WO2007081901A2 - Pyrimidinone derivatives as protein kinase inhibitors - Google Patents

Pyrimidinone derivatives as protein kinase inhibitors Download PDF

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WO2007081901A2
WO2007081901A2 PCT/US2007/000441 US2007000441W WO2007081901A2 WO 2007081901 A2 WO2007081901 A2 WO 2007081901A2 US 2007000441 W US2007000441 W US 2007000441W WO 2007081901 A2 WO2007081901 A2 WO 2007081901A2
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mmol
compound according
following structure
methyl
oxo
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PCT/US2007/000441
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WO2007081901A3 (en
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Congxin Liang
Marcel Koenig
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The Scripps Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms

Definitions

  • the invention relates to protein kinase inhibitors and to their use in treating disorders related to abnormal protein kinase activities such as cancer and inflammation. More particularly, the invention relates to pyrimidinone derivatives and their pharmaceutically acceptable salts employable as protein kinase inhibitors.
  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups of tyrosine, serine, and threonine residues of proteins.
  • Many aspects of cell life for example, cell growth, differentiation, proliferation, cell cycle and survival) depend on protein kinase activities.
  • abnormal protein kinase activity has been related to a host of disorders such as cancer and inflammation. Therefore, considerable effort has been directed to identifying ways to modulate protein kinase activities. In particular, many attempts have been made to identify small molecules that act as protein kinase inhibitors.
  • One aspect of the invention is directed to a compound represented by Formula (I) as follows:
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halo, (C1-C6) alkyl and (C1-C6) alkoxy; and R 6 is selected from the group consisting of a 3-8 membered heterocycle having at least one ring oxygen or nitrogen and an optional carbonyl; and a radical represented by the following structure:
  • X 1 is selected from the group consisting of hydroxyl and (C1- C6) alkoxy;
  • R 7 is selected from the group consisting of hydroxy, (C1-C6) alkoxy, and an amino group represented by -NR 8 R 9 , wherein R 8 and R 9 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and (C1-C6) alkoxy, or, alternatively, said amino group represented by -NR 8 R 9 forms a saturated or unsaturated 3-8 membered heterocyclic ring optionally including an oxygen; m is 0, 1 or 2; and n is 1 or 2.
  • R 6 is represented by the following structure:
  • R 6 is said 3-8 membered.
  • Preferred species of the first subgenus where R 6 is structure Ia are represented by the following structures:
  • Preferred species of the second subgenus where R 6 is NHR 10 are represented by the following structures:
  • a second aspect of the invention is directed to a method for the modulation of the catalytic activity of a protein kinase with a compound or salt of Formula (I).
  • the protein kinase is p38 ⁇ .
  • the present invention provides compounds capable of regulating and/or modulating protein kinase activities of, but not limited to, p38 ⁇ .
  • the present invention provides a therapeutic approach to the treatment of disorders related to the abnormal functioning of this kinase.
  • disorders include, but are not limited to, inflammatory diseases and certain types of cancer.
  • Example 1 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]- ⁇ /-(3-dimethylcarbamoyl-2-hydroxy-propyl)-4-methyl- benzamide.
  • Step 2 The product from step 1 was dissolved in Methanol (3 ml) and 1 N NaOH (0.5 ml). It was stirred for 1 h at rt. It was diluted with EtOAc, washed with 0.01 N HCI and brine, dried over sodiumsulfate, the solvent was removed and the residue was purified by prep. HPLC. MS (m/z): 566, 568 [M+1] + .
  • Example 2 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]- ⁇ /-(2-dimethylcarbamoyl-2-hydroxy-ethyl)-4-methyl- benzamide.
  • Step i 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4- methyl-benzoic acid (29 mg, 0.062 mmol), 3-Amino-2-hydroxy-propionic acid methyl ester hydrochloride (24 mg, 0.15 mmol), HOBt (11 mg, 0.11 mmol), EDCI (19 mg, 0.099 mmol) and TEA (17 ⁇ l, 0.12 mmol) were dissolved in DCM (3 ml). It was stirred for 16 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine.
  • step 1 The product from, step 1 (32 mg, 0.056 mmol) was dissolved in Methanol (3 ml) and 1 N NaOH (0.5 ml). It was stirred for 1 h at rt. It was diluted with EtOAc, washed with 0.01 N HCI and brine, dried over sodiumsulfate, the solvent was removed and the residue was purified by prep. HPLC. MS (m/z): 552, 554 [M+1] + .
  • Example 3 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]- ⁇ /-(2-hydroxy-3-morpholin-4-yl-3-oxo-propyl)-4-methyl- benzamide.
  • Example 4 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-i-yll-JV-tZ-cyclopropylcarbamoyl ⁇ -hydroxy-ethylJ ⁇ -methyl- benzamide.
  • Example 5 3-[5-Bromo-4- ⁇ 2,4-difluoro-benzyIoxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]- ⁇ /-(2-carbamoyN2-hydroxy-ethyl)-4-methyl-benzamide.
  • Example 6 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]- ⁇ /-(2-dimethyIcarbamoyl-2-methoxy-ethyl)-4-methyl- benzamide.
  • step 1 The product from step 1 (31 mg, 0.053 mmol) was dissolved in Methanol (3 ml) and 1 N NaOH (0.5 ml). It was stirred for 2 h at rt. It was diluted with EtOAc, washed with 0.01 N HCI and brine, dried over sodiumsulfate, the solvent was removed and the residue was purified by prep. HPLC. MS (m/z): 566, 568 [M+1] + .
  • Step 3 The product from step 2 (21 mg, 0.037 mmol), dimethylamine, 2 M in THF (0.05 ml), HOBt (11 mg, 0.081 mmol), EDCI (14 mg, 0.073 mmol) and TEA (6 ⁇ l, 0.043 mmol) were dissolved in DCM (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid.
  • Example 7 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-yV-(2-methoxy-3-morpholin-4-yl-3-oxo-propyl)-4-methyl- benzamide.
  • Example 8 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-/V-(2-carbamoyI-2-methoxy-ethyI)-4-methyl-benzamide
  • Example 9 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-/V-(2-cyclopropylcarbamoyl-2-methoxy-ethyl)-4-methyl- benzamide.
  • Step 1
  • Step 2 The product from step 1 (60 mg, 0.10 mmol) was dissolved in Methanol (3 ml) and 1 N LiOH (0.5 ml). It was stirred for 1.5 h at rt. It was diluted with EtOAc 1 washed with 0.01 N HCI and brine, dried over sodiumsulfate, the solvent was removed and the residue was purified by prep. HPLC.
  • Example 11 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]- ⁇ /-((S)-3-dimethylcarbamoyl-3-methoxy-propyl)-4-methyl- benzamide.
  • step 1 The product from step 1 (26 mg, 0.042 mmol) was dissolved in Methanol (3 ml) and 1 N LiOH (0.5 ml). It was stirred for 2 h at rt. It was diluted with EtOAc 1 washed with 0.01 N HCI and brine, dried over sodiumsulfate, the solvent was removed and the residue was purified by prep. HPLC. MS (m/z): 580, 582 [M+1] + .
  • Example 12 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-/V-(2-dimethylcarbamoyl-2-ethoxy-ethyl)-4-methyl- benzamide.
  • step 1 The product from step 1 (45 mg, 0.074 mmol) was dissolved in Methanol (3 ml) and 1 N LiOH (0.5 ml). It was stirred for 2.5 h at rt. It was diluted with EtOAc, washed with 0.01 N HCI and brine, dried over sodiumsulfate, the solvent was removed and the residue was purified by prep. HPLC. MS (m/z): 580, 582 [M+1] + .
