TRIAZINE DERIVATIVES FOR TREATING DISEASES RELATING TO NEUROTROPHINS

Abstract

There is provided herein a compound of formula I,

##STR00001##

wherein R.sup.1, R.sup.2, n, X, Q, L, m, R.sup.3 and p are as defined herein, which compounds are useful in the treatment of treatment of diseases characterised by impaired signalling of neurotrophins and/or other trophic factors, such as Alzheimer's disease and the like.

Claims

1. A method of treatment and/or prevention of a disease characterised by impaired signalling of neurotrophins and/or other trophic factors, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, ##STR00202## wherein: R.sup.1 represents methyl; phenyl, optionally substituted by one or more G.sup.1 groups; or a 5- to 9-membered heteroaryl group, optionally substituted by one or more G.sup.2 groups; G.sup.1 represents halo; phenyl, optionally substituted by one or more G.sup.a1 groups; phenoxy, optionally substituted by one or more G.sup.a2 groups; cyano; —N(R.sup.a1)R.sup.a2; —C(O)N(R.sup.a3)R.sup.a4, a 4-to 7-membered heterocyclyl ring, optionally substituted by one or more G.sup.a3 groups; a 5- to 6-membered heteroaryl group, optionally substituted by one or more G.sup.a4 groups; a C.sub.1-4 alkyl group or a C.sub.1-4 alkoxy group, which latter two groups are optionally substituted by one or more fluoro atoms; or any two G.sup.1 groups may be joined together to form a 5- to 6-membered heterocyclyl ring, which may be optionally substituted by one or more G.sup.a5 groups; G.sup.2 represents halo; phenyl, optionally substituted by one or more G.sup.a6 groups; phenoxy, optionally substituted by one or more G.sup.a7 groups; cyano; —N(R.sup.a5)R.sup.a6; —C(O)N(R.sup.a7)R.sup.a8, a 4-to 7-membered heterocyclyl ring, optionally substituted by one or more G.sup.a8 groups; a C.sub.1-4 alkyl group or a C.sub.1-4 alkoxy group, which latter two groups are optionally substituted by one or more fluoro groups; n represents 0, 1 or 2; R.sup.2 represents halo; cyano; —N(R.sup.a9)R.sup.a10; a 4- to 7-membered heterocyclyl ring, optionally substituted by one or more G.sup.a9 groups; or a phenyl group, optionally substituted by one or more G.sup.a10 groups, which latter two groups are optionally linked to the relevant phenyl group in the compound of formula I via an O atom; or a C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group or a —S(O).sub.qC.sub.1-6 alkyl group which latter three groups are optionally substituted by one or more fluoro, ═O, hydroxy, C.sub.1-2 alkoxy or —N(R.sup.a11)R.sup.a12 groups, and/or are optionally substituted by a 4- to 7-membered heterocyclyl ring, optionally substituted by one or more G.sup.a11 groups; or a phenyl group, optionally substituted by one or more G.sup.a12 groups; q represents 0, 1 or 2; Q represents —N—, —CH—; X represents —C(R.sup.4)R.sup.5—, —O—, —S— or —N(R.sup.6)—; m represents 0 or 1; L represents —C(R.sup.7)R.sup.8—; p represents 0 to 1; R.sup.3 represents halo; hydroxy; cyano; or C.sub.1-4 alkyl or C.sub.1-4 alkoxy, wherein each alkyl group or alkoxy group is optionally substituted by one or more fluoro groups; R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 each independently represent H or C.sub.1-2 alkyl; R.sup.a1, R.sup.a2, R.sup.a3, R.sup.a4, R.sup.a5, R.sup.a6, R.sup.a7, R.sup.a8, R.sup.a9, R.sup.a10, R.sup.a11 and R.sup.a12 each independently represent H or C.sub.1-3 alkyl; or R.sup.a1 and R.sup.a2, R.sup.a3 and R.sup.a4, R.sup.a5 and R.sup.a6, R.sup.a7 and R.sup.a8, R.sup.a9 and R.sup.a10 and R.sup.a11 and R.sup.a12 may independently be joined together to form, together with the atom to which they are attached, a 4- to 7-membered heterocyclyl ring; G.sup.a1, G.sup.2, G.sup.a4, G.sup.a6, G.sup.a7, G.sup.a10 and G.sup.a12 each independently represent C.sub.1-2 alkyl or halo; G.sup.a3, G.sup.a5, G.sup.a8, G.sup.a9 and G.sup.a11 each independently represent C.sub.1-2 alkyl, halo or ═O; and wherein an R.sup.2 group may also be joined together with any one of R.sup.4, R.sup.5, R.sup.6, R.sup.7 or R.sup.8 to form a 4- to 7-membered heterocyclyl ring, or a 5- to 6-membered heteroaryl ring, wherein said heterocyclyl or heteroaryl rings are optionally substituted by one or more substituents selected from G.sup.3; and G.sup.3 represents halo, C.sub.1-2 alkyl or C.sub.1-2 alkoxy; or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein G.sup.1 represents halo; phenyl; phenoxy; cyano; —N(R.sup.a1)R.sup.a2; a 4- to 7-membered heterocyclyl ring; a C.sub.1-4 alkyl group or a C.sub.1-4 alkoxy group, which latter two groups are optionally substituted by one or more fluoro atoms; or any two G.sup.1 groups may be joined together to form a 5- to 6-membered heterocyclyl ring.

3. The method of claim 1 or claim 2, wherein G.sup.2 represents halo; phenyl; phenoxy; cyano; —N(R.sup.a3)R.sup.a4; a 4- to 7-membered heterocyclyl ring; a C.sub.1-4 alkyl group or a C.sub.1-4 alkoxy group, which latter two groups are optionally substituted by one or more fluoro groups.

4. The method of any one of claims 1 to 3, wherein R.sup.2 represents halo; cyano; —N(R.sup.a9)R.sup.a10; a 4- to 7-membered heterocyclyl ring or a phenyl group, which latter two groups are optionally linked to the relevant phenyl group in the compound of formula I via an O atom; or a C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, which latter two groups are optionally substituted by one or more fluoro, ═O, hydroxy, C.sub.1-2 alkoxy or —N(R.sup.a11)R.sup.a12 groups, and/or are optionally substituted by a 4- to 7-membered heterocyclyl ring or a phenyl group.

5. The method of any one of claims 1 to 4, wherein Q represents —CH—.

6. The method of any one of claims 1 to 5, wherein R.sup.1 represents phenyl, optionally substituted by a fluoro, a chloro, a methyl, a methoxy, a trifluoromethyl, or a trifluoromethoxy substituent in the 3- or the 4-position relative to the point of attachment of the benzene ring.

7. The method of any one of claims 1 to 5, wherein R.sup.1 represents a pyridinyl, an indolyl, a thiazolyl, a benzofuranyl, a thiophenyl, group, which thiophenyl group is optionally substituted by a methyl group, or a pyrazolyl group, which pyrazolyl group is optionally substituted by a phenyl group.

8. The method of any one of claims 1 to 7, wherein, when n is 2, R.sup.2 represents C.sub.1-2 alkyl or C.sub.1-2 alkoxy, both of which are optionally substituted with one or more fluoro groups, located at the 2- and 5-positions, relative to the triazine ring.

9. The method of any one claims 1 to 7, wherein n is 1.

10. The method of claim 9, wherein R.sup.2 represents linear or branched C.sub.1-4 alkyl, optionally substituted with one or more fluoro, ═O or —N(R.sup.a7)R.sup.a8 groups; or C.sub.1-5 alkoxy, optionally substituted with one or more fluoro, ═O, —N(R.sup.a7)R.sup.a8 or C.sub.1-2 alkoxy groups, located at the 3-position, relative to the triazine ring.

11. The method of any one of claims 1 to 10, wherein X represents —C(R.sup.4)R.sup.5—, —O— or —N(R.sup.6)—.

12. The method of any one of claims 1 to 11, wherein X represents —O—.

13. The method of any one of claims 1 to 12, wherein, when p is 1, R.sup.3 represents C.sub.1-2 alkyl or C.sub.1-2 alkoxy, optionally substituted with one or more fluoro groups.

14. The method of any one of claims 1 to 13, wherein m is 0 and p is 0.

15. The method of any one of claims 1 to 14, wherein the disease is selected from the group consisting of Alzheimer's disease, depression, Parkinson's disease, other Parkinsonian disorders and/or other tauopathies, Lewy body dementia, multiple sclerosis, Huntington's disease, mild cognitive impairment, brain injuries, traumatic brain injuries, stroke, other dementia disorders, motorneurone diseases, Pick disease, spinal chord injury, hypoxic ischemia injury, cognitive dysfunction, coronary artery disease, obesity, metabolic syndrome, diabetes, Charcot-Marie-Tooth disease, diabetic neuropathy, tissue regeneration, diabetes-induced osteoporosis, motor function, nerve injury, hearing loss, blindness, posterior eye diseases, anterior eye diseases, dry eye disease, neurotrophic keratitis, glaucoma, high intraocular pressure (IOP), retinitis pigmentosa, post-traumatic stress disorders, WAGR syndrome, Prader-Willi syndrome, diseases of the olfactory tract, olfactory decline, olfactory dysfunction, anxiety, fragile X syndrome, congenital central hypoventilation syndrome, obsessive-compulsive disorder, generalized anxiety disorder, eating disorders, bipolar disorder, chronic fatigue syndrome, neuromyelitis optica, Rett syndrome, Friedrich's ataxia and obstructive sleep apnea-hypopnea syndrome.

16. The method of claim 15, wherein the disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, another Parkinsonian disease, another tauopathy, Lewy body dementia, motorneuron disease, Pick disease, obesity, metabolic syndrome, diabetes, Rett syndrome, posterior eye diseases and cognitive dysfunction.

Description

BRIEF DESCRIPTION OF THE FIGURE

[0352] FIG. 1 shows the results of the passive avoidance task described in the biological examples. The graph demonstrates that administering the compound of Example 5 to mice treated with scopolamine improves cognitive function, as illustrated by the increased retention latency within the bright area.

EXAMPLES

[0353] The present invention will be further described by reference to the following examples, which are not intended to limit the scope of the invention.

Experimental Procedures

[0354] Starting materials and intermediates used in the synthesis of compounds described herein are commercially available or can be prepared by the methods described herein or by methods known in the art.

[0355] Experiments were generally carried out under inert atmosphere (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were used.

[0356] Mass spectrometry data are reported from liquid chromatography-mass spectrometry (LC-MS) using electrospray ionization. Chemical shifts for NMR data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvent used.

[0357] For syntheses referencing general procedures, reaction conditions (such as length of reaction or temperature) may vary. In general, reactions were followed by thin layer chromatography or LC-MS, and subjected to work-up when appropriate. Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluents/gradients were chosen to provide an appropriate R.sub.f and/or retention time.

[0358] General Methods:

[0359] All solvents were of analytical grade and commercially available anhydrous solvents were routinely used for reactions. Starting materials used were available from commercial sources or prepared according to literature procedures, Room temperature refers to 20-25° C. Solvent mixture compositions are given as volume percentages or volume ratios. MW heating was performed in a standard MW reactor producing continuous irradiation at 2450 MHz. It is understood that MWs can be used for the heating of reaction mixtures.

[0360] Thin layer chromatography (TLC) was performed on Merck TLC-plates (Silica gel 60 F.sub.254) and spots were UV visualized. TLC was generally used to monitor reaction progression and solvents used were for example: ethyl acetate or acetonitrile or DCM with 1-10% of MeOH, ethyl acetate with 0-95% hexane. Straight phase flash column chromatography (“flash chromatography”/“column chromatography”) was manually performed on Merck Silica gel 60 (0.040-0.063 mm) or basic aluminum oxide or neutral aluminum oxide, or automatically using ISCO Combiflash® Companion™ system using RediSep™ normal-phase flash columns (“Combiflash”) using the solvent system indicated.

[0361] NMR spectra was recorded on a 400 MHz NMR spectrometer (Bruker 400 MHz Avance-Ill) fitted with a probe of suitable configuration. Spectra were recorded at ambient temperature unless otherwise stated. Chemical fields are given in ppm down- and upfield from TMS (0.00 ppm). The following reference signals were used in .sup.1H-NMR: TMS ∂ 0.00, or residual solvent signal of DMSO-d6 δ 2.49, CDCL3 δ 7.25 (unless otherwise indicated). Resonance multiplicities are denoted s, d, t, q, m, dd, tt, dt br and app for singlet, doublet, triplet, quartet, doublet of doublet, triplet of triplet, doublet of triplet, multiplet, broad and apparent, respectively. In some cases only diagnostic signals are reported.

[0362] High pressure liquid chromatography (HPLC) was performed on a reversed phase (RP) column. A gradient was applied using for example mobile phase A (5 mM Ammonium acetate+0.1% Formic acid in water) and B (0.1% Formic acid in Acetonitrile) or A (0.1% NH3 in water) and B (0.1% NH3 in acetonitrile) or A (10 mM Ammonium acetate in water) and B (Acetonitrile).

[0363] Reversed phase columns used were for example: BEH C18 (50*2.1 mm), 1.7 μm; X-Bridge C18 (50*4.6 mm), 3.5 μm; X-Bridge/YMCC18 (150*4.6 mm), 5 μm; BEH C18 (50*2.1 mm), 1.7 μm; X-Bridge C8 (250*19) mm, 5 μm. The flowrate used was for example 0.55 ml/min or 1.00 ml/min Mass spectrometry (MS) analysis were performed in positive and/or negative ion mode using electrospray ionization (ESI+/−).

[0364] Preparative HPLC chromatography was run on a Waters e2695 Separation Module with a PDA Detector. Column; X-BRIDGE C18, 150*4.6 mm, 5 μm or X-Bridge C18 (250*19 mm) 5 μm or GEMINI C18 (250*21.2 mm) 5 μm.

[0365] A gradient was applied using for example mobile phase A (0.1% NH.sub.3 in water) and B (0.1% NH3 in acetonitrile); A (0.1% TFA in water) and B (Acetonitrile); A (5 mM ammonium bicarbonate+0.05% ammonia in water) and B (Acetonitrile); A (5 mM ammonium bicarbonate) and B (acetonitrile) for LC-separation at a flow rate 1 ml/min.

[0366] High pressure liquid chromatography (HPLC) was performed on a straight phase column. A linear gradient or isocratic flow was applied using for example phase A (Hexane) and B (XX)

[0367] Compounds have been named using CDD vault from Collaborative Drug Discovery Inc. Burlingame Calif., USA or ChemDoodle 8.1.0 from iChemLabs LLC, USA or ACD/ChemSketch 2012 (14.01) from Advanced Chemistry Development (ACD/labs) Ontario, Canada. In case of inconsistency between a name of a compound and the structural formula of the same compound, it is the structural formula that is decisive for the molecular structure of the compound.

[0368] In the event that there is a discrepancy between nomenclature and any compounds depicted graphically, then it is the latter that presides (unless contradicted by any experimental details that may be given or unless it is clear from the context).

Intermediate 1

1-(4-phenoxyphenyl)-3-phenylurea

[0369] ##STR00015##

[0370] Phenyl isocyanate (0.115 g, 0.00097 mol) was added to a solution of 4-phenoxyaniline (commercially available, 0.150 g, 0.00081 mol) in pyridine under N.sub.2 (g). The reaction mixture was heated to 90° C. for 1 hour. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified on silica gel (100-200 mesh) using 50% ethyl acetate in hexane as an eluent to obtain 0.200 g (81% yield) of the title compound.

[0371] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 6.93-7.04 (m, 5H) 7.09 (m, 1H) 7.28 (m, 2H) 7.37 (m, 2H) 7.47 (m, 4H) 8.67 (m, 2H); MS (ES+) m/z 305 [M+H].sup.+

Intermediate 2

1-(4-methoxyphenyl)-3-(4-phenoxyphenyl)urea

[0372] ##STR00016##

[0373] To a solution of phenyl (4-phenoxyphenyl)carbamate (commercially available, 0.300 g, 0.00091 mol) in THF (3.0 mL), TEA (0.273 g, 0.0019 mol) and 4-Methoxy Aniline (0.145 g, 0.0011 mol) were added at 0° C. under N.sub.2 (g). The reaction mixture was heated at 70° C. 16 h. The reaction mixture was quenched with ice-water (30 ml) and extracted with Ethyl Acetate (3×40 ml). The combined organic layers were washed with brine (50 ml). The Organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified on column chromatography using 45% Ethyl acetate in Hexane as a mobile phase and 60-120 silica as stationary phase to yield 0.214 g (77% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3H) 6.91-6.83 (m, 2H) 7.02-6.91 (m, 4H) 7.09 (app tt, 1H) 7.42-7.30 (m, 4H) 7.50-7.43 (m, 2H) 8.45 (s, 1H) 8.59 (s, 1H); MS (ES+) m/z 335 [M+H].sup.+

Intermediate 3

1-(3-cyanophenyl)-3-(4-phenoxyphenyl)urea

[0374] ##STR00017##

[0375] TEA (0.273 g, 0.0019 mol) was added dropwise to phenyl (4-phenoxyphenyl)carbamate (commercially available, 0.30 g, 0.00098 mol) followed by 3-amino-benzonitrile (0.139 g, 0.0011 mol) in THF (3.00 mL) under N.sub.2 (g) at 0° C. The reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was quenched with ice-water (20 ml) and product was extracted with Ethyl Acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on column chromatography using 30% ethyl acetate in hexane as a mobile phase and 60-120 silica as stationary phase to yield 0.139 g (46% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 6.92-7.05 (m, 4H) 7.10 (app tt, 1H) 7.32-7.46 (m, 3H) 7.44-7.54 (m, 3H) 7.68 (app ddd, 1H) 7.98 (app t, 1H) 8.86 (s, 1H) 9.01 (s, 1H).

Intermediate 4

1-(3-methoxyphenyl)-3-(4-phenoxyphenyl)urea

[0376] ##STR00018##

m-Anisidine (0.145 g, 0.00170 mol) and TEA (0.273 g, 0.00196 mol) were added to a solution of phenyl-(4-phenoxyphenyl)carbamate (commercially available, 0.300 g, 0.00098 mol) in THF (3.0 mL) under stirring at 0° C. under N2 (g). The reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was quenched with ice-water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified by column chromatography using 55% ethyl acetate in hexane as a mobile phase and 60-120 silica as stationary phase to yield 0.200 g (66% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3H) 6.55 (m, 1H) 6.81-7.03 (m, 5H) 7.09 (app tt, 1H) 7.13-7.22 (m, 2H) 7.32-7.42 (m, 2H) 7.42-7.51 (m, 2H) 8.66 (app s, 2H); MS (ES+) m/z 335 [M+H].sup.+

Intermediate 5

1-(3-methyl-4-phenoxyphenyl)-3-phenylurea

[0377] ##STR00019##

[0378] Phenyl isocyanate (6.53 g, 0.0548 mol) was added to a solution of 3-methyl-4-phenoxyaniline (commercially available, 8.40 g, 0.0390 mol) and TEA (11.76 mL, 0.084 mol) in DCM at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The solid produced was filtered off and wash with n-pentane (20 ml) to yield 8.4 g (67% yield) of the title compound. This material was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.12 (s, 3H) 6.81-6.91 (m, 3H) 6.88-7.08 (m, 3H) 7.24-7.38 (m, 4H) 7.40-7.50 (m, 3H) 8.64 (app d, 2H); MS (ES+) m/z 319 [M+H].sup.+

Intermediate 6

4-(benzyloxy)aniline

[0379] ##STR00020##

[0380] In a 30 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon Potassium tert-butoxide (0.76 mg, 0.0068 mol) was added portion wise to a solution of 4-aminophenol (0.50 g, 0.0045 mol) in DMF (5.0 mL) at 0° C. After stirring for 1 h, benzylbromde (0.860 g, 0.005 mol) was added portion wise. The reaction mixture was allowed to come at 25° C. than heated at 120° C. for 16 hours. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (3×40 ml). The combine organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on silica gel (60-120 mesh) using 30% ethyl acetate in hexane as an eluent to obtained 0.400 g (44% yield) of the pure title product.

[0381] MS (ES+) m/z 200 [M+H].sup.+

Intermediate 7

1-[4-(benzyloxy)phenyl]-3-phenylurea

[0382] ##STR00021##

[0383] Phenylisocyanate (0.286 g, 0.0024 mol) was added to a solution of 4-(benzyloxy)aniline (Intermediate 6, 0.400 g, 0.0020) and TEA (0.404 ml, 0.0040 mol) in DCM (4.00 ml) at 0° C. The resulting reaction mixture was allowed to come to 25° C. and stirred at 25° C. for 2 hrs. The solvent was evaporated under reduce pressure to obtain 0.450 g (71% yield) of the title compound. This material was used without further purification in the next step. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 5.06 (s, 2H) 6.95 (app dd, 3H) 7.22-7.33 (m, 3H) 7.34 (app dd, 3H) 7.41 (app dt, 5H) 8.58 (s, 1H), 8.47 (s, 1H); MS (ES+) m/z 319 [M+H].sup.+

Intermediate 8

1-[4-(4-chlorophenoxy)phenyl]-3-phenylurea

[0384] ##STR00022##

[0385] Phenyl isocyanate (0.140 g, 0.00110 mol) was added to a solution of 4-(4-chlorophenoxy)aniline (commercially available, 0.200 g, 0.00091 mol) and TEA (0.255 ml, 0.00180 mol) in DCM (4.00 mL) under stirring at 0° C. The resulting reaction mixture was allowed to reach 25° C. and stirred for 16 h. The solid formed was filtered off and washed with n-pentane (3×15 ml) to yield 0.310 g of title compound. This solid was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 6.99 (m, 5H) 7.28 (m, 3H), 7.36-7.54 (m, 5H), 8.66 (s, 1H) 8.71 (s, 1H); MS (ES+) m/z 339 [M+H].sup.+

Intermediate 9

4-(4-aminophenoxy)benzonitrile

[0386] ##STR00023##

[0387] Potassium tert-butoxide (1.02 g, 0.0091 mol) was added portion wise to the solution of 4-aminophenol (0.500 g, 0.0015 mol) in DMF (5.00 mL) at 0° C. under N.sub.2 (g). After 1 hour, 4-bromobenzonitrile (0.830 g, 0.0045 mol) was added portion wise and the reaction mixture was stirred at 120° C. for 16 hours. The reaction mixture was quenched with ice-water (50 ml) and product was extracted with Ethyl Acetate (3×40 ml). The combined organic layer was washed with brine (30 ml). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified on column chromatography using 100% Ethyl acetate in hexane as a mobile phase and 60-120 silica to yield 0.350 g (36% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 5.12 (s, 2H) 6.57-6.65 (m, 2H) 6.79-6.86 (m, 2H) 6.94-7.00 (m, 2H) 7.73-7.80 (m, 2H).

Intermediate 10

1-[4-(4-cyanophenoxy)phenyl]-3-phenylurea

[0388] ##STR00024##

[0389] Phenyl isocyanate was added to a solution of 4-(4-aminophenoxy)benzonitrile (Intermediate 9, 0.150 g, 0.00071 mol) and TEA (0.100 ml, 0.00071 mol) in DCM (5.00 mL) at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated and the reaction mixture was quenched with water (25 ml) and was extracted with Ethyl Acetate (3×30 ml). The combined organic layer was washed with brine (30 ml). The organic layer was dried over sodium sulfate and evaporated under reduce pressure to obtain a crude product. The crude product was purified on column chromatography using 40% ethyl acetate in hexane as a mobile phase and 60-120 silica as stationary phase to yield 0.250 g of the title compound that was used in the next step without further purification. MS (ES+) m/z 330 [M+H].sup.+

Intermediate 11

1-(2-methoxy-4-phenoxyphenyl)-3-phenylurea

[0390] ##STR00025##

[0391] 2-methoxy-4-phenoxyaniline (commercially available, 0.250 g, 0.0011 mol) was added to TEA (0.234 mL, 0.0023 mol) in DCM (2.5 mL) and the mixture was cooled to 0° C. To the mixture phenyl isocyanate (0.179 g, 0.0015 mol) was added and the reaction mixture was stirred at 25° C. for 16 h. The solid material produced was filtered off and washed with n-pentane (5 ml) to yield 0.300 g (77% yield) of the title compound. This was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.86 (s, 3H) 6.56 (app dd, 1H) 6.81 (app d, 1H) 6.92-7.02 (m, 3H) 7.09 (app tt, 1H) 7.23-7.33 (m, 2H) 7.32-7.42 (m, 2H) 7.41-7.49 (m, 2H) 8.08 (app d, 1H) 8.19 (s, 1H) 9.26 (s, 1H); MS (ES+) m/z 335 [M+H].sup.+

Intermediate 12

1-(4-Morpholinophenyl)-3-_(4-phenoxyphenyl)urea

[0392] ##STR00026##

[0393] 4-(4-isocyanatophenyl)morpholine (commercially available, 0.500 g, 0.0024 mol) was added to a solution of 4-phenoxyaniline (commercially available, 0.340 g, 0.0018 mol) and TEA (0.380 g, 0.0037 mol) in DCM (5.0 mL) at 0° C. The reaction mixture was allowed to come to 25° C. and stirred for 16 h. The reaction mixture was quenched with ice-water (50 ml) and product extracted with DCM (3×40 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on silica gel (100-200 mesh) using 1.5% methanol in dichloromethane as an eluent to obtain 0.080 g (11% yield) of the title compound. MS (ES+) m/z 390 [M+H].sup.+

Intermediate 13

1-(3-methoxy-4-phenoxyphenyl)-3-phenylurea

[0394] ##STR00027##

[0395] In a 50 ml RBF previously equipped with a magnetic stirrer phenyl isocyanate (0.297 g, 0.0024 mol) was added to a solution of 3-methoxy-4-phenoxyaniline (commercially available, 0.450 g, 0.0020 mol) and TEA (0.406 mL, 0.0040 mol) in DCM (4.50 mL) at 0° C. The resulting reaction mixture was allowed to reach 25° C. and stirred for 2 h. The solvent was evaporated under reduce pressure to obtain 0.500 g of crude product. This was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3H) 6.76-6.85 (m, 2H) 6.91-7.06 (m, 4H) 7.29 (app ddt, 4H) 7.46 (app ddd, 3H) 8.69 (s, 1H) 8.77 (s, 1H).

Intermediate 14

1-(3-cyano-4-phenoxyphenyl)-3-phenylurea

[0396] ##STR00028##

[0397] Phenyl isocyanate (0.373 g, 0.0017 mol) was added to a solution of 5-amino-2-phenoxybenzonitrile (commercially available, 0.600 g, 0.0015 mol) and TEA (0.521 ml, 0.0023 mol) in DCM (6.00 mL) at 0° C. The reaction mixture was stirred at 25° C. for 16 h.

[0398] The solid produced was filtered to obtain the solid. The obtained solid was stirred in n-pentane (10 ml) for 15 min and the n-pentane was filtered off to yield 0.330 g (35% yield) of the solid title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 7.00 (app tt, 1H) 7.12-7.01 (m, 2H) 7.10 (app t, 1H) 7.17-7.26 (m, 1H) 7.25-7.34 (m, 2H) 7.39-7.50 (m, 4H) 7.66 (app dd, 1H) 8.01 (app d, 1H), 8.80 (s, 1H) 8.96 (s, 1H); MS (ES+) m/z 330 [M+H].sup.+

Intermediate 15

1-methoxy-4-methyl-2-nitro-5-phenoxybenzene

[0399] ##STR00029##

[0400] To a solution of taken Phenol (0.200 g, 0.0021 mol) in DMF (2.0 mL) in a seal tube flask, NaH (0.056 g, 0.0023 mol) was added portion wise at 0° C. under N.sub.2 (g). The reaction mixture was stirred for 1 hour. 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (0.432 g, 0.0023 mol) was added portion wise and the reaction mixture was stirred at 120° C. for 5 h. The reaction mixture was quenched with ice-water (15 ml) and extracted with Diethyl ether (3×20 ml). The combined organic layers was washed with brine (30 ml). Organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified on combi flash chromatography by using 20% Ethyl acetate in Hexane as a mobile phase and 60-120 silica to yield 0.550 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.18 (s, 3H) 2.74 (s, 3H) 6.63-6.76 (m, 1H) 6.95 (app dt, 2H) 6.98-7.11 (m, 3H) 8.47 (s, 1H).

