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Definitions

• the present invention relates to novel compounds and methods of using those compounds to treat anti-inflammatory diseases.
• each X and Y is individually selected from the group consisting of -O-, -S-, -NR 6 -, -NR O SO 2 -, -NR 6 CO-, alkynyls (preferably C 1 -C 18 , and more preferably C 1 -C 12 ), alkenyls (preferably C 1 - Ci 8 , and more preferably C 1 -C 12 ), alkylenes (preferably C 1 -C 1 s, and more preferably C 1 -C 12 ), -O(CH 2 ) h -, and -NR 6 (CH 2 )H-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes (preferably C 1 -C 18 , and more preferably C 1 - C 12), -O(CH 2 )h-, and -NR 6 (CH 2 ) I i-, one of the methylene groups present therein may be optionally double-bonded to a side-chain
• each Rio is alkyl (preferably Cl-C6alkyl) or fluoroalkyl (preferably C1-C3) wherein the fluoroalkyl moiety is partially or fully fluorinated;
• One aspect of the invention provides a method of modulating the activation state of a kinase, preferably p38 ⁇ -kinase and including both the consensus wild type sequence and disease polymorphs thereof.
• the activation state is generally selected from an upregulated or downregulated state.
• the method generally comprises the step of contacting the kinase with a molecule having the general formula (I). When such contact occurs, the molecule will bind to a particular switch control pocket and the switch control ligand will have a greater propensity to interact with the other of the switch control pockets (i.e., the unoccupied one) and a lesser propensity to interact with the occupied switch control pocket.
• Figure 1 is a schematic representation of a naturally occurring mammalian protein in accordance with the invention including "on” and “off switch control pockets 102 and 104, respectively, a transiently modifiable switch control ligand 106, and an active ATP site 108;
• aldehydes 71 Reductive amination of 71 with amines 8 gives rise to compounds of Formula 1-72.
• aldehydes 71 may be reacted with ammonium acetate under reductive alkylation conditions to give rise to the primary amine 73.
• Reaction of 73 with isocyanates 2 affords compounds of Formula 1-74.
• Scheme 17.2 illustrates the synthetic sequences for converting intermediates 104 to compounds of Formula I.
• Reaction of amines 104.2 and 104.3 with 26 under Buchwald palladium(O) catalyzed amination conditions affords compounds of Formulae 1-105.2 and 1-105.3.
• Reaction of acetylene 104.4 with 26 under Sonogashira coupling conditions affords compounds of Formula 1-105.4.
• Compounds 1-105.4 may optionally be reduced to the corresponding saturated analogs I; 105.5 by standard hydrogenation.
• Scheme 19.2 illustrates the conversion of intermediates 113 into compounds of Formula 1-115, 1-118, or 117.
• Treatment of 113 with aqueous copper oxide or an alkaline hydroxide affords compounds of Formula 1-115.
• treatment of 113 with t- butylmercaptan under copper(I) catalysis in the presence of ethylene glycol and potassium carbonate gives rise to 116 (see F.Y. Kwong and S. L. Buchwald, Organic Letters (2002) 4:3517.
• Treatment of the t-butyl sulfide 116 with acid affords the desired thiols of Formula 1-118.
• 113 may be treated with excess ammonia under pressurized conditions to afford compound 117.
• Scheme 37 illustrates the preparation of compounds wherein Q is Q-40.
• Readily available amine 200 wherein P is a suitable amine-protecting group or a group convertible to an amine group, is reacted with p-nitrophenyl chloroformate to give rise to carbamate 201.
• Intermediate 201 is reacted with a substituted amino acid ester with a suitable base to afford urea 202. Further treatment with base results in cyclization to afford hydantoin 203.
• the protecting group P is removed to afford the key amine-containing intermediate 204.
• Scheme 51 illustrates an approach to the preparation of compounds of formula I wherein Q is Q-58.
• Amine 273 is reacted with a cyclic anhydride e.g. succinic anhydride in the presence of base under standard conditions to give rise to imide 274.
• Conversion of 274 to the substituted hydrazine 275 is accomplished by standard procedures. Hydrazine 275 can be converted into compounds of formula I using the methods previously outlined in Scheme 35.
• Scheme 54 illustrates an approach to the preparation of compounds of formula I wherein Q is Q-52, Q-52A, and Q-53.