  • Step 3 The product from step 2 (19 mg, 0.032 mmol), dimethylamine, 2 M in THF (0.04 ml), HOBt (8 mg, 0.059 mmol), EDCI (11 mg, 0.057 mmol) and TEA (5 ⁇ l, 0.036 mmol) were dissolved in DMF (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed, the residue was purified by reversed phase HPLC and the product was lyophilized to yield the title compound as a white, fluffy solid.
  • Example 13 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-4-methyl-W-((/?)-3-oxo-isoxazolidin-4-yl)-benzamide
  • Example 14 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-4-methyl- ⁇ /-((S)-3-oxo-isoxazolidin-4-yl)-benzamide
  • Example 15 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-W-((S)-2-dimethylcarbamoyl-2-hydroxy-ethyl)-4-methyl- benzamide.
  • Example 16 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]- ⁇ /-((R)-2-dimethylcarbamoyl-2-hydroxy-ethyl)-4-methyl- benzamide.
  • Step 1 Benzyl chloride (21.8 g, 0.155 mol) was added drop-wise to a well- stirred solution of ammonium thiocyanate (13.0 g, 0.171 mo! in acetone (200 ml_). The mixture was refluxed for 15 min, compound A1 (25.6 g, 0.455 mol) was added slowly portion-wise. After 1h, the reaction mixture was poured into water (500 mL) and the bright yellow solid was isolated by filtration. The crude solid was stirred at room temperature with an excess anhydrous potassium carbonate in methanol (700 mL) for 2 h. Then the solvent was removed under reduced pressure and the crude product was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous NaaSCv* and concentrated to give a white solid. The solid was stirred in ether for 15 min and filtered to give compound A2 (11.5 g, 33% yield) as white solid.
  • Step 2 To a suspension of compound A2 (28.3 g, 0.126 mol) in methanol (280 mL) at 0 0 C, was added iodomethane (20.6 g, 0.145 mol) and stirred at room temperature for 30 min. The reaction mixture was then heated to reflux for 15 min to give a clear solution. It was concentrated under reduced pressure and the residue was dried in vacuo, dissolved in DCM
  • Step 1 To a solution of A (1.0 g, 3.3 mmol) in DMF (5 mL) was added K 2 CO 3 (0.677 g, 4.9 mnnol), followed by the addition of B1 (0.744 g, 3.6 mmol) and stirred at 0 °C for 15 min. After stirring at room temperature for 30 min, DMF was evaporated in vacuo and the residue was portioned between EA (ethyl acetate, 20 mL) and water (15 mL). The organic phase was washed with water, dried with Na 2 SO 4 and concentrated. The resulting material was purified by column chromatography to afford B2 (1.06 g, 75% yield) as white solid.
  • K 2 CO 3 0.677 g, 4.9 mnnol
  • B1 0.744 g, 3.6 mmol
  • Step 2 A mixture of B2 (1.06 g, 2.45 mmol) in 2N aq. NaOH (4.9 mL, 9.81 mmol) and dioxane (2.7 mL) was stirred at room temperature for 1.5 h. The resulting clear solution was diluted with water, acidified with 5% citric acid and extracted with EA. The combined organic extracts were washed with water, dried and concentrated to afford B3 (1.01 g, 98% yield).
  • Step 3 A mixture of B3 (1.01 g, 2.45 mmol) and NCS (N-chlorosuccinimide, 0.36 g, 2.7 mmol) in dichloroethane (20 mL) containing dichloroacetic acid (0.791 g, 6.13 mmol) was heated at 65 0 C for 3 h under N 2 atmosphere. The mixture was concentrated under reduced pressure and the residue was partitioned between EA and water. The organic phase was washed with water, dried and concentrated under reduced pressure to provide B (0.986 g, 89% yield).
  • Step 1 A suspension of B (0.586 g, 1.3 mmol) in DCM (15 mL) was treated with a few drops of DMF 1 followed by oxalyl chloride (0.329 g, 2.6 mmol) at ⁇ 0 0 C. The mixture was stirred at room temperature overnight. The solution was concentrated to give an off-white solid. The solid was again suspended in DCM (10 ml_) and added drop-wise to a solution of (2S) ⁇ 3-amino-2-hydroxy- N,N-dimethylpropanamide (0.514 g, 3.9 mmol) in DCM (10 ml_) at 0 0 C. The mixture was then stirred at room temperature for 1 h, evaporated to dryness.
  • Step 2 A mixture of 3-[5-Chloro-4-(2,4-difluoro-benzyloxy)-2-methylsulfanyl- 6-oxo-6H-pyrimidin-1-yl]-N-((S)-2-dimethylcarbamoyl-2-hydroxy-ethyl)-4- methyl- benzamide (362 mg, 0.64 mmol) and Raney Ni (wet weight: 2.0 g) in ethanol (45 mL) was refluxed for several hours. LC-MS was used to detect completion of the reaction. The mixture was cooled and the catalyst was filtered off. The catalyst was washed with ethanol several times.
  • Example 20 Preparation of 3-[5-Chloro-4-(2,4-difluoro-benzyloxy)-6-oxo- 6H- pyrimidin-1-yl]-4-methyl-N-(2-oxo-pyrrolidin-3-yl)-benzamide
  • p38 ⁇ biochemical activity was measured by Upstate Ltd in Dundee, UK following this procedure: In a final reaction volume of 25 ⁇ l, p38 ⁇ (h) (5-10 mU) is incubated with 25 mM Tris pH 7.5, 0.02 mM EGTA, 0.33 mg/ml myelin basic protein, 10 mM MgAcetate and Jy- 33 P-ATP] (specific activity approx. 500 cpm/pmol concentration as required). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 min. at room temperature, the reaction is stopped by the addition of 5 ⁇ l of a 3% phosphoric acid solution. 10 ⁇ l of the reaction is then spotted onto a P30 filtermat and washed three times for 5 min. in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
  • THP-1 cells were maintained in RPMI 1640, containing 10% FBS at 37 0 C and 5% CO 2 .
  • THP-1 cells were plated at a density of 2x105 cells/ml and 150 ⁇ l/well (96 well plate) in RPMI-1640 +3% FBS (3X105 cells/well).
  • Compounds were serial diluted in DMSO and added to the THP-1 cells to a final concentration of 1% DMSO.
  • Cells were incubated for 1hr at 37°C. Cytokine secretion was induced by stimulation with 100ng/ml LPS for 4 hours at 37°C. Culture supernatant was harvested and Cytokine secretion into the supernatant was quantitated by ELISA.
  • R&D human TNF- ⁇ /TNFSF1A (Minneapolis, Minnesota, cat# DY210) ELISA used as per kit instructions with antibody dilutions as follows: 3 ⁇ g/ml capture antibody, 50ng/ml detection antibody and 1:200 strepavidin-HRP dilution.

Abstract

Pyrimidinone derivatives have enhanced and unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as inflammatory diseases and certain types of cancer.

Description

PYRIMIDINONE DERIVATIVES AS PROTEIN KINASE INHIBITORS
Description
Field of Invention:
The invention relates to protein kinase inhibitors and to their use in treating disorders related to abnormal protein kinase activities such as cancer and inflammation. More particularly, the invention relates to pyrimidinone derivatives and their pharmaceutically acceptable salts employable as protein kinase inhibitors.