Intermediate 16

2-methoxy-5-methyl-4-phenoxyaniline

[0401] ##STR00030##

[0402] 1-methoxy-4-methyl-2-nitro-5-phenoxybenzene (Intermediate 15, 0.540 g, 0.00208 mol) and SnCl.sub.2.2H.sub.2O (1.870 g, 0.0833 mol) were dissolved in Ethanol (5.40 mL) and cooled to 0° C. 35% HCl (0.540 mL) was added and the reaction mixture was stirred at 50° C. for 5 h. The reaction mixture was diluted with ethyl acetate (50 ml) and basified with 30% aqueous ammonia solution to maintain pH 7-8. The precipitate was filtered through a celite pad and washed with ethyl acetate (3×5 ml). The filtrate was washed with H.sub.2O (3×40 ml) and brine (40 ml). Organic layer was dried over sodium sulfate and evaporated under reduce pressured to obtain 0.450 g of the title compound which was used without further purification in the next step. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.91 (s, 3H) 3.71 (s, 3H) 4.59 (s, 2H) 6.52 (app d, 2H) 6.72-6.81 (m, 2H) 6.92-7.01 (m, 1H) 7.23-7.33 (m, 2H).

Intermediate 17

1-(2-methoxy-5-methyl-4-phenoxyphenyl)-3-phenylurea

[0403] ##STR00031##

[0404] 2-methoxy-5-methyl-4-phenoxyaniline (Intermediate 16, 0.440 g, 0.00191 mol) and TEA (0.400 mL, 0.00287 mol) were dissolved in DCM (4.50 mL) cooled to 0° C. Phenyl isocyanate (0.251 g, 0.00211 mol) was added and the resulting reaction mixture was stirred at 25° C. for 16 h. The solid produced was filtered off and filtered to obtain the solid. The obtained solid was stirred with n-pentane (15 ml) for 15 min and the n-pentane was filtered off to yield 0.285 g (43% yield) of the solid title compound which was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.04 (s, 3H) 3.81 (s, 3H) 6.72 (s, 1H) 6.80-6.88 (m, 2H) 7.00 (app dt, 2H) 7.24-7.38 (m, 4H) 7.42-7.50 (m, 2H) 8.07 (s, 1H) 8.19 (s, 1H) 9.28 (s, 1H).

Intermediate 18

1-methoxy-3-methyl-5-nitro-2-phenoxybenzene

[0405] ##STR00032##

[0406] 2-methoxy-6-methyl-4-nitrophenol (0.230 g, 0.0012 mol) and phenyl boronic acid (0.336 g, 0.0027 mol) were dissolved in DCM (11.9 mL) with 4A molecular sieves (11.5 g) at 25° C. under N.sub.2 (g). The reaction mixture was cooled to 0° C. and TEA (0.881 mL, 0.0062) was added followed by the addition of calcium acetate (0.228 g, 0.0012 mol). The reaction mixture was stirred for 6 h at 0° C. then allowed to come to 25° C. and stirred for 16 h. The reaction mixture was filtered through a celite pad and washed with DCM (2×40 ml). The filtrate was washed with water (2×15 ml) followed by the washing with brine (20 ml), dried over sodium sulfate and evaporated under reduced pressure to obtained the crude product. The crude product was purified on silica gel (60-120 mesh) using 10% ethyl acetate in hexane as an eluent to obtained 0.340 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.21 (s, 3H) 3.81 (s, 3H) 6.76-6.83 (m, 2H) 6.97-7.09 (m, 1H) 7.32-7.26 (m, 2H) 7.82 (d, 1H) 7.93 (dd, 1H).

Intermediate 19

3-methoxy-5-methyl-4-phenoxyaniline

[0407] ##STR00033##

[0408] HCl (35%) (0.34 mL) was added drop wise under stirring to a solution of 1-methoxy-3-methyl-5-nitro-2-phenoxybenzene (Intermediate 18, 0.340 g, 0.0013 mol) and SnCl.sub.2.2H.sub.2O (1.18 g, 0.0052 mol) in ethanol at 0° C. under N.sub.2 (g). The reaction mixture was allowed to come to 25° C. and then heated at 50° C. for 4 h. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (50 ml) and basified using ammonia solution up to pH 7-8. The product was extracted in ethyl acetate (2×30 ml). The combine organic layer was washed with brine (50 ml), dried over sodium sulfate and evaporated under reduce pressure to obtained 0.290 g (97% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.91 (s, 3H) 3.59 (s, 3H) 6.05 (d, 1H) 6.20 (d, 1H) 6.66-6.81 (m, 2H) 6.91 (m, 1H) 7.18-7.30 (m, 2H); MS (ES+) m/z 230 [M+H].sup.+

Intermediate 20

1-(3-methoxy-5-methyl-4-phenoxyphenyl)-3-phenylurea

[0409] ##STR00034##

[0410] In a 10 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon, phenyl isocyanate (0.190 ml, 0.00099 mol) was added drop wise to a solution of 3-methoxy-5-methyl-4-phenoxyaniline (Intermediate 19, 0.190 g, 0.00082 mol) and TEA (0.232 mL, 0.0016 mol) in DCM (2.0 mL) at 0° C. The reaction mixture was allowed to reach 25° C. and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to obtained crude product. The crude product was purified on combi flash using 50% ethyl acetate in hexane as an eluent to to yield 0.100 g (34% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.04 (s, 3H) 3.67 (s, 3H) 6.69-6.78 (m, 2H) 6.86-7.02 (m, 3H) 7.22-7.33 (m, 5H) 7.42-7.50 (m, 2H) 8.71 (app d, 2H); MS (ES+) m/z 349 [M+H].sup.+

Intermediate 21

2-(cyclopentyloxy)-4-nitro-1-phenoxybenzene

[0411] ##STR00035##

[0412] Phenol (0.325 g, 0.0034 mol) dissolved in DMF (9.00 mL), in a 30 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon, was cooled to 0° C. NaH (0.113 g, 0.0047 mol) was added portion wise and stirred for 1 h. 1-bromo-2-(cyclopentyloxy)-4-nitrobenzene (commercially available, 0.900 g, 0.0031 mol) was added portion wise and the reaction mixture was stirred at 120° C. for 16 h. The reaction mixture was quenched with ice-water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (30 ml). Organic layer was dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified on column chromatography using 20% ethyl acetate in hexane as a mobile phase and 60-120 silica to yield 0.550 g (59% yield) of the title product. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.59-1.75 (m, 4H) 1.79-2.05 (m, 4H) 4.80-4.90 (m, 1H) 6.93-7.09 (m, 3H) 7.10-7.21 (m, 1H) 7.31-7.42 (m, 2H) 7.81-7.91 (m, 2H).

Intermediate 22

3-(cyclopentyloxy)-4-phenoxyaniline

[0413] ##STR00036##

[0414] 2-(cyclopentyloxy)-4-nitro-1-phenoxybenzene (Intermediate 21, 0.500 g, 0.0016 mol) SnCl.sub.2.2H.sub.2O (1.50 g, 0.0066 mol) were dissolved in ethanol (5.0 mL) and cooled to 0° C. HCl (35%, 0.50 mL) was added and the reaction mixture was stirred at 50° C. for 5 h. The reaction mixture was diluted with ethyl acetate (20 ml) and basified with 30% aqueous ammonia solution to maintain pH 7-8. The obtained solid was filtered and discarded. The filtrate was washed with H.sub.2O (3×15 ml) and brine (20 ml). Organic layer was dried over sodium sulfate and evaporated under reduced pressure to yield 0.480 g of the title compound which was used without further purification in the next step.

Intermediate 23

1-[3-(cyclopentyloxy)-4-phenoxyphenyl]-3-methylurea

[0415] ##STR00037##

[0416] 3-(cyclopentyloxy)-4-phenoxyaniline (Intermediate 22, 0.240 g, 0.00089 mol) and TEA (0.135 ml, 0.00130 mol) were dissolved in DCM (2.50 mL) and to 0° C. N-Methyl formyl chloride (0.099 g, 0.00100 mol) was added and the resulting reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated and the reaction mixture was quenched with water (10 ml) and product was extracted with ethyl acetate (3×30 ml). The combined organic layer was washed with brine (30 ml). Organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified on Combi flash chromatography using 1% MeOH in DCM as a mobile phase and 60-120 silica as stationary phase to yield 0.180 g (62% yield) of the title compound. MS (ES+) m/z 327 [M+H].sup.+

Intermediate 24

1-(3-ethoxy-4-phenoxyphenyl)-3-phenylurea

[0417] ##STR00038##

[0418] In a 30 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon, phenyl isocyanate (0.226 mL, 0.0019 mol) was added drop wise to the solution of 3-ethoxy-4-phenoxyaniline (0.400 g, 0.0017 mol) and TEA (0.489 mL, 0.0034 mol) in DCM (4.0 mL) at 0° C. The reaction mixture was allowed to slowly reach 25° C. and stirred for 16 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified on silica gel (60-120 mesh) using 30% ethyl acetate in hexane as an eluent to obtain 0.230 g (38% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) b ppm 1.16 (t, 3H) 3.94-4.04 (m, 2H) 6.79-6.86 (m, 1H) 6.87-7.01 (m, 1H) 7.11-7.20 (m, 1H) 7.24-7.34 (m, 4H) 7.39-7.50 (m, 6H) 8.62-8.69 (m, 1H) 8.72 (s, 1H); MS (ES+) m/z 349 [M+H].sup.+

Intermediate 25

3-(5-nitro-2-phenoxyphenoxy)tetrahydrofuran

[0419] ##STR00039##

[0420] In a 30 ml seal tube flask previously equipped with a magnetic stirrer and nitrogen balloon, NaH (0.109 g, 0.0045 mol) was added portion wise to a solution of Phenol (0.391 g, 0.0041 mol) in DMF (12 mL) at 0° C. and stirred for 1 h. 3-(2-bromo-5-nitrophenoxy)tetrahydrofuran (commercially available, 1.200 g, 0.0041 mol) was added portion wise and the reaction mixture was stirred at 120° C. for 16 h. The reaction mixture was quenched with ice-water (50 ml) and product extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (30 ml). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified on column chromatography using 20% Ethyl acetate in hexane as a mobile phase on 60-120 silica to yield 0.900 g (76% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (m, 1H) 2.19 (m, 1H) 3.56-3.66 (m, 1H) 3.68-3.79 (m, 2H) 3.85-3.95 (m, 1H) 5.25 (m, 1H) 7.01-7.12 (m, 3H) 7.16-7.23 (m, 1H) 7.38-7.48 (m, 2H) 7.85-7.94 (m, 2H).

Intermediate 26

4-phenoxy-3-(tetrahydrofuran-3-yloxy)aniline

[0421] ##STR00040##

[0422] In a 50 ml RBF previously equipped with a magnetic stirrer 35% HCl in water (0.30 mL) was added to a solution of 3-(5-nitro-2-phenoxyphenoxy)tetrahydrofuran (Intermediate 25, 0.90 g, 0.0029 mol) and SnCl.sub.2.2H.sub.2O (2.69 g, 0.0011 mol) in ethanol (20 mL) at 0° C. The reaction mixture was stirred at 50° C. for 5 h. The reaction mixture was diluted with ethyl acetate (50 ml) and basified with 30% aqueous ammonia solution to maintain pH 7-8. The precipitate was filtered through a celite pad and washed with ethyl acetate (3×5 ml). The filtrate was washed with water (3×40 ml) followed by washing with brine (40 ml), dried over sodium sulfate and evaporated under reduced pressure to to yield 0.750 g (85% yield) the title compound that was used without further purification in the next step. .sup.1H NMR (400 MHz, DMSO-d6) δ 1.70-1.82 (m, 1H) 1.94-2.08 (m, 1H) 3.39-3.51 (m, 1H) 3.55-3.83 (m, 2H) 3.80-3.95 (m, 1H) 5.04 (s, 1H) 6.17 (dd, 1H) 6.32 (d, 1H) 6.75 (m, 3H) 6.82-6.98 (m, 1H) 7.11-7.29 (m, 2H).

Intermediate 27

1-[4-Phenoxy-3-(tetrahydrofur-3-yloxy)phenyl]-3-phenylurea

[0423] ##STR00041##

[0424] In a 50 ml RBF previously equipped with a magnetic stirrer phenyl isocyanate (0.144 g, 0.0011 mol) was added to a solution of 4-phenoxy-3-(tetrahydrofuran-3-yloxy)aniline (Intermediate 26

Intermediate 28

1-(3-methyl-4-phenoxyphenyl-3-pyridin-2-ylurea

[0425] ##STR00042##

[0426] In a 50 ml RBF previously equipped with a magnetic stirrer was taken 3-methyl-4-phenoxyaniline (commercially available, 0.500 g, 0.0025 mol) and NaHCO.sub.3 (0.63 g, 0.0075 mol) were added to DCM (5.0 mL) and cooled to 0° C. To the mixture, triphosgene (0.491 g, 0.0016 mol) was added and the resulting reaction mixture was stirred at 0° C. for 4 h. 2-amino pyridine (0.236 g, 0.0025 mol) and NaHCO.sub.3 (0.63 g, 0.0075 mol) were added to the reaction mixture. The resulting reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated and the reaction mixture was quenched with water (25 ml) and product was extracted with DCM (3×30 ml). The combined organic layer was washed with brine (30 ml). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified by using 0.02% ammonia as a modifier and water:acetonitrile (0-100% gradient system) as a mobile phase in preparative HPLC purification to yield 0.4 g (50% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.13 (s, 3H) 6.84-6.93 (m, 4H) 6.99-7.07 (m, 3H) 7.31-7.48 (m, 3H) 7.77 (m, 1H) 8.29 (m, 1H) 9.47 (s, 1H) 10.50 (s, 1H); MS (ES+) m/z 320 [M+H].sup.+

Intermediate 29

1-phenyl-3-(1-phenyl-1H-indazol-5-yl)urea

[0427] ##STR00043##

[0428] Phenyl isocyanate was added to a solution of 1-phenyl-1H-indazol-5-amine (commercially available, 0.187 g, 0.0008 mol) and TEA (0.240 mL, 0.0017 mol) in DCM (1.80 mL) at 0° C. The resulting reaction mixture was allowed to reach 25° C. and stirred for 16 h. The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified on silica gel (60-120 mesh) using 2% ethyl acetate in hexane as an eluent to yield 0.150 g (92% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 6.98 (m, 1H) 7.25-7.34 (m, 2H), 7.35-7.46 (m, 1H) 7.48 (m, 3H) 7.55-7.65 (m, 2H) 7.74-7.85 (m, 3H) 8.07 (d, 1H) 8.32 (d, 1H) 8.67 (s, 1H) 8.79 (s, 1H); MS (ES+) m/z 329 [M+H].sup.+

Intermediate 30

1-(3-ethoxy-4-phenoxyphenyl)-3-methylurea

[0429] ##STR00044##

[0430] In a 30 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon, methylaminoformyl chloride (0.090 g, 0.00095 mol) was added drop wise to a solution of 3-ethoxy-4-phenoxyaniline (0.20 g, 0.00087 mol) and TEA (0.244 mL, 0.0017 mol) in DCM (2.0 ml) at 0° C. The reaction mixture was allowed to reach 25° C. and stirred for 16 h. The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified on silica gel (60-120 mesh) using 3% methanol in dichloromethane as an eluent to yield 0.093 g (37% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (m, 3H) 2.62 (s, 3H) 3.94 (m, 2H) 6.76-7.02 (m, 4H) 7.03-7.15 (m, 2H) 7.23-7.32 (m, 2H) 7.36 (s, 1H) 8.46 (s, 1H); MS (ES+) m/z 287 [M+H].sup.+

Intermediate 31

1-methyl-3-[4-phenoxy-3-(tetrahydrofuran-3-yloxy)phenyl]urea

[0431] ##STR00045##

[0432] Methylaminoformyl chloride (0.075 g, 0.0008 mol) was added to a solution of 4-phenoxy-3-(tetrahydrofuran-3-yloxy)aniline (Intermediate 26, 0.200 g, 0.0007 mol) and TEA (0.115 mL, 0.0011 mol) in DCM (2.0 mL) at 0° C. The reaction mixture was allowed to reach 25° C. and stirred for 16 h. The reaction mixture was quenched with water (25 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on silica gel (60-120 mesh) using 90% ethyl acetate in hexane as an eluent to yield 0.120 g (66% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (m, 1H) 2.05 (m, 1H) 2.63 (s, 3H) 3.48 (m, 1H) 3.56 (m, 1H) 3.64 (m, 1H) 3.79 (m, 1H) 4.87 (m, 1H) 6.80 (m, 2H) 6.90 (m, 2H) 6.92-7.02 (m, 2H) 7.23-7.32 (m, 2H) 7.35 (s, 1H) 8.56 (s, 1H).

Intermediate 32

1-[3-(Cyclopentyloxy)-4-phenoxyphenyl]-3-phenylurea

[0433] ##STR00046##

[0434] Phenyl isocyanate (0.126 g, 0.0010 mol) was added to a solution of 3-(cyclopentyloxy)-4-phenoxyaniline (Intermediate 22, 0.240 g, 0.0008 mol) and TEA (0.135 mL, 0.0013 mol) in DCM (2.50 mL) at 0° C. The resulting reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated and the reaction mixture was quenched with water (25 ml) and product extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (30 ml). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on combi flash chromatography by using 5% MeOH in DCM as a mobile phase and 60-120 silica as stationary phase to yield 0.125 g (58% yield) of the title compound.

Intermediate 33

3-[(2-bromo-5-nitrophenoxy)methyl]oxetane

[0435] ##STR00047##

[0436] In RB flask previously equipped with a magnetic stirrer and nitrogen balloon, DEAD (1.298 g, 0.0064 mol) was added drop wise to a solution of 2-bromo-5-nitrophenol (0.700 g, 0.0032 mol), oxetan-3-ylmethanol (0.310 g, 0.0035 mol) and triphenyl phosphine (1.685 g, 0.0062 mol) in THF (7.0 mL) at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was evaporated under reduced pressure to obtain the crude product. The crude product was purified on column chromatography on 100-200 silica by using 15% ethyl acetate in hexane as a mobile phase to yield 1.3 g (quantitative yield) of the title compound that was directly used in the next step. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.39-3.52 (m, 1H) 4.39-4.44 (m, 2H) 4.45-4.52 (m, 2H) 4.67-4.75 (m, 2H) 7.72-7.80 (m, 1H) 7.89-7.95 (m, 2H).

Intermediate 34

3-[(5-nitro-2-phenoxyphenoxy)methyl]oxetane

[0437] ##STR00048##

[0438] In a 30 ml seal tube flask previously equipped with a magnetic stirrer and nitrogen balloon, NaH (0.030 g, 0.0012 mol) was added portion wise to the solution of Phenol (0.119 g, 0.0012 mol) in DMF (2.80 mL) at 0° C. After stirring for 1 h, 3-[(2-bromo-5-nitrophenoxy)methyl]oxetane (Intermediate 33, 0.280 g, 0.0009 mol) was added portion wise and the reaction mixture was stirred at 120° C. for 16 h. The reaction mixture was quenched with ice-water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (30 ml). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified on column chromatography by 15% ethyl acetate in hexane as a mobile phase and 60-120 silica as the stationary phase to yield 0.160 g (62% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.29 (m, 1H) 4.25 (m, 2H) 4.36 (m, 2H) 4.60-4.41 (m, 2H) 6.99-7.07 (m, 2H) 7.09-7.24 (m, 2H) 7.36-7.46 (m, 2H) 7.87-7.96 (m, 1H) 7.99 (d, 1H).

Intermediate 35

3-(oxetan-3-ylmethoxy)-4-phenoxyaniline

[0439] ##STR00049##

[0440] 10% Pd/C (0.042 g) was added to a solution of 3-[(5-nitro-2-phenoxyphenoxy)methyl]oxetane (Intermediate 34, 0.160 g, 0.0005 mol) in methanol (1.60 mL) at 25° C. The resulting reaction mixture was stirred for 16 h under a hydrogen balloon.

[0441] The reaction mixture was filtered through a celite bed, which was washed with MeOH (3×10 ml). The filtrate was evaporated under reduced pressure to obtain 0.100 g (66% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.14 (m, 1H) 3.98-4.11 (m, 4H) 4.35-4.46 (m, 2H) 5.06 (s, 2H) 6.18 (dd, J=8.4, 2.4 Hz, 1H) 6.38 (d, J=2.5 Hz, 1H) 6.71-6.81 (m, 3H) 6.93 (m, 1H) 7.19-7.28 (m, 2H); MS (ES+) m/z 272 [M+H].sup.+

Intermediate 36

1-methyl-3-[3-(oxetan-3-ylmethoxy)-4-phenoxyphenyl]urea

[0442] ##STR00050##

[0443] Methylaminoformyl chloride (0.041 g, 0.00043 mol) was added to a solution of 3-(oxetan-3-ylmethoxy)-4-phenoxyaniline (Intermediate 35, 0.041 g, 0.00037 mol) and TEA (0.103 ml, 0.0007 mol) in DCM (1.0 mL) at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified on chromatography by using 0-5% MeOH in DCM (gradient) as a mobile phase and 60-120 silica as stationary phase to produce 0.120 g of the title compound in quantitative yield. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.65 (d, 1H) 3.19-3.03 (m, 2H) 4.15-4.04 (m, 3H) 4.43 (m, 2H) 5.75 (m, 2H) 6.04 (s, 1H) 6.78 (m, 2H) 7.02-6.86 (m, 3H) 7.27 (m, 2H) 7.41 (s, 1H) 8.62 (s, 1H); MS (ES+) m/z 329 [M+H].sup.+

Intermediate 37

1-{3-[(3-Oxetanyl)methoxy]-4-phenoxyphenyl}-3-phenylurea

[0444] ##STR00051##

[0445] Phenyl isocyanate (0.283 mL, 0.0025 mol)) was added to a solution of 3-(oxetan-3-ylmethoxy)-4-phenoxyaniline (Intermediate 35, 0.640 g, 0.0023 mol) and TEA (0.662 mL, 0.0047 mol) in DCM (6.4 mL) under stirring at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified on column chromatography by using 70% ethyl acetate in hexane as a mobile phase and 60-120 silica as stationary phase to produce 0.840 g of the title compound in quantitative yield. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.17 (m, 1H) 4.11 (m, 4H) 4.44 (m, 2H) 6.78-6.85 (m, 2H) 6.87-7.08 (m, 4H) 7.29-7.39 (m, 4H) 7.41-7.50 (m, 3H) 8.68 (s, 1H) 8.75 (s, 1H); MS (ES+) m/z 391 [M+H].sup.+

Intermediate 38

4-nitro-1-phenoxy-2-(propan-2-yloxy)benzene

[0446] ##STR00052##

[0447] NaH (0.153 g, 0.0063 mol) was added portion wise to a solution of Phenol (0.119 g, 0.0012 mol) stirred in DMF (8.30 mL) under N.sub.2 (g) and cooled at 0° C. After 1 h stirring, 1-Bromo-2-isopropoxy-4-nitrobenzene (commercially available, 0.830 g, 0.0031 mol) was added portion wise and the reaction mixture was heated at 120° C. for 16 h. The reaction mixture was quenched with ice-water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and the solvent was evaporated under reduced pressure. The crude product was purified on silica gel (60-120 mesh) using 20% ethyl acetate in hexane as an eluent to obtain 0.638 g (79% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, 6H) 4.79 (m, 1H) 6.98-7.13 (m, 2H) 7.12-7.25 (m, 1H) 7.28-7.38 (m, 1H) 7.37-7.47 (m, 2H) 7.81-7.94 (m, 2H).

Intermediate 39

4-phenoxy-3-(propan-2-yloxy)aniline

[0448] ##STR00053##

[0449] 35% HCl (0.6 mL) was added to a solution of 4-nitro-1-phenoxy-2-(propan-2-yloxy)benzene (Intermediate 38, 0.638 g, 0.0024 mol) and SnCl.sub.2.2H.sub.2O (2.490 g, 0.0098 mol) in ethanol (6 mL) at 0° C. The reaction mixture was allowed to slowly reach 25° C. and then heated at 50° C. for 3 h. The reaction mixture was diluted with ethyl acetate (50 ml) and basified with 30% aqueous ammonia to maintained pH 7-8. The precipitate was filter through celite pad and washed with ethyl acetate (2×10 ml). The filtrate was washed with water (3×40 ml) followed by the washing with brine (40 ml), dried over sodium sulfate and the solvent evaporated under reduce pressure to obtain 0.510 g (76% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (m, 6H) 4.40 (m, 1H) 4.95 (s 2H) 6.00-6.19 (m, 1H) 6.35 (d, 1H) 6.69-6.81 (m, 1H) 6.82-6.99 (m, 1H) 6.99-7.19 (m, 2H) 7.19-7.28 (m, 2H); MS (ES+) m/z 244 [M+H].sup.+

Intermediate 40

1-methyl-3-[4-phenoxy-3-(propan-2-yloxy)phenyl]urea

[0450] ##STR00054##

[0451] Methylaminoformyl chloride (0.074 ml, 0.0008 mol) was added to a solution of 4-phenoxy-3-(propan-2-yloxy)aniline (Intermediate 39, 0.200 g, 0.0007 mol) and TEA (0.205 mL, 0.0014 mol) in DCM (2 mL) under stirring at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated under reduced pressure to obtain crude product. The crude product was purified on silica gel (60-120 mesh) using 2% methanol in dichloromethane as an eluent to obtain 0.103 g (41% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.32 (m, 6H) 4.35-4.55 (m, 1H) 2.61 (s, 3H) 6.75-7.02 (m, 4H) 7.02-7.15 (m, 2H) 7.27 (m, 2H) 7.37 (s, 1H) 8.53 (s, 1H); MS (ES+) m/z 301 [M+H].sup.+

Intermediate 41

1-[4-phenoxy-3-(propan-2-yloxy)phenyl]-3-phenylurea

[0452] ##STR00055##

[0453] Phenyl isocyanate (0.143 mL, 0.0012 mol) was added to a solution of 4-phenoxy-3-(propan-2-yloxy)aniline (Intermediate 39, 0.300 g, 0.0010 mol) and TEA (0.307 mL, 0.0021 mol) in DCM (3 mL) under stirring at 0° C. The reaction mixture was allowed to reach 25° C. and stirred for 16 h. The solvent was evaporated under reduced pressure. The crude product was purified on silica gel (60-120 mesh) using 2% methanol in dichloromethane as an eluent to yield 0.103 g (53% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.37 (m, 6H) 4.51 (m, 1H) 6.76-6.92 (m, 1H) 6.89-7.05 (m, 3H) 7.11-7.19 (m, 1H) 7.24-7.33 (m, 4H) 7.40-7.50 (m, 4H), 8.60-8.73 (brs, 2H); MS (ES+) m/z 363 [M+H].sup.+

Intermediate 42

2-(2-methoxyethoxy)-4-nitro-1-phenoxybenzene

[0454] ##STR00056##

[0455] In a 30 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon, NaH (0.109 g, 0.0045 mol) was added portion wise to a solution of Phenol (0.224 g, 0.0022 mol) in DMF (6.3 mL) cooled at 0° C. After 1 h, 1-bromo-2-(2-methoxyethoxy)-4-nitrobenzene (commercially available, 0.630 g, 0.0022 mol) was added portion wise and the reaction mixture was heated at 120° C. for 16 h. The reaction mixture was quenched with ice-water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on silica gel (60-120 mesh) using 10% ethyl acetate in hexane as an eluent to yield 0.450 g (68% yield) of the title compound.

[0456] .sup.1H NMR (400 MHz, DMSO-d6) δ 3.35 (s, 3H) 3.70-3.77 (m, 2H) 4.32-4.39 (m, 2H) 7.76 (m, 3H) 7.85-7.94 (m, 5H).