• Amine 341 is converted to 342A by reaction with an isocyanate; 341 is converted to amide 342B by reaction with an acid chloride, acid anhydride, or a suitable activated carboxylic acid in the presence of a suitable base; 341 is converted to carbamate 342C by reaction with a substituted alkyl or aryl chloroformate in the presence of a suitable base.
• Nitroacid 397 (readily available by anyone with normal skills in the art) is reacted with thiomorpholine sulphone to yield amide 398, which upon reduction to the amine and conversion of the nitro group under standard conditions results in hydrazine 399.
• This hydrazine can be converted into compounds of formula I using the methods previously outlined in Scheme 35.
• Example E (100 mg, 0.23 mmol) was added and the reaction was allowed to stir at RT overnight, quenched with H 2 O, and extracted with CH 2 Cl 2 . The combined organic layers were concentrated in vacuo and the residue was purified by preparative HPLC to yield 1-(3-t-butyl-1- ⁇ [3-(l,l,3-trioxo-[l,2,5]thiadiazolidin-2- yl)methyl]phenyl ⁇ -lH-pyrazol-5-yl)-3-(naphthalen-1-yl)urea (18 mg) as a white powder.
• Example L 0.2 g, 0.58 mmol
• 1- naphthylisocyanate (0.10 g, 0.6 mmol) in dry CH 2 Cl 2 (4 ml) was stirred at RT under NT for 18 h.
• the reaction mixture was stirred at 0 °C for 3 h.
• the pH was adjusted to pH 14 with 50 % aqueous NaOH solution and extracted with ethyl acetate.
• the combined organic extracts were concentrated in vacuo provided 2-(3-hydrazinophenyl)acetamide.
• Example N A mixture of Example N (2 g, 0.73 mmol) and 1- naphthylisocyanate (0.124 g, 0.73 mmol) in dry CH 2 Cl 2 (4 ml) was stirred at RT under N 2 for 18 h. The solvent was removed in vacuo and the crude product was washed with ethyl acetate (8 ml) and dried in vacuo to yield 1 - ⁇ 3-t-butyl- 1 -[3- (carbamoylmethyl)phenyl)- lH-pyrazol-5-yl ⁇ -3-(naphthalene- 1 - yl)urea as a white solid (0.22 g).
• Example BB A solution of Example BB (13.8 g, 56.00 mmol) and SOCl 2 (8.27 mL, 0.11 mol) in THF (200 mL) was refluxed for 3 h and concentrated under reduced pressure to yield 5-t-butyl-2-(3-chloromethyl-phenyl)-2H- pyrazol-3-yl amine (14.5 g, 98%) as white powder which was used without further purification.
• 1 H NMR (DMSO-d6), 57.62 (s, 1 H), 7.53 (d, J 8.0
• Example CC 0.263 g, 1.0 mmol
• THF 2.0 mL
• l-fluoro-4-isocyanato- benzene 0.114 mL, 1.10 mmol
• THF 5.0 mL
• the mixture was stirred at RT for Ih then heated until all solids were dissolved.
• the mixture was stirred at RT for 3 h and poured into water (20 mL).
• Example HH was synthesized according to literature procedures starting from 4,4-dimethyl-3-oxo-pentanenitrile (10 mmole) in absolute ethanol and HCl in quantitative afford.
• Example TT 70 mg, 0.29 mmol
• 3-chlorophenyl isocyanate 44 mg, 0.29 mmol
• Example TT 50 mg, 0.20 mmol
• 3-(trifluoromethyl)phenyl isocyanate 30 mmg, 0.20 mmol
• Example A2 (100.0 mg, 0.25 mmol) was transformed to afford 1-(3-t-butyl-1- ⁇ 3-[(2,5- dioxopyrrolidin-1-yl)methyl]phenyl ⁇ -lH- pyrazol-5-yl)-3-(4- chlorophenyl)urea (35 mg, 29% yield).
• 1 H NMR 300 MHz, DMSOd 6 ): ⁇ 9.01 (s, 1 H), 8.46 (s, 1 H), 7.35-7.45 (m, 5 H), 7.25- 7.30 (m, 2 H), 6.34 (s, 1 H), 4.60 (s, 2 H), 2.64 (s, 2 H), 1.27 (s, 9
• Example TT 70 mg, 0.29 mmol
• 4-(N,N-dimethylamino)phenyl isocyanate 46 mg, 0.29 mmol
• Example TT 45 mg, 0.18 mmol
• 3-cyanophenyl isocyanate 26mg, 0.18 mmol
• Example TT 70 mg, 0.29 mmol
• 3-thienyl isocyanate 36 mg, 0.29 mmol
• Example TT 70 mg, 0.29 mmol
• 3-thienyl isocyanate 36 mg, 0.29 mmol
• 1-(3-t-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5- yl)-3-(thi ⁇ phen-3-yl)urea 45 mg, 43% yield.