Background: Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups of tyrosine, serine, and threonine residues of proteins. Many aspects of cell life (for example, cell growth, differentiation, proliferation, cell cycle and survival) depend on protein kinase activities. Furthermore, abnormal protein kinase activity has been related to a host of disorders such as cancer and inflammation. Therefore, considerable effort has been directed to identifying ways to modulate protein kinase activities. In particular, many attempts have been made to identify small molecules that act as protein kinase inhibitors.
Several pyrimidinone derivatives have demonstrated excellent activity as inhibitors of protein kinases (WO2004/087677). The clinical utility of these compounds has been promising, but has been partially compromised due to the relatively poor aqueous solubility and/or other drug properties. What is needed is a class of modified pyrimidinone derivatives having both inhibitory activity and enhanced drug properties. Summarv:
One aspect of the invention is directed to a compound represented by Formula (I) as follows:
Formula I
Figure imgf000003_0001
In Formula (I), R1, R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, halo, (C1-C6) alkyl and (C1-C6) alkoxy; and R6 is selected from the group consisting of a 3-8 membered heterocycle having at least one ring oxygen or nitrogen and an optional carbonyl; and a radical represented by the following structure:
Formula Ia A^ A
In Formula (Ia), X1 is selected from the group consisting of hydroxyl and (C1- C6) alkoxy; R7 is selected from the group consisting of hydroxy, (C1-C6) alkoxy, and an amino group represented by -NR8R9, wherein R8 and R9 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and (C1-C6) alkoxy, or, alternatively, said amino group represented by -NR8R9 forms a saturated or unsaturated 3-8 membered heterocyclic ring optionally including an oxygen; m is 0, 1 or 2; and n is 1 or 2. In a first subgenus of this first aspect of the invention, R6 is represented by the following structure:
Formula Ia
Figure imgf000003_0002
In a second subgenus of this first aspect of the invention, R6 is said 3-8 membered. Preferred species of the first subgenus where R6 is structure Ia are represented by the following structures:
Figure imgf000004_0001
Figure imgf000005_0001
Figure imgf000005_0003
and
Figure imgf000005_0002
- S -
Preferred species of the second subgenus where R6 is NHR10 are represented by the following structures:
Figure imgf000006_0001
A second aspect of the invention is directed to a method for the modulation of the catalytic activity of a protein kinase with a compound or salt of Formula (I). In a preferred embodiment of this second aspect of the invention, the protein kinase is p38α.
The present invention provides compounds capable of regulating and/or modulating protein kinase activities of, but not limited to, p38α. Thus, the present invention provides a therapeutic approach to the treatment of disorders related to the abnormal functioning of this kinase. Such disorders include, but are not limited to, inflammatory diseases and certain types of cancer.
Detailed Description:
Example 1 : 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-Λ/-(3-dimethylcarbamoyl-2-hydroxy-propyl)-4-methyl- benzamide.
HOBt
HOBt,
Figure imgf000007_0002
Figure imgf000007_0001
StBP i: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4- methyl-benzoic acid (39 mg, 0.084 mmol), 4-Amino-3-hydroxy-butyric acid methyl ester hydrochloride (36 mg, 0.21 mmol), HOBt (22 mg, 0.16 mmol), EDCI (29 mg, 0.15 mmol) and TEA (23 μl, 0.17 mmol) were dissolved in DCM (3 ml). It was stirred for 16 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the product of step 1 as a white solid. Physical Data: 1H-NMR (400 MHz, dβ-DMSO) δ 8.43 (q, 1 H), 7.89 (dd, J = 1.6, 7.6 Hz, 1 H), 7.79 (br s, 1 H), 7.69-7.63 (m, 1H), 7.53 (d, J = 8.4 Hz1 1H), 7.36-7.30 (m, 1H), 7.19-7.14 (m, 1H), 5.55 (d, J = 12.0 Hz, 1 H), 5.47 (d, J = 12.4 Hz, 1H), 4.06-4.01 (m, 1H), 3.56 (s, 3H), 3.28-3.20 (m, 2H), 2.53 (dd, J = 3.8, 15.0 Hz1 1 H), 2.29 (dd, J = 8.8, 15.2 Hz, 1 H), 2.11, 2.10 (2 s, 3H), 2.06 (s, 3H); MS (m/z): 580, 582 [M+ 1]+.
Step 2: The product from step 1 was dissolved in Methanol (3 ml) and 1 N NaOH (0.5 ml). It was stirred for 1 h at rt. It was diluted with EtOAc, washed with 0.01 N HCI and brine, dried over sodiumsulfate, the solvent was removed and the residue was purified by prep. HPLC. MS (m/z): 566, 568 [M+1]+.
Step 3:
The product from step 2 (46 mg, 0.81 mmol), dimethylamine, 2 M in THF (0.16 ml), HOBt (18 mg, 0.13 mmol), EDCI (26 mg, 0.14 mmol) and TEΞA (11 μl, 0.08 mmol) were dissolved in DMF (3 ml). It was stirred for 16 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. Physical Data: 1H-NMR (400 MHz, de-DMSO) δ 8.45 (q, J = 4.4 Hz, 1 H), 7.90 (dd, J = 1.6, 8.0 Hz, 1 H), 7.91 (s, 1 H)1 7.70-7.64 (m, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.34 (dt, J = 2.4 Hz, 10.0 Hz, 1H), 7.20-7.15 (m, 1 H), 5.56 (d, J = 12.4 Hz, 1 H)1 5.48 (d, J = 12.4 Hz, 1 H), 4.94 (t, J = 5.6 Hz, 1H), 4.09- 4.03 (m, 1H), 2.96 (s, 3H), 2.80 (s, 3H), 2.45-2.40 (m, 2H), 2.11 (s, 3H), 2.07 (S1 3H); MS (m/z): 593, 595 [M+1]\
Example 2: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-Λ/-(2-dimethylcarbamoyl-2-hydroxy-ethyl)-4-methyl- benzamide.
HOBt
HOBt,
Figure imgf000008_0002
Figure imgf000008_0001
Step i: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4- methyl-benzoic acid (29 mg, 0.062 mmol), 3-Amino-2-hydroxy-propionic acid methyl ester hydrochloride (24 mg, 0.15 mmol), HOBt (11 mg, 0.11 mmol), EDCI (19 mg, 0.099 mmol) and TEA (17 μl, 0.12 mmol) were dissolved in DCM (3 ml). It was stirred for 16 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the product of step 1 as a white solid. Physical Data: MS (m/z): 566, 568 [M+ 1]+.
Step 2:
The product from, step 1 (32 mg, 0.056 mmol) was dissolved in Methanol (3 ml) and 1 N NaOH (0.5 ml). It was stirred for 1 h at rt. It was diluted with EtOAc, washed with 0.01 N HCI and brine, dried over sodiumsulfate, the solvent was removed and the residue was purified by prep. HPLC. MS (m/z): 552, 554 [M+1]+.
Step 3:
The product from step 2 (21 mg, 0.038 mmol), dimethylamine, 2 M in THF (0.05 ml), HOBt (10 mg, 0.074 mmol), EDCI (13 mg, 0.068 mmol) and TEA (6 μl, 0.043 mmol) were dissolved in DCM (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. Physical Data: 1H-NMR (400 MHz, d6-DMSO) δ 8.60, 8.56 (2 t, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.82 (dd, J =1.6, 6.8 Hz, 1H), 7.67 (q, J = 7.9 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.34 (dt, 1H), 7.17 (dt, 1H), 5.56 (d, J = 12.4 Hz1 1H), 5.48 (d, J = 12.4 Hz, 1H), 5.17 (t, J = 7.0 Hz, 1H), 4.54-4.49 (m, 1H),
3.07, 3.06 (2 s, 3H), 2.84, 2.83, (2 s, 3H), 2.11 (s, 3H), 2.06 (s, 3H); MS (m/z): 579, 581 [M+1]+.