Intermediate 43

3-(2-methoxyethoxy)-4-phenoxyaniline

[0457] ##STR00057##

[0458] 35% HCl.sub.(aq) (0.30 mL) and water (0.1 mL) were added to a solution of 2-(2-methoxyethoxy)-4-nitro-1-phenoxybenzene (Intermediate 42, 0.450 g, 0.0015 mol) and SnCl.sub.2.2H.sub.2O (1.400 g, 0.0062 mol) in ethanol under stirring at 0° C. The reaction mixture was allowed to reach 25° C. and then heated at 50° C. for 3 h. The reaction mixture was diluted with ethyl acetate (50 ml) and basified with 30% aqueous ammonia to maintain pH 7-8. The precipitate was filter through celite pad and washed with ethyl acetate (2×10 ml). The filtrate was washed with water (3×40 ml) and brine (40 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain 0.310 g (77% yield) of the title compound which was used directly in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.13 (s, 3H) 3.41-3.48 (m, 2H) 3.86-3.97 (m, 2H) 5.04 (s, 2H) 6.16 (m, 1H) 6.36 (d, 1H) 6.70-6.81 (m, 3H) 6.83-6.98 (m, 1H) 7.20-7.29 (m, 2H); MS (ES+) m/z 260 [M+H].sup.+

Intermediate 44

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-methylurea

[0459] ##STR00058##

[0460] Methylaminoformyl chloride (0.056 g, 0.0006 mol) was added to a solution of 3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.180 g, 0.0005 mol) and TEA (0.130 mL, 0.0010 mol) in DCM (1.30 mL) at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated under reduced pressure and the crude product was purified on silica gel (60-120 mesh) using 50% ethyl acetate in hexane as an eluent to 0.063 g (28% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6)) δ ppm 2.62-2.66 (m, 3H) 3.15 (s, 3H) 3.44-3.50 (m, 2H) 3.95-4.05 (m, 2H) 6.01 (m, 1H) 6.77-6.84 (m, 2H) 6.86-6.94 (m, 2H) 6.95-7.01 (m, 1H) 7.23-7.31 (m, 2H) 7.36 (s, 1H) 8.52 (s, 1H); MS (ES+) m/z 317 [M+H].sup.+

Intermediate 45

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-phenylurea

[0461] ##STR00059##

[0462] Phenyl isocyanate (0.090 g, 0.0007 mol) was added to a solution of 3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.180 g, 0.0006 mol) and TEA (0.140 mL, 0.0010 mol) in DCM (2.0 mL) under stirring at 0° C. The reaction mixture was stirred at 25° C. for 16 h.

[0463] The solvent was evaporated and the reaction mixture was quenched with water (25 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (30 ml). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified on silica gel (60-120 mesh) using 50% ethyl acetate in hexane as an eluent to obtain 0.135 g (51% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.13 (s, 3H) 3.43-3.52 (m, 2H) 4.00-4.09 (m, 2H) 6.79-6.87 (m, 2H) 6.90-7.03 (m, 4H) 7.20-7.35 (m, 4H) 7.39-7.50 (m, 3H) 8.67 (s, 1H), 8.72 (s, 1H); MS (ES+) m/z 379 [M+H].sup.+

Intermediate 46

2-(benzyloxy)-4-nitro-1-phenoxybenzene

[0464] ##STR00060##

[0465] In a 30 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon, NaH (0.046 g, 1.95 mmol) was added portion wise to a solution of Phenol (0.183 g, 1.95 mmol) in DMF (6.0 mL) cooled at 0° C. After 1 hour, benzyl 2-bromo-5-nitrophenyl ether (commercially available, 0.600 g, 1.95 mmol) was added portion wise and the reaction mixture was heated at 120° C. for 16 h. The reaction mixture was quenched with ice-water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified on silica gel (60-120 mesh) using 20% ethyl acetate in hexane as an eluent to obtained 0.386 g (82% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 5.29 (s, 2H) 7.03-7.14 (m, 3H) 7.22 (m, 1H) 7.27-7.40 (m, 5H) 7.39-7.48 (m, 2H) 7.90 (m, 1H) 8.05 (m, 1H); MS (ES+) m/z 322 [M+H].sup.+

Intermediate 47

3-(benzyloxy)-4-phenoxyaniline

[0466] ##STR00061##

[0467] 35% HCl.sub.(aq) (0.35 ml) was added to a solution of 2-(benzyloxy)-4-nitro-1-phenoxybenzene (Intermediate 46, 0.386 g, 1.2012 mmol) and SnCl.sub.2.2H.sub.2O (0.854 g, 3.788 mmol) in ethanol under stirring at 0° C. The reaction mixture was heated at 50° C. for 5 h. The reaction mixture was diluted with ethyl acetate (50 ml) and basified with 30% aqueous ammonia to maintain pH 7-8. The mixture was filtered through celite pad and washed with ethyl acetate (3×5 ml). The filtrate was washed with water (3×40 ml) and with brine (40 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain 0.330 g of the title compound in quantitative yield. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 5.06 (s, 2H) 5.15 (s, 2H) 6.18 (m, 1H) 6.43 (m, 1H) 6.56-6.70 (m, 1H) 6.72-6.88 (m, 2H) 6.85-7.00 (m, 1H) 7.08-7.21 (m, 2H) 7.21-7.31 (m, 3H) 7.31-7.51 (m, 2H); MS (ES+) m/z 292 [M+H].sup.+

Intermediate 48

1-[3-(benzyloxy)-4-phenoxyphenyl]-3-methylurea

[0468] ##STR00062##

[0469] Methylaminoformyl chloride (0.036 g, 0.386 mmol) was added to a solution of 3-(benzyloxy)-4-phenoxyaniline (Intermediate 47, 0.125 g, 0.429 mmol) and TEA (0.060 mL, 0.429 mmol) in DCM (2.0 mL) under stirring at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was quenched with water (20 ml) and extracted with DCM (3×30 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified on silica gel (60-120 mesh) using 100% ethyl acetate as an eluent to obtained 0.100 g (67% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.97 (s, 3H) 5.05 (s, 2H) 6.17 (m, 1H) 6.42 (m, 1H) 6.73-6.84 (m, 3H) 6.91-7.00 (m, 1H) 7.08-7.17 (m, 2H) 7.19-7.32 (m, 5H) 7.62 (s, 1H) 8.56 (s, 1H); MS (ES+) m/z 349 [M+H].sup.+

Intermediate 49

1-methyl-3-(1-phenyl-1H-indazol-5-yl)urea

[0470] ##STR00063##

[0471] Methylaminoformyl chloride (0.100 g, 0.0010 mol) was added to a stirred solution of 1-phenyl-1H-indazol-5-amine (commercially available, 0.187 g, 0.0008 mol) and TEA (0.240 ml, 0.0017 mol) in DCM (1.80 mL) at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated under reduced pressure. The crude product was purified on silica gel (60-120 mesh) using 50% ethyl acetate in hexane as an eluent to yield 0.085 g (35% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ 2.66 (s, 3H) 6.00 (m, 1H) 7.32-7.41 (m, 2H) 7.53-7.61 (m, 2H) 7.73-7.78 (m, 3H) 8.00 (s, 1H) 8.26 (s, 1H) 8.61 (s, 1H).

Intermediate 50

1-(3-methoxy-5-methyl-4-phenoxyphenyl)-3-methylurea

[0472] ##STR00064##

[0473] In a 10 ml seal tube flask previously equipped with a magnetic stirrer and nitrogen balloon, methylaminoformyl chloride (0.048 ml, 0.0052 mol) was added portion wise to a solution of 3-methoxy-5-methyl-4-phenoxyaniline (Intermediate 19, 0.100 g, 0.00043 mol) and TEA (0.122 mL, 0.00087 mol) in DCM (1.0 mL) at 0° C. The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was concentrate under reduced pressure to obtain the crude product. The crude product was purified on silica gel using 10% methanol in dichloromethane as an eluent to 0.080 g (66% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.00 (s, 3H) 3.18 (s, 3H) 3.63 (s, 3H) 6.05 (s, 1H) 6.68-6.75 (m, 1H) 6.82 (m, 2H) 6.94 (m, 2H) 7.18-7.30 (m, 2H) 8.57 (s, 1H); MS (ES+) m/z 287 [M+H].sup.+

Intermediate 51

2-methoxy-3-methyl-1-nitro-4-phenoxybenzene

[0474] ##STR00065##

[0475] In a 30 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon, NaH (0.273 g, 0.0113 mol) was added portion wise to a solution of Phenol (0.588 g, 0.0062 mol) in DMF (14.0 mL) cooled at 0° C. After 1 hour, 1-bromo-3-methoxy-2-methyl-4-nitrobenzene (commercially available, 1.40 g, 0.0056 mol) was added portion wise and then the reaction mixture was heated at 120° C. for 16 h. The reaction mixture was quenched with ice-water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduce pressure to obtain crude product. The crude product was purified on silica gel (60-120 mesh) using 5% ethyl acetate in hexane as an eluent to yield 0.815 g (55% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H) 3.87 (s, 3H) 7.20-7.07 (m, 2H) 7.34-7.21 (m, 1H) 7.52-7.42 (m, 2H) 7.81 (m, 1H) 7.93 (d, 1H).

Intermediate 52

2-methoxy-3-methyl-4-phenoxyaniline

[0476] ##STR00066##

[0477] 35% HCl.sub.(aq) (0.80 mL) was added to a solution of 2-methoxy-3-methyl-1-nitro-4-phenoxybenzene (Intermediate 51, 0.815 g, 0.0031 mol) and SnCl.sub.2.2H.sub.2O (2.83 g, 0.0120 mol) in ethanol (10.0 mL) under stirring at 0° C. The resulting reaction mixture was heated at 50° C. for 3 h. The reaction mixture was diluted with ethyl acetate (50 ml) and basified with 30% aqueous ammonia to maintain pH 7-8. The mixture was filtered through a celite pad and washed with ethyl acetate (2×5 ml). The filtrate were washed with water (3×40 ml) followed by washing with brine (40 ml), dried over sodium sulfate and evaporated under reduced pressure to yield 0.715 g of the title compound. MS (ES+) m/z 230 [M+H].sup.+

Intermediate 53

1-(2-methoxy-3-methyl-4-phenoxyphenyl)-3-phenylurea

[0478] ##STR00067##

[0479] Phenyl isocyanate (0.446 g, 0.0037 mol) was added to a solution of 2-methoxy-3-methyl-4-phenoxyaniline (Intermediate 52, 0.715 g, 0.0031 mol) and TEA (0.875 mL, 0.0062 mol) in DCM (7.10 mL) under stirring at 0° C. The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was quenched with water (25 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure to yield 0.394 g (36% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.09 (s, 3H) 3.75 (s, 3H) 6.73 (d, 1H) 6.86 (m, 2H) 6.97 (m, 1H) 7.05 (m, 1H) 7.25-7.38 (m, 4H) 7.47 (m, 2H) 8.04 (d, 1H) 8.33 (s, 1H) 9.30 (s, 1H); MS (ES+) m/z 349 [M+H].sup.+

Intermediate 54

1-[3-methyl-4-(phenylsulfanyl)phenyl]-3-phenylurea

[0480] ##STR00068##

[0481] Phenyl isocyanate (1.05 g, 0.0088 mol) was added to a solution of 3-methyl-4-(phenylsulfanyl)aniline (commercially available, 1.74 g, 0.0080 mol) and TEA (2.27 mL, 0.0161 mol) in DCM (17.4 mL) under stirring at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated and the reaction mixture was quenched with water (25 ml) and extracted with Ethyl Acetate (3×30 ml). The combined organic layers were washed with brine (25 ml). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on column chromatography by using 15% ethyl acetate in hexane as a mobile phase and 100-200 silica as stationary phase to yield 1.10 g (40% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H) 6.93-7.08 (m, 3H) 7.12-7.21 (m, 1H) 7.26-7.36 (m, 4H) 7.38 (m, 2H) 7.41-7.53 (m, 3H) 8.74 (s, 1H) 8.83 (s, 1H); MS (ES+) m/z 335 [M+H].sup.+

Intermediate 55

3-methyl-5-nitro-1-phenyl-1H-indole

[0482] ##STR00069##

[0483] To a solution of 3-methyl-5-nitro-1H-indole (commercially available, 0.500 g, 0.0028 mol) in 1,4-dioxane (5.0 mL) was added dry cesium carbonate (2.770 g, 0.0085 mol) followed by the addition of Iodobenzene (0.753 g, 0.0036 mol) at 0° C. After 10 minutes of degassing with argon gas, X-phos (0.270 g, 0.00056 mol) and Pd(OAc).sub.2 (0.063 g, 0.00028 mol) were added under argon atmosphere. The reaction mixture was heated at 110° C. for 16 h under argon atmosphere. The reaction mixture was quenched with ice-water (30 ml) and extracted with ethyl acetate (3×25 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated under reduce pressure to obtain crude product. The crude product was purified on silica gel (60-120 mesh) using 2% ethyl acetate in hexane as an eluent to yield 0.430 g (56% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3H) 7.40-7.50 (m, 2H) 7.58-7.80 (4H) 8.02-8.11 (m, 2H) 8.60 (d, 1H); MS (ES+) m/z 253 [M+H].sup.+

Intermediate 56

3-methyl-1-phenyl-1H-indol-5-amine

[0484] ##STR00070##

[0485] To a solution of 3-methyl-5-nitro-1-phenyl-1H-indole (Intermediate 55, 0.430 g, 0.0017 mol) in ethanol (4.30 mL) SnCl.sub.2.2H.sub.2O (1.538 g, 0.0068 mol) was added followed by the addition of 35% HCl (0.430 mL) at 0° C. The reaction mixture was heated at 50° C. for 5 h. The reaction mixture was diluted with ethyl acetate (40 ml) and basified with 30% ammonia aqueous solution. The precipitated was filtered and washed with ethyl acetate (3×25 ml).

[0486] The combined organic layer was washed with water (3×20 ml) and brine (20 ml), dried over sodium sulfate and the solvent was evaporated under reduced pressure. The crude product was purified on basic alumina oxide using 40% ethyl acetate in hexane as an eluent to yield 0.200 g (55% yield) of the title compound. MS (ES+) m/z 223 [M+H].sup.+

Intermediate 57

1-(3-methyl-1-phenyl-1H-indol-5-yl)-3-phenylurea

[0487] ##STR00071##

[0488] To a solution of 3-methyl-1-phenyl-1H-indol-5-amine (Intermediate 56, 0.200 g, 0.0009 mol) in DCM (3.00 mL), sodium bicarbonate (0.23 g, 0.0027 mol) was added followed by addition of Triphosgene (0.176 g, 0.00059 mol) at 0° C. under nitrogen atmosphere. After stirring for 4 h at 0° C., aniline (0.092 g, 0.00099 mol) and sodium bicarbonate (0.23 g, 0.0027 mol) were added at 0° C. under nitrogen atmosphere. The resulting reaction mixture was allowed reach 25° C. and stirred for 16 hours. The reaction mixture was quenched with water (25 ml) and extracted with dichloromethane (3×30 ml). The combined organic layer was washed with brine (30 ml), dried over sodium sulfate and the solvent evaporated under reduced pressure to yield 0.310 g (quantitative yield) of the title compound that was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H) 6.91-7.01 (m, 1H) 7.11-7.16 (m, 1H), 7.23-7.37 (m, 3H), 7.42-7.51 (m, 4H) 7.53-7.58 (m, 3H) 7.68-7.81 (m, 2H) 8.61 (s, 1H) 8.69 (s, 1H); MS (ES+) m/z 342 [M+H].sup.+

Intermediate 58

1-benzyl-3-methyl-5-nitro-1H-indole

[0489] ##STR00072##

[0490] To a solution of 3-methyl-5-nitro-1H-indole (commercially available, 1.00 g, 0.0056 mol) in DMF (10.0 mL) was added potassium tert-butoxide (0.764 g, 0.0068 mol) at 0° C. After min of stirring at 0° C., benzylbromide (0.970 g, 0.0056 mol) was added dropwise and the reaction mixture was allowed to slowly reach 25° C. and stirred for 18 h under nitrogen atmosphere. The reaction mixture was quenched with ice-water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layer was washed with brine (30 ml), dried over sodium sulfate and the solvent evaporated under reduced pressure. The crude product was purified using flash chromatography on silica gel (60-120 mesh) using 10% ethyl acetate in hexane as eluent to yield 0.935 g (62% yield) of the title compound. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ ppm 2.33 (s, 3H). 5.46 (s, 2H), 7.35-7.20 (m, 5H), 7.53 (s, 1H), 7.65 (d, 1H), 8.00 (dd, 1H), 8.50 (d, 1H). MS (ES+) m/z 267 [M+H].sup.+

Intermediate 59

1-benzyl-3-methyl-1H-indol-5-amine

[0491] ##STR00073##

[0492] To a solution of 1-benzyl-3-methyl-5-nitro-1H-indole (Intermediate 58, 0.0081 mol) in ethanol (9.30 mL) was added SnCl.sub.2.2H.sub.2O (3.151 g, 0.0326 mol) followed by the addition of 35% HCl (0.930 mL) at 0° C. The reaction mixture was heated at 50° C. for 5 h. The reaction mixture was diluted with ethyl acetate (50 ml) and basified with 30% ammonia aqueous solution. The precipitated was filtered off and washed with ethyl acetate (3×5 ml). The combined organic layer was washed with water (3×40 ml) followed by the washing with brine (40 ml), dried over sodium sulfate and the solvent evaporated under reduce pressure. The crude product was purified on flash chromatography with basic alumina oxide using 50% ethyl acetate in hexane as an eluent to obtained 0.630 g (71% yield) of the title compound. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ ppm 2.11 (s, 3H) 4.45 (s, 2H) 5.71 (s, 2H) 6.44 (d, 1H) 6.59 (s, 1H) 7.07-6.99 (m, 2H) 7.10-7.13 (m, 2H) 7.18-7.28 (m, 3H); MS (ES+) m/z 237 [M+H].sup.+

Intermediate 60

1-(1-benzyl-3-methyl-1H-indol-5-yl)-3-phenylurea

[0493] ##STR00074##

[0494] To a solution of 1-benzyl-3-methyl-1H-indol-5-amine (Intermediate 59, 0.300 g, 0.0012 mol) in DCM (3.00 mL) was added TEA (0.356 mL, 0.0025 mol) followed by the addition of phenyl isocyanate (0.166 g, 0.0013 mol) to 0° C. under nitrogen atmosphere. The reaction mixture was allowed to reach at 25° C. and stirred for 16 h. The solid obtained was filtered off and retained. The obtained solid was stirred in n-pentane (10 mL) for 15 min. The solid was filtered of and washed with n-pentane (5 mL) to obtain 0.425 g (94% yield) of the solid title compound. The compound was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 5.31 (s, 2H) 6.91-6.99 (m, 1H) 7.02 (dd, 1H) 7.16-7.19 (m, 2H) 7.20-7.32 (m, 7H) 7.45 (app d, 2H) 7.67 (d, 1H) 8.43 (s, 1H) 8.56 (s, 1H); MS (ES+) m/z 356 [M+H].sup.+

Intermediate 61

1-methyl-3-(3-methyl-1-phenyl-1H-indol-5-yl)urea

[0495] ##STR00075##

[0496] To a solution of 3-methyl-1-phenyl-1H-indol-5-amine (Intermediate 56, 0.150 g, 0.00067 mol) in DCM (1.50 ml) was added sodium bicarbonate (0.172 g, 0.0020 mol) followed by addition of triphosgene (0.132 g, 0.00044 mol) at 0° C. under nitrogen atmosphere. After stirring for 4 h at 0° C., 33% methylamine solution in EtOH (0.069 mL, 0.00074 mol) and sodium bicarbonate (0.172 g, 0.0020 mol) were added. The reaction mixture was allowed to reach 25° C. and stirred for 16 h. The reaction mixture was quenched with water (15 ml) and extracted with dichloromethane (3×20 ml). The combined organic layer was washed with brine (15 ml), dried over sodium sulfate and the solvent was evaporated under reduce pressure to yield 0.070 g (37% yield) of the title compound that was used in the next step without further purification. MS (ES+) m/z 280 [M+H].sup.+

Intermediate 62

1-(1-benzyl-3-methyl-1H-indol-5-yl)-3-methylurea

[0497] ##STR00076##

[0498] To a solution of 1-benzyl-3-methyl-1H-indol-5-amine (Intermediate 59, 0.480 g, 0.0020 mol) in DCM (4.80 mL) cooled to 0° C. and under N.sub.2(g), TEA (0.410 mL, 0.0040 mol) was added under stirring followed by addition of N-methylformyl chloride (0.187 g, 0.0020 mol).

[0499] The reaction mixture was allowed to reach 25° C. and stirred for 16 h.

[0500] The solid precipitates were filtered off and washed with n-pentane (10 ml) to yield 0.230 g (38%) of the title compound. The crude product was used in the next step without further purification. MS (ES+) m/z 294 [M+H].sup.+

Intermediate 63

1-(3-chloro-4-phenoxyphenyl)-3-phenylurea

[0501] ##STR00077##

[0502] A solution of 3-chloro-4-phenoxyaniline (commercially available, 1.2 g, 0.0054 mol) and TEA (1.53 ml, 0.0109 mol) in DCM (12 ml) was stirred at 0° C. Phenyl isocyanate (0.781 g, 0.0065 mol) was added and the resulting reaction mixture was allowed to reach 25° C. and stirred for 16 h. The solvent was removed under reduced pressure and the reaction mixture was quenched with ice-water (30 ml). The resulting solution was extracted with Ethyl Acetate (3×40 ml) and the combined organic layer was washed with brine (30 ml).

[0503] The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain 1.19 g (64%) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 6.86-6.97 (m, 2H) 6.99 (t, J=7.6 Hz, 1H) 7.04-7.16 (m, 2H) 7.24-7.41 (m, 5H) 7.42-7.50 (m, 2H) 7.86 (d, J=2.6 Hz, 1H) 8.76 (s, 1H) 8.90 (s, 1H); MS (ES+) m/z 339 [M+H].sup.+

Intermediate 64

1-(3-methyl-4-phenoxyphenyl)-3-(5-methylthiophen-2-yl)urea

[0504] ##STR00078##

[0505] A solution of 5-methyl-2-thiophenamine (0.670 g, 0.0045 mol), NaHCO.sub.3 (0.984 g, 0.0112 mol) in DCM (7.5 mL) was stirred at 0° C. To the reaction mixture, Triphosgene (0.722 g, 0.0024 mol) was added and the resulting reaction mixture was stirred at 0° C. for 4 hours. To the reaction mixture 3-methyl-4-phenoxyaniline (0.750 g, 0.0037 mol) and NaHCO.sub.3 (0.984 g, 0.0112 mol) were added and the mixture was allowed to reach 25° C. and stirred for 16 hours. The solvent was evaporated and the reaction mixture was diluted with water (30 ml) and the product was extracted with ethyl acetate (3×40 ml). The combined organic layer was washed with brine (30 ml) and dried over sodium sulphate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on combi-flash chromatography using 50% ethyl acetate in hexanes as an eluent to obtain 1.07 g (84% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.11 (s, 3H), 2.33 (S, 3H), 6.33 (d, J=3.6 Hz, 1H), 6.48 (d, J=3.5, 1.4 Hz, 1H), 6.93-6.81 (m, 3H), 7.04 (t, J=7.3 Hz, 1H), 7.31 (m, 3H), 7.41 (d, J=2.6 Hz, 1H), 8.67 (s, 1H), 9.43 (s, 1H); MS (ES+) m/z 339 [M+H].sup.+

Intermediate 65

1-4-fluorophenyl)-3-(3-methyl-4-phenoxyphenyl)urea

[0506] ##STR00079##

[0507] A mixture of 3-methyl-4-phenoxyaniline (0.375 g, 0.0018 mol), NaHCO.sub.3 (0.474 g, 0.0056 mol) in DCM (3.75 ml) was stirred and cooled to 0° C. Triphosgene (0.368 g, 0.0012 mol) was added and the resulting reaction mixture was stirred at 0° C. for 4 h. 4-fluro-aniline (0.209 g, 0.0018 mol) and NaHCO.sub.3 (0.474 g, 0.0056 mol) were added to the reaction mixture and stirred at 25° C. for 16 h. The solvent was evaporated, and the reaction mixture was quenched with water (20 ml) and the product was extracted with EtOAc (3×30 ml). The combined organic layer was washed with brine (20 ml) and dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain crude product.

[0508] The crude product was purified by Combi-flash chromatography using 40% ethyl acetate in hexanes as an eluent to obtain 0.110 g (17% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.11 (s, 3H), 6.81-6.93 (m, 3H), 6.99-7.13 (m, 1H), 7.14 (d, J=8.9 Hz, 2H), 7.25-7.38 (m, 4H), 7.39-7.52 (m, 2H), 8.63 (s, 1H), 8.69 (s, 1H); MS (ES+) m/z 337 [M+H].sup.+

Intermediate 66

1-(benzofuran-5-yl)-3-(3-methyl-4-phenoxyphenyl)urea

[0509] ##STR00080##

Benzofuran-5-amine (10 mg, 0.08 mmol) and triphosgene (7.5 mg, 0.02 mmol) were dissolved in 2 ml DCM and the solution was cooled to 0° C. Triethylamine (21 μl, 0.15 mmol) was added and the solution was stirred at 0° C. for 1 h. A solution of 3-methyl-4-phenoxy-aniline (16.5 mg, 0.08 mmol) and trimethylamine (21 μl, 0.15 mmol) in DCM (0.25 ml) was added. The reaction mixture was allowed to reach RT and the reaction was left to stir overnight. The reaction was quenched with 0.5 ml of H.sub.2O. NH4Cl (aq.Math.sat) and DCM were added and the water phase was extracted further with DCM (×3). The solid present in the combined organic phases was filtered off. The solution was dried over MgSO.sub.4 and concentrated at reduced pressure to yield 0.026 g (96% yield) of the title compound that was used without further purification in the next step. MS (ESI+) m/z 359 (M+H)+

Intermediate 67

1-(1H-indol-5-yl)-3-(3-methyl-4-phenoxyphenyl)urea

[0510] ##STR00081##

[0511] 1H-indol-5-amine (50 mg, 0.38 mmol) and triphosgene (37 mg, 0.12 mmol) were dispersed in 5 ml DCM and the solution was cooled to 0° C. Triethylamine (105 μl, 0.76 mmol) was added and the mixture was stirred at 0° C. for 1.5 h. A solution of 3-methyl-4-phenoxy-aniline (83 mg, 0.42 mmol) and trimethylamine (105 μl, 0.76 mmol) in 0.5 ml DCM was then added. The reaction mixture was allowed to reach room temperature and was stirred for 4 h. The reaction was quenched with 0.5 ml of H.sub.2O. NH4Cl (aq sat.) and DCM were added and the water phase was extracted further with DCM (×3). The combined organic phases were concentrated at reduced pressure and dried at 35° C. under vacuum overnight.

[0512] The product was dissolved in DCM/MeOH solvent mix and was concentrated onto silica.

[0513] It was purified by column chromatography (Isolera, Biotage silica column 25 g) eluting with gradients of MeOH in DCM (0-4.5%) to yield 69 mg (51% yield) of title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 7.68 (d, J=1.9 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.37-7.25 (m, 5H), 7.07 (dd, J=8.7, 2.0 Hz, 1H), 7.03 (t, J=7.4 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.86-6.81 (m, 2H), 6.38-6.32 (m, 1H), 2.11 (s, 3H).