• 1 H NMR (CDCl 3 ): ⁇ 7.05 -7.3 (m, 4H), 6.8 -7.0 (m, 4H), 6.76 (s, 1H), 6.40 (s, 1H), 3.76 (s,
• Example UU 70 mg, 0.23 mmol
• 4-chlorophenylisocyanate 36 mg, 0.23 mmol
• Example UU 70 mg, 0.23 mmol
• 4-chlorophenylisocyanate 36 mg, 0.23 mmol
• 1-(4-chlorophenyl)- (3- methoxyphenyl)-3-phenyl-/H-pyrazol-5-yl)urea 75 mg, 77% yield.
• Example UU 50 mg, 0.17 mmol
• 3-bromophenylisocyanate 25 mg, 0.17 mmol
• 1-(3-bromophenyl)-(3- methoxyphenyl)-3-phenyl-1H-pyrazol-5-yl)urea 46 mg, 60% yield.
• Example UU 50 mg, 0.17 mmol
• 3-trifluoromethylphenyl isocyanate 31 mg, 0.17 mmol
• Example VV 50 mg, 0.21 mmol
• 3-bromophenyl isocyanate 41 mg, 0.21 mmol
• Example YY (123 mg, 0.5 mmol) and l-isocyanato-3-trifluoromethyl-benzene (93 mg, 0.5 mmol) were combined to afford 1 -[3-t-butyl- 1-(4- methoxyphenyl)-1H-pyrazol-5-yl]-3-(3- trifluoromethylphenyl)urea (65 mg, 30% yield).
• 1 H-NMR 300 MHz, DMSO-d 6 ): ⁇ 9.38 (s, 1 H), 8.40 (s, 1 H), 7.94 (br s, 1 H),
• Example YY (123 mg, 0.5 mmol) and l-Isocyanato-3-methoxy-benzene (93 mg, 0.5 mmol) were combined to afford 1-[3-t-butyl-1-(4- methoxyphenyl)-1H-pyrazol-5-yl]-3-(3-methoxy-phenyl)urea (65 mg, 33% yield).
• Example YY 123 mg, 0.5 mmol
• l-bromo-3-isocyanato-benzene 98 mg, 0.5 mmol
• Example YY (123 mg, 0.5 mmol) and l-chloro-3-isocyanato-benzene (76 mg, 0.5 mmol) were combined to afford 1 -[3-t-butyl- 1 -(4- methoxyphenyl)-1H-pyrazol-5-yl]-3-(3-chlorophenyl)urea (65 mg, 33% yield).
• Example YY (6.0 g, 20 mmol) and formamide (1.8 g, 40 mmol) in DMF (20 mL) was added NaOMe (2.1 g, 40 mmol) at RT. The mixture was heated to reflux for Ih, concentrated and the residue was purified via column chromatography to afford 2-[3-(5-amino-3-t- butyl-1H-pyrazol-1-yl)phenyl]acetamide (2.0 g, 40% yield).
• Example ZZ 2.0 g, 6.6 mmol
• l,2-dichloro-3-isocyanato-benzene 1.1 g, 7.5 mmol
• Example AAA 136 mg, 0.5 mmol
• 1 -fluoro-2-isocyanatobenzene 68 mg, 0.5 mmol
• Example AAA 136 mg, 0.5 mmol
• 1 -fluoro-2-isocyanatobenzene 68 mg, 0.5 mmol
• 55 mg of 1- ⁇ 1-[3-(2-amino-2- oxoethyl)phenyl]-3-t-butyl-1H-pyrazol-5-yl ⁇ -3-(2-fluorophenyl)urea 55 mg, 27% yield.
• 1 H NMR 300 MHz, DMSO-d 6 ): ⁇ 8.90 (br s, 1
• Example T To a solution of Example T (14.4 g, 50 mmol) and formamide (4.5 g, 0.1 mol) in DMF (50 mL) was added NaOMe (5.4 g 0.1 mol) at RT. The mixture was stirred at 100 °C for Ih, concentrated and the residue purified by column chromatography to afford 3-(5-amino-3-t-butyl-1H- pyrazol-1-yl)benzamide (6 g, 48 % yield).