Example 3: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-Λ/-(2-hydroxy-3-morpholin-4-yl-3-oxo-propyl)-4-methyl- benzamide.
Figure imgf000010_0001
3-{3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1 -yll-Φmethyl-benzoylaminoJ-Z-hydroxy-propionic acid (28 mg, 0.051 mmol), morpholine (9 μl, 0.10 mmol), HOBt (13 mg, 0.096 mmol), EDCI (17 mg, 0.088 mmol) and TEA (7 μl, 0.050 mmol) were dissolved in DCM (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. Physical Data: MS (m/z): 621 , 623 [M+ 1]+.
Example 4: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-i-yll-JV-tZ-cyclopropylcarbamoyl^-hydroxy-ethylJ^-methyl- benzamide.
Figure imgf000010_0002
3-{3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1 -yl]-4-methyl-benzoylamino}-2-hydroxy-propionic acid (28 mg, 0.051 mmol), cyclopropylamine (7 μl, 0.10 mmol), HOBt (11 mg, 0.081 mmol), EDCI (15 mg, 0.078 mmol) and TEA (7 μl, 0.050 mmol) were dissolved in DCM (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. Physical Data: MS (m/z): 591 , 593 [M+ 1]+.
Example 5: 3-[5-Bromo-4-{2,4-difluoro-benzyIoxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-Λ/-(2-carbamoyN2-hydroxy-ethyl)-4-methyl-benzamide.
Figure imgf000011_0001
3-{3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1 -yl]-4-methyl-benzoylamino}-2-hydroxy-propionic acid (21 mg, 0.038 mmol), ammoniumchloride (10 mg, 0.19 mmol), HOBt (10 mg, 0.074 mmol), EDCI (14 mg, 0.073 mmol) and TEA (11 μl, 0.079 mmol) were dissolved in DMF (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. Physical Data: 1H-NMR (400 MHz, dβ-DMSO) δ 8.47 (q, J = 4.9 Hz, 1 H), 7.91 (dd, J = 1.8, 7.8 Hz, 1 H), 7.82 (dd, J = 1.4, 6.6 Hz, 1H), 7.70-7.64 (m, 1H), 7.55 (d, J = 8.0 Hz, 1 H), 7.34 (dt, J = 2.3, 9.9 Hz, 1H), 7.22 (s, 1 H), 7.21-7.15 (s, dt, 2H), 5.56 (d, J = 12.4 Hz, 1H), 5.49 (d, J = 12.4 Hz, 1H), 4.04-4.00 (m, 1H), 3.69-3.63 (m, 0.5H), 3.59-3.51 (m, 0.5H), 3.32-3.22 (m, 1H), 2.12, 2.11 (2 s, 3H)1 2.07 (s, 3H); MS (m/z): 551 , 553 [M+1f. Example 6: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-Λ/-(2-dimethyIcarbamoyl-2-methoxy-ethyl)-4-methyl- benzamide.
HOBt
HOBt,
Figure imgf000012_0002
Figure imgf000012_0001
Step 1:
3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4- methyl-benzoic acid (26 mg, 0.056 mmol), 3-Amino-2-methoxy-propionic acid methyl ester trifluoroacetate (24 mg, 0.097 mmol), HOBt (14 mg, 0.10 mmol), EDCI (20 mg, 0.10 mmol) and TEA (16 μl, 0.11 mmol) were dissolved in DMF (3 ml). It was stirred for 18 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the product of step 1 as a white solid. MS (m/z): 580, 582 [M+1]+.
Step 2:
The product from step 1 (31 mg, 0.053 mmol) was dissolved in Methanol (3 ml) and 1 N NaOH (0.5 ml). It was stirred for 2 h at rt. It was diluted with EtOAc, washed with 0.01 N HCI and brine, dried over sodiumsulfate, the solvent was removed and the residue was purified by prep. HPLC. MS (m/z): 566, 568 [M+1]+.
Step 3: The product from step 2 (21 mg, 0.037 mmol), dimethylamine, 2 M in THF (0.05 ml), HOBt (11 mg, 0.081 mmol), EDCI (14 mg, 0.073 mmol) and TEA (6 μl, 0.043 mmol) were dissolved in DCM (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. Physical Data: 1H-NMR (400 MHz1 d6-DMSO) δ 8.72-8.66 (m, 1H)1 7.91 (dt, J = 1.8, 8.0 Hz, 1H), 7.81 (dd, J = 1.6 Hz, 1H)1 7.70-7.64 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.34 (dt, J = 2.1, 9.9 Hz, 1H), 7.17 (dt, J =1.9, 8.5 Hz, 1 H), 5.56 (d, J = 12.4 Hz, 1H), 5.48 (d, J = 12.4 Hz, 1H), 4.37 (dd, J = 4.2 Hz, 1H), 3.22, 3.21 (2 s, 3H), 3.10, 3.09 (2 s, 3H), 2.85 (2 s, 3H), 2.11 (s, 3H), 2.07 (s, 3H); MS (m/z): 593, 595 [M+1]*.
Example 7: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-yV-(2-methoxy-3-morpholin-4-yl-3-oxo-propyl)-4-methyl- benzamide.
Figure imgf000013_0001
3-{3-[5-B rom o-4-(2 ,4-difl uoro-benzyloxy)-2-methyl-6-oxo-6H-pyri mid in- 1 -yl]-4-methyl-benzoylamino}-2-methoxy-propionic acid (34 mg, 0.060 mmol), morpholine (11 μl, 0.13 mmol), HOBt (14 mg, 0.10 mmol), EDCI (20 mg, 0.10 mmol) and TEA (8 μl, 0.057 mmol) were dissolved in DCM (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. Physical Data: 1H-NMR (400 MHz, de-DMSO) δ 8.74-8.69 (m, 1 H), 7.91 (d, J = 8.0 Hz, 1 H)1 7.82 (dd, J = 1.6, 4.4 Hz, 1 H), 7.70-7.64 (m, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.34 (dt, J = 2.4, 9.9 Hz, 1H), 7.17 (dt, J = 2.3, 8.5 Hz, 1H), 5.56 (d, J = 12.4 Hz, 1H). 5.49 (d, J = 12.4 Hz, 1H)1 4.36 (dd, J = 4.4, 7.2 Hz, 1H), 3.71-3.32 (m, 10H), 3.24, 3.23 (2 s, 3H), 2.11 (S, 3H), 2.07 (s, 3H); MS (m/z): 635, 637 [M+1]+.
Example 8: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-/V-(2-carbamoyI-2-methoxy-ethyI)-4-methyl-benzamide
Figure imgf000014_0001
3-{3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1 -yl]-4-methyl-benzoylamino}-2-methoxy-propionic acid (20 mg, 0.035 mmol), ammoniumchloride (6.5 mg, 0.12 mmol), HOBt (7.5 mg, 0.056 mmol), EDCI
(10 mg, 0.052 mmol) and TEA (10 μl, 0.072 mmol) were dissolved in DMF (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the titie compound as a white solid.
MS (m/z): 565, 567 [M+1]+.