[0514] MS (ESI+) m/z 358 (M+H)+

Intermediate 68

1-(1,3-benzodioxol-5-yl)-3-(3-methyl-4-phenoxyphenyl)urea

[0515] ##STR00082##

1,3-benzodioxol-5-amine (83 mg, 0.61 mmol) and triphosgene (54 mg, 0.18 mmol) were dispersed in 10 ml DCM and the solution was cooled to 0° C. Triethylamine (0.15 ml, 1.1 mmol) was added and the mixture was stirred at 0° C. for 1.5 h. A solution of 3-methyl-4-phenoxy-aniline (110 mg, 0.55 mmol) and triethylamine (0.15 ml, 1.1 mmol) in 1 ml DCM was added. The reaction mixture was allowed to reach room temperature and stirred for 2 h. The reaction was quenched with H.sub.2O. NH4Cl (aq. sat.) and DCM were added and the phases were separated. The organic phase was concentrated at reduced pressure and further dried under vacuum at 40° C. for 3 h to yield 215 mg of the crude title compound that was used without further purification the next step. MS(ESI+) m/z 363 (M+H)+

Intermediate 69

1-(1H-indol-4-yl)-3-(3-methyl-4-phenoxyphenyl)urea

[0516] ##STR00083##

[0517] 1H-indol-4-amine (50 mg, 0.38 mmol) and triphosgene (37 mg, 0.12 mmol) were dispersed in 5 ml DCM and the solution was cooled to 0° C. Triethylamine (105 μl, 0.76 mmol) was added and the mixture was stirred at 0° C. for 1.5 h. A solution of 3-methyl-4-phenoxy-aniline (83 mg, 0.42 mmol) and triethylamine (105 μl, 0.76 mmol) in 0.5 ml DCM was added. The reaction mixture was allowed to reach room temperature and stirred for 2 h.

[0518] The reaction was quenched with H2O. NH4Cl (aq. sat.) and DCM were added and the phases were separated. The organic phase was concentrated at reduced pressure. The solid was washed with pentane and dried under vacuum at 35° C. to yield 118 mg of the crude title compound that was used without further purification in the next step. MS(ESI+) m/z 358 (M+H)+

Intermediate 70

1-(3-methoxyphenyl)-3-(3-methyl-4-phenoxyphenyl)urea

[0519] ##STR00084##

[0520] 3-methoxyaniline (90 μl, 0.80 mmol) and triphosgene (79 mg, 0.26 mmol) were dispersed in 10 ml DCM and the solution was cooled to 0° C. Triethylamine (223 μl, 1.61 mmol) was added and the mixture was stirred at 0° C. After stirring the reaction mixture for a total of 1.5 h, a solution of 3-methyl-4-phenoxy-aniline (176 mg, 0.88 mmol) and triethylamine (223 μl, 1.61 mmol) in 1 ml DCM was added. The solution was allowed to reach room temperature and the reaction mixture was left at RT overnight. The reaction was quenched with H2O. NH4Cl (aq.Math.sat.) and DCM were added and the phases were separated, the organic phase was dried over MgSO4. The solution was thereafter divided in half and was concentrated at reduced pressure, dried under vacuum at 30° C. overnight and further purified by column chromatography (Grace 40 g column, Biotage Isolera) eluting with gradients of MeOH in DCM (0-5%) to yield 115 mg (36% yield) of the title compound. MS(ESI+) m/z 349 (M+H)+

Intermediate 71

1-(2-methoxyphenyl)-3-(3-methyl-4-phenoxyphenyl)urea

[0521] ##STR00085##

[0522] 2-methoxyaniline (99 μl, 0.88 mmol) and triphosgene (87 mg, 0.29 mmol) were dispersed in 10 ml DCM and the solution was cooled to 0° C. Triethylamine (243 μl, 1.75 mmol) was added and the mixture was stirred at 0° C. After stirring the reaction mixture for a total of 1.5 h, a solution of 3-methyl-4-phenoxy-aniline (192 mg, 0.96 mmol) and triethylamine (243 μl, 1.75 mmol) in 1 ml DCM was added. The solution was allowed to reach room temperature and was left to stir a RT overnight. The reaction was quenched with H.sub.2O.

[0523] NH4Cl (aq.Math.sat.) and DCM were added and the phases were separated, the organic phase was dried over MgSO.sub.4. The solution was thereafter divided equally into 2 vials and was concentrated at reduced pressure. Half of the material taken out, concentrated at reduced pressure and dried under vaccum at 30° C. overnight and further purified by column chromatography (Grace 40 g column, Biotage Isolera) eluting with gradients of MeOH in DCM (0-5%) to yield 119 mg (35% yield) of the title compound. MS(ESI+) m/z 349 (M+H)+

Intermediate 72

1-(3-methoxy-4-phenoxyphenyl)-3-(3-methoxyphenyl)urea

[0524] ##STR00086##

[0525] 3-methoxyaniline (108 mg, 0.88 mmol) and triphosgene (87 mg, 0.29 mmol) were dispersed in 10 ml DCM and the solution was cooled to 0° C. Triethylamine (243 μl, 1.75 mmol) was added and the mixture was stirred at 0° C. for 1.5 h. 3-Methoxy-4-phenoxy-aniline (207 mg, 0.96 mmol) and triethylamine (243 μl, 1.75 mmol) were dissolved in DCM (1 ml) and was added to the mixture. The mixture was stirred at RT over night. The reaction mixture was quenched with H.sub.2O. NH4Cl (aq.Math.sat.) and DCM were added and the phases were separated, the organic phase was dried over MgSO4. The solution was concentrated at reduced pressure and the product was purified by column chromatography (Biotage Isolera, 80 g silica column) eluting with gradents of MeOH in DCM (0 to 5%) to yield 225 mg (70% yield) of the title compound. MS(ESI+) m/z 365 (M+H)+

Intermediate 73

1-(3-methoxy-4-phenoxyphenyl)-3-(4-methoxyphenyl)urea

[0526] ##STR00087##

[0527] 4-Methoxyaniline (108 mg, 0.88 mmol) and triphosgene (87 mg, 0.29 mmol) were dispersed in 10 ml DCM and the solution was cooled to 0° C. Triethylamine (243 μl, 1.75 mmol) was added and the mixture was stirred at 0° C. for 1.5 h. 3-methoxy-4-phenoxy-aniline (207 mg, 0.96 mmol) and triethylamine (243 μl, 1.75 mmol) were dissolved in DCM (1 ml) and was added to the mixture. The mixture was stirred at RT over night. The reaction mixture was quenched with H2O. NH4Cl (aq.Math.sat.) and DCM were added and the phases were separated. The organic phase was dried over MgSO4 and concentrated at reduced pressure. The crude was dissolved in DCM/MeOH and was evaporated onto silica. The product/silica mix was applied to a silica column and the product was purified by column chromatography (Biotage Isolera, 80 g silica column) eluting with gradents of MeOH in DCM (0 to 5%) to yield 288 mg (90% yield) of the title compound. MS(ESI+) m/z 365 (M+H)+

Intermediate 74

1-(4-benzyl-3-methylphenyl)-3-phenylurea

[0528] ##STR00088##

[0529] 4-benzyl-3-methylaniline (0.70 g, 0.0035 mol) and TEA (0.99 ml) in DCM (7.0 ml) was stirred at 0° C. To the mixture, Phenyl isocyanate (0.63 g, 0.0053 mol) was added and the resulting reaction mixture was allowed to reach 25° C. and stirred for 16 h. The reaction was quenched with mixture of ice-water (20 ml). Product was extracted with DCM (3×30 ml) and the combined organic layer was washed with brine (20 ml). The organic layer was dried over sodium sulphate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 20% ethyl acetate in hexanes as an eluent to obtain 0.6 g (53% yield) of the title compound. MS(ESI+) m/z 317 (M+H)+

Intermediate 75

1-(3-chlorophenyl)-3-(3-methyl-4-phenoxyphenyl)urea

[0530] ##STR00089##

3-methyl-4-phenoxy-aniline (0.50 g, 0.0025 mol) NaHCO.sub.3 (0.63 g, 0.0075 mol) in DCM (5.0 ml) was stirred and cooled to 0° C. Triphosgene (0.29 g, 0.0010 mol) was added to the mixture and it was stirred for 4 h. 3-Chloro aniline and NaHCO.sub.3 ((0.63 g, 0.0075 mol)) were added. The resulting reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated under reduced pressure and the reaction mixture was quenched with water (30 ml) and product was extracted with EtOAc (3×40 ml). The combined organic layer was washed with brine (30 ml) and dried over sodium sulphate and evaporated under reduced pressure to obtain crude product. The crude product was purified by Combi-flash chromatography using 20% ethyl acetate in hexanes as an eluent to yield 0.470 g (53% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (s, 1H), 8.72 (s, 1H), 7.77-7.68 (m, 1H), 7.44 (d, J=2.6 Hz, 1H), 7.38-7.23 (m, 5H), 7.08-6.98 (m, 2H), 6.88 (dd, J=20.6, 8.3 Hz, 3H), 2.12 (s, 3H); MS(ESI+) m/z 353 (M+H)+

Intermediate 76

1-(3-methyl-4-phenoxyphenyl)-3-[3-(trifluoromethoxy)phenyl]urea

[0531] ##STR00090##

3-methyl-4-phenoxy-aniline (0.5 g, 0.0025 mol) and NaHCO.sub.3 (0.63 g, 0.0075 mol) was added to DCM (5.0 ml) and stirred at 0° C. Triphosgene (0.29 g, 0.0010 mol) was added and the resulting reaction mixture was stirred at 0° C. for 4 h. 3-(trifluromethoxy)-aniline (0.44 g, 0.0025 mol) and NaHCO.sub.3 (0.63 g, 0.0075 mol) were added. The resulting reaction mixture was stirred at 25° C. for 16h. The solvent was evaporated and the reaction mixture was quenched with water (25 ml) and product was extracted with EtOAc (3×30 ml). The combined organic layer was washed with brine (25 ml). The combined organic layer was dried over sodium sulphate and evaporated under reduced pressure to obtain crude product. The crude product was purified by Combi-flash chromatography using 30% ethyl acetate in hexanes as an eluent to obtain 0.450 g (44% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (s, 1H), 8.73 (s, 1H), 7.72 (s, 1H), 7.47-7.36 (m, 2H), 7.39-7.26 (m, 4H), 7.04 (t, J=7.3 Hz, 1H), 6.92 (dd, J=16.7, 8.5 Hz, 2H), 6.85 (d, J=8.0 Hz, 2H), 2.13 (s, 3H); MS(ESI+) m/z 403 (M+H)+

Intermediate 77

1-(3-methyl-4-phenoxyphenyl) 3-(4-methylphenyl)urea

[0532] ##STR00091##

3-methyl-4-phenoxy-aniline (0.50 g, 0.0025 mol) and NaHCO.sub.3 (0.63 g, 0.0075 mol) was added to DCM (5.0 ml) and the mixture was cooled to 0° C. Triphosgene (0.49 g, 0.0016 mol) was added and the resulting reaction mixture was stirred at 0° C. for 4 h. p-Toluidine (0.26 g, 0.0025 mol) and NaHCO.sub.3 (0.63 g, 0.0075 mol) were added and resulting reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated under reduced pressure and the reaction mixture was quenched with water (20 ml) and product was extracted with EtOAc (3×30 ml). The combined organic layer was washed with brine (20 ml) and dried over sodium sulphate and the solvent evaporated under reduced pressure to obtain crude product that was purified by Combi-flash chromatography using 30% ethyl acetate in hexanes as an eluent to yield 0.240 (28% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.61-8.47 (m, 2H), 7.37-7.25 (m, 6H), 7.12-6.99 (m, 4H), 6.93-6.81 (m, 2H), 2.24 (s, 3H), 2.11 (s, 3H); MS(ESI+) m/z 333 (M+H)+

Intermediate 78

1-methyl-3-(3-methyl-4-phenoxyphenyl)urea

[0533] ##STR00092##

3-methyl-4-phenoxy-aniline (0.5 g, 0.0025 mol) and NaHCO.sub.3 (0.63 g, 0.0075 mol) was added to DCM (5.0 ml) and stirred at 0° C. Triphosgene (0.49 g, 0.0016 mol) was added and the reaction mixture was stirred at 0° C. for 4 h. Methyl amine (33% in ethanol, 0.25 ml, 0.0025 mol) and NaHCO.sub.3 (0.63 g, 0.0075 mol) were added and reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was quenched with water (20 ml) and extracted with DCM (3×35 ml). The combined organic layer was washed with brine (20 ml) and dried over sodium sulfate and the solvent evaporated under reduced pressure.

[0534] The crude product was purified by column chromatography on silica gel (100-200 mesh) using 30% ethyl acetate in hexanes as an eluent to yield 0.350 g (54% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1H), 7.33-7.24 (m, 4H), 7.03 (t, J=7.3 Hz, 1H), 6.84 (t, J=8.1 Hz, 3H), 5.99 (q, J=4.6 Hz, 1H), 2.65 (d, J=4.6 Hz, 3H), 2.08 (s, 3H); MS(ESI+) m/z 257 (M+H)+

Intermediate 79

1-(2,5-dimethyl-4-phenoxyphenyl)-3-phenylurea

[0535] ##STR00093##

[0536] A solution of 2,5-dimethyl-4-phenoxyaniline (commercially available, 1.40 g, 0.0065 mol) in DCM (14.0 ml) and TEA (1.84 ml, 0.0131 mol) was stirred and cooled to 0° C. Phenyl Isocyanate (0.93 g, 0.0078 mol) was added and the reaction mixture was allowed to reach 25° C. and stirred for 16 h. The obtained solid precipitates were filtered out and washed with n-pentane (20 ml) to yield 1.3 g (59% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (s, 1H), 7.89 (s, 1H), 7.74 (s, 1H), 7.40-7.52 (m, 2H), 7.22-7.38 (m, 4H), 7.04 (t, J=7.4 Hz, 1H), 6.97 (t, J=7.3 Hz, 1H), 6.89-6.79 (m, 3H), 2.19 (s, 3H), 2.09 (s, 3H); MS(ESI+) m/z 333 (M+H)+

Intermediate 80

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-methylphenyl)urea

[0537] ##STR00094##

[0538] A solution of 3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.30 g, 0.0011 mol) and NaHCO.sub.3 (0.29 g, 0.0035 mol) in DCM (3.0 ml) was stirred and cooled to 0° C. Triphosgene (0.22 g, 0.0007 mol) was added and the reaction mixture was stirred at 0° C. for 4 h. 4-methylaniline (0.16 g, 0.0015 mol) and NaHCO.sub.3 (0.29 g, 0.0035 mol) were added and the reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated under reduced pressure and the reaction mixture was quenched with water (30 ml) and extracted with DCM (3×40 ml). The combined organic layer was washed with brine (30 ml) and dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified by Combi-flash chromatography using 20% ethyl acetate in hexanes as an eluent to yield 0.210 g (46% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) b ppm 8.67 (s, 1H), 8.56 (s, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.38-7.24 (m, 4H), 7.09-7.12 (m, 2H), 6.97 (m, 3H), 6.82-6.89 (m, 2H), 4.04 (t, J=4.6 Hz, 2H), 3.49 (t, J=4.6 Hz, 2H), 3.16 (s, 3H), 2.25 (s, 3H); MS(ESI+) m/z 393 (M+H)+

Intermediate 81

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-methylphenyl)urea

[0539] ##STR00095##

[0540] A solution of 3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.50 g, 0.0019 mol) and NaHCO.sub.3 (0.48 g, 0.0057 mol) in DCM (5.0 ml) was stirred and cooled to 0° C. Triphosgene (0.37 g, 0.0012 mol) was added and the reaction mixture was stirred at 0° C. for 4 h. 3-methylaniline (0.20 g, 0.0019 mol) and NaHCO.sub.3 (0.48 g, 0.0057 mol) were added and the reaction mixture was stirred at 25° C. for 16 h. The solvent was removed under reduced pressure and the reaction mixture was quenched with water (40 ml) and the product was extracted with EtOAc (3×50 ml). The combined organic layer was washed with brine (40 ml) and dried over sodium sulfate and evaporated under reduced pressure.

[0541] The crude product was purified by Combi-flash chromatography using 40% ethyl acetate in hexanes as an eluent to yield 0.30 g (39%) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (s, 1H), 8.60 (s, 1H), 7.44 (d, J=2.2 Hz, 1H), 7.36-7.22 (m, 4H), 7.26-7.13 (m, 1H), 7.06-6.92 (m, 3H), 6.89-6.77 (m, 3H), 4.06 (t, J=4.4 Hz, 2H), 3.51 (t, J=4.8 Hz, 2H), 3.17 (s, 3H), 2.29 (s, 3H); MS(ESI+) m/z 393 (M+H)+

Intermediate 82

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-chlorophenyl)urea

[0542] ##STR00096##

[0543] A solution of 3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.30 g, 0.0011 mol) and NaHCO.sub.3 (0.29 g, 0.0034 mol) in DCM (3.0 ml) was stirred and cooled to 0° C. Triphosgene (0.22 g, 0.0007 mol) was added and the reaction mixture was stirred at 0° C. for 4 h. 3-chloroaniline (0.11 g, 0.0008 mol) and NaHCO.sub.3 (0.29 g, 0.0034 mol) were added and the reaction mixture was stirred at 25° C. for 16 h. The solvent was removed under reduced pressure and the reaction mixture was quenched with water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic layer was washed with brine (50 ml) and dried over sodium sulfate and the solvent evaporated under reduced pressure.

[0544] The crude product was purified by Combi-flash chromatography using 40% ethyl acetate in hexanes as an eluent to yield 0.120 g (25% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.81 (s, 1H), 7.73 (s, 1H), 7.42 (s, 1H), 7.36-7.23 (m, 4H), 7.06-6.92 (m, 4H), 6.81-6.90 (m, 2H), 4.05 (t, J=4.6 Hz, 2H), 3.50 (t, J=4.6 Hz, 2H), 3.16 (s, 3H); MS(ESI+) m/z 413 (M+H)+

Intermediate 83

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-chlorophenyl)urea

[0545] ##STR00097##

3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.30 g, 0.0011 mol) and NaHCO.sub.3 (0.29 g, 0.0034 mol) in DCM (3.0 ml) was cooled under stirring to 0° C. Triphosgene (0.22 g, 0.0007 mol) was added and the resulting reaction mixture was stirred at 0° C. for 4 h. 4-Chloroaniline (0.19 g, 0.0015 mol) and NaHCO.sub.3 (0.29 g, 0.0034 mol) were added and the reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated under reduced pressure and the reaction mixture was quenched with water (30 ml) and extracted with DCM (3×45 ml). The combined organic layer was washed with brine (30 ml) and dried over sodium sulfate and the solvent removed under reduced pressure. The crude product was purified by Combi-flash chromatography using 22% ethyl acetate in hexanes as an eluent to yield 0.230 g (48% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 1H), 8.77 (s, 1H), 7.54-7.47 (m, 2H), 7.42 (d, J=2.1 Hz, 1H), 7.39-7.26 (m, 4H), 7.06-6.93 (m, 3H), 6.80-6.90 (m, 2H), 4.05 (t, J=4.7 Hz, 2H), 3.51 (t, J=4.7 Hz, 2H), 3.17 (s, 3H); MS(ESI+) m/z 413 (M+H)+

Intermediate 84

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-methoxyphenyl)urea

[0546] ##STR00098##

3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.50 g, 0.0019 mol) and NaHCO.sub.3 (0.48 g, 0.0057 mol) were added to DCM (5.0 ml) and the mixture was stirred and cooled to 0° C. Triphosgene (0.37 g, 0.0012 mol) was added and the reaction mixture was stirred at 0° C. for 4 h. 4-methoxyaniline (0.30 g, 0.0025 mol) and NaHCO.sub.3 (0.48 g, 0.0057 mol) were added and the reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated and the reaction mixture was quenched with water (30 ml) and extracted with DCM (3×50 ml). The combined organic layer was washed with brine (30 ml) and dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by the Combi-flash chromatography using 30% ethyl acetate in hexanes as an eluent to yield 0.250 g (31% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) b ppm 8.64 (s, 1H), 8.49 (s, 1H), 7.44-7.25 (m, 6H), 7.05-6.81 (m, 8H), 4.05 (t, J=4.6 Hz, 2H), 3.73 (s, 3H), 3.50 (t, J=4.7 Hz, 2H), 3.17 (s, 3H). MS(ESI+) m/z 409 (M+H)+

Intermediate 85

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-methoxyphenyl)urea

[0547] ##STR00099##

3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.50 g, 0.0019 mol) and NaHCO.sub.3 (0.48 g, 0.0057 mol) in DCM (5.0 ml) was stirred and cooled to 0° C. Triphosgene (0.37 g, 0.0012 mol) was added and the reaction mixture was stirred at 0° C. for 4 h. 3-methoxyaniline (0.23 g, 0.0019 mol) and NaHCO.sub.3 (0.48 g, 0.0057 mol) were added and the reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated and the reaction mixture was quenched with water (100 ml) and extracted with EtOAc (3×50 ml).

[0548] The combined organic layer was washed with brine (50 ml) and dried over sodium sulfate and concentrated under reduced. The crude product was purified by Combi-flash chromatography using 40% ethyl acetate in hexanes as an eluent to yield 0.35 g (44% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (s, 1H), 8.69 (s, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.35-7.28 (m, 2H), 7.21-7.15 (m, 2H), 7.06-6.92 (m, 4H), 6.85-6.80 (m, 2H), 6.57 (dd, J=8.2, 2.5 Hz, 1H), 4.06 (t, J=4.7 Hz, 2H), 3.75 (s, 3H), 3.51 (t, J=4.6 Hz, 2H), 3.17 (s, 3H); MS(ESI+) m/z 409 (M+H)+

Intermediate 86

1-[3-methyl-4-(2-methylphenoxy)phenyl]-3-phenylurea

[0549] ##STR00100##

3-methyl-4-(2-methylphenoxy)aniline (commercially available, 0.25 g, 0.0011 mol) was dissolved in DCM (2.5 ml) under stirring. TEA (0.32 ml, 0.0023 mol) was added at 0° C. followed by the addition of phenyl isocyanate (0.15 g, 0.0012 mol). Reaction mixture was allowed to reach 25° C. and stirred for 16 h. The obtained solid precipitates were filtered out and washed with n-pentane (15 ml) to yield 0.25 g (64%) of the title compound that was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.69-8.57 (m, 2H), 7.50-7.39 (m, 3H), 7.28 (m, 4H), 7.13 (t, J=3.2 Hz, 1H), 7.04-6.93 (m, 2H), 6.75 (d, J=8.7 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 2.27 (s, 3H), 2.16 (s, 3H); MS(ESI+) m/z 333 (M+H)+

Intermediate 87

1-(3-methyl-4-phenoxyphenyl)-3-(1,3-thiazol-4-yl)urea

[0550] ##STR00101##

[0551] A solution of 1,3-Thiazole-4-carboxylic acid (0.50 g, 0.0038 mol) in toluene (5.0 ml) was stirred and cooled to 0° C. and TEA (1.63 ml, 0.0116 mol) was added drop wise. To the resulting mixture diphenyl phosphoryl azide (DPPA, 1.17 g, 0.0042 mol) was added dropwise and stirred at 0° C. for 1 h. 3-methyl-4-phenoxy-aniline (0.50 g, 0.0025 mol) in toluene was added dropwise and resulting reaction mixture was stirred at 110° C. for 16 h.

[0552] The solvent was evaporated and the reaction mixture was quenched with water (40 ml) and extracted with EtOAc (3×50 ml). The combined organic layer was washed with brine (40 ml) and dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by Combi-flash chromatography using 30% ethyl acetate in hexanes as an eluent to yield 0.400 g (49% yield) the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.95 (d, J=2.2 Hz, 1H), 8.78 (s, 1H), 7.43 (d, J=2.6 Hz, 1H), 7.38-7.27 (m, 4H), 7.04 (t, J=7.4 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 6.89-6.79 (m, 2H), 2.12 (s, 3H). MS(ESI+) m/z 326 (M+H)+

Intermediate 88

1-[4-(4-chlorophenoxy)phenyl]-3-methylurea

[0553] ##STR00102##

[0554] In a microwave vial previously equipped with a magnetic stirrer and nitrogen balloon, triethylamine (0.383 g, 0.0027 mol) was added drop wise to a solution of 4-(4-chlorophenoxy)aniline (0.300 g, 0.0045 mol) and N-methyl formyl chloride (0.125 g, 0.0045 mol) in DCM (3.0 ml) at 0° C. The reaction mixture was allowed to reach 25° C. and stirred for 16 h. The reaction mixture was quenched with ice-water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layer was washed with brine (30 ml), dried over sodium sulfate and the solvent removed under reduced pressure. The crude product was purified on silica gel (60-120 mesh) using 10% methanol in dichloromethane as an eluent to yield 0.130 g (34% yield) of the title compound.

Intermediate 89

1-(3-Chloro-4-phenoxyphenyl)-3-methylurea

[0555] ##STR00103##

[0556] 3-Chloro-4-phenoxyaniline (commercially available, 0.340 g, 0.0015 mol) dissolved in DCM (3.4 ml) was stirred and cooled to 0° C. Triethylamine (0.435 ml, 0.0030 mol) followed by N-methyl formyl chloride (0.144 g, 0.0015 mol) were added at 0° C. under nitrogen atmosphere. The reaction mixture was allowed reach 25° C. and stirred for 16 h. The solvent was removed under reduced pressure and the mixture was diluted with water (20 ml). The aqueous layer was extracted with EtOAc (3×25 ml). The combined organic layer was washed with brine (20 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified on combi-flash chromatography using 50% Ethyl acetate in hexanes as an eluent to yield 0.150 g (35% yield) of the title compound. MS(ESI+) m/z 277 (M+H)+

Intermediate 90

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(5-methylthiophen-2-yl)urea

[0557] ##STR00104##

[0558] In a microwave vial, previously equipped magnetic stirrer, was added 5-methylthiophene-2-carboxylic acid (0.30 g, 0.0021 mol) and Toluene (10 ml). This solution was cooled to 0° C. and triethylamine (0.59 ml, 0.0042 mol) was added drop wise. Diphenyl phosphoryl azide (DPPA, 0.63 g, 0.0023 mol) was added drop wise to the resulting mixture and stirred at 0° C. for 1 h. 3-(2-methoxyethoxy)-4-phenoxyaniline (Intermediate 43, 0.32 g, 0.0012 mol) was added drop wise in Toluene (8 ml). The resulting reaction mixture was stirred at 110° C. for 16 h. The solvent was evaporated, and the reaction mixture was quenched with water (40 ml). The product was extracted with Ethyl acetate (3×50 ml). The combined organic layer was washed with brine (40 ml) and dried over sodium sulphate and the solvent evaporated under reduced pressure. The crude product was purified by Combi-flash chromatography using 30% ethyl acetate in hexanes as an eluent to obtain 0.32 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.41 (s, 1H), 8.71 (s, 1H), 7.38 (s, 1H), 7.29 (t, J=7.6 Hz, 2H), 7.02-6.95 (m, 3H), 6.83 (d, J=7.6, 2H), 6.48 (d, J=2.4 Hz, 1H), 6.35 (d, J=3.6 Hz, 1H), 4.04 (t, J=4.4 Hz, 2H), 3.49 (t, J=4.8 Hz, 2H), 3.15 (s, 3H), 2.33 (s, 3H). MS(ESI+) m/z 399 (M+H)+

Intermediate 91 1,3-bis(3-methyl-4-phenoxyphenyl)urea

[0559] ##STR00105##

[0560] In a RBF previously equipped with a magnetic stirrer was added 3-methyl-4-phenoxyaniline (commercially available, 0.3 g, 0.0015 mol), NaHCO.sub.3 (0.75 g, 0.009 mol) and DCM (6 ml). The mixture was cooled to 0° C., and triphosgene (0.589 g, 0.0019 mol) was added and reaction mixture was stirred for 4 h. 3-methyl-4-phenoxyaniline (commercially available, 0.3 g, 0.0015 mol) and NaHCO.sub.3 (0.75 g, 0.009 mol) were added. The resulting reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated and the reaction mixture was quenched with water (30 ml) and product was extracted with EtOAc (3×40 ml). The combined organic layer was washed with brine (30 ml) and the organic layer was dried over sodium sulphate and the solvent evaporated under reduced pressure to obtain crude product. The crude product was purified by Combi-flash chromatography using 20% ethyl acetate in hexanes as an eluent to yield 0.30 g (46% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (s, 2H), 7.44 (d, J=2.0 Hz, 2H), 7.38-7.26 (m, 6H), 7.04 (t, J=7.2 Hz, 2H), 6.93-6.81 (m, 6H), 2.12 (s, 6H). MS (ES+) m/z 425 [M+H].sup.+

Intermediate 92

phenyl (3-methyl-4-phenoxyphenyl)carbamate

[0561] ##STR00106##

[0562] In a RBF previously equipped with a magnetic stirrer was added 3-methyl-4-phenoxyaniline (commercially available, 1.00 g, 0.005 mol) in DCM (10 ml) and the mixture was cooled to 0° C. Triethylamine (1.41 ml, 0.010 mol) was added and then phenyl chloroformate (0.67 ml, 0.0055 mol) was added drop wise. The reaction mixture was allowed to reach room temperature and stirred at 25° C. for 2 h. The reaction mixture was quenched with water (50 ml) and product was extracted with DCM (3×50 ml). The combined organic layer was washed with brine (50 ml) dried over sodium sulphate and the solvent evaporated under reduced pressure. The crude product was purified by Combi-flash chromatography using 30% ethyl acetate in hexanes as an eluent to yield 1.0 g (62% yield) of the title compound. MS (ES+) m/z 320 [M+H].sup.+

Intermediate 93

1-(3-methyl-4-phenoxyphenyl)-3-(1-phenyl-1H-pyrazol-4-yl)urea

[0563] ##STR00107##

[0564] In a RBF previously equipped with a magnetic stirrer phenyl (3-methyl-4-phenoxyphenyl)carbamate (Intermediate 92, 1.0 g, 0.0031 mol) in DMF (7 ml) was added and the mixture cooled to 0° C. Triethylamine (0.88 ml, 0.0063 mol) was added drop wise followed drop-wise addition of 1-Phenyl-1H-pyrazol-4-ylamine (0.335 g, 0.0031 mol) in DMF (3 ml). The resulting reaction mixture was allowed to reach room temperature and stirred at 90° C. for 16 h. The reaction mixture was allowed cool at room temperature and n-hexane was added. The solid product precipitated and filtered through Buchner funnel to get crude product. The crude product was purified by Combi-flash chromatography using 30% ethyl acetate in hexanes as an eluent to yield 0.23 g (19% yield of the title compound. MS (ES+) m/z 385 [M+H].sup.+

Intermediate 94

1-(3-bromo-4-phenoxyphenyl)-3-phenylurea

[0565] ##STR00108##

[0566] In a RBF previously equipped with a magnetic stirrer 3-bromo-4-phenoxyaniline (commercially available, 1.00 g, 0.0038 mol) and DCM (10 ml) was added. Triethylamine (1.06 ml, 0.0076 mol) was added at 0° C. followed by the addition of phenyl isocyanate (0.45 g, 0.0038 mol). The reaction mixture was allowed to reach 25° C. and stirred for 2 h.