• Example CCC A solution of Example CCC (5.2 g, 20 mmol) in SOCl 2 (50 mL) was heated to reflux for 6h. After removal of the solvent, the residue was dissolved in EtOAc (100 mL). The organic layer was washed with saturated NaHCO 3 and brine, dried (Na 2 SO 4 ), filtered, and purified by column chromatography to afford 3-(5-amino-3-t-butyl-1H-pyrazol-1- yl)benzonitrile (3.5 g, 73 % yield).
• Example DDD 120 mg, 0.5 mmol
• l-fluoro-2-isocynate-benzene 68 mg, 0.5 mmol
• 1-[3-t-butyl-1-(3-cyanophenyl)-1H-pyrazol- 5-yl]-3-(2-fluorophenyl)urea 55 mg, 29 % yield
• Example DDD 120 mg, 0.5 mmol
• 2,3-difluoro-phenylamine 129 mg, 1.0 mmol
• 1-[3-t-butyl-1-(3-cyan-phenyl)- 1H-pyrazol-5-yl]-3-(2,3-difluorophenyl)urea 55 mg, 28 % yield.
• 1 H NMR 300 MHz, DMSO-d 6 ): ⁇ 9.07 (br s, 1 H), 8.92 (s, 1 H),
• Example DDD (0.500 g, 1.81 mmol, 1.00 eq) and 3,4-(methylenedioxy)phenyl isocyanate (0.59 g, 3.62 mmol) were combined to afford 1- (benzo[d][l,3]dioxol-5-yl)-3 ⁇ (3-t-butyl-1-(3-cyanophenyl)-1H- pyrazol-5-yl)urea as an off-white solid (107.4 mg, 15 % yield).
• Example DDD 0.0500 g, 0.208 mmol
• 2,3-dichlorophenylisocyanate 0.0549 mL, 0.416 mmol
• Example DDD 0.0500 g, 0.208 mmol
• 3-methoxyphenyl isocyanate 0.0545 mL, 0.416 mmol
• Example 256 (100 mg, 0.221 mmol) was saponified to afford 3-(3- ⁇ 3-t-butyl-5-[3-(2- fluorophenyl)ureido]-1H-pyrazol-1-yl ⁇ - phenyl)propionic acid (80 mg, 85% yield).
• Example EEE 300 mg, 1.0 mmol
• l,2-dichloro-3-isocyanato-benzene 187 mg, 1.0 mmol
• 3-(3- ⁇ 3-t-butyl-5-[3-(2,3- dichlorophenyl)ureido] - 1H-pyrazol- 1 -yl ⁇ phenyl)propionic acid ethyl ester 210 mg, 42 % yield
• Example 262 (100 mg, 0.199 mmol) was saponified to afford 3-(3- ⁇ 3-t-Butyl- 5-[3- (2,3-dichloro-phenyl)ureido]-1H-pyrazol-1-yl ⁇ - phenyl)propionic acid (60 mg, 63% yield).
• Example 263 (70 mg, 0.14 mmol) was saponified to afford 3-(3- ⁇ 3-t-butyl-5-[3-(quinolin-8- yl)ureidoJ-1H-pyrazol-1-yl ⁇ phenyl)- propionic acid (50 mg, 78 % yield).
• Example 265 (100 mg, 0.199 mmol) was saponified to afford 60 mg of 3-(3- ⁇ 3-t- Butyl-5-[3-(2,3-dichloro-phenyl)-ureido]- pyrazol-1-yl ⁇ -phenyl- propionic acid (60 mg, 64% yield).
• Methyl 2-(3-nitrophenyl)acetate (9.6 g, 49 mmol) was treated with cone. NH 4 OH (24 ml, 172 mmol). The suspension was stirred briskly at RT until complete, then chilled thoroughly in an ice bath. The solids were collected by filtration, rinsed sparingly with ice water and dried to yield pure 2-(3-nitrophenyl)acetamide as an off-white solid (7.47 g, 84% yield)).