Example 9: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-/V-(2-cyclopropylcarbamoyl-2-methoxy-ethyl)-4-methyl- benzamide.
Figure imgf000015_0001
3-{3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1 -yl]-4-methyl-benzoylamino}-2-methoxy-propionic acid (20 mg, 0.035 mmol), cyclopropylamine (7 μl, 0.10 mmol), HOBt (9.5 mg, 0.070 mmol), EDCI (12 mg, 0.063 mmol) and TEA (5 I, 0.036 mmol) were dissolved in DCM (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. Physical Data: 1H-NMR (400 MHz, de-DMSO) δ 8.51 (t, J = 5.8 Hz, 1 H), 8.05 (d, J = 4.4 Hz, 1 H)1 7.88 (d, J = 8.0 Hz, 1 H), 7.77 (dd, J = 1.6, 6.4 Hz, 1 H), 7.70-7.64 (m, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.34 (dt, J = 2.3, 9.9 Hz, 1 H), 7.17 (dt, J = 2.1 , 8.6 Hz, 1 H), 5.56 (d, J = 12.4 Hz1 1 H), 5.48 (d, J = 12.4 Hz, 1H), 3.74 (t, J = 6.0 Hz1 1 H), 3.55-3.48 (m, 1 H), 3.47-3.38 (m 1 H), 3.24 (s, 3H), 2.67-2.64 (s, 1 H), 2.11 (2 s, 3H), 2.07 (s, 3H), 0.57-0.55 (m, 2H), 0.47-0.43 (m, 2H); MS (m/z): 605, 607 [M+1)+.
Example 10: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-yV-((S)-3-dimethylcarbamoyl-3-hydroxy-propyl)-4-methyl- benzamide. HOBt
HOBt,
Figure imgf000016_0002
Figure imgf000016_0001
Step 1 :
3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yI]-4- methyl-benzoic acid (38 nng, 0.082 mmol), (S)-4-Amino-2-hydroxy-butyric acid methyl ester hydrochloride (26 mg, 0.15 mmol), HOBt (17 mg, 0.13 mmol), EDCI (24 mg, 0.13 mmol) and TEA (23 μl, 0.17 mmol) were dissolved in DMF (3 ml). It was stirred for 16 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the product of step 1 as a white solid. MS (m/z): 580, 582 [M+1]+.
Step 2: The product from step 1 (60 mg, 0.10 mmol) was dissolved in Methanol (3 ml) and 1 N LiOH (0.5 ml). It was stirred for 1.5 h at rt. It was diluted with EtOAc1 washed with 0.01 N HCI and brine, dried over sodiumsulfate, the solvent was removed and the residue was purified by prep. HPLC.
MS (m/z): 566, 568 [M+1f.
Step 3:
The product from step 2 (21 mg, 0.037 mmol), dimethylamine, 2 M in THF
(0.05 ml), HOBt (11 mg, 0.081 mmol), EDCI (14 mg, 0.073 mmol) and TEA (6 μl, 0.043 mmol) were dissolved in DCM (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. Physical Data: 1H-NMR (400 MHz, d6-DMSO) δ 8.49 (d, J = 4.6 Hz, 1 H)1 7.88 (dd, J = 1.6, 8 0 Hz, 1 H), 7.78 (d, J = 1.6 Hz1 1 H), 7.70-7.64 (m, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.35 (dt, J - 2.3, 9.8 Hz, 1 H), 7.20 (dt, 1 H), 5.35 (d, J = 12.4 Hz, 1H), 5.48 (d, J = 12.4 Hz, 1H), 4.86 (dd, J = 0.8, 7.2 Hz, 1 H), 4.40-4.36 (m, 1 H)1 2.97 (s, 3H), 2.82 (s, 3H), 2.11 , 2.10 (2 s, 3H), 2.06 (s, 3H), 1.92-1.84 (m, 1H), 1.68-1.61 (m, 1H); MS (m/z): 593, 595 [M+1]+.
Example 11 : 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-Λ/-((S)-3-dimethylcarbamoyl-3-methoxy-propyl)-4-methyl- benzamide.
HOBt
HOBt,
Figure imgf000017_0002
Figure imgf000017_0001
Step 1:
3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4- methyl-benzoic acid (37 mg, 0.080 mmol), (S)-4-Amino-2~methoxy-butyric acid methyl ester trifluoracetic acid salt (64 mg, 0.25 mmol), HOBt (17 mg, 0.13 mmol), EDCi (24 mg, 0.13 mmol) and TEA (44 μl, 0.31 mmol) were dissolved in DCM (3 ml). It was stirred for 15 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the product of step 1 as a white solid. MS (m/z): 594, 596 [M+1]+. Step 2:
The product from step 1 (26 mg, 0.042 mmol) was dissolved in Methanol (3 ml) and 1 N LiOH (0.5 ml). It was stirred for 2 h at rt. It was diluted with EtOAc1 washed with 0.01 N HCI and brine, dried over sodiumsulfate, the solvent was removed and the residue was purified by prep. HPLC. MS (m/z): 580, 582 [M+1]+.
Step 3:
The product from step 2 (21 mg, 0.037 mmol), dimethylamine, 2 M in THF (0.05 ml), HOBt (11 mg, 0.081 mmol), EDCI (14 mg, 0.073 mmol) and TEA (6 μl, 0.043 mmol) were dissolved in DCM (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. Physical Data: 1H-NMR (400 MHz, d6-DMSO) δ 8.50 (t, J = 5.4 Hz,
1 H), 7.88 (d, J = 1.6, 8.0 Hz, 1 H), 7.78 (d, J = 1.6 Hz1 1 H), 7.70-7.64 (m, 1 H), 7.54 (d, J = 8.0 Hz, 1H), 7.34 (dt, J = 2.0, 10.0 Hz, 1H), 7.17 (dt, J = 2.0, 8.4 Hz, 1H), 5.57 (d, J = 12.4 Hz, 1H), 5.48 (d, J = 12.4 Hz, 1H), 4.21-4.17 (m, 1H), 3.19 (2 s, 3H), 2.99 (s, 3H), 2.82 (s, 3H), 2.52-2.49 (m, 2H), 2.10 (s, 3H)1 2.07 (S, 3H), 1.90-1.75 (m, 2H); MS (m/z): 607, 609 [M+1]+.
Example 12: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-/V-(2-dimethylcarbamoyl-2-ethoxy-ethyl)-4-methyl- benzamide.
HOBt
HOBt,
Figure imgf000018_0001
Figure imgf000018_0002
Step 1:
3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6~oxo-6H-pyrimidin-1-yl]-4- methyl-benzoic acid (32 mg, 0.069 mmol), 3-Amino-2-ethoxy-propionic acid ethyl ester trifluoroacidic acid salt (63 mg, 0.22 mmol), HOBt (15 mg, 0.11 mmol), EDCI (20 mg, 0.10 mmol) and TEA (44 μl, 0.14 mmol) were dissolved in DMF (3 ml). It was stirred for 24 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the product of step 1 as a white solid. MS (m/z): 608, 610 [M+1]+.
Step 2:
The product from step 1 (45 mg, 0.074 mmol) was dissolved in Methanol (3 ml) and 1 N LiOH (0.5 ml). It was stirred for 2.5 h at rt. It was diluted with EtOAc, washed with 0.01 N HCI and brine, dried over sodiumsulfate, the solvent was removed and the residue was purified by prep. HPLC. MS (m/z): 580, 582 [M+1]+.