[0567] The obtained solid precipitates were filtered out and washed with n-pentane (15 ml) to yield 0.90 (62% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (s, 1H), 8.78 (s, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.48 (app d, 2H), 7.39-7.28 (m, 5H), 7.11-7.07 (m, 2H), 7.00 (t, J=7.2 Hz, 1H), 6.90 (app d, 2H). MS(ESI+) m/z 383 (M+H)+

Intermediate 95

1-(2-methyl-4-phenoxyphenyl)-3-phenylurea

[0568] ##STR00109##

[0569] In a RBF previously equipped with a magnetic stirrer was added 2-methyl-4-phenoxyaniline (commercially available, 0.35 g, 0.0017 mol) and triethylamine (0.49 ml, 0.0035 ml) in DCM (3.5 ml) and the mixture was cooled to 0° C. Phenyl isocyanate (0.20 g, 0.0017 mol) was added and the reaction mixture was allowed to reach 25° C. and stirred for 3 h. The solid product was filtered off and washed with n-pentane and dried under vacuum to yield 0.370 g (66% yield) of the title compound. MS(ESI+) m/z 319 (M+H)+

Intermediate 96

phenyl (2-methyl-4-phenoxyphenyl)carbamate

[0570] ##STR00110##

[0571] In a RBF previously equipped with a magnetic stirrer was taken 2-methyl-4-phenoxyaniline (commercially available, 0.90 g, 0.0045 mol) in DCM (9.0 ml) and the mixture was cooled to 0° C. Triethylamine (1.90 ml, 0.0135 mol) was added followed by drop wise addition of phenyl chloroformate (1.65 ml, 0.0135 mol). The reaction mixture was allowed to reach 25° C. and stirred for 2 h. The reaction mixture was quenched with water (50 ml) and the product was extracted with DCM (3×50 ml). The combined organic layer was washed with brine (50 ml). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to obtain 2.0 g crude title compound that was used in next step.

[0572] MS(ESI+) m/z 320 (M+H)+

Intermediate 97

1-(2-methyl-4-phenoxyphenyl)-3-(4-methylphenyl)urea

[0573] ##STR00111##

[0574] In a RBF previously equipped with a magnetic stirrer was taken phenyl (2-methyl-4-phenoxyphenyl)carbamate (Intermediate 96, 1.00 g, 0.0031 mol) in DMF (7 ml) and the mixture was cooled to 0° C. Triethylamine (0.88 ml, 0.0063 mol) was added drop wise followed by 4-methyl-aniline (0.335 g, 0.0031 mol) in DMF (8 ml). The reaction mixture allowed to reach room temperature and then stirred at 100° C. for 16 h. The reaction mixture was allowed to cool to room temperature and n-hexane was added. The solid product precipitated and was filtered through Buchner funnel to get 0.50 g crude title compound that was used in next step without further purification. MS(ESI+) m/z 320 (M+H).sup.+

Intermediate 98

1-(1-benzofuran-4-yl)-3-(3-methyl-4-phenoxyphenyl)urea

[0575] ##STR00112##

[0576] In a RBF previously equipped with a magnetic stirrer was added phenyl (3-methyl-4-phenoxyphenyl)carbamate (Intermediate 92, 0.50 g, 0.00156 mol) in DMF (3 ml) and the mixture was cooled to 0° C. Triethylamine (0.44 ml, 0.00313 mol) was added drop wise and followed by drop wise addition of 4-amino-benzofuran (0.208 g, 0.00156 mol) in DMF (2 ml). The reaction mixture was stirred at 100° C. for 16 h. The reaction mixture was allowed cool at room temperature and n-hexane was added and stirred for 5 min. The obtained solid was collected by filtration to yield 0.25 g of crude title compound that was used in the next step without further purification. MS(ESI+) m/z 359 (M+H).sup.+

Intermediate 99

1-(1-benzofuran-7-yl)-3-(3-methyl-4-phenoxyphenyl)urea

[0577] ##STR00113##

[0578] In a RBF previously equipped with a magnetic stirrer was taken phenyl (3-methyl-4-phenoxyphenyl)carbamate (Intermediate 92, 1.0 g, 0.00313 mol) in DMF (7 ml) and the mixture was cooled to 0° C. Triethylamine (0.88 ml, 0.0063 mol) was added followed by drop wise addition of 7-amino-benzofuran (0.417, 0.00313 mol) in DMF (3 ml). The reaction mixture was stirred at 100° C. for 16 h. The reaction mixture was allowed to cool to room temperature and n-hexanes was added. After stirring for 5 min the obtained solid was collected by filtration to yield 0.60 g of the crude title compound that was used without further purification in the next step. MS(ESI+) m/z 359 (M+H).sup.+

Intermediate 100

2-(2-fluro-5-nitrophenyl)-N,N-dimethylacetamide

[0579] ##STR00114##

[0580] 2-Fluoro-5-nitrophenyl)acetic acid (commercially available, 3.0 g, 15 mmol), dimethyl amine (10% in THF, 10.1 g, 22.6 mmol) and HATU (11.45 g, 30.1 mmol) in DMF (30 ml) was added to a RBF previously equipped with a magnetic stirrer and nitrogen balloon and the mixture was cooled to 0° C. After 30 minutes, N,N-Diisopropylethylamine (5.20 ml) was added drop wise and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (150 ml). The product was extracted with ethyl acetate (3×100 ml) and the combined organic layer was washed with brine (100 ml). The organic layer was dried over sodium sulphate and the solvent evaporated under reduced pressure. The crude product was purified by combi flash chromatography using 2% Methanol in DCM as an eluent to obtain 3.6 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.27-8.20 (m, 2H), 7.48 (t, J=9.0 Hz, 1H), 3.92 (s, 2H), 3.10 (s, 3H), 2.87 (s, 3H); MS (ES+) m/z 227 [M+H].sup.+

Intermediate 101

N,N-dimethyl-2-(5-nitro-2-phenoxyphenyl)acetamide

[0581] ##STR00115##

[0582] Phenol (1.79 g, 19.0 mmol) and NMP (20 ml) was added to a RBF previously equipped with a magnetic stirrer and nitrogen balloon, and K.sub.2CO.sub.3 (6.60 g, 47.7 mmol) was added at RT. After stirring for 1 h, 2-(2-fluoro-5-nitrophenyl)-N,N-dimethylacetamide (Intermediate 90, 3.6 g, 15.9 mmol) in NMP (16 ml) was added to mixture and the reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with water (150 ml) and extracted with Ethyl acetate (3×100 ml). The combined organic layer was washed with brine (100 ml). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure. The crude product was purified by combi flash chromatography using 30% Ethyl acetate in hexane as an eluent to obtain 3.6 g (75% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.24 (d, J=2.4 Hz, 1H), 8.12 (dd, J=9.2, 2.8 Hz, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.29 (t, J=7.4 Hz, 1H), 7.14 (d, J=7.6 Hz, 2H), 6.83 (d, J=9.2 Hz, 1H), 3.92 (s, 2H), 3.07 (s, 3H), 2.85 (s, 3H); MS (ES+) m/z 301 [M+H].sup.+

Intermediate 102

2-(5-amino-2-phenoxyphenyl)-N,N-dimethylacetamide

[0583] ##STR00116##

[0584] N,N-Dimethyl-2-(5-nitro-2-phenoxyphenyl)acetamide (Intermediate 101, 3.50 g, 11.6 mmol) in Methanol (70 ml) was added to a RBF previously equipped with a magnetic stirrer and nitrogen balloon. 10% Pd/C (50% wet, 0.35 g) was added to the stirred solution under N.sub.2 atmosphere. The reaction mixture was stirred for 1 hours under H.sub.2 (gas). The reaction mixture was filtered through a celite bed, washed with methanol and the solvent was removed under reduced pressure to obtain 3.2 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.34-7.24 (m, 2H), 6.99 (t, J=7.2 Hz, 1H), 6.82 (d, J=7.6 Hz, 2H), 6.67 (d, J=8.0 Hz, 1H), 6.50-6.46 (m, 2H), 5.01 (s, 2H), 3.40 (s, 2H), 2.87 (s, 3H), 2.75 (s, 3H); MS (ES+) m/z 271 [M+H].sup.+

Intermediate 103

1-(Dimethylamino)-2-[2-phenoxy-5-(3-phenylureido)phenyl]-1-ethanone

[0585] ##STR00117##

2-(5-Amino-2-phenoxyphenyl)-N,N-dimethylacetamide (Intermediate 102, 1.00 g, 3.6 mmol) and triethylamine (0.50 ml, 3.6 mmol) in DCM (10 ml) was added to a RBF previously equipped with a magnetic stirrer and nitrogen balloon, and the mixture was cooled to 0° C. Phenyl isocyanate (0.44 g, 3.6 mmol) was added, and the reaction mixture was allowed to reach 25° C. and stirred for 3 h. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with brine (50 ml). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to obtain 0.80 g (55% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.69 (s, 1H), 8.61 (s, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.41-7.26 (m, 6H), 7.06 (t, J=7.0 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 6.90 (d, J=7.6 Hz, 2H), 6.85 (d, J=9.2 Hz, 1H), 3.59 (s, 2H), 2.93 (s, 3H), 2.77 (s, 3H); MS (ES+) m/z 388 [M+H].sup.+

Intermediate 104

2-(2-fluoro-5-nitrophenoxy)-N,N-dimethylacetamide

[0586] ##STR00118##

2-Fluoro-5-nitrophenol (commercially available, 5.00 g, 31.8 mmol) in acetonitrile (30 ml) was added to a RBF previously equipped with a magnetic stirrer and nitrogen balloon.

[0587] K.sub.2CO.sub.3 (13.19 g, 95.4 mmol) was added at room temperature. After 15 min, 2-chloro-N,N-dimethylacetamide (3.87 g, 31.8 mmol) in acetonitrile (20 ml) was added to the mixture and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was filtered through celite bed, the bed washed with acetonitrile and the solvent was removed under reduced pressure to obtain 6.10 g (79% yield) the title compound which used in next step without any further purification. MS (ES+) m/z 243 [M+H].sup.+

Intermediate 105

N,N-dimethyl-2-(5-nitro-2-phenoxyphenoxy)acetamide

[0588] ##STR00119##

[0589] Phenol (2.84 g, 30.2 mmol) in NMP (41 ml) and K.sub.2CO.sub.3 (13.91 g, 100 mmol) was added to a RBF previously equipped with a magnetic stirrer and nitrogen balloon, and stirred at room temperature. After 1 h, 2-(2-fluoro-5-nitrophenoxy)-N,N-dimethylacetamide (Intermediate 104, 6.10 g, 25.1 mmol) in NMP (20 ml) was added and the reaction mixture was heated at 85° C. for 16 h. The reaction mixture was quenched with water (150 ml) and extracted with Ethyl acetate (3×100 ml). The combined organic layer was washed with brine (100 ml). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to obtain 7.20 g (90% yield) of the title compound that used in next step without any further purification. MS (ES+) m/z 317 [M+H].sup.+

Intermediate 106

2-(5-amino-2-phenoxyphenoxy)-N,N-dimethylacetamide

[0590] ##STR00120##

N,N-Dimethyl-2-(5-nitro-2-phenoxyphenoxy)acetamide (Intermediate 105, 7.20 g, 22.7 mmol) in methanol (72 ml) was added to a RBF previously equipped with a magnetic stirrer and nitrogen balloon. 10% Pd/C (50% wet, 0.72 g) was added to the stirred mixture under N.sub.2 atmosphere. The reaction mixture was stirred for 2 hours under H.sub.2 (gas). The reaction mixture was filtered through a celite bed, the bed was washed with methanol and the solvent was removed under reduced pressure to obtain 3.0 g (46% yield) of the title compound. MS (ES+) m/z 287 [M+H].sup.+

Intermediate 107

1-(Dimethylamino)-2-[2-phenoxy-5-(3-phenylureido)phenoxy]-1-ethanone

[0591] ##STR00121##

2-(5-amino-2-phenoxyphenoxy)-N,N-dimethylacetamide (Intermediate 106, 1.50 g, 5.2 mmol) and triethylamine (0.73 ml, 5.2 mmol) in DCM (15 ml) was added to a RBF previously equipped with a magnetic stirrer and nitrogen balloon, and stirred at 0° C.

[0592] Phenyl isocyanate (0.62 g, 5.2 mmol) was added and the reaction mixture was allowed to reach 25° C. and stirred for 3 h. The reaction mixture was quenched with water (30 ml) and product was extracted with DCM (3×50 ml). The combined organic layer was washed with brine (30 ml) and dried over sodium sulphate. The solvent was removed under reduced pressure. The crude product was purified by combi flash chromatography using 80% ethyl acetate in hexanes as an eluent to yield 0.720 g (33% yield) of the title compound. MS (ES+) m/z 406 [M+H].sup.+

Intermediate 108

3-Methyl-2-phenoxy-5-(phenoxycarbonylamino)pyridine

[0593] ##STR00122##

[0594] In a RBF previously equipped with a magnetic stirrer was taken 5-Methyl-6-phenoxy-3-pyridylamine (commercially available, 0.5 g, 0.0025 mol) in DCM and the mixture was cooled to 0° C. TEA (0.35 ml, 0.0025 mol) was added followed by drop wise addition of Phenyl Chloroformate (0.39 ml, 0.0025 mol). The reaction mixture was allowed to reach 25° C. and stirred for 2 h. The reaction mixture was quenched with water (50 ml) and both the layers were separated. The aqueous layer was extracted with DCM (2×50 ml). The combined organic layer was washed with brine (50 ml), dried over sodium sulphate and the solvent removed under reduced pressure to obtain crude product. The crude product was purified by Combi-flash chromatography using 15% ethyl acetate in hexanes as an eluent to yield 0.5 g (62% yield) of the title compound. MS (ES+) m/z 321 [M−H]+.

Intermediate 109

3-(5-Methyl-6-phenoxy-3-pyridyl)-1-(4-methylphenyl)urea

[0595] ##STR00123##

[0596] In a RBF previously equipped with a magnetic stirrer was taken 3-Methyl-2-phenoxy-5-(phenoxycarbonylamino)pyridine (Intermediate 108, 0.5 g, 0.0015 mol) in DMF (2 ml) and the mixture was cooled to 0° C. To the reaction mixture TEA (0.21 ml, 0.0031 mol) was added followed by drop wise addition of 4-methyl-aniline (0.16 g, 0.0015 mol) in DMF (3 ml. The reaction mixture was allowed to reach room temperature and then heated to 100° C. and stirred for 2 h. The reaction mixture was quenched with water (50 ml) and product was extracted with DCM (3×30 ml). The combined organic layer was washed with brine (25 ml), dried over sodium sulphate and the solvent removed under reduced pressure to obtain 0.30 g (57% yield) of the title compound which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.66 (s, 2H), 7.99 (s, 1H), 7.91 (s, 1H), 7.40-7.33 (m, 4H), 7.15 (t, J=7.2 Hz, 1H), 7.10 (app d, 2H), 7.05 (app d, 2H), 2.28 (s, 3H), 2.25 (s, 3H). MS (ES+) m/z 334 [M−H]+.

EXAMPLES

Example 1

[0597] 1-(4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

##STR00124##

[0598] In a microwave tube 1-(4-phenoxyphenyl)-3-phenylurea (Intermediate 1, 0.110 g, 0.00082 mol) and ethoxycarbonyl isocyanate (0.042 g, 0.00036 mol) were taken in bromo benzene (1.10 mL) and heated in a microwave reactor at 150° C. for 1 h. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×40 ml). The combine organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified by combi flash chromatography using 0-100% ethyl acetate in hexanes as a mobile phase and 60-120 silica as stationary phase. The obtained product was further purified using 5 mM ammonia acetate as a modifier and water:Acetonitrile (0-100% gradient system) as a mobile phase using prep HPLC purification to obtain 0.033 g (24% yield) of the title compound. .sup.1H NMR (400 MHz, CDCl3) δ ppm 7.07-7.12 (m, 4H) 7.19 (br. t, 1H) 7.31 (m, 2H) 7.34-7.42 (m, 4H) 7.47-7.56 (m, 3H) 8.24 (s, 1H); MS (ES−) m/z 372 [M−H].sup.−

Example 2

1-(4-methoxyphenyl)-3-(4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0599] ##STR00125##

[0600] Ethoxycarbonyl isocyanate (0.103 g, 0.00089 mol) was added to a solution of 1-(4-methoxyphenyl)-3-(4-phenoxyphenyl)urea (Intermediate 2, 0.200 g, 0.00059 mol) under stirring in toluene (2.0 mL) at 0° C. The reaction mixture was stirred at 110° C. for 16.0 hrs in a sealed tube. The reaction mixture was quenched with ice-water (30 ml) and extracted with Ethyl Acetate (3×30 ml). The combined organic layers were washed with brine (30 ml). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified by preparative HPLC using 0.1% ammonia as a modifier and water:Acetonitrile (0-100% gradient system) as a mobile phase to yield 0.018 g (9% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.79 (s, 3H) 6.98-7.12 (m, 6H) 7.17-7.23 (m, 1H) 7.26-7.31 (m, 2H) 7.34-7.39 (m, 2H) 7.42-7.48 (m, 2H) 11.92 (s, 1H); MS (ES+) m/z 404 [M+H].sup.+ Example 3

3-[2,4,6-trioxo-3-(4-phenoxyphenyl)-1,3,5-triazinan-1-yl]benzonitrile

[0601] ##STR00126##

[0602] Ethoxycarbonyl isocyanate (0.083 g, 0.00072 mol) was added to a solution of (Intermediate 3, 0.160 g, 0.00048 mol) in toluene (1.60 mL) at 0° C. The reaction mixture was stirred at 110° C. for 16 h in a sealed tube. The reaction mixture was quenched with ice-water (50 ml) and product was extracted with Ethyl Acetate (3×40 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduce pressure to obtain crude product. The crude product was purified on column chromatography by 70% ethyl acetate in hexane as a mobile phase and 60-120 silica as stationary phase. The obtained product was further purified on preparative HPLC using mM ammonium acetate as a modifier and water:Acetonitrile (0-100% gradient system) as a mobile phase to yield 0.020 g (10% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 7.04-7.12 (m, 4H) 7.18-7.24 (m, 1H) 7.33-7.38 (m, 2H) 7.42-7.48 (m, 2H) 7.60-7.80 (m, 2H) 7.89-8.01 (m, 2H) 12.18 (s, 1H); MS (ES−) m/z 397 [M−H].sup.−

Example 4

1-(3-methoxyphenyl)-3-(4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0603] ##STR00127##

[0604] Ethoxycarbonyl isocyanate (0.077 g, 0.00044 mol) was added to the solution of 1-(3-methoxyphenyl)-3-(4-phenoxyphenyl)urea (Intermediate 4, 0.150 g, 0.00029 mol) in toluene (1.5 mL) at 0° C. The reaction mixture was stirred at 110° C. for 16 h in a sealed tube. The reaction mixture was quenched with ice-water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain a crude product. The crude product was purified by ethyl acetate as a mobile phase and 60-120 silica as stationary phase on column chromatography. The obtained product was further purified using preparative HPLC purification using 5 mM ammonium acetate as a modifier and water:Acetonitrile (0-100% gradient system) as a mobile phase to yield 0.012 g (6.7% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.77 (s, 3H) 6.93-7.03 (m, 3H) 7.04-7.12 (m, 4H) 7.17-7.24 (m, 1H) 7.34-7.48 (m, 5H) 11.99 (s, 1H); MS (ES+) m/z 404 [M+H].sup.+ Example 5

1-(3-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0605] ##STR00128##

[0606] Ethoxycarbonyl isocyanate (0.108 g, 0.00094 mol) was added to the solution of 1-(3-methyl-4-phenoxyphenyl)-3-phenylurea (Intermediate 5, 0.200 g, 0.00062 mol) in Toluene (2.0 mL) at 0° C. The resulting reaction mixture was stirred at 110° C. for 16 h in a microwave vial. Reaction mixture was quenched with ice-water (50 ml) and extracted with Ethyl Acetate (3×40 ml). The combine organic layers were washed with brine (30 ml). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified on combi flash chromatography using 30% ethyl acetate in hexane as a mobile phase and 60-120 silica as stationary phase. The obtained product was further purified using preparative HPLC purification using mM ammonium acetate as a modifier and water:acetonitrile (0-100% gradient system) as a mobile phase to yield 0.050 g (20% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H) 6.88-7.01 (m, 3H) 7.11-7.24 (m, 2H) 7.30-7.53 (m, 8H) 12.02 (s, 1H); MS (ES+) m/z 388 [M+H].sup.+ Example 6

1-[4-(benzyloxy)phenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0607] ##STR00129##

[0608] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.181 g, 0.0015 mol) was added to a solution of 1-[4-(benzyloxy)phenyl]-3-phenylurea (Intermediate 7, 0.250 g, 0.0007) in toluene (2.5 mL) at 0° C. The reaction mixture was allowed to come to 25° C. and then heated at 110° C. for 16 h. The reaction mixture was quenched with ice-water (50 ml) and product extracted with ethyl acetate (3×40 ml). The combined organic layers washed with brine (30 ml), dried over sodium sulfate and evaporated under reduce pressure to obtain crude product. The crude product was purified on silica gel (60-120 mesh) using 30% ethyl acetate in hexane as an eluent to obtained 0.030 g (10% yield) the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 5.14 (s, 2H) 7.04-7.12 (m, 2H) 7.26-7.52 (m, 12H) 11.97 (s, 1H); MS (ES−) m/z 386 [M−H].sup.−

Example 7

1-[4-(4-chlorophenoxy)phenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0609] ##STR00130##

[0610] In a 30 ml seal tube previously equipped with a magnetic stirrer ethoxycarbonyl isocyanate (0.135 g, 0.00110 mol) was added to a solution of 1-[4-(4-chlorophenoxy)phenyl]-3-phenylurea (Intermediate 8, 0.265 g, 0.00078) in toluene (2.60 mL) at 0° C. The reaction mixture was allowed to come at 25° C. and heated at 110° C. for 16 h. The reaction mixture was quenched with NaHCO.sub.3 (50 ml) and product extracted with ethyl acetate (3×40 ml).

[0611] The combine organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified on silica gel (60-120 mesh) using 40% ethyl acetate in hexane as an eluent to yield 0.010 g (3% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 7.07 (m, 4H) 7.35-7.52 (m, 9H) 12.02 (s,1H); MS (ES−) m/z 406 [M−H].sup.−

Example 8

4-[4-(2,4,6-trioxo-3-phenyl-1,3,5-triazinan-1-yl)phenoxy]benzonitrile

[0612] ##STR00131##

[0613] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.130 g, 0.0011 mol) was added to the solution of 1-[4-(4-cyanophenoxy)phenyl]-3-phenylurea (Intermediate 10, 0.250 g, 0.00076 mol) in toluene (3.00 mL) at 0° C. The reaction mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain crude product. The crude product was purified by 0-30% Ethyl acetate in Hexane as a mobile phase and 60-120 silica as stationary phase on Combi flash chromatography. The obtained material was further purified by preparative HPLC purification using 0.1% ammonia in water and acetonitrile as mobile phases ((0-100% gradient system) to yield 0.007 g (2% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 7.14-7.27 (m, 4H) 7.36-7.40 (m, 2H) 7.42-7.52 (m, 5H) 7.87-7.93 (m, 2H) 12.06 (s, 1H); MS (ES−) m/z 397 [M−H].sup.−

Example 9

1-(2-methoxy-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0614] ##STR00132##

[0615] 1-(2-methoxy-4-phenoxyphenyl)-3-phenylurea (Intermediate 11, 0.300 g, 0.00089 mol) in dry toluene (3.00 mL) was added to a seal tube previously equipped with a magnetic stirrer and cooled to 0° C. Ethoxycarbonyl isocynate (0.100 g, 0.00089 mol) was added and the reaction mixture was stirred at 110° C. for 16 h. The reaction mixture was quenched with ice-water (20 ml) and product extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (30 ml). and dried over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on column chromatography using 35% ethyl acetate in hexane as a mobile phase and 60-120 silica to yield 0.015 g (4% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3H) 6.50-6.58 (m, 1H) 6.85-6.89 (m, 1H) 7.08-7.15 (m, 2H) 7.18-7.24 (m, 1H) 7.29-7.34 (m, 1H) 7.35-7.40 (m, 2H) 7.41-7.52 (5H) 12.09 (s, 1H); MS (ES−) m/z 402 [M−H].sup.−

Example 10

1-[4-(morpholin-4-yl)phenyl]-3-(4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0616] ##STR00133##

[0617] Ethoxycarbonyl isocyanate (0.038 g, 0.00033 mol) was added to a solution of 1-(4-Morpholinophenyl)-3-(4-phenoxyphenyl)urea (Intermediate 12, 0.130 g, 0.00033 mol)) in dry toluene (1.30 ml) at 0° C. in a 30 ml seal tube previously equipped with a magnetic stirrer. The reaction mixture was allowed to come to 25° C. and then heated at 110° C. for 16 h. The reaction mixture was quenched with ice-water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on silica gel (100-200 mesh) using 80% ethyl acetate in hexane as an eluent to yield 0.010 g (6.5% yield) of the title compound.