• Example GGG To a stirring solution of Example GGG (0.18 g, 0.73 mmol) in absolute EtOH (5 ml) at RT was added pivaloylacetonitrile (0.11 g, 0.87 mmol) and sat'd. HCl/EtOH (3 drops from a pipet). The resulting solution was stirred at 75-80 °C overnight, then cooled to RT and concentrated. The residue was dissolved in Et 2 O and washed with sat'd. NaHCO 3 . The aqueous was extracted with Et 2 O (Ix).
• Example HHH (0.180 g, 0.51 mmol) in dry CH 2 Cl 2 (5 ml) at RT was added 4-chlorophenyl isocyanate (82 mg, 0.53 mmol). The resulting mixture was stirred at RT overnight. More 4-chlorophenyl isocyanate was added (40 mg, 0.26 mmol) and stirring was continued.
• Example 267 To a stirring solution of Example 267 (0.134 g, 0.264 mmol) in MeOH (10 ml) and H 2 O (0.6 ml) at RT was added potassium carbonate (0.182 g, 1.32 mmol). The resulting suspension was stirred at 60-65 °C for 2h, then cooled to RT and the volatiles evaporated. The residue was carefully dissolved in IM HCl to pH 1-2 and extracted with Et 2 O (2x). The aqueous was then basified (pH 13-14) with 3M NaOH and extracted with CH 2 Cl 2 (4x).
• Example 268 To a stirring solution of Example 268 (50 mg, 0.12 mmol) in MeOH (1.2 ml) at RT was added aq. formaldehyde (37 wt%, 0.036 ml, 0.49 mmol) and cone, formic acid (0.037 ml, 0.97 mmol). The reaction was sth ⁇ ed at 60-65 °C overnight, then cooled to RT, diluted with IM HCl and filtered. The filtrate was made basic (pH 13) with 3M NaOH and extracted with CH 2 Cl 2 (2x).
• Example HHH 50 mg, 0.14 mmol
• dry THF 1.0 ml
• pyridine 0.11 ml, 1.4 mmol
• 2,3-dichlorophenyl isocyanate 0.037 ml, 0.28 mmol
• the reaction was stirred overnight at RT, then diluted with IM HCl (10 ml) and stirred for Ih.
• the mixture was extracted with EtOAc (3x). The combined organic extracts were washed with H 2 O (Ix), satd.
• Example HHH 50 mg, 0.14 mmol
• 3-bromophenyl isocyanate 0.035 ml, 0.28 mmol
• Example HHH 50 mg, 0.14 mmol
• 3-bromophenyl isocyanate 0.035 ml, 0.28 mmol
• 1-(3-bromophenyl)-3-(3-t-butyl- 1- ⁇ 3-[2-(2,2,2-trifluoroacetamido)ethyl]phenyl ⁇ -1H-pyrazol-5- yl)urea (20.6 mg, 26% yield).
• Example 272 (20.6 mg, 0.037 mmol) was deprotected to provide 1- ⁇ 1-[3-(2- aminoethyl)phenyl]-3-t-butyl-1H-pyrazol-5-yl ⁇ -3- (3- bromophenyl)urea (22.4 mg).
• Example HHH 50 mg, 0.14 mmol
• 3-chlorophenyl isocyanate 0.034 ml, 0.28 mmol
• Example 274 Using the same procedure as for Example 271, Example 274 (32.2 mg, 0.063 mmol) was deprotected to afford 1- ⁇ 1-[3-(2- aminoethyl)phenyl]-3-t-butyl-/H-pyrazol-5-yl ⁇ -3- (3- chlorophenyl)urea (19.1 mg, 73% yield).
• Example HHH 50 mg, 0.14 mmol
• ⁇ , ⁇ , ⁇ -trifluoro-m-tolyl isocyanate 0.039 ml, 0.28 mmol
• Example lib (31.1 mg, 0.057 mmol) was deprotected to provide 1- ⁇ 1-[3-(2- aminoethyl)phenyl]-3-/-butyl-1H-pyrazol-5-yl ⁇ -3-[3- (trifluoromethyl)phenyl]urea (24.8 mg, 97% yield).
• Example 278 (29.6 mg, 0.059 mmol) was deprotected to provide 1- ⁇ 1-[3-(2- aminoethyl)phenyl]-3-t-butyl-1H-pyrazol-5-yl ⁇ -3-(3- methoxyphenyl)urea (16.4 mg, 69% yield).
