is important to facilitate the incorporation of the pharmaceutically active ingredient into pharmaceutical formulations. If the pharmaceutically active substance is hygroscopic (“sticky”) in the sense that it absorbs water over time it is almost impossible to reliably formulate the pharmaceutically active substance into a drug as the amount of substance to be added to provide the same dosage will vary greatly depending upon the degree of hydration. Furthermore, variations in hydration or solid form (“polymorphism”) can lead to changes in physico-chemical properties, such as solubility or dissolution rate, which can in turn lead to inconsistent oral absorption in a patient.

Accordingly, chemical stability, solid state stability, and “shelf life” of the pharmaceutically active agent are very important factors. In an ideal situation the pharmaceutically active agent and any compositions containing it, should be capable of being effectively stored over appreciable periods of time without exhibiting a significant change in the physico-chemical characteristics of the active component such as its activity, moisture content, solubility characteristics, solid form and the like.

In relation to 9E-15-(2-pyrrolidin-1-yl-ethoxy)-7,12,25-trioxa-19,21 ,24-triaza-tetracyclo[18.3.1.1 (2,5).1(14,18)]hexacosa-1(24),2,4,9,14,16,18(26),20,22-nonaene

initial studies were carried out on the hydrochloride salt and indicated that polymorphism was prevalent, with the compound being found to adopt more than one crystalline form depending upon the manufacturing conditions. In addition it was observed that the ratio of the polymorphs varied from batch to batch even when the manufacturing conditions remained constant. These batch-to-batch inconsistencies made the hydrochloride salt less desirable from a commercial viewpoint.

Accordingly it would be desirable to develop salts of 9E-15-(2-pyrrolidin-1-yl-ethoxy)-7, 12,25-trioxa-i 9,21 ,24-triaza-tetracyclo[18.3.1.1 (2,5).1 (14,18)]hexacosa-1(24)l2,4,9,14,16,18(26),20,22-nonaene which overcome or ameliorate one or more of the above identified problems.

Figure 22 shows a 1H NMR spectrum for Batch 4 in d6-DMSO.

Figure 23 shows a 1H NMR spectrum for Batch 4 in D2O.

List of hydrochloride and citrate salt batches used for comparative studies

Example 4 – Formation of the Citrate salt (Batch 4) in THF as solvent:

The free base of compound 1 (0.30Og, 0.648mmoles, 1.eq) was added to 12mL of THF. The solution was heated to reflux until complete dissolution was observed and maintained for 1h. A solution of citric acid (0.149g, 0.778mmoles, 1.2eq) dissolved in 12mL THF was then added slowly at reflux conditions. The mixture was refluxed for a further 15min then cooled. Crystallization was observed on gradual cooling. The crystals were stirred at room temperature for 12h and filtered under vacuum. The product was dried under vacuum to afford 250mg.

PATENT

http://www.google.im/patents/WO2007058627A1?cl=en

Representative procedure for the synthesis of compounds type (XVIIIf)

5-(2-Chloro-pyrimidin-4-yl)-furan-2-carbaldehyde (XIIIfI) 

(XIIfI) (XIIIH) .

Compound (XIIIfI) was obtained using the same procedure described for compound (XIIIeI); LC-MS (ESI positive mode) /τVz 209 ([M+H]+)

[5-(2-Chloro-pyrimidin-4-yl)-furan-2-yl]-methanol (Xlllf2)

Compound (Xlllf2) was obtained using the same procedure described for compound (XXIb); LC-MS (ESI positive mode) m/z 211 ([M+H]+).

4-(5-Allyloxymethyl-furan-2-yl)-2-chloro-pyrimidine (XVfI)

Compound (XVfI) was obtained using the same procedure described for compound (XXIIb); LC-MS (ESI positive mode) m/z 251 ([M+H]+).

^-(S-Allyloxymethyl-furan-Σ-yO-pyrimidin^-yll-IS-allyloxymethyl^^-pyrrolidin-i-yl- ethoxy)-phenyl]-amine (XVIIfI)

(XVIb2) (XVIIfI)

Compound (XVIIfI) was obtained using the same procedure described for compound (XVIIbI); LC-MS (ESI positive mode) m/z 491.

Macrocycle Example 6 (Compound 38)

(XVIIfI)

Compound (38) was obtained using the same procedure described for compound (1) HPLC purity at 254nm: 99%; LC-MS (ESI positive mode) m/z 463 ([M+H]+); 1H NMR (MeOD-d4) δ 8.90 (d, 1 H), 8.33 (d, 1 H), 7.37 (d, 1 H), 7.17 (d, 1 H), 7.14-7.11 (m, 1 H)1 7.04 (d, 1 H), 6.67 (d, 1 H), 6.04 (dt, 1 H, CH, J = 5.2Hz, Jtrans = 15.8Hz), 5.96 (dt, 1 H, CH, J = 5.0Hz, Jtrans = 15.8Hz), 4.65 (s, 2H), 4.62 (s, 2H), 4.37 (t, 2H), 4.14 (d, 2H), 4.09 (d, 2H), 3.81 (br s, 2H), 3.66 (t, 2H), 3.33 (s, 2H), 2.21-1.98 (m, 4H).