[0618] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.13-3.18 (m, 4H) 3.72-3.78 (m, 4H) 6.97-7.02 (m, 2H) 7.03-7.13 (m, 4H) 7.17-7.24 (m, 3H) 7.34-7.40 (m, 2H) 7.41-7.49 (m, 2H) 11.92 (s, 1H); MS (ES+) m/z 459 [M+H].sup.+

Example 11

1-(3-methoxy-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0619] ##STR00134##

[0620] Ethoxycarbonyl isocyanate was added (0.103 g, 0.0008 mol) to the solution of 1-(3-methoxy-4-phenoxyphenyl)-3-phenylurea (Intermediate 13, 0.200 g, 0.0005 mol) in toluene (2.00 mL) at 0° C. in a 30 ml seal tube previously equipped with a magnetic stirrer. The reaction mixture was stirred and allowed to reach 25° C. and then heated at 110° C. for 16 h. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified on silica gel (60-120 mesh) using 60% ethyl acetate in hexane as an eluent. The compound was recrystallized in dichloromethane/hexane to yield 0.045 g (18% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3H) 6.86-6.92 (m, 2H) 6.97-7.03 (m, 1H) 7.05-7.12 (m, 2H) 7.24-7.27 (m, 1H) 7.32-7.41 (m, 4H) 7.42-7.53 (m, 3H) 12.06 (s, 1H); MS (ES−) m/z 402 [M−H].sup.−

Example 12

2-phenoxy-5-(2,4,6-trioxo-3-phenyl-1,3,5-triazinan-1-yl)benzonitrile

[0621] ##STR00135##

[0622] Ethoxycarbonyl isocyanate (0.140 g, 0.00110 mol) was added to 1-(3-cyano-4-phenoxyphenyl)-3-phenylurea (Intermediate 14, 0.250 g, 0.00075 mol) in dry toluene (2.5 mL) at 0° C. in a 30 ml seal tube previously equipped with a magnetic stirrer. The reaction mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by using 0.1% TFA in water and acetonitrile as a mobile phase (0-100% gradient system) in preparative HPLC purification to yield 0.034 g (11% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO d6) δ ppm 7.00 (d, 1H) 7.23-7.29 (m, 2H) 7.31-7.39 (m, 3H) 7.40-7.78 (m, 5H) 7.69 (dd, 1H) 7.95 (d, 1H) 12.16 (s, 1H); MS (ES−) m/z 397 [M−H].sup.−

Example 13

1-(2-methoxy-5-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0623] ##STR00136##

[0624] 1-(2-methoxy-5-methyl-4-phenoxyphenyl)-3-phenylurea (Intermediate 17, 0.260 g, 0.00074 mol) was dissolved in dry toluene (2.60 mL) in a seal tube and cooled to 0° C. Ethoxycarbonyl isocyanate (0.094 g, 0.00082 mol) was added and the reaction mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified on Combi flash chromatography by using ethyl acetate as a mobile phase and 60-120 silica as stationary phase. The obtained product was further purified by using 10 mM ammonium bicarbonate as modifier and water:acetonitrile (0-100% gradient system) as a mobile phase phase in preparative HPLC purification to yield 0.042 g (13% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 3H) 3.67 (s, 3H) 6.72 (s, 1H) 6.91-6.97 (m, 2H) 7.07-7.14 (m, 1H) 7.28 (s, 1H) 7.33-7.51 (m, 7H) 12.06 (s, 1H); MS (ES+) m/z 418 [M+H].sup.+

Example 14

1-(3-methoxy-5-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0625] ##STR00137##

[0626] In a 10 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon, ethoxycarbonyl isocyanate (0.033 g, 0.00030 mol) was added drop wise to the solution of 1-(3-methoxy-5-methyl-4-phenoxyphenyl)-3-phenylurea (Intermediate 20, 0.090 g, 0.00025 mol) in dry toluene (0.9 mL) at 25° C. The reaction mixture was heated at 110° C. for 16 h. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC with 5 mM ammonium acetate in water:acetonitrile as mobile phase (0-100% gradient system) to yield 0.008 g (8% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6 5 ppm 2.10 (s, 3H) 3.67 (s, 3H) 6.72-6.77 (m, 2H) 6.93-6.96 (m, 1H) 6.97-7.03 (m, 1H) 7.08-7.12 (m, 1H) 7.26-7.33 (m, 2H) 7.36-7.53 (m, 5H) 12.04 (s, 1H); MS (ES−) m/z 416 [M−H].sup.−

Example 15

1-[3-(cyclopentyloxy)-4-phenoxyphenyl]-3-methyl-1,3,5-triazinane-2,4,6-trione

[0627] ##STR00138##

[0628] 1-[3-(cyclopentyloxy)-4-phenoxyphenyl]-3-methylurea (Intermediate 23, 0.180 g, 0.0005516 mol) was dissolved in toluene (1.80 mL) in a 30 ml seal tube previously equipped with a magnetic stirrer and cooled to 0° C. Ethoxycarbonyl isocyanate (0.069 g, 0.0006067 mol) was added and the reaction mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified on combi flash chromatography by using a 0-100% ethyl acetate gradient in hexane as a mobile phase and 60-120 silica as stationary phase. The product was further purified by prep HPLC purification using 3 mM ammonium acetate in water:acetonitrile as a mobile phase (0-100% gradient system) to yield 0.049 g (22% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.30-1.48 (m, 4H) 1.49-1.60 (m, 2H) 1.67-1.80 (m, 2H) 3.16 (s, 3H) 4.69 (m, 1H) 6.84-6.93 (m, 3H) 7.02-7.08 (m, 1H) 7.10-7.18 (m, 2H) 7.30-7.37 (m, 2H) 11.84 (s, 1H); MS (ES−) m/z 394 [M−H].sup.−

Example 16

1-(3-ethoxy-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0629] ##STR00139##

[0630] In a 30 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon, Ethoxycarbonyl isocyanate (0.083 ml, 0.00072 mol) was added drop wise to a solution of 1-(3-ethoxy-4-phenoxyphenyl)-3-phenylurea (Intermediate 24, 0.230 g, 0.00066 mol) in dry toluene (2.3 mL) at 0° C. The reaction mixture was allowed to reach to 25° C. and then heated at 120° C. for 12 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by using using 0.1% ammonia as a modifier and water:acetonitrile (0-100% as a gradient system) as a mobile phase in preparative HPLC purification to yield 0.0145 g (5% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (t, 3H) 3.99 (q, 2H) 6.88-6.93 (m, 2H) 6.94-6.99 (m, 1H) 7.04-7.11 (m, 2H) 7.20-7.24 (m, 1H) 7.31-7.39 (m, 4H) 7.4.0-7.52 (m, 3H) 12.05 (s, 1H); MS (ES−) m/z 416 [M−H].sup.−

Example 17

1-[3-(oxolan-3-yloxy)-4-phenoxyphenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0631] ##STR00140##

[0632] In a 30 ml seal tube previously equipped with a magnetic stirrer Ethoxycarbonyl isocyanate (0.130 g, 0.0011 mol) was added to the solution of 1-[4-Phenoxy-3-(tetrahydrofur-3-yloxy)phenyl]-3-phenylurea (Intermediate 27, 0.400 g, 0.0010 mol) in toluene (4 mL) at 0° C. The reaction mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain crude product. The crude product was purified on combi flash chromatography using ethyl acetate as a mobile phase and 60-120 silica as stationary phase. The crude product was further purified by prep HPLC purification using using 0.1% ammonia as a modifier and water:acetonitrile (0-100% gradient system) as a mobile phase to yield 0.028 g (7% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.85 (m, 1H) 2.02-2.15 (m, 1H) 3.49-3.70 (m, 3H) 3.79-3.85 (m, 1H) 4.88-4.95 (m, 1H) 6.88-6.94 (m, 2H) 6.99-7.04 (m, 1H) 7.05-7.14 (m, 2H) 7.22-7.25 (m, 1H) 7.31-7.53 (m, 7H) 12.06 (s, 1H); MS (ES−) m/z 458 [M−H].sup.−

Example 18

1-(3-methyl-4-phenoxyphenyl)-3-(pyridin-2-yl)-1,3,5-triazinane-2,4,6-trione

[0633] ##STR00141##

[0634] In a 30 ml seal tube previously equipped with a magnetic stirrer, 1-(3-methyl-4-phenoxyphenyl)-3-pyridin-2-ylurea (Intermediate 28, 0.250 g, 0.0007 mol) was dissolved in Bromo Benzene (2.5 mL) at 0° C. To the mixture Ethoxycarbonyl isocyanate (0.099 g, 0.0008 mol) was added. The resulting reaction mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain crude product. The crude product was purified on combi flash chromatography by using 0-100% ethyl acetate in hexane as a mobile phase and 60-120 silica as stationary phase. The obtained product was further purified using 5 mM ammonia acetate as a modifier and water:acetonitrile (0-100% gradient system) as a mobile phase using preparative HPLC purification to yield 0.036 g (12% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.21 (s, 3H) 6.91 (d, 1H) 6.95-7.00 (m, 2H) 7.14 (t, 1H) 7.23 (dd, 1H) 7.35 (d, 1H) 7.37-7.43 (m, 2H) 7.49-7.57 (m 2H) 8.01 (dt, 1H) 8.57-8.62 (m, 1H) 12.12 (s, 1H); MS (ES−) m/z 387 [M−H].sup.−

Example 19

1-phenyl-3-(1-phenyl-1H-indazol-5-yl)-1,3,5-triazinane-2,4,6-trione

[0635] ##STR00142##

[0636] In a 30 ml seal tube previously equipped with a magnetic stirrer Ethoxycarbonyl isocyanate (0.053 g, 0.0004 mol) was added to a solution of 1-phenyl-3-(1-phenyl-1H-indazol-5-yl)urea (Intermediate 29, 0.140 g, 0.0004 mol) in Toluene (1.4 mL) at 0° C. The reaction mixture was allowed to reach 25° C. and then heated at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by using 0.01% ammonia as a modifier and water:acetonitrile (0-100% gradient system) as a mobile phase in prep HPLC purification to yield 0.007 g (4% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 7.38-7.53 (m, 7H) 7.59-7.66 (m, 2H) 7.78-7.83 (m, 2H) 7.90-7.95 (m, 2H) 8.47-8.49 (m, 1H) 12.05 (s, 1H); MS (ES−) m/z 396 [M−H].sup.−

Example 20

1-phenyl-3-[4-(phenylamino)phenyl]-1,3,5-triazinane-2,4,6-trione

[0637] ##STR00143##

[0638] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.125 g, 0.0010 mol) was added to a solution of 1-phenyl-3-[4-(phenylamino)phenyl]urea (commercially available, 0.300 g, 0.0009 mol) in Bromobenzene (3.0 mL) at 0° C. The reaction mixture was stirred in a microwave reactor at 150° C. for 3 h. The solvent was evaporated under reduce pressure to obtain a crude product. The crude product was purified on combi flash chromatography by using ethyl acetate in hexane as a mobile phase and 60-120 silica as stationary phase. The obtained product was further purified by using 3 mM ammonia as modifier and water:acetonitrile (0-100% gradient system) as a mobile phase in preparative HPLC purification to yield 0.008 g (3% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 6.83-6.92 (m, 1H) 7.05-7.57 (m, 13H) 8.34 (s, 1H) 11.94 (s, 1H); MS (ES+) m/z 373 [M+H].sup.+

Example 21

1-(3-ethoxy-4-phenoxyphenyl)-3-methyl-1,3,5-triazinane-2,4,6-trione

[0639] ##STR00144##

[0640] In a 30 ml seal tube previously equipped with a magnetic stirrer and nitrogen balloon, ethoxycarbonyl isocyanate (0.083 mL, 0.00035 mol) was added drop wise to a solution of (Intermediate 30, 0.093 g, 0.00032 mol) in dry toluene (2.3 mL) at 0° C. The reaction mixture was allowed to reach 25° C. and then heated at 120° C. for 12 h. The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC purification using 0.1% ammonia as modifier and water:acetonitrile (0-100% gradient system) as a mobile phase to yield 0.026 g (22% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (t, 3H) 3.16 (s, 3H) 3.97 (q, 2H) 6.88-6.95 (m, 3H) 7.03-7.12 (m, 2H) 7.16-7.20 (m, 1H) 7.32-7.40 (m, 2H) 11.83 (s, 1H); MS (ES−) m/z 354 [M−H].sup.−

Example 22

1-methyl-3-[3-(oxolan-3-yloxy)-4-phenoxyphenyl]-1,3,5-triazinane-2,4,6-trione

[0641] ##STR00145##

[0642] In a 30 ml seal tube previously equipped with a magnetic stirrer, Ethoxycarbonyl isocyanate (0.042 g, 0.0003 mol) was added to a solution of 1-methyl-3-[4-phenoxy-3-(tetrahydrofuran-3-yloxy)phenyl]urea (Intermediate 31, 0.110 g, 0.0003 mol) in Toluene (1.10 mL) at 0° C. The resulting reaction mixture was heated at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain crude product. The crude product was purified on silica gel (60-120 mesh) using ethyl acetate as an eluent and re-purified by preparative HPLC purification using 0.1% formic acid in water:acetonitrile as a mobile phase (0-100% gradient system) to yield 0.039 g (29% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.76-1.84 (m, 1H) 2.02-2.14 (m, 1H) 3.16 (s, 3H) 3.49-3.70 (m, 3H) 3.78-3.85 (m, 1H) 4.85-4.91 (m, 1H) 6.88-6.98 (m, 3H) 7.05-7.14 (m, 2H) 7.19 (d, 1H) 7.32-7.39 (m, 2H) 11.87 (s, 1H); MS (ES−) m/z 396 [M−H].sup.−

Example 23

1-[3-(cyclopentyloxy)-4-phenoxyphenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0643] ##STR00146##

[0644] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.069 g, 0.0006 mol) was added to a solution of 1-[3-(Cyclopentyloxy)-4-phenoxyphenyl]-3-phenylurea (Intermediate 32, 0.180 g, 0.0005 mol) in bromobenzene (2.0 mL) at 0° C. The reaction mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified on combi flash chromatography by using a 0-100% ethyl acetate in hexane (gradient) as a mobile phase and 60-120 silica as stationary phase and further purified by using preparative HPLC purification using 3 mM ammonia acetate in water:acetonitrile as a mobile phase (0-100% gradient system) to yield 0.015 g (9% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.48 (m, 4H) 1.50-1.60 (m, 2H) 1.69-1.80 (m, 2H) 4.71 (s, 1H) 6.83-6.88 (m, 2H) 6.94-6.98 (m, 1H) 7.02-7.07 (m, 1H) 7.11-7.15 (m, 1H) 7.18-7.21 (m, 1H) 7.29-7.52 (m, 7H) 12.04 (s, 1H); MS (ES−) m/z 456 [M−H].sup.−

Example 24

1-methyl-3-[3-(oxetan-3-ylmethoxy)-4-phenoxyphenyl]-1,3,5-triazinane-2,4,6-trione

[0645] ##STR00147##

[0646] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.042 g, 0.0003 mol) was added to a solution of 1-methyl-3-[3-(oxetan-3-ylmethoxy)-4-phenoxyphenyl]urea (Intermediate 36, 0.110 g, 0.0003 mol) in Toluene (1.10 mL) at 0° C. The reaction mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified on combi flash chromatography by using 0-5% MeOH in DCM as a mobile phase and 60-120 silica as stationary phase. The product was further purified by using 3 mM ammonia acetate as modifier and water:acetonitrile (0-100% gradient system) as a mobile phase in preparative HPLC purification to yield 0.006 g (4.5% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.13-3.23 (m, 1H) 3.16 (s, 3H) 4.08-4.15 (m, 4H) 4.45-4.51 (m, 2H) 6.87-6.92 (m, 2H) 6.96 (dd, 1H) 7.05-7.10 (m, 1H) 7.14 (d, 1H) 7.23 (d, 1H) 7.32-7.39 (m, 2H) 11.87 (s, 1H); MS (ES−) m/z 396 [M−H].sup.−

Example 25

1-[3-(oxetan-3-ylmethoxy)-4-phenoxyphenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0647] ##STR00148##

[0648] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.205 g, 0.0017 mol) was added to a solution of 1-{3-[(3-Oxetanyl)methoxy]-4-phenoxyphenyl}-3-phenylurea (Intermediate 37, 0.580 g, 0.0014 mol) in toluene (5.8 mL) at 0° C. The reaction mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified using preparative HPLC purification by using 0.1% formic acid as a modifier and water:acetonitrile (0-100% gradient system) as a mobile phase to yield 0.0049 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.12-3.25 (m, 1H) 4.09-4.19 (m, 4H) 4.41-4.55 (m, 2H) 6.86-6.92 (m, 2H) 6.99-7.10 (m, 2H) 7.20-7.17 (m, 1H) 7.25-7.52 (m, 8H) 12.08 (s, 1H); MS (ES−) m/z 458 [M−H].sup.−

Example 26

1-methyl-3-[4-phenoxy-3-(propan-2-yloxy)phenyl]-1,3,5-triazinane-2,4,6-trione

[0649] ##STR00149##

[0650] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.043 g, 0.37 mmol) was added to a solution of 1-methyl-3-[4-phenoxy-3-(propan-2-yloxy)phenyl]urea (Intermediate 40, 0.103 g, 0.34 mmol) in Toluene (1.3 mL) at 0° C. The reaction mixture was heated at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by using preparative HPLC purification with 0.1% ammonia as modifier and water:acetonitrile (0-100% gradient system) as a mobile phase to yield 0.035 g (27% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, 6H) 3.16 (s, 3H) 4.40-4.52 (m, 1H) 6.88-6.93 (m, 3H) 7.04-7.11 (m, 2H) 7.16-7.21 (d, 1H) 7.32-7.38 (m, 2H) 11.75 (s, 1H); MS (ES−) m/z 368 [M−H].sup.−

Example 27

1-[4-phenoxy-3-(propan-2-yloxy)phenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0651] ##STR00150##

[0652] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.115 g, 0.0010 mol) was added to the solution of 1-[4-phenoxy-3-(propan-2-yloxy)phenyl]-3-phenylurea (Intermediate 41, 0.343 g, 0.0009 mol) in toluene (3.4 mL) at 0° C. The reaction mixture was heated at 110° C. for 16 h. The solvent was evaporated under reduced pressure. The crude product was purified using preparative HPLC purification with 0.1% ammonia as modifier and water:acetonitrile (0-100% gradient system) as a mobile phase to yield 0.009 g (2% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, 6H) 4.40-4.52 (m, 1H) 6.86-6.92 (m, 2H) 6.96 (dd, 1H) 7.04-7.11 (m, 2H) 7.23 (d, 1H) 7.30-7.52 (m, 7H) 12.01 (s, 1H); MS (ES−) m/z 430 [M−H].sup.−

Example 28

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-methyl-1,3,5-triazinane-2,4,6-trione

[0653] ##STR00151##

[0654] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.023 g, 0.199 mmol) was added to a solution of 1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-methylurea (Intermediate 44, 0.062 g, 0.196 mmol) in Toluene (0.60 mL) at 0° C. The reaction mixture was heated at 110° C. for 16 h. The solvent was evaporated under reduce pressure and the crude product was purified on preparative HPLC using 0.1% ammonium acetate as modifier and water:acetonitrile (0-100% gradient system) as a mobile phase in prep HPLC purification to yield 0.027 g (36% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.15 (s, 3H) 3.18 (s 3H) 3.52 (t, 2H) 4.03 (t, 2H) 6.90-6.96 (m, 3H) 7.03-7.12 (m, 2H) 7.18-7.21 (m, 1H) 7.33-7.40 (m, 2H) 11.86 (s, 1H); MS (ES−) m/z 384 [M−H].sup.−

Example 29

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0655] ##STR00152##

[0656] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.045 g, 0.0003 mol) was added to the solution of 1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-phenylurea (Intermediate 45, 0.135 g, 0.0003 mol) in toluene (1.30 mL) under stirring at 0° C. The reaction mixture was heated at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified using preparative HPLC by using 0.1% ammonium acetate as a modifier and water:acetonitrile (0-100% gradient system) as a mobile phase to yield 0.012 g (7% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.18 (s, 3H) 3.53 (t, 2H) 4.06 (t, 2H) 6.90-6.96 (m, 2H) 6.97-7.02 (m, 1H) 7.04-7.12 (m, 2H) 7.25 (d, 1H) 7.32-7.53 (m, 7H) 12.05 (s, 1H); MS (ES−) m/z 446 [M−H].sup.−

Example 30

1-[3-(benzyloxy)-4-phenoxyphenyl]-3-methyl-1,3,5-triazinane-2,4,6-trione

[0657] ##STR00153##

[0658] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.072 g, 0.63 mmol) was added to the solution of 1-[3-(benzyloxy)-4-phenoxyphenyl]-3-methylurea (Intermediate 48, 0.200 g, 0.574 mmol) in Toluene (2.0 mL) at 0° C. The reaction mixture was heated at 110° C. for 16 h. The solvent was evaporated under reduced pressure. The crude was purified by preparative HPLC using 3 mM ammonium acetate as modifier and water:acetonitrile (0-100% gradient system) as a mobile phase to yield 0.030 g (12% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.15 (s, 3H) 5.01 (s, 2H) 6.90-6.97 (m, 3H) 7.06-7.20 (m, 4H) 7.25-7.32 (m, 4H) 7.33-7.40 (m, 2H) 11.87 (s, 1H); MS (ES−) m/z 416 [M−H].sup.−

Example 31

1-methyl-3-(1-phenyl-1H-indazol-5-yl)-1,3,5-triazinane-2,4,6-trione

[0659] ##STR00154##

[0660] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.035 g, 0.304 mmol) was added to the solution of (Intermediate 49, 0.075 g, 0.282 mmol) in Toluene (0.75 mL) at 0° C. The reaction mixture was heated at 110° C. for 16 h. The solvent was evaporated under reduce pressure. The crude product was purified using preparative HPLC purification with 0.1% ammonia in water and 100% Acetonitrile as a mobile phase to yield 0.055 g (58% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.17 (s, 3H) 7.40-7.48 (m, 2H) 7.58-7.66 (m, 2H) 7.78-7.84 (m, 2H) 7.86-7.93 (m, 2H) 8.47 (d, 1H) 11.87 (s, 1H); MS (ES−) m/z 334 [M−H].sup.−

Example 32

1-(3-methoxy-5-methyl-4-phenoxyphenyl)-3-methyl-1,3,5-triazinane-2,4,6-trione

[0661] ##STR00155##

[0662] In a 10 ml seal tube flask previously equipped with a magnetic stirrer and nitrogen balloon, ethylcarbonyl isocyanate (0.033 g, 0.29 mmol) was added drop wise to a solution of 1-(3-methoxy-5-methyl-4-phenoxyphenyl)-3-methylurea (Intermediate 50, 0.070 g, 0.24 mmol) in dry toluene (0.7 mL) at 25° C. The reaction mixture was heated at 110° C. for 16 h. The reaction mixture was concentrated under reduced pressure to obtain the crude product.

[0663] The crude product was purified on preparative HPLC using 0.1% ammonium acetate as a modifier and water:acetonitrile (0-100% as a gradient system) as mobile phase to yield 0.017 g (19% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 3H) 3.16 (s, 3H) 3.65 (s, 3H) 6.73-6.79 (m, 2H) 6.87-6.91 (m, 1H) 6.98-7.07 (m, 2H) 7.28-7.35 (m, 2H) 11.87 (s, 1H); MS (ES−) m/z 354 [M−H].sup.−

Example 33

1-(2-methoxy-3-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0664] ##STR00156##

[0665] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethylcarbonyl isocyanate (0.138 g, 0.0011 mol) was added to a solution of 1-(2-methoxy-3-methyl-4-phenoxyphenyl)-3-phenylurea (Intermediate 53, 0.380 g, 0.0010 mol) in toluene (3.80 mL) under stirring at 0° C. The reaction mixture was heated at 110° C. for 16 h. The solvent was evaporated under reduced pressure and the crude product was purified by preparative HPLC using 0.1% ammonia as a modifier and water:acetonitrile (0-100% as a gradient system) as a mobile phase to yield 0.094 g (20% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.17 (s, 3H) 3.71 (s, 3H) 6.70 (d, 1H) 6.97-7.05 (m, 2H) 7.13-7.19 (m, 1H) 7.23 (d, 1H) 7.37-7.53 (m, 7H) 12.11 (s, 1H); MS (ES−) m/z 416 [M−H].sup.−

Example 34

1-[3-methyl-4-(phenylsulfanyl)phenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0666] ##STR00157##

[0667] In a 30 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.150 g, 0.0014 mol) was added to a solution of 1-[3-methyl-4-(phenylsulfanyl)phenyl]-3-phenylurea (Intermediate 54, 0.400 g, 0.0011 mol) in toluene (4.00 mL) stirred at 0° C. The reaction mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified on combi flash chromatography by using 100% Ethyl acetate as a mobile phase and 60-120 silica as stationary phase. The obtained product was further purified by preparative HPLC purification, using 5 mM ammonium bicarbonate as a modifier and water:Acetonitrile (0-100% gradient system) as a mobile phase to yield 0.020 g (4% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3H) 7.15-7.25 (m, 2H) 7.30-7.53 (m, 11H) 12.01 (s, 1H); MS (ES−) m/z 402 [M−H].sup.−

Example 35

1-(3-Methyl-1-phenyl-1H-indol-5-yl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0668] ##STR00158##

[0669] To a solution 1-(3-methyl-1-phenyl-1H-indol-5-yl)-3-phenylurea (Intermediate 57, 0.310 g, 0.00090 mol) in toluene (3.10 mL), was added ethoxycarbonyl isocyanate (0.209 g, 0.00180 mol) at 0° C. under nitrogen atmosphere. The resulting reaction mixture was heated at 110° C. for 16 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified on preparative chromatography using 0.1% ammonia as a modifier and water:acetonitrile (0-100% gradient system) as mobile phases to obtain 0.015 g (4% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3H) 7.16-7.22 (m, 1H) 7.36-7.52 (m, 6H) 7.53-7.64 (m, 7H) 11.98 (s, 1H); MS (ES−) m/z 409 [M−H].sup.−

Example 36

1-(1-Benzyl-3-methyl-1H-indol-5-yl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0670] ##STR00159##

[0671] To a solution of 1-(1-benzyl-3-methyl-1H-indol-5-yl)-3-phenylurea (Intermediate 60, 0.300 g, 0.0084 mol) in toluene (3.00 mL) was added ethoxycarbonyl isocyanate (0.194 g, 0.0016 mol) at 0° C. under nitrogen atmosphere. The resulting reaction mixture was heated at 110° C. for 16 h under nitrogen atmosphere. The reaction mixture was concentrated under reduce pressure to obtained the crude product. The crude product was purified on preparative chromatography using 5 mM ammonium bicarbonate+0.05% ammonia as a modifier in water:acetonitrile (0-100 as a gradient system) as mobile phases to obtain 0.016 g (4% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H) 5.38 (s, 2H) 7.04-7.09 (m, 1H) 7.21-7.27 (m, 3H) 7.28-7.36 (m, 3H) 7.37-7.52 (m, 7H) 11.89 (s, 1H); MS (ES−) m/z 423 [M−H].sup.−

Example 37

1-methyl-3-(3-methyl-1-phenyl-1H-indol-5-yl)-1,3,5-triazinane-2,4,6-trione

[0672] ##STR00160##

[0673] To a solution of 1-methyl-3-(3-methyl-1-phenyl-1H-indol-5-yl)urea (Intermediate 61, 0.070 g, 0.00025 mol) in toluene (0.70 mL) was added ethoxycarbonyl isocyanate (0.057 g, 0.00050 mol) at 0° C. under nitrogen atmosphere. The resulting reaction mixture was heated at 110° C. for 16 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtained the crude product. The crude product was purified on preparative chromatography using (5 mM ammonium bicarbonate+0.1% ammonia as a modifier) in water:acetonitrile (0-100% gradient system) as mobile phases to obtained 0.030 g (34% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) b ppm 2.32 (s, 3H) 3.17 (s, 3H) 7.08-7.13 (m, 1H) 7.35-7.44 (m, 1H) 7.52-7.64 (m, 7H) 11.75 (s, 1H); MS (ES+) m/z 349 [M+H].sup.+