• Example 271 Using the same procedure as for Example 269, Example 271 (54.2 mg, 0.121 mmol) was obtained 1-(3-t-butyl-1- ⁇ 3-[2- (dimethylamino)ethyl]phenyl ⁇ -1H-pyrazol-5-yl)-3-(2,3-di- chlorophenyl)urea (17.4 mg, 30% yield).
• Example 253 To a stirring solution of Example 253 (0.17 g, 0.39 mmol) in dry THF (4 ml) at RT was added LOM LAH in THF (0.58 ml, 0.58 mmol). After 2h at RT additional LOM LiA1H4 in THF (0.58 ml, 0.58 mmol) was added and the reaction was stirred an Ih. The reaction was carefully quenched by the addition of H 2 O (0.044 ml), 3M NaOH (0.044 ml) and H 2 O (0.088 ml) and stirred overnight at RT. The mixture was filtered through Celite, rinsing generously with EtOAc.
• Example DDD 0.0500 g, 0.208 mmol
• 3-chlorophenyl isocyanate 0.0507 mL, 0.416 mmol
• Example 112 (0.11 g, 0.28 mmol) was reduced to afford 1- ⁇ 1-[3- (ammomethyl)phenyl]-3-/-butyl ⁇ iH-pyrazol-5-yl ⁇ -3-(3-chloro- phenyl)urea as an off-white HCl salt (77.2 mg, 64% yield).
• Example 258 (0.120 g, 0.28 mmol) was reduced to afford 1- ⁇ 1-[3- (aminomethyl)phenyl]-3-t-butyl-1H-pyrazol-5-yl ⁇ -3-(3- (trifluoro- methyl)phenyl)ureaas an off-white HCl salt (73.9 mg, 56% yield).
• Example 257 (0.16 g, 0.411 mmol) was reduced to afford 1- ⁇ 1-[3- (aminomethyl)phenyl]-3-/-butyl-1H-pyrazol-5-yl ⁇ -3-(3- methoxy- phenyl)urea as an off-white HCl salt (137 mg, 77% yield).
• Example 256 (50 mg, 0.12 mmol) was reduced to afford 1- ⁇ 1-[3- (aminomethyl)phenyl]-3-t-butyl-1H-pyrazol-5-yl ⁇ -3-(2,3- dichloro- phenyl)urea as a white solid (20.6 mg, 41% yield).
• Example 255 (87 mg, 0.22 mmol) was reduced to afford 1- ⁇ 1-[3- (aminomethyl)phenyl]-3-t-butyl-1H-pyrazol-5-yl ⁇ -3-(4-chloro- phenyl)urea as the HCl salt (78 mg, 82% yield).
• Example 254 (0.100 g, 0.25 mmol) was reduced to afford 1- ⁇ 1-[3- (aminomethyl)phenyl]-3-t-butyl-1H-pyrazol-5-yl ⁇ -3-(benzo- [d][l,3]dioxol-5-yl)ureaas its TFA salt as a white powder (67.1 mg, 66% yield).
• Example 256 (80 mg, 0.19 mmol) was suspended in cone. HCl (0.93 ml) and briskly stirred. More cone. HCl (1 ml) was added several times to maintain good stirring and keep the solids wetted. The reaction was stirred at RT 5h and 24 h at 40 °C. The reaction was cooled to RT, diluted with H 2 O and EtOAc and the layers separated. The aqueous was extracted with EtOAc (2x). Solids in the aqueous layer were collected by filtration, rinsed sparingly with H 2 O and dried.
• Example 255 (0.174 g, 0.442 mmol) was transformed to provide 1-[3-*-butyl-1-(3- carbamoylphenyl)-1H-pyrazol-5-yl]-3- (4-chlorophenyl)urea as a pale yellow fluffy solid (47.4 mg).
• Example SS 143 mg, 0.5 mmol
• 2,3-difluorophenylamine 67 mg, 0.5 mmol
• ethyl 3- ⁇ 3-t-butyl-5-[3-(2,3- difluorophenyl)ureido]-/H-pyrazol-1-yl ⁇ benzoate 50 mg, 23% yield.
• Example 291 (45 mg, 0.10 mmol) was reduced to afford 1- ⁇ 3-t-butyl-1-[3- (hydroxymethyl)phenyl]-1H-pyrazol-5-yl ⁇ -3-(2,3- difluorophenyl)urea (30 mg, 75% yield).
• Example SS 500 mg, 1.74 mmol
• 5-isocyanato-benzo[l,3]dioxole 290 mg, 1.8 mmol

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