Step 3: The product from step 2 (19 mg, 0.032 mmol), dimethylamine, 2 M in THF (0.04 ml), HOBt (8 mg, 0.059 mmol), EDCI (11 mg, 0.057 mmol) and TEA (5 μl, 0.036 mmol) were dissolved in DMF (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed, the residue was purified by reversed phase HPLC and the product was lyophilized to yield the title compound as a white, fluffy solid. Physical Data: 1H-NMR (400 MHz, dβ- DMSO) δ 8.69-8.64 (m, 1 H), 7.90 (dd, J = 1.8, 7.8 Hz, 1 H), 7.81 (dd, J = 1.6, 3.6 Hz, 1H), 7.70-7.64 (m, 1 H), 7.55 (d, J = 8.0 Hz, 1H), 7.35 (dt, J = 2.4, 9.9 Hz, 1 H)1 7.17 (dt, J = 2.1, 8.5 Hz, 1H), 5.55 (d, J = 12.4 Hz, 1 H), 5.48 (d, J = 12.4 Hz, 1H), 4.45-4.41 (m, 1H), 3.55-3.38 (m, 4H), 3.09, 3.08 (2 s, 3H), 2.84 (2 s, 3H), 2.11 (s, 3H), 2.07 (s, 3H)1 1.08 (2 t, 3H); MS (m/z): 607, 609 [M+1]+. Example 13: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-4-methyl-W-((/?)-3-oxo-isoxazolidin-4-yl)-benzamide
*NNH' 'Z* HATU, DIEA, DMF
Figure imgf000020_0002
Figure imgf000020_0001
3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4- methyl-benzoic acid (40 mg, 0.086 mmol), D-cycloserine (16 mg, 0.16 mmol), HATU (37 mg, 0.097 mmol), DIEA (18 μl, 0.10 mmol) were dissolved in DMF (4 ml). It was stirred for 48 h at rt, concentrated, purified by prep. HPLC and lyophilized to yield the title compound as a white, fluffy solid. Physical Data: 1H-NMR (400 MHz, d6-DMSO) δ 11.57 (br s, 1H), 9.00 (m, 1H), 7.94-7.92 (m, 1 H), 7.84-7.83 (m, 1 H), 7.70-7.64 (m, 1 H), 7.57 (d, J = 8.00 Hz, 1 H), 7.34 (dt, J = 2.1, 10.0 Hz, 1 H), 7.17 (dt, J = 2.1, 8.5 Hz, 1H), 5.56 (d, J = 12.0 Hz, 1H), 5.48 (d, J = 12.4 Hz, 1 H), 5.08-5.02 (m, 1 H), 4.58 (dt, J = 3.1 , 8.5 Hz, 1 H), 4.08 (q, J = 9.1 Hz, 1H), 2.12, 2.11 (2s, 3H), 2.08 (s, 3H); MS (m/z): 549, 551 [M+ 1]+.
Example 14: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-4-methyl-Λ/-((S)-3-oxo-isoxazolidin-4-yl)-benzamide
Figure imgf000020_0003
3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4- methyl-benzoic acid (36 mg, 0.078 mmol), L-cycloserine (16 mg, 0.16 mmol), HATU (32 mg, 0.084 mmol), DIEA (18 μl, 0.086 mmol) were dissolved in DMF (4 ml). It was stirred for 48 h at rt, concentrated, purified by prep. HPLC and lyophilized to yield the title compound as a white, fluffy solid. Physical Data: 1H-NMR (400 MHz1 d6-DMSO) δ 11.57 (br s, 1 H), 9.00 (br s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.83 (dd, J = 1.6, 4.0 Hz, 1H), 7.67 (q, J = 7.9 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1 H), 7.34 (dt, J = 2.1, 9.8 Hz, 1H), 7.17 (dt, J = 2.4, 8.4 Hz, 1 H)1 5.56 (d, J = 12.0 Hz, 1H), 5.48 (d, J = 12.4 Hz, 1H), 5.08-4.98 (m, 1H), 4.58 (dt, 1H), 4.08 (q, J = 9.1 Hz, 1 H), 2.12, 2.11 (2 s, 3H), 2.08 (s, 3H); MS (m/z): 549, 551 [M+1]+.
Example 15: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-W-((S)-2-dimethylcarbamoyl-2-hydroxy-ethyl)-4-methyl- benzamide.
Figure imgf000021_0001
3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrirnidin-1-yl]-4- methyl-benzoic acid (31 mg, 0.066 mmol), (S)-3-Amino-2-hydroxy-Λ/,Λ/- dimethyl-propionamide (20 mg, 0.15 mmol), HOBt (16 mg, 0.12 mmol), EDCI (18 mg, 0.093 mmol) and TEA (9 μl, 0.065 mmol) were dissolved in DCM (3 ml). It was stirred for 16 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. Physical Data: 1H-NMR (400 MHz, de-DMSO) δ 8.60, 8.56 (2 t, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.83 (dd, J = 1.6, 6.8 Hz, 1H)1 7.70-7.64 (m, 1H), 7.54 (d, J =8.0 Hz, 1H), 7.34 (dt, J = 2.1, 10.0 Hz, 1H),7.17 (dt, J = 2.1 8.6 Hz, 1H), 5.56 (d, J = 12.4 Hz, 1H), 5.48 (d, J = 12.4 Hz, 1H), 5.16 (t, J = 7.2 Hz, 1H), 4.54-4.49 (m, 1 H), 3.55-3.45 (m, 1H), 3.26-3.20 (m, 1H), 3.07, 3.06 (2 s, 3H), 2.84 , 2.83 (2 s, 3H), 2.11 <s, 3H)1 2.07 (S, 3H); MS (m/z): 579, 581 [M+1]+.
Example 16: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimidin-1-yl]-Λ/-((R)-2-dimethylcarbamoyl-2-hydroxy-ethyl)-4-methyl- benzamide.
Figure imgf000022_0001
3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4- methyl-benzoic acid (30 mg, 0.064 mmol), (/3)-3-Amino-2-hydroxy-Λ/,Λ/- dimethyl-propionamide (22 mg, 0.17 mmol), HOBt (14 mg, 0.10 mmol), EDCI (18 mg, 0.094 mmol) and TEA (9 μl, 0.065 mmol) were dissolved in DCM (3 ml). It was stirred for 16 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. Physical Data: 1H-NMR (400 MHz, de-DMSO) δ 8.60, 8.56 (2 t, 1H), 7.91 (d, J = 7.6 Hz, 1 H)1 7.82 (dd, J = 1.6, 6.4 Hz, 1H), 7.70-7.64 (m, 1H), 7.54 (d, J = 8.0 Hz1 1H), 7.34 (dt, J = 2.4, 9.9 Hz1 1H)1 7.17 (dt, J = 2.3, 8.5 Hz, 1 H), 5.56 (d, J = 12.4 Hz, 1H), 5.48 (d, J = 12.8 Hz, 1H), 5.17 (t, J = 6.8 Hz1 1H), 5.54-5.49 (m, 1H)1 3.54-3.43 (m, 1H)1 3.26-3.20 (m, 1H)1 3.07, 3.06 (2 S, 3H), 2.84, 2.83 (2 s, 3H), 2.11 (s, 3H), 2.07 (s, 3H); MS (m/z): 579, 581 [M+1]\ Example 17: 3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H- pyrimϊdin-1-yl]-/V-((S)-2-hydroxy-3-oxo-3-pyrrolidin-1-yl-propyl)-4-methyI- benzamide.