Example 38

1-(1-benzyl-3-methyl-1H-indol-5-yl)-3-methyl-1,3,5-triazinane-2,4,6-trione

[0674] ##STR00161##

[0675] In a 10 ml seal tube previously equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.078 g, 0.00068 mol) was added to a solution of 1-(1-benzyl-3-methyl-1H-indol-5-yl)-3-methylurea (Intermediate 62, 0.100 g, 0.00034 mol) in toluene (1 mL) at 0° C. under N.sub.2(g). The reaction mixture was heated at 110° C. for 16 h under N.sub.2(g). The reaction mixture was concentrated under reduce pressure to obtained crude product. The crude product was purified by preparative HPLC purification with 5 mM ammonium bicarbonate+0.1% ammonia as modifier and water:acetonitrile (0-100% gradient system) as a mobile phase to yield 0.067 g (54% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 3.15 (s, 3H) 5.38 (s, 2H) 6.95-7.02 (m, 1H) 7.21-7.28 (m, 3H) 7.28-7.38 (m, 3H) 7.41-7.48 (m, 2H) 11.75 (s, 1H); MS (ES+) m/z 363 [M+H].sup.+

Example 39

1-(3-chloro-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0676] ##STR00162##

[0677] To a 10 ml microwave tube previously equipped with a magnetic stirrer, 1-(3-chloro-4-phenoxyphenyl)-3-phenylurea (Intermediate 63, 0.150 g, 0.0004 mol) and Bromobenzene (1.50 ml) was added and cooled to 0° C. Ethoxycarbonyl isocyanate (0.101 g, 0.0008 mol) was added and reaction mixture was allowed to reach to room temperature. The resulting reaction mixture was heated at 150° C. for 2 hours in a microwave oven. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC using 0.1% formic acid as modifier in water:acetonitrile (0-100% gradient system) as a mobile phase to yield 0.010 g (5.5% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 6.99-7.05 (m, 2H) 7.06-7.13 (m, 1H) 7.15-7.22 (m, 1H) 7.30-7.38 (m, 3H) 7.38-7.51 (m, 5H) 7.64-7.69 (m, 1H) 12.10 (s, 1H); MS (ES−) m/z 406 [M−H].sup.−

Example 40

1-(3-methyl-4-phenoxyphenyl)-3-(5-methylthiophen-2-yl)-1,3,5-triazinane-2,4,6-trione

[0678] ##STR00163##

[0679] In a microwave tube previously equipped with a magnetic stirrer 1-(3-methyl-4-phenoxyphenyl)-3-(5-methylthiophen-2-yl)urea (Intermediate 64, 0.200 g, 0.00059 mol) was dissolved in Chlorobenzene (2.0 ml) and cooled to 0° C. Ethyoxy carbonyl isocyanate (0.136 g, 0.00118 mol) was added to the mixture and the reaction mixture was allowed to reach room temperature and then heated at 130° C. for 4 hours in a microwave oven. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (55-100% Acetonitrile:Methanol (1:1) in water [0.1% Formic acid]) to yield 0.035 g (14% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.19 (s, 3H), 3.95 (s, 3H), 6.66-6.70 (m, 1H), 6.77-6.81 (m, 1H) 6.85-6.91 (m, 1H) 6.92-6.98 (m, 2H), 7.08-7.16 (m, 2H), 7.25 (s, 1H), 7.34-7.41 (m, 2H), 11.96 (s, 1H); MS (ES−) m/z 406 [M−H].sup.−

Example 41

1-(3-methyl-4-phenoxyphenyl)-3-(4-methylphenyl)-1,3,5-triazinane-2,4,6-trione

[0680] ##STR00164##

[0681] In a microwave vial previously equipped with a magnetic stirrer 1-(3-methyl-4-phenoxyphenyl)-3-(4-methylphenyl)urea (Intermediate 77, 0.23 g, 0.0006 mol) and bromobenzene (2.3 ml) was added and cooled to 0° C. Ethoxy carbonyl isocyanate (0.15 g, 0.0013 mol) was added and resulting reaction mixture was allowed to reach RT and then heated at 150° C. for 2 h in a microwave synthesizer. The solvent was evaporated under reduced pressure to obtain crude product that was purified by preparative HPLC (40-100% Acetonitrile in water [0.1% Formic acid]) to yield 0.023 g (8% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (s, 1H), 7.42-7.35 (m, 2H), 7.32-7.28 (m, 1H), 7.27-7.22 (m, 3H), 7.22-7.08 (m, 3H), 6.98-6.93 (m, 2H), 6.93-6.85 (m, 1H), 2.32 (s, 3H), 2.19 (s, 3H); MS (ES−) m/z 400 [M−H].sup.−

Example 42

1-(4-benzyl-3-methylphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0682] ##STR00165##

[0683] 1-(4-benzyl-3-methylphenyl)-3-phenylurea (Intermediate 74, 0.50 g, 0.0015 mol) and bromobenzene (5 ml) was added to a microwave vial with a magnetic stirrer and cooled to 0° C. Ethoxy carbonyl isocyanate (0.36 g, 0.0031 mol) was added and reaction mixture was allowed to reach RT. The resulting reaction mixture was heated at 150° C. for 2 hours in a microwave oven. The solvent was evaporated under reduced pressure and the crude product was purified by using preparative HPLC (15-100% acetonitrile in water [0.1% Formic acid]) to yield 40 mg (6% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (s, 1H), 7.53-7.29 (m, 7H), 7.26-7.11 (m, 6H), 4.00 (s, 2H), 2.25 (s, 3H); MS (ES−) m/z 384 [M−H].sup.−

Example 43

1-(3-chlorophenyl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0684] ##STR00166##

[0685] In a microwave vial previously equipped with a magnetic stirrer, 1-(3-chlorophenyl)-3-(3-methyl-4-phenoxyphenyl)urea (Intermediate 75, 0.30 g, 0.0008 mol) was added to bromobenzene (3.0 ml) and the mixture was cooled to 0° C. Ethoxy carbonyl isocyanate (0.19 g, 0.0017 mol) was added and resulting reaction mixture was allowed to reach RT and then heated at 150° C. for 2 h in microwave oven. The solvent was evaporated under reduce pressure to obtain crude product which was purified by preparative HPLC (20-100% Acetonitrile in water [0.1% Formic acid]) to yield 0.019 g (5% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.12 (s, 1H), 7.57-7.51 (m, 3H), 7.46-7.37 (m, 3H), 7.32 (d, J=2.5 Hz, 1H), 7.24-7.11 (m, 2H), 7.02-6.91 (m, 3H), 2.24 (s, 3H); MS (ES−) m/z 420 [M−H].sup.−

Example 44

1-(3-methyl-4-phenoxyphenyl)-3-[3-(trifluoromethoxy)phenyl]-1,3,5-triazinane-2,4,6-trione

[0686] ##STR00167##

[0687] In a microwave vial previously equipped with a magnetic stirrer 1-(3-methyl-4-phenoxyphenyl)-3-[3-(trifluoromethoxy)phenyl]urea (Intermediate 76, 0.40 g, 0.0009 mol) was added to bromobenzene (4.0 ml) the mixture was cooled to 0° C. Ethoxy carbonyl isocyanate (0.22 g, 0.0019 mol) was added and reaction mixture was allowed to reach RT and then heated at 150° C. for 2 h in a microwave synthesizer. The solvent was evaporated under reduced pressure to obtain crude product which was purified by preparative HPLC (25-100% Acetonitrile in water [5 mM Ammonium bicarbonate+0.1% NH3]) to yield 0.039 g (8% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.13 (s, 1H), 7.69-7.60 (m, 1H), 7.52-7.37 (m, 5H), 7.32 (d, J=2.5 Hz, 1H), 7.24-7.11 (m, 2H), 7.02-6.91 (m, 3H), 2.24 (s, 3H); MS (ES−) m/z 470 [M−H].sup.−

Example 45

1-(4-fluorophenyl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0688] ##STR00168##

[0689] In a microwave tube previously equipped with a magnetic stirrer 1-(4-fluorophenyl)-3-(3-methyl-4-phenoxyphenyl)urea (Intermediate 65, 0.100 g, 0.0002 mol) in bromobenzene (1.00 ml) was cooled to 0° C. Ethoxy carbonyl isocyanate was added and reaction mixture was allowed to reach RT and then heated at 150° C. for 2 h in microwave oven. The solvent was evaporated under reduced pressure and the crude product was purified by preparative HPLC (20-100% Acetonitrile in water [0.1% formic acid] to yield 0.011 g (9% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 6.90-7.01 (m, 3H), 7.11-7.24 (m, 2H), 7.28-7.38 (m, 3H), 7.38-7.48 (m, 4H), 12.07 (s, 1H); MS (ES−) m/z 404 [M−H].sup.−

Example 46

1-(1-benzofuran-5-yl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0690] ##STR00169##

[0691] Sodium hydride (60% in mineral oil, 7.25 mg, 0.18 mmol).) was added to a microwave vial containing a magnetic stirring bar. The vial was sealed and put under an inert atmosphere and the sodium hydride was washed with pentane. The pentane was thereafter removed, DMF (1 ml) was added and the dispersion was cooled to 0° C. 1-(benzofuran-5-yl)-3-(3-methyl-4-phenoxy-phenyl)urea (Intermediate 66, 26 mg, 0.07 mmol) was dissolved in DMF (1.5 ml) and added dropwise to the reaction vessel. The ice bath was removed and the reaction mixture was stirred for another 10 min. The solution was again cooled to 0° C. and ethoxycarbonyl isocyanate (11 μl, 0.11 mmol) was thereafter added, the ice bath was removed and the reaction mixture was stirred for 5 additional minutes before addition of water and EtOAc. The solvents were removed under reduced pressure. The crude from the water phase was purified by preparative RP-HPLC (30-90% acetonitrile in water [0.05% HCOOH]) to yield 8.8 mg (28% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.01 (br. s, 1H), 8.08 (d, J=2.2 Hz, 1H), 7.71-7.64 (m, 2H), 7.43-7.36 (m, 2H), 7.35-7.28 (m, 2H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 7.17-7.10 (m, 1H), 7.05-7.02 (m, 1H), 7.00-6.93 (m, 2H), 6.91 (d, J=8.6 Hz, 1H), 2.22 (s, 3H); ESI+m/z 428 (M+H)+

Example 47

1-(1H-indol-5-yl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0692] ##STR00170##

[0693] 1-(1H-indol-5-yl)-3-(3-methyl-4-phenoxy-phenyl)urea (Intermediate 67, 21 mg, 0.06 mmol) was dispersed in toluene (0.5 ml) in a microwave vial (0.5-2 ml), ethoxycarbonyl isocyanate (6 μl, 0.06 mmol) was added and the mixture was heated at 110° C. in an oil bath for 5 h and was thereafter left at room temperature overnight. The crude was concentrated at reduced pressure and the product was purified by preparative RP-HPLC (20-80% acetonitrile in water [0.05% HCOOH]) to yield 2 mg (6% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (br. s, 1H), 11.25 (s, 1H), 7.51 (d, J=1.9 Hz, 1H), 7.45-7.36 (m, 4H), 7.36-7.32 (m, 1H), 7.22 (dd, J=8.6, 2.4 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 7.04 (dd, J=8.6, 1.8 Hz, 1H), 6.99-6.94 (m, 2H), 6.91 (d, J=8.6 Hz, 1H), 6.50-6.45 (m, 1H), 2.21 (s, 3H); MS(ESI+) m/z 427 (M+H)+

Example 48

1-(2H-1,3-benzodioxol-5-yl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0694] ##STR00171##

[0695] Sodium hydride (60% in mineral oil, 33 mg, 0.82 mmol) was added to a microwave vial containing a magnetic stirring bar. The vial was sealed and put under an inert atmosphere and the sodium hydride was washed with pentane. The pentane was thereafter removed, DMF (1 ml) was added and the dispersion was cooled to 0° C. 1-(1,3-benzodioxol-5-yl)-3-(3-methyl-4-phenoxy-phenyl)urea (Intermediate 68, 119 mg, 0.33 mmol) was dissolved in DMF (2 ml) and added dropwise to the reaction vessel. The ice bath was removed and the reaction mixture was stirred for another 10 min. The solution was again cooled to 0° C. and ethoxycarbonyl isocyanate (51 μl, 0.49 mmol) was thereafter added, the ice bath was removed and the reaction mixture was stirred for 5 additional minutes before addition of water and EtOAc. The phases were separated and concentrated under reduced pressure.

[0696] The crude product originating from the water phase was purified by preparative RP-HPLC (20-80% acetonitrile in water [0.05% HCOOH]) to yield 10 mg (7% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (s, 1H), 7.44-7.36 (m, 2H), 7.30 (d, J=1.9 Hz, 1H), 7.18 (dd, J=8.8, 2.3 Hz, 1H), 7.14 (t, J=7.4 Hz, 1H), 7.01-6.94 (m, 4H), 6.91 (d, J=8.6 Hz, 1H), 6.85 (dd, J=8.2, 2.0 Hz, 1H), 6.09 (s, 2H), 2.22 (s, 3H).

[0697] MS(ESI+) m/z 432 (M+H)+

Example 49

1-(1H-indol-4-yl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0698] ##STR00172##

[0699] 1-(1H-indol-4-yl)-3(3-methyl-4-phenoxy-phenyl)urea (Intermediate 69, 118 mg, 0.33 mmol) was dispersed in toluene (2.5 ml) in a microwave vial, ethoxycarbonyl isocyanate (34 μl, 0.33 mmol) was added and the mixture was heated at 110° C. for 5 h and was thereafter left at room temperature overnight. The crude was concentrated at reduced pressure and the product was purified by preparative RP-HPLC (40-80% acetonitrile in water [0.05% HCOOH]) to yield 5 mg (3.5% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.96 (s, 1H), 11.26 (s, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.42-7.35 (m, 4H), 7.26 (dd, J=8.6, 2.4 Hz, 1H), 7.17-7.10 (m, 2H), 7.01 (d, J=7.5 Hz, 1H), 6.98-6.93 (m, 2H), 6.91 (d, J=8.6 Hz, 1H), 6.59-6.54 (m, 1H), 2.21 (s, 3H); MS(ESI+) m/z 427 (M+H)+

Example 50

1-(3-methoxyphenyl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0700] ##STR00173##

[0701] Sodium hydride (60% in mineral oil, 33 mg, 0.83 mmol) was weighed up in a microwave vial and a stirring bar was added. was added to a microwave vial containing a magnetic stirring bar. The vial was sealed and put under an inert atmosphere and the sodium hydride was washed with pentane. The pentane was thereafter removed, DMF (2 ml) was added and the dispersion was cooled to 0° C. 1-(3-methoxyphenyl)-3-(3-methyl-4-phenoxy-phenyl)urea (Intermediate 70,115 mg, 0.33 mmol) was dissolved in DMF (2 ml) and added dropwise to the reaction vessel. The ice bath was removed and the reaction mixture was stirred for another 10 min. The solution was again cooled to 0° C. and ethoxycarbonyl isocyanate (51 μl, 0.50 mmol) was added, the ice bath was removed and the reaction mixture was stirred for 5 additional minutes before addition of water and EtOAc. The phases were separated and concentrated under reduced pressure. The product in the concentrated water phase was purified by preparative RP-HPLC (40-80% acetonitrile in water [0.05% HCOOH]) to yield 40 mg (29% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (s, 1H), 7.44-7.34 (m, 3H), 7.32 (d, J=2.2 Hz, 1H), 7.22-7.17 (m, 1H), 7.17-7.10 (m, 1H), 7.03-6.94 (m, 5H), 6.92 (d, J=8.6 Hz, 1H), 3.77 (s, 3H), 2.22 (s, 3H); MS(ESI+) m/z 418 (M+H)+

Example 51

1-(2-methoxyphenyl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0702] ##STR00174##

[0703] Sodium hydride (60% in mineral oil, 34 mg, 0.85 mmol) was added to a microwave vial containing a magnetic stirring bar. The vial was sealed and put under an inert atmosphere and the sodium hydride was washed with pentane. The pentane was thereafter removed, DMF (2 ml) was added and the dispersion was cooled to 0° C. 1-(2-methoxyphenyl)-3-(3-methyl-4-phenoxy-phenyl)urea (Intermediate 71, 119 mg, 0.34 mmol) was dissolved in DMF solution (2 ml) and was added dropwise to the reaction vessel. The ice bath was removed and the reaction mixture was stirred for another 10 min. The solution was again cooled to 0° C. and ethoxycarbonyl isocyanate (53 μl, 0.51 mmol) was added, the ice bath was removed and the reaction mixture was stirred for 5 additional minutes before addition of water and EtOAc. The phases were separated and concentrated by reduced pressure.

[0704] The crude product originating from the water phase was purified by preparative RP-HPLC (40-80% acetonitrile in water [0.05% HCOOH]) to yield 54 mg (37% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.07 (br. s, 1H), 7.46-7.30 (m, 5H), 7.20 (dd, J=8.6, 2.5 Hz, 1H), 7.18-7.10 (m, 2H), 7.03 (td, J=7.6, 1.2 Hz, 1H), 6.99-6.93 (m, 2H), 6.91 (d, J=8.6 Hz, 1H), 3.79 (s, 3H), 2.22 (s, 3H); MS(ESI+) m/z 418 (M+H)+

Example 52

1-(3-methoxy-4-phenoxyphenyl)-3-(3-methoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0705] ##STR00175##

[0706] Sodium hydride (60% in mineral oil, 62 mg, 1.5 mmol) was added to a microwave vial containing a magnetic stirring bar. The vial was sealed and put under an inert atmosphere and the sodium hydride was washed with pentane. The pentane was thereafter removed, and the vessel was cooled to 0° C. 1-(3-methoxy-4-phenoxy-phenyl)-3-(3-methoxyphenyl)urea (Intermediate 72, 225 mg, 0.617 mmol) was dissolved in DMF (2 ml) and added dropwise to the reaction vessel containing the sodium hydride. The ice bath was removed and the reaction mixture was stirred for another 10 min. The solution was again cooled to 0° C. and ethoxycarbonyl isocyanate (96 μl, 0.93 mmol) was added, the ice bath was removed and the reaction mixture was stirred for 5 additional minutes before addition of water and EtOAc. The phases were separated and concentrated under reduced pressure. The crude product from the water phase was purified by preparative RP-HPLC (30-80% acetonitrile in water [0.05% HCOOH]) to yield 77 mg (28%) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.02 (br. s, 1H), 7.42-7.31 (m, 3H), 7.23 (d, J=2.3 Hz, 1H), 7.10-6.93 (m, 6H), 6.92-6.86 (m, 2H), 3.77 (s, 3H), 3.73 (s, 3H) MS(ESI+) m/z 434 (M+H)+

Example 53

1-(3-methoxy-4-phenoxyphenyl)-3-(4-methoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0707] ##STR00176##

[0708] Sodium hydride (60% in mineral oil, 36 mg, 0.90 mmol) was added to a microwave vial containing a magnetic stirring bar. The vial was sealed and put under an inert atmosphere and the sodium hydride was washed with pentane. The pentane was removed and the vial cooled to 0° C. 1-(3-methoxy-4-phenoxy-phenyl)-3-(4-methoxyphenyl)urea (Intermediate 73, 131 mg, 0.359 mmol) was dissolved in DMF solution (2 ml) and was added dropwise to the reaction vessel containing the sodium hydride. The ice bath was removed and the reaction mixture was stirred for another 10 min. The solution was again cooled to 0° C. and ethoxycarbonyl isocyanate (56 μl, 0.54 mmol) was added, the ice bath was removed and the reaction mixture was stirred for 5 additional minutes before addition of water and EtOAc. The phases were separated and concentrated under reduced pressure. The crude product from the water phase was purified by preparative RP-HPLC (30-80% acetonitrile in water [0.05% HCOOH]) to yield 11 mg (7% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.98 (br. s, 1H), 7.38-7.32 (m, 2H), 7.31-7.25 (m, 2H), 7.24 (d, J=2.3 Hz, 1H), 7.10-7.04 (m, 2H), 7.04-6.99 (m, 2H), 6.99-6.96 (m, 1H), 6.92-6.86 (m, 2H), 3.79 (s, 3H), 3.73 (s, 3H); MS(ESI+) m/z 434 (M+H)+

Example 54

1-(2,5-dimethyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0709] ##STR00177##

[0710] In a microwave vial previously equipped with a magnetic stirrer 1-(2,5-dimethyl-4-phenoxyphenyl)-3-phenylurea (Intermediate 79, 0.20 g, 0.0006 mol) and chlorobenzene (2.0 ml) was added. The solution was cooled to 0° C. and Ethoxy carbonyl isocyanate (0.20 g, 0.0018 mol) was added and reaction mixture was allowed to reach RT and then heated at 130° C. for 2 hours in a microwave synthesizer. The solvent was evaporated under reduced pressure and the crude product was purified by preparative HPLC (45-100% Acetonitrile in water [0.1% Formic acid]) to yield 0.093 g (38%) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.07 (s, 1H), 7.54-7.45 (m, 3H), 7.45-7.37 (m, 4H), 7.30 (s, 1H), 7.18-7.10 (m, 1H), 6.99-6.92 (m, 2H), 6.82 (s, 1H), 2.17 (s, 3H), 2.10 (s, 3H); MS(ESI−) m/z 400 (M−H)−

Example 55

1-methyl-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0711] ##STR00178##

[0712] In a microwave vial previously equipped with a magnetic stirrer 1-methyl-3-(3-methyl-4-phenoxyphenyl)urea (Intermediate 78, 0.35 g, 0.0013 mol) and bromobenzene (3.5 ml) was added and the solution cooled to 0° C. Ethoxy carbonyl isocyanate (0.31 g, 0.0027 mol) was added and reaction mixture was allowed to reach RT and then heated at 150° C. for 2 h in a microwave synthesizer. The solvent was evaporated under reduced pressure and the crude product was purified by preparative HPLC (30-100% Acetonitrile in water [0.1% Formic acid]) to yield 0.070 g (15% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.84 (s, 1H), 7.47-7.37 (m, 2H), 7.30-7.27 (m, 1H), 7.21-7.11 (m, 2H), 7.04-6.96 (m, 2H), 6.95-6.88 (m, 1H), 3.16 (s, 3H), 2.22 (s, 3H); MS(ESI−) m/z 324 (M−H)−

Example 56

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-methylphenyl)-1,3,5-triazinane-2,4,6-trione

[0713] ##STR00179##

[0714] In a microwave vial previously equipped with a magnetic stirrer 1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-methylphenyl)urea (Intermediate 80, 0.20 g, 0.0005 mol) and bromobenzene (2.0 ml) was added and the solution cooled to 0° C., Ethoxy carbonyl isocyanate (0.17 g, 0.0015 mol) was added and reaction mixture was heated at 150° C. for 3 h in a microwave synthesizer. The solvent was evaporated under reduced pressure and the crude product was purified by preparative HPLC (40-100% Acetonitrile in water [0.1% Formic acid]) to yield 0.032 g (13% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.02 (s, 1H), 6 7.42-7.33 (m, 2H), 7.33-7.19 (m, 5H), 7.13-7.03 (m, 2H), 7.02-6.90 (m, 3H), 4.06 (t, J=4.6 Hz, 2H), 3.53 (t, J=4.5 Hz, 2H), 3.19 (s, 3H), 2.36 (s, 3H); MS(ESI−) m/z 460 (M−H)−

Example 57

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-methylphenyl)-1,3,5-triazinane-2,4,6-trione

[0715] ##STR00180##

[0716] In a microwave vial previously equipped with a magnetic stirrer 1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-methylphenyl)urea (Intermediate 81, 0.29 g, 0.0007 mol) and bromobenzene (2.90 ml) was added and cooled to 0° C. Ethoxy carbonyl isocyanate (0.25 g, 0.0022 mol) was added and the reaction mixture was heated at 150° C. for 2 h. The solvent was evaporated under reduced and the crude product was purified by preparative HPLC (30-100% Acetonitrile in water [0.1% Formic acid]) to yield 0.030 g (8% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.04 (s, 1H), 7.42-7.33 (m, 3H), 7.30-7.22 (m, 2H), 7.21-7.15 (m, 2H), 7.14-7.06 (m, 2H), 7.04-6.97 (m, 1H), 6.97-6.91 (m, 2H), 4.06 (t, J=4.5 Hz, 2H), 3.54 (t, J=4.4 Hz, 2H), 3.19 (s, 3H), 2.36 (s, 3H); MS(ESI−) m/z 460 (M−H)−

Example 58

1-(3-chlorophenyl)-3-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-1,3,5-triazinane-2,4,6-trione

[0717] ##STR00181##

[0718] In a microwave vial previously equipped with a magnetic stirrer 1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-chlorophenyl)urea (Intermediate 82, 0.12 g, 0.0002 mol) and bromobenzene (1.2 ml) was added and cooled to 0° C., Ethoxy carbonyl isocyanate (0.060 g, 0.0005 mol) was added and the reaction mixture was heated to 150° C. for 2 h. The solvent was evaporated under reduced pressure and the crude product was purified by preparative HPLC (15-100% Acetonitrile in water [5 mM Ammonium bicarbonate+0.1% NH3]) to yield 8.5 mg (6% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) b ppm 12.14 (s, 1H), 7.60-7.50 (m, 3H), 7.42-7.32 (m, 3H), 7.20 (d, J=2.3 Hz, 1H), 7.12-7.05 (m, 2H), 7.00-6.90 (m, 3H), 4.06 (t, J=4.6 Hz, 2H), 3.53 (t, J=4.5 Hz, 2H), 3.18 (s, 3H); MS(ESI−) m/z 480 (M−H)−

Example 59

1-(4-chlorophenyl)-3-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-1,3,5-triazinane-2,4,6-trione

[0719] ##STR00182##

[0720] In a microwave vial previously equipped with a magnetic stirrer, 1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-chlorophenyl)urea (Intermediate 83, 0.22 g, 0.0005 mol) and bromobenzene (2.20 ml) was added and the solution was cooled to 0° C. Ethoxy carbonyl isocyanate (0.18 g, 0.00159 mol) was added and the reaction mixture was heated at 150° C. in a microwave synthesizer for 3 h. The solvent was evaporated under reduced pressure to obtain crude product that was purified by preparative HPLC (40-100% Acetonitrile:Methanol (1:1) in water [0.1% Formic acid]) to yield 10 mg (3.8% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.14 (s, 1H), 7.60-7.54 (m, 2H), 7.46-7.33 (m, 4H), 7.22 (d, J=2.3 Hz, 1H), 7.13-7.05 (m, 2H), 7.00-6.91 (m, 3H), 4.06 (t, J=4.6 Hz, 2H), 3.54 (t, J=4.5 Hz, 2H), 3.19 (s, 3H); MS(ESI−) m/z 480 (M−H)−

Example 60

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-methoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0721] ##STR00183##

[0722] In a microwave vial previously equipped with a magnetic stirrer 1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(4-methoxyphenyl)urea (Intermediate 84, 0.24 g, 0.0005 mol) and bromobenzene (2.4 ml) was added and the solution was cooled to 0° C. Ethoxy carbonyl isocyanate (0.27 g, 0.0023 mol) was added to the reaction mixture and it was heated at 150° C. in a microwave synthesizer for 3 h. The solvent was evaporated under reduced pressure to obtain crude product that was purified by preparative HPLC (30-100% Acetonitrile in water [0.1% Formic acid]) to yield 16 mg (5% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.01 (s, 1H), 7.42-7.32 (m, 2H), 7.32-7.22 (m, 3H), 7.15-6.91 (m, 7H), 4.07 (t, J=4.5 Hz, 2H), 3.81 (s, 3H), 3.54 (t, J=4.6 Hz, 2H), 3.19 (s, 3H); MS(ESI−) m/z 476 (M−H)−

Example 61

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-methoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0723] ##STR00184##

[0724] In a microwave vial, previously equipped with a magnetic stirrer, 1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(3-methoxyphenyl)urea (Intermediate 85, 0.25 g, 0.0006 mol) and bromobenzene (2.5 ml) was added and the solution was cooled to 0° C. Ethoxy carbonyl isocyanate (0.28 g, 0.0024 mol) was slowly added and reaction mixture was heated at 150° C. for 3 h. The solvent was evaporated under reduced pressure and the crude product was purified by preparative HPLC (45-100% Acetonitrile in water [0.1% Formic acid]) to yield 0.025 g (8% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.04 (s, 1H), 7.45-7.33 (m, 3H), 7.25 (d, J=2.3 Hz, 1H), 7.15-7.01 (m, 2H), 7.05-6.91 (m, 6H), 4.07 (t, J=4.6 Hz, 2H), 3.79 (s, 3H), 3.54 (t, J=4.6 Hz, 2H), 3.19 (s, 3H); MS(ESI−) m/z 476 (M−H)−

Example 62

1-[3-methyl-4-(2-methylphenoxy)phenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0725] ##STR00185##

[0726] In a microwave vial previously equipped with a magnetic stirrer, 1-[3-methyl-4-(2-methylphenoxy)phenyl]-3-phenylurea (Intermediate 86, 0.23 g, 0.0006 mol) in chlorobenzene (2.30 ml) was added and cooled to 0° C. Ethoxy carbonyl isocyanate (0.23 g, 0.0020 mol) was added and reaction mixture was heated at 130° C. for 2 h. The solvent was evaporated under reduced pressure and the crude product was purified by the preparative HPLC (55-100% Acetonitrile:Methanol (1:1) in water [0.1% Formic acid]) to yield 9 mg (3% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.93 (s, 1H), 7.52-7.40 (m, 3H), 7.40-7.32 (m, 3H), 7.31-7.27 (m, 1H), 7.25-7.18 (m, 1H), 7.17-7.06 (m, 2H), 6.82 (d, J=7.9 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 2.27 (s, 3H), 2.21 (s, 3H); MS(ESI−) m/z 400 (M−H)−

Example 63

1-(3-methyl-4-phenoxyphenyl)-3-(1,3-thiazol-4-yl)-1,3,5-triazinane-2,4,6-trione

[0727] ##STR00186##

[0728] In a microwave vial previously equipped with a magnetic stirrer, 1-(3-methyl-4-phenoxyphenyl)-3-(1,3-thiazol-4-yl)urea (Intermediate 87, 0.30 g, 0.0009 mol) in bromobenzene (3.0 ml) was added and cooled to 0° C. Ethoxy carbonyl isocyanate (0.42 g, 0.0036 mol) was added at 0° C. and the reaction mixture was allowed to reach RT and then heated at 150° C. for 3 h in a microwave synthesizer. The solvent was evaporated under reduced pressure and the crude product was purified by Combi-flash chromatography using 45% ethyl acetate in hexanes as an eluent to yield 16 mg (4% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.13 (s, 1H), 9.14 (d, J=2.2 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.45-7.32 (m, 3H), 7.23 (dd, J=8.5, 2.6 Hz, 1H), 7.14 (t, J=7.4 Hz, 1H), 7.01-6.95 (m, 2H), 6.93-6.88 (m, 1H), 2.22 (s, 3H); MS(ESI−) m/z 393 (M−H)−

Example 64

1-[4-(4-chlorophenoxy)phenyl]-3-methyl-1,3,5-triazinane-2,4,6-trione

[0729] ##STR00187##

[0730] In a microwave vial previously equipped with a magnetic stirrer, Ethoxy carbonyl isocyanate (0.074 g, 0.00065 mol) was added to a solution of 1-[4-(4-chlorophenoxy)phenyl]-3-methylurea (Intermediate 88, 0.120 g, 0.00043 mol) in Toluene (1.20 ml) at 0° C. The reaction mixture was heated at 110° C. for 16 h and quenched with ice-water (50 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layer was washed with brine (30 ml), dried over sodium sulfate and the solvent removed under reduced pressure to obtain 0.140 g (93% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.15 (s, 3H) 7.06-7.15 (m, 4H) 7.31-7.37 (m, 2H) 7.46-7.52 (m, 2H) 11.82 (s, 1H); MS (ES−) m/z 344 [M−H].sup.−

Example 65

1-(3-chloro-4-phenoxyphenyl)-3-methyl-1,3,5-triazinane-2,4,6-trione

[0731] ##STR00188##

[0732] 1-(3-Chloro-4-phenoxyphenyl)-3-methylurea (Intermediate 89, 0.145 g, 0.00052 mol) in bromobenzene (1.45 ml) was added to a microwave tube previously equipped with a magnetic stirrer and cooled to 0° C. Ethoxy carbonyl isocyanate (0.120 g, 0.00104 mol) was added and reaction mixture was heated at 150° C. for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (30-100% Acetonitrile in water [5 mM ammonium bicarbonate and 0.1% ammonia]) to yield 0.020 g (11% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6): δ 11.86 (s, 1H), 6 7.64 (d, J=2.4 Hz, 1H), 7.45 (t, J=7.9 Hz, 2H), 7.32 (dd, J=8.7, 2.5 Hz, 1H), 7.21 (t, J=7.4 Hz, 1H), 7.11 (d, J=8.7 Hz, 1H), 7.05 (d, J=8.1 Hz, 2H), 3.15 (s, 3H). MS(ESI−) m/z 344.49 (M−H)−

Example 66

1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(5-methylthiophen-2-yl)-1,3,5-triazinane-2,4,6-trione

[0733] ##STR00189##

[0734] In a microwave vial previously equipped with a magnetic stirrer was taken 1-[3-(2-methoxyethoxy)-4-phenoxyphenyl]-3-(5-methylthiophen-2-yl)urea (Intermediate 90, 0.32 g, 0.0008 mol) and chlorobenzene (6.4 ml). The solution was cooled to 0° C. and Ethoxy carbonyl isocyanate (0.37 g, 0.0032 mol) was added. The reaction mixture was allowed to reach room temperature and then heated at 130° C. for 3 h in an Anton paar microwave synthesizer-300. The solvent was evaporated under reduced pressure and the crude product was purified by preparative RP-HPLC (15-100% acetonitrile in water [10 mM Ammonium acetate]) to yield 5 mg (1.3% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.10 (s, 1H), 7.42-7.33 (m, 2H), 7.24 (d, J=2.0 Hz, 1H), 7.12-7.06 (m, 2H), 6.99-6.93 (m, 3H), 6.87 (d, J=3.6 Hz, 1H), 6.74 (m, 1H), 4.06 (t, J=4.0 Hz, 2H), 3.53 (t, J=4.4 Hz, 2H), 3.19 (s, 3H), 2.46 (s, 3H). MS (ES−) m/z 466 [M−H].sup.−

Example 67

1,3-bis(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0735] ##STR00190##

[0736] In a microwave vial previously equipped with a magnetic stirrer, 1,3-bis(3-methyl-4-phenoxyphenyl)urea (Intermediate 91, 0.30 g, 0.0007 mol) in Bromobenzene (3 ml) was added and the mixture was cooled to 0° C. Ethoxy carbonyl isocyanate (0.32 g, 0.0028 mol) was added and the resulting reaction mixture was allowed to reach room temperature and then heated at 150° C. for 3 h in an Anton paar microwave synthesizer-300. The solvent was evaporated under reduce pressure to obtain crude product. The crude product was purified by preparative RP-HPLC (40-100% acetonitrile in water [0.1% formic acid]) to yield 52 mg (14% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (s, 1H), 7.46-7.37 (m, 4H), 7.33 (d, J=2.5 Hz, 2H), 7.21 (dd, J=8.8, 2.4 Hz, 2H), 7.15 (t, J=7.6 Hz, 2H), 7.02-6.90 (m, 6H), 2.11 (s, 6H). MS(ESI−) m/z 492 [M−H].sup.−

Example 68

1-(3-methyl-4-phenoxyphenyl)-3-(1-phenyl-1H-pyrazol-4-yl)-1,3,5-triazinane-2,4,6-trione

[0737] ##STR00191##

[0738] In a microwave tube previously equipped with a magnetic stirrer 1-(3-methyl-4-phenoxyphenyl)-3-(1-phenyl-1H-pyrazol-4-yl)urea (Intermediate 93, 0.23 g, 0.0008 mol) in Bromobenzene (3.0 ml) was added and the mixture was cooled to 0° C. Ethoxy carbonyl isocyanate (0.19 g, 0.0017 mol) was added and the reaction mixture was allowed to reach room temperature and heated at 150° C. for 2 h in an Anton paar microwave synthesizer-300. The solvent was evaporated under reduce pressure and the crude product was purified by preparative RP-HPLC (25-100% acetonitrile in water [5 mM ammonium bicarbonate+0.1% NH.sub.3]) to yield 52 mg (19% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.15 (s, 1H), 8.67 (s, 1H), 7.88-7.83 (m, 3H), 7.62-7.50 (m, 2H), 7.45-7.33 (m, 4H), 7.23 (d, J=8.4, 1H), 7.15 (t, J=7.2 Hz, 1H), 7.03-6.91 (m, 3H), 2.24 (s, 3H). MS (ES−) m/z 452 [M−H].sup.−

Example 69

1-(3-bromo-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0739] ##STR00192##

[0740] In a microwave vial previously equipped with a magnetic stirrer 1-(3-bromo-4-phenoxyphenyl)-3-phenylurea (Intermediate 94, 0.50 g, 0.0013 mol) in bromobenzene (5.0 ml) was added and the mixture was cooled to 0° C. Ethoxy carbonyl Isocyanate (0.60 g, 0.0052 mol) was added at 0° C. and the resulting reaction mixture was allowed to reach room temperature and heated at 150° C. for 3 h in an Anton paar microwave synthesizer-300. The solvent was evaporated under reduced pressure and the crude product was purified by using preparative RP-HPLC (50-100% acetonitrile in water [0.1% formic acid]) to yield 5 mg (0.85% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) b ppm 12.11 (s, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.52-7.36 (m, 8H), 7.22 (app t, J=7.2 Hz, 1H), 7.13-7.02 (m, 3H). MS (ES−) m/z 452 [M−H].sup.−

Example 70

1-(2-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0741] ##STR00193##

[0742] In a microwave vial previously equipped with a magnetic stirrer 1-(2-methyl-4-phenoxyphenyl)-3-phenylurea (Intermediate 95, 0.20 g, 0.0006 mol) in bromobenzene (2.0 ml) was added and the mixture was cooled to 0° C. Ethoxy carbonyl isocyanate (0.28 g, 0.0025 mol) was added and the reaction mixture was allowed to reach room temperature and heated at 150° C. for 3 h in an Anton paar microwave synthesizer-300. The solvent was evaporated under reduced pressure and the crude product was purified by preparative RP-HPLC (40-100% acetonitrile in water [0.1% formic acid]) to yield 30 mg (yield 12%) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.06 (s, 1H), 7.53-7.31 (m, 8H), 7.19 (t, J=7.2 Hz, 1H), 7.12-7.05 (m, 2H), 6.98-6.83 (m, 2H), 2.15 (s, 3H). MS (ES−) m/z 386 [M−H].sup.−

Example 71

1-(2-methyl-4-phenoxyphenyl)-3-(4-methylphenyl)-1,3,5-triazinane-2,4,6-trione

[0743] ##STR00194##

[0744] In a microwave via previously equipped with a magnetic stirrer 1-(2-methyl-4-phenoxyphenyl)-3-(4-methylphenyl)urea (Intermediate 97, 0.40 g, 0.0012 mol) in bromobenzene (4.0 ml) was added and the mixture was cooled to 0° C. Ethoxy carbonyl isocyanate (0.55 g, 0.0048 mol) was added and reaction mixture was allowed to reach room temperature and heated at 150° C. for 3 h in an Anton paar microwave synthesizer-300. The solvent was removed under reduced pressure to obtain crude product that was purified by preparative RP-HPLC (30-100% acetonitrile in water [0.1% formic acid]) to yield 12 mg (2% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.03 (s, 1H), 7.48-7.40 (m, 2H), 7.34 (d, J=8.8 Hz, 1H), 7.27 (app s, 4H), 7.20 (t, J=7.2 Hz, 1H), 7.10-7.05 (m, 2H), 6.95 (d, J=2.4 Hz, 1H), 6.88 (dd, J=8.4, 2.8 Hz, 1H), 2.35 (s, 3H), 2.14 (s, 3H). MS (ES−) m/z 400 [M−H].sup.−

Example 72

1-(1-benzofuran-4-yl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0745] ##STR00195##

[0746] In a microwave tube previously equipped with a magnetic stirrer 1-(1-benzofuran-4-yl)-3-(3-methyl-4-phenoxyphenyl)urea (Intermediate 98, 0.25 g, 0.0006 mol) in bromobenzene (2.5 ml) was added and the mixture was cooled to 0° C. Ethoxy carbonyl isocyanate (0.32 g, 0.0027 mol) was added at 0° C. and the reaction mixture was allowed to reach room temperature and heated at 150° C. for 3 h in an Anton paar microwave synthesizer-300. The solvent was removed under reduced pressure to obtain the crude product that was purified by preparative RP-HPLC (20-100% acetonitrile in water [0.1% formic acid]) to yield 16 mg (5% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.10 (s, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.42-7.38 (m, 4H), 7.31-7.25 (m, 2H), 7.21-7.10 (m, 2H), 7.00-6.90 (m, 3H), 2.23 (s, 3H). MS (ES−) m/z 426 [M−H].sup.−

Example 73

1-(1-benzofuran-7-yl)-3-(3-methyl-4-phenoxyphenyl)-1,3,5-triazinane-2,4,6-trione

[0747] ##STR00196##

[0748] In a microwave vial previously equipped with a magnetic stirrer, 1-(1-benzofuran-7-yl)-3-(3-methyl-4-phenoxyphenyl)urea (Intermediate 99, 0.50 g, 0.00139 mol) in bromobenzene (5.0 ml) was added and the mixture was cooled to 0° C. Ethoxy carbonyl Isocyanate (0.64 g, 0.00558 mol) was added at 0° C. and reaction mixture was allowed to reach room temperature and heated at 150° C. for 3 h in an Anton paar microwave synthesizer-300. The solvent was removed under reduced pressure to obtain crude product that was purified by preparative RP-HPLC (40-100% acetonitrile in water [0.1% formic acid]) to yield mg (5% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.25 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.76 (dd, J=7.6, 1.2 Hz, 1H), 7.45-7.33 (m, 5H), 7.27 (dd, J=8.4, 2.4 Hz, 1H), 7.13 (t, J=7.2 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.00-6.90 (m, 3H), 2.22 (s, 3H). MS (ES−) m/z 426 [M−H].sup.−

Example 74

methyl 2-phenoxy-5-(2,4,6-trioxo-3-phenyl-1,3,5-triazinan-1-yl)benzoate

[0749] ##STR00197##

[0750] In a microwave tube previously equipped with a magnetic stirrer and nitrogen balloon was taken methyl 2-phenoxy-5-[(phenylcarbamoyl)amino]benzoate (1.75 g, 4.8 mmol) (described in WO 2003029199) in bromobenzene (8.75 ml) and the mixture was cooled to 0° C. Ethoxy carbonyl isocyanate (2.2 g, 19.3 mmol) was added and reaction mixture was allowed to reach room temperature and heated at 150° C. for 3 h in a microwave synthesizer. The solvent was evaporated under reduced pressure the crude product was purified by column chromatography using silica gel (100-200 mesh) and 50% ethyl acetate in hexanes as an eluent to obtain 0.260 g (12% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.07 (s, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.60 (dd, J=8.8, 2.4 Hz, 1H), 7.50-7.36 (m, 7H), 7.19 (t, J=7.2 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 7.03 (d, J=7.6 Hz, 2H), 3.76 (s, 3H); MS (ES−) m/z 430 [M−H].sup.−.

Example 75

1-[3-(hydroxymethyl)-4-phenoxyphenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0751] ##STR00198##

[0752] In a RBF previously equipped with a magnetic stirrer and nitrogen balloon was taken methyl 2-phenoxy-5-(2,4,6-trioxo-3-phenyl-1,3,5-triazinan-1-yl)benzoate (Example 74, 0.20 g, 0.4 mmol) in THF (2.0 ml) and the solution was cooled to 0° C. A 60% Red-Al solution in Toluene (0.186 ml, 0.5 mmol) was added drop wise and the reaction mixture was stirred for 3 h at 25° C. The reaction mixture was quenched with water (15 ml) and ethyl acetate (20 ml) was added and the mixture was stirred for 10 min. The organic layer was separated and the aqeuous layer was extracted with ethyl acetate (20 ml). The combined organic layer was washed with brine (20 ml), dried over sodium sulphate and the solvent removed under reduced pressure. The crude product was purified by preparative HPLC (using 25-100% acetonitrile in water [0.1% formic acid] as mobile phase) to yield 0.006 g (13% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.00 (s, 1H), 7.58 (d, J=2.5 Hz, 1H), 7.51-7.39 (m, 7H), 7.25 (dd, J=8.4, 2.0 Hz, 1H), 7.17 (t, J=7.2 Hz, 1H), 7.01 (d, J=7.6 Hz, 2H), 6.89 (d, J=8.4 Hz, 1H), 5.37 (t, J=5.2 Hz, 1H), 4.58 (d, J=5.2 Hz, 2H). MS (ES−) m/z 402 [M−H].sup.−.

Example 76

[0753] 1-{3-[2-(Dimethylamino)-2-oxoethyl]-4-phenoxyphenyl}-3-phenyl-1,3,5-triazinane-2,4,6-trione

##STR00199##

[0754] 1-(Dimethylamino)-2-[2-phenoxy-5-(3-phenylureido)phenyl]-1-ethanone (Intermediate 103, 0.05 g, 0.1 mmol) in Bromobenzene (0.5 ml) was added to a microwave vial previously equipped with a magnetic stirrer and nitrogen balloon and the mixture was cooled to 0° C. Ethoxy carbonyl isocyanate (0.05 g, 0.5 mmol) was added and the reaction mixture was allowed to reach room temperature and heated at 150° C. for 3 h in a microwave synthesizer. The solvent was removed under reduced pressure to give a crude product. The above steps were performed with equivalent ways in 4 parallel reaction vials, which were combined during purification. The crude product was purified by preparative RP-HPLC (using 10-100% acetonitrile in water [0.1% formic acid] as mobile phase) to yield 0.006 g (2.5% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 12.02 (s, 1H), 7.49-7.36 (m, 7H), 7.28-7.13 (m, 3H), 7.04 (d, J=7.6 Hz, 2H), 6.84 (d, J=8.0 Hz, 1H), 3.72 (s, 2H), 2.99 (s, 3H), 2.80 (s, 3H); MS (ES−) m/z 457 [M−H].sup.−.

Example 77

1-{3-[2-(Dimethylamino)-2-oxoethoxy]-4-phenoxyphenyl}-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0755] ##STR00200##

[0756] 1-(Dimethylamino)-2-[2-phenoxy-5-(3-phenylureido)phenoxy]-1-ethanone (Intermediate 107, 0.50 g, 1.2 mmol) in Bromobenzene (5 ml) was added to a microwave tube previously equipped with a magnetic stirrer and nitrogen balloon, and the mixture was cooled to 0° C. Ethoxy carbonyl isocyanate (0.56 g, 4.9 mmol) was added and reaction mixture was allowed to reach room temperature and heated at 150° C. for 3 h in a microwave synthesizer. The solvent was removed under reduced pressure and the crude product was purified by preparative RP-HPLC (using 20-100% acetonitrile in water [0.1% formic acid] as mobile phase) to yield 0.022 g (3.7% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.07 (s, 1H), 7.52-7.34 (m, 7H), 7.18-7.07 (m, 3H), 7.02-6.96 (m, 3H), 4.79 (s, 2H), 2.89 (s, 3H), 2.81 (s, 3H); MS (ES−) m/z 473 [M−H].sup.−.

[0757] The compounds below has been prepared according to analogous methods to those described above.

Example 78

1-(5-Methyl-6-phenoxypyridin-3-yl)-3-(p-tolyl)-1,3,5-triazinane-2,4,6-trione

[0758] ##STR00201##

[0759] In a microwave tube previously equipped with a magnetic stirrer and nitrogen balloon was taken 3-(5-Methyl-6-phenoxy-3-pyridyl)-1-(4-methylphenyl)urea (Intermediate 109, 0.3 g, 0.00089 mol) in Bromobenzene (3.0 ml). The solution was cooled to 0° C. and Ethoxy carbonyl isocyanate (0.44 g, 0.00359 mol) was added and resulting reaction mixture was allowed to reach room temperature and heated at 150° C. for 3 h in an Anton paar microwave synthesizer-300. The solvent was evaporated under reduced pressure to obtain crude product that was purified purified by preparative RP-HPLC (using 25-100% acetonitrile in water [0.1% formic acid] as mobile phase) to yield 0.012 g (3.3% yield) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.09 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.75 (s, 1H), 7.49-7.41 (m, 2H), 7.29-7.23 (m, 5H), 7.20-7.13 (m, 2H), 2.35 (s, 6H). MS (ES−) m/z 401 [M−H].sup.−.

Biological Examples

[0760] In Vitro Assay

[0761] A high throughput cell-based screen has been used to identify positive modulators of TrkA, TrkB and TrkC. The screen involves the use of cell-based assay overexpressing TrkA, TrkB or TrkC. The purpose of the assay is to identify compounds that modulate neurotrophin signalling (Forsell et al 2012). The assay can be used in inhibitor mode using a high concentration of ligand, in modulator mode using an intermediate concentration and in agonist mode using a low concentration of ligand.

[0762] The assay uses Enzyme Fragment Complementation (EFC) technique, which is a proximity-based assay. Briefly, cells used in this assay over-express two fusion proteins, i.e. the receptor, which can be either one of TrkA, TrkB, TrkC, IGF1R or FGFR1, fused to a small peptide of beta-galactosidase and an adaptor protein, i.e. SHC1 (or any other Trk-adaptor protein) fused to the major part of beta-galactosidase. Ligand binding to the receptor induces phosphorylation of the intracellular domain and hence, recruitment of the adaptor protein to the receptor. The proximity between the small activating peptide on the receptor and the major part of beta-galactosidase on the adaptor protein leads to an active beta-galactosidase enzyme. The activation of the receptor is quantified by measuring the amount of active beta-galactosidase by its conversion of a non-luminescent substrate into a luminescent product.

[0763] U2OS-cells, over-expressing TrkA or TrkB or TrkC, are plated in 96- or 384-well plates and incubated overnight. Alternatively, cryopreserved HEK293-cells expressing IGFR1 or cryopreserved U2OS-cells expressing FGFR1 were plated in 96- or 384-well plates. On the following day, test compound was pre-mixed with ligand (NGF, BDNF, NT-3, IGF-1 or basic fibroblast growth factor (bFGF(FGF-2))) and the ligand-compound mixture is then added to the cells to yield a final ligand concentration of 10 ng/mL. After 3 hours of incubation at room temperature, the incubation is stopped by the addition of a beta-galactosidase substrate mixture containing detergents. The substrate mixture is incubated for 60 minutes at ambient temperature. The luminescence is thereafter read by the use of a plate reader.

Results

[0764] Data from these assays for representative compounds is shown in the Table below. The potency is expressed as EC50 (μM) for the individual receptors. The data indicate that the compounds of the invention are expected to possess useful therapeutic properties.

Results

[0765]

TABLE-US-00001 Example TrkA TrkB TrkC FGFR1 IGF1R 1 1.3 1.4 1.4 0.89 1.8 2 1.4 2.4 3 6.7 4 0.83 0.95 0.58 0.84 5 0.34 0.39 0.29 0.25 6 4.4 4.4 7 3.9 2.6 8 1.6 2.2 9 0.23 0.27 0.17 0.27 10 1.1 2.2 2.8 11 0.32 0.45 0.34 0.22 12 5.9 2.4 4.7 13 0.62 0.45 14 0.49 15 0.59 0.65 1.1 16 0.39 0.37 0.51 17 0.78 0.75 0.48 18 0.87 0.14 19 0.82 0.88 20 6.9 8.9 3.2 21 2.1 2.3 1.2 22 1.3 3.6 3.0 23 1.0 0.92 0.77 24 0.5 0.61 0.22 25 0.55 0.79 1.0 26 1.1 1.5 2.0 27 0.36 0.37 0.33 28 1.0 0.99 0.52 29 0.56 0.5 0.34 30 1.1 7.5 0.89 31 46 69 32 0.8 33 0.23 0.1 34 1.6 2.0 1.2 35 0.98 0.26 0.50 36 0.95 0.46 1.5 37 0.39 0.04 38 4.5 4.2 2.4 39 1.4 0.68 0.88 40 0.26 0.28 0.14 41 0.25 0.21 0.14 42 0.19 0.28 43 0.16 0.12 44 0.33 0.26 45 0.47 0.36 46 0.48 0.24 47 0.48 0.27 48 0.5 0.26 49 0.19 0.79 2.0 50 0.31 0.19 51 0.18 0.26 52 0.38 0.41 53 0.96 0.78 54 0.44 0.31 55 0.39 1.4 56 0.29 0.11 0.17 57 0.18 0.12 0.09 58 0.22 0.23 0.18 59 0.48 0.46 0.33 60 0.3 0.22 61 0.42 0.38 62 0.93 3.18 63 2.38 0.95 64 4.4 5.9 9.6 65 4.5 1.6 0.32 66 0.37 0.37 67 3.2 26 68 0.23 0.36 1.1 69 0.22 0.25 0.19 70 0.66 0.35 71 1.66 0.61 72 0.20 0.11 73 0.14 0.10 74 0.58 0.54 75 1.17 1.8 76 33 4.53 77 0.43 0.36 78 3.51 3.83

In Vivo Assay

Passive Avoidance Task

[0766] Passive avoidance (PA) is an aversive learning task based on classical (Pavlovian) fear conditioning that allows for analysis of both facilitation and impairment of memory function by adjusting the unconditioned stimulus, i.e. the electrical foot shock. Commonly a cognitive-impairing agent is administered to the animals to mimic the neurochemical disturbances present in various cognitive disorders e.g. cholinergic (scopolamine) and glutamatergic (MK-801) deficits.

[0767] Prior to testing, the animals are brought to the experimental room where they are allowed to habituate for 60 min. The test is conducted using a modified shuttle box with two communicating compartments of equal size with a small sliding door built into the separating wall and a stainless-steel bar floor. One of the compartments is not illuminated and thus black whereas the other compartment (the light one) is illuminated by an electric bulb, installed on the top of a plexiglass cover. The PA training is conducted in a single session. The animals are allowed to explore the compartment for 60 sec, after which the sliding door is automatically opened and the mouse is allowed to cross over into the dark compartment. Once the mouse has entered the dark chamber with all four feet, the sliding door is automatically closed and a scrambled electrical current is delivered through the grid floor. Latency to cross over into the dark compartment (training latency) is recorded. Retention latencies as well as total time spent in bright compartment are tested 24 h later (day two). The animals are placed in the light compartment and allowed to explore for 15 sec, where upon the sliding door is opened allowing free access to the dark compartment for a period of 300 sec. The latency to cross over into the dark compartment with all four feet is measured (retention latency) as well as time in bright compartment and a number of other relevant parameters (e.g. number of visits in the dark compartment).

[0768] In in vivo study 1, vehicle (20% DMSO in 0.1M PBS) or different doses of Example 5 were administered to C57/Bl6 mice once per day (s.c. administration) for 4 days prior to PA training. PA training was then performed according to the procedure described above. On the day of PA training, scopolamine at 0.3 mg/kg, or vehicle, was administered subcutaneously 30 min prior to training. Data on retention latency shown in FIG. 1.

Abbreviations

DCM—Dichloromethane

[0769] MeOH—methanol
TEA—triethylamine
RBF—round bottom flask
EtOAC—ethyl acetate
ACN—acetonitrile
RT—room Temperature
TFA—trifluoroacetic acid
DEAD—diethyl azodicarboxylate
RB—round bottom
THF—tetrahydrofuran
Pd/C—palladium on carbon
h—hours
min—minutes
combi chromatography—combi flash chromatography
column chromatography—flash chromatography
HATU—1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
DMF—dimethylformamide
NMP—N-methyl-2-pyrrolidone
RP-HPLC—reverse phase high performance liquid chromatography