PAPER

Discovery of the Macrocycle (9E)-15-(2-(Pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a Potent Inhibitor of Janus Kinase 2/Fms-LikeTyrosine Kinase-3 (JAK2/FLT3) for the Treatment of Rheumatoid Arthritis

Anthony D. William*, Angeline C.-H. Lee, Anders Poulsen, Kee Chuan Goh,Babita Madan, Stefan Hart, Evelyn Tan, Haishan Wang, Harish Nagaraj,Dizhong Chen, Chai Ping Lee, Eric T. Sun, Ramesh Jayaraman, Mohammad Khalid Pasha, Kantharaj Ethirajulu, Jeanette M. Wood, and Brian W. Dymock

S*BIO Pte. Ltd., 1 Science Park Road, #05-09 The Capricorn, Singapore Science Park II, Singapore 117528

J. Med. Chem., 2012, 55 (6), pp 2623–2640

DOI: 10.1021/jm201454n

Publication Date (Web): February 17, 2012

Copyright © 2012 American Chemical Society

*Tel: +65 62195443. E-mail: wanthony11@yahoo.com.

http://pubs.acs.org/doi/abs/10.1021/jm201454n

Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.

(9E)-15-(2-(Pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26), 15,17,20,22-nonaene (14l)

The title compound was synthesized from 12n (yield, 46%; mixture of cis/trans 33:67 by 1H NMR).

LC-MS (ESI positive mode) m/z 474 ([M + H]+);

1H NMR (MeOD-d4) δ 8.91 (d, 1H), 8.57–8.54 (m, 1H), 8.28 (d, 1H), 7.70 (s, 1H), 7.51–7.46 (m, 1H), 7.38–7.32 (m, 1H), 7.14–7.12 (m, 1H), 7.05 (s, 1H), 5.93–5.85 (m, 1H), 5.68–5.62 (m, 1H), 4.46 (s, 2H), 4.58 (m, 2H), 4.46–4.34 (m, 2H), 4.12 (d, 2H), 3.82 (m, 2H), 3.72 (m, 2H), 3.37 (m, 2H), 2.52 (m, 2H), 2.25 (m, 2H), 2.10 (m, 2H).

REF

Madan B, Goh KC, Hart S, William AD, Jayaraman R, Ethirajulu K, Dymock BW, Wood JM. SB1578, a novel inhibitor of JAK2, FLT3, and c-Fms for the treatment of rheumatoid arthritis. J Immunol. 2012 Oct 15;189(8):4123-34. doi: 10.4049/jimmunol.1200675. Epub 2012 Sep 7. PubMed PMID: 22962687.

2: Poulsen A, William A, Blanchard S, Lee A, Nagaraj H, Wang H, Teo E, Tan E, Goh KC, Dymock B. Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3). J Comput Aided Mol Des. 2012 Apr;26(4):437-50. doi: 10.1007/s10822-012-9572-z. Epub 2012 Apr 22. PubMed PMID: 22527961.

3: William AD, Lee AC, Poulsen A, Goh KC, Madan B, Hart S, Tan E, Wang H, Nagaraj H, Chen D, Lee CP, Sun ET, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW. Discovery of the macrocycle (9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18. 3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a potent inhibitor of janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) for the treatment of rheumatoid arthritis. J Med Chem. 2012 Mar 22;55(6):2623-40. doi: 10.1021/jm201454n. Epub 2012 Mar 6. PubMed PMID: 22339472.

WO2007058627A1 *	15 Nov 2006	24 May 2007	S Bio Pte Ltd	Oxygen linked pyrimidine derivatives
SG2006000352W				Title not available

S*Bio Pte Ltd  

Address: 1 Science Park Rd, Singapore 117528

Phone:+65 6827 5000

S*BIO Pte Ltd. provides research and clinical development services for small molecule drugs for the treatment of cancer in Singapore. The company’s products include JAK2 inhibitors, such as SB1518 for leukemia/myelofibrosis, lymphoma, and polycythemia; and SB1578 for RA/psoriasis. The company also offers SB939, a histone deacetylases for MDS/AML+combo, prostate cancer, sarcoma, pediatric tumor, and myelofibrosis; SB2602, a mTOR inhibitor; SB2343, a mTOR/PI3K inhibitor; and SB1317, a CDK/Flt3 inhibitor. The company was founded in 2000 and is based in Singapore. S*BIO Pte Ltd. operates as a subsidiary of Chiron Corporation Limited.

Anthony william

Doctor of Philosophy

Team Leader

Agency for Science, Technology…, Singapore ·

Institute of Chemical and Engineering Sciences (ICES)

Agency for Science, Technology and Research (A*STAR)

Agency for Science, Technology…, Singapore · Institute of Chemical and Engineering Sciences (ICES)

Highlights
• Principle lead and inventor of 3 clinical stage candidates,
1) SB1518 (Pacritinib)-A selective JAK2 inhibitor for myleofibrosis into phase 2,
2) SB1317 (TG02)-A mutikinase inhibitor CDK, JAK2, FLT3, and ERK5 into phase 1 and
3) SB1578-A more selective JAK2 inhibitor than pracritinib for autoimmune diseases such as Rheumatoid Arthritis (RA) and Psoriasis into phase 1

https://www.researchgate.net/profile/Anthony_William

SEE..............http://newdrugapprovals.org/2016/01/18/sb-1578/

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N3=C1NC(=CC=N1)c2oc(cc2)COCC=CCOCc5cc3ccc5OCCN4CCCC4

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C1(C2=CC=C(O2)COC/C=C/COCC3=CC(N4)=CC=C3OCCN5CCCC5)=NC4=NC=C1

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