Figure imgf000023_0001
3-[5-Bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H~pyrimidin-1-yl]-4- methyl-benzoic acid (39 mg, 0.084 mmol), (S)-3-Amino-2-hydroxy-1- pyrrolidin-1-yl-propan-1-one (21 mg, 0.13 mmol), HOBt (17 mg, 0.13 mmol), EDCI (25 mg, 0.13 mmol) and TEA (86 μl, 0.065 mmol) were dissolved in DCM (3 ml). It was stirred for 20 h at rt, diluted with EtOAc and washed with sat. sodiumbicarbonate and brine. It was dried over sodiumsulfate, the solvent was removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. Physical Data: MS (m/z): 605, 607 [M+1]+.
Example 18: Preparation of 3-[5-Chloro-4-(2,4-difluoro-benzyloxy)-6-oxo- 6H- pyrimidin-1-yl]-N-((S)-2-dimethylcarbamoyl-2-hydroxy-ethyl)-4- methyl- benzamide
Figure imgf000023_0002
Preparation of advanced intermediate A: 3-(4-Hydroxy-2-methylsulfanyl-6-oxo -δH-pyrimidin-i-yO-^-methyl-benzoic acid methyl ester
Figure imgf000024_0001
Step 1: Benzyl chloride (21.8 g, 0.155 mol) was added drop-wise to a well- stirred solution of ammonium thiocyanate (13.0 g, 0.171 mo!) in acetone (200 ml_). The mixture was refluxed for 15 min, compound A1 (25.6 g, 0.455 mol) was added slowly portion-wise. After 1h, the reaction mixture was poured into water (500 mL) and the bright yellow solid was isolated by filtration. The crude solid was stirred at room temperature with an excess anhydrous potassium carbonate in methanol (700 mL) for 2 h. Then the solvent was removed under reduced pressure and the crude product was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous NaaSCv* and concentrated to give a white solid. The solid was stirred in ether for 15 min and filtered to give compound A2 (11.5 g, 33% yield) as white solid.
Step 2: To a suspension of compound A2 (28.3 g, 0.126 mol) in methanol (280 mL) at 0 0C, was added iodomethane (20.6 g, 0.145 mol) and stirred at room temperature for 30 min. The reaction mixture was then heated to reflux for 15 min to give a clear solution. It was concentrated under reduced pressure and the residue was dried in vacuo, dissolved in DCM
(Dichloromethane, 500 mL). The solution was cooled to -50C, added NMM (N-Methyl morpholine, 25.56 g, 0.253 mol), followed by the drop-wise addition of a solution of compound A4 (25.87 g, 0.19 mol) in DCM (60 mL). The resulting mixture was stirred at room temperature overnight under N2 atmosphere. The mixture was cooled to -5 °C and added an additional amount of NMM (8.9 g, 0.088 mol) and A4 (12.07 g, 0.088 mol). The mixture was stirred at room temperature for 2 h, cooled to 100C, added water (400 mL). The mixture was stirred for 30 min. The interfacial solid was filtered, washed with water and dried to give compound A (27.9 g, 72.0% yield). Preparation of advanced intermediate B: 3-[5-Chloro-4-(2,4-difluoro- benzyloxy)- 2-methylsulfanyl-6-oxo-6H-pyrimidin-1 -yl]-4-methyl-benzoic acid
Figure imgf000025_0001
Step 1 : To a solution of A (1.0 g, 3.3 mmol) in DMF (5 mL) was added K2CO3 (0.677 g, 4.9 mnnol), followed by the addition of B1 (0.744 g, 3.6 mmol) and stirred at 0 °C for 15 min. After stirring at room temperature for 30 min, DMF was evaporated in vacuo and the residue was portioned between EA (ethyl acetate, 20 mL) and water (15 mL). The organic phase was washed with water, dried with Na2SO4 and concentrated. The resulting material was purified by column chromatography to afford B2 (1.06 g, 75% yield) as white solid.
Step 2: A mixture of B2 (1.06 g, 2.45 mmol) in 2N aq. NaOH (4.9 mL, 9.81 mmol) and dioxane (2.7 mL) was stirred at room temperature for 1.5 h. The resulting clear solution was diluted with water, acidified with 5% citric acid and extracted with EA. The combined organic extracts were washed with water, dried and concentrated to afford B3 (1.01 g, 98% yield).
Step 3: A mixture of B3 (1.01 g, 2.45 mmol) and NCS (N-chlorosuccinimide, 0.36 g, 2.7 mmol) in dichloroethane (20 mL) containing dichloroacetic acid (0.791 g, 6.13 mmol) was heated at 650C for 3 h under N2 atmosphere. The mixture was concentrated under reduced pressure and the residue was partitioned between EA and water. The organic phase was washed with water, dried and concentrated under reduced pressure to provide B (0.986 g, 89% yield).
Preparation of title compound
Step 1 : A suspension of B (0.586 g, 1.3 mmol) in DCM (15 mL) was treated with a few drops of DMF1 followed by oxalyl chloride (0.329 g, 2.6 mmol) at ■ 0 0C. The mixture was stirred at room temperature overnight. The solution was concentrated to give an off-white solid. The solid was again suspended in DCM (10 ml_) and added drop-wise to a solution of (2S)~3-amino-2-hydroxy- N,N-dimethylpropanamide (0.514 g, 3.9 mmol) in DCM (10 ml_) at 0 0C. The mixture was then stirred at room temperature for 1 h, evaporated to dryness. The residue was purified by column chromatography to provide 3-[5-Chloro-4- (2,4-difluoro-benzyloxy)-2-methylsulfanyl- 6-oxo-6H-pyrimidin-1-yl]-N-((S)-2- dimethylcarbamoyl-2-hydroxy-ethyl)-4-methyl- benzamide (373 mg, 51 % yield).
Step 2: A mixture of 3-[5-Chloro-4-(2,4-difluoro-benzyloxy)-2-methylsulfanyl- 6-oxo-6H-pyrimidin-1-yl]-N-((S)-2-dimethylcarbamoyl-2-hydroxy-ethyl)-4- methyl- benzamide (362 mg, 0.64 mmol) and Raney Ni (wet weight: 2.0 g) in ethanol (45 mL) was refluxed for several hours. LC-MS was used to detect completion of the reaction. The mixture was cooled and the catalyst was filtered off. The catalyst was washed with ethanol several times. The combined ethanol layer was concentrated and the residue was purified by Prep-TLC to provide title compound (30 mg, 9.0% yield). 1H NMR (CDCI3, 300MHz): δ 7.90-7.91 (d, 1 H), 7.26-7.76 (m, 5H), 6.86-6.95 (m, 2H), 5.51-5.23 (d, 2H), 4.62-4.64 (m, 1H), 3.76-3.85 (m, 1 H), 3.30-3.38 (m, 1H), 3.17 (s, 3H), 2.97 (s, 3H), 2.18 (s, 3H). LC-MS: 521.1 (M+1)+.
Example 19: Preparation of 3-[5-Chloro-4-(2,4-difluoro-benzyloxy)-6-oxo- 6H- pyrimidin-1 -yI]-4-methyl-N-(tetrahydro-pyran-4-yl)-benzamide
Figure imgf000026_0001
The title compound is prepared according to procedures of examples 13 and 18. Example 20: Preparation of 3-[5-Chloro-4-(2,4-difluoro-benzyloxy)-6-oxo- 6H- pyrimidin-1-yl]-4-methyl-N-(2-oxo-pyrrolidin-3-yl)-benzamide
Figure imgf000027_0001
The title compound is prepared according to procedures of examples 13 and 18.
p38α Biochemical Assay
The p38α biochemical activity was measured by Upstate Ltd in Dundee, UK following this procedure: In a final reaction volume of 25 μl, p38α (h) (5-10 mU) is incubated with 25 mM Tris pH 7.5, 0.02 mM EGTA, 0.33 mg/ml myelin basic protein, 10 mM MgAcetate and Jy-33P-ATP] (specific activity approx. 500 cpm/pmol concentration as required). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 min. at room temperature, the reaction is stopped by the addition of 5 μl of a 3% phosphoric acid solution. 10 μl of the reaction is then spotted onto a P30 filtermat and washed three times for 5 min. in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
Cellular Assay: Inhibition of LPS stimulated TNF-α production in THP-1 cells
THP-1 cells were maintained in RPMI 1640, containing 10% FBS at 370C and 5% CO2. THP-1 cells were plated at a density of 2x105 cells/ml and 150 μl/well (96 well plate) in RPMI-1640 +3% FBS (3X105 cells/well). Compounds were serial diluted in DMSO and added to the THP-1 cells to a final concentration of 1% DMSO. Cells were incubated for 1hr at 37°C. Cytokine secretion was induced by stimulation with 100ng/ml LPS for 4 hours at 37°C. Culture supernatant was harvested and Cytokine secretion into the supernatant was quantitated by ELISA.
R&D human TNF-α/TNFSF1A (Minneapolis, Minnesota, cat# DY210) ELISA used as per kit instructions with antibody dilutions as follows: 3μg/ml capture antibody, 50ng/ml detection antibody and 1:200 strepavidin-HRP dilution.

Claims

What is claimed is:
1. A compound represented by Formula (I) as follows:
Formula I
Figure imgf000029_0001
wherein:
R1, R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, halo, (C1-C6) alkyl and (C1-C6) alkoxy;
R6 is selected from the group consisting of
a 3-8 membered heterocycle having at least one ring oxygen or nitrogen and an optional carbonyl; and a radical represented by the following structure:
Formula Ia R?ϊ^φ
wherein:
X1 is selected from the group consisting of hydroxyl and (C1-C6) alkoxy;
R7 is selected from the group consisting of hydroxy, (C1-C6) alkoxy, and an amino group represented by -NR8R9, wherein R8 and R9 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and (C1-C6) alkoxy, or, alternatively, said amino group represented by -NR8R9 forms a saturated or unsaturated 3-8 membered heterocyclic ring optionally including an oxygen;
m is 0, 1 or 2; and n is 1 or 2.
2. A compound according to claim 1 wherein R6 is represented by the following structure:
FOrmUla la RA
3. A compound according to claim 1 wherein R6 is said 3-8 membered heterocycle.
4. A compound according to claim 2 having the following structure:
Figure imgf000030_0001
5. A compound according to claim 2 having the following structure:
Figure imgf000030_0002
6. A compound according to claim 2 having the following structure:
2007/000441
- 30 -
7. A compound according to claim 2 having the following structure:
Figure imgf000031_0001
8. A compound according to claim 2 having the following structure:
Figure imgf000031_0002
9. A compound according to claim 2 having the following structure:
Figure imgf000031_0003
10. A compound according to claim 2 having the following structure:
Figure imgf000031_0004
11. A compound according to claim 2 having the following structure:
Figure imgf000032_0001
12. A compound according to claim 2 having the following structure:
Figure imgf000032_0002
13. A compound according to claim 2 having the following structure:
Figure imgf000032_0003
14. A compound according to claim 2 having the following structure:
Figure imgf000032_0004
15. A compound according to claim 2 having the following structure:
Figure imgf000033_0001
16. A compound according to claim 2 having the following structure:
Figure imgf000033_0002
17. A compound according to claim 2 having the following structure:
Figure imgf000033_0003
18. A compound according to claim 2 having the following structure:
Figure imgf000033_0004
19. A compound according to claim 2 having the following structure:
Figure imgf000034_0001
20. A compound according to claim 2 having the following structure:
Figure imgf000034_0002
21. A compound according to claim 2 having the following structure:
Figure imgf000034_0003
22. A compound according to claim 2 having the following structure:
Figure imgf000034_0004
23. A compound according to claim 2 having the following structure:
Figure imgf000035_0001
24. A compound according to claim 2 having the following structure:
Figure imgf000035_0002
25. A compound according to claim 2 having the following structure:
Figure imgf000035_0003
26. A compound according to claim 2 having the following structure:
Figure imgf000035_0004
27. A compound according to claim 3 having the following structure:
Figure imgf000036_0001
28.A compound according to claim 3 having the following structure:
Figure imgf000036_0002
29.A compound according to claim 3 having the following structure:
Figure imgf000036_0003
30. A compound according to claim 3 having the following structure:
Figure imgf000036_0004
31. A method for the modulation of the catalytic activity of a protein kinase with a compound or salt of any one of claims 1-30.
32. The method of claim 31, wherein said protein kinase is p38α.
PCT/US2007/000441 2006-01-05 2007-01-05 Pyrimidinone derivatives as protein kinase inhibitors WO2007081901A2 (en)

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US8507499B2 (en) 2010-12-06 2013-08-13 Confluence Life Sciences, Inc. Substituted indole/indazole-pyrimidinyl compounds
US8563558B2 (en) 2010-12-06 2013-10-22 Confluence Life Sciences, Inc. Substituted pyridine urea compounds
US9056110B2 (en) 2011-12-06 2015-06-16 Confluence Life Sciences, Inc. Substituted pyrimidinone-phenyl-pyrimidinyl compounds
US9115089B2 (en) 2013-06-07 2015-08-25 Confluence Life Sciences, Inc. Methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
US9359300B2 (en) 2010-12-06 2016-06-07 Confluence Life Sciences, Inc. Methyl/difluorophenyl-methoxy substituted pyridinone-pyridinyl compounds, methyl-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds, and methyl-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
US9365547B2 (en) 2010-12-06 2016-06-14 Confluence Life Sciences Inc. Substituted pyridinone-pyridinyl compounds
US11844801B2 (en) 2020-03-27 2023-12-19 Aclaris Therapeutics, Inc. Oral compositions of MK2 pathway inhibitor for treatment of immune conditions

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EP2166857A1 (en) * 2007-06-06 2010-03-31 Xcovery, INC. Kinase inhibitor compounds
CN101827525A (en) * 2007-06-06 2010-09-08 蒂罗格内克斯公司 Kinase inhibitor compounds
EP2166857A4 (en) * 2007-06-06 2011-03-30 Xcovery Inc Kinase inhibitor compounds
US8198276B2 (en) 2007-06-06 2012-06-12 Xcovery Holding Company Llc Kinase inhibitor compounds
US9365547B2 (en) 2010-12-06 2016-06-14 Confluence Life Sciences Inc. Substituted pyridinone-pyridinyl compounds
US8563558B2 (en) 2010-12-06 2013-10-22 Confluence Life Sciences, Inc. Substituted pyridine urea compounds
US9359300B2 (en) 2010-12-06 2016-06-07 Confluence Life Sciences, Inc. Methyl/difluorophenyl-methoxy substituted pyridinone-pyridinyl compounds, methyl-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds, and methyl-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
US8507499B2 (en) 2010-12-06 2013-08-13 Confluence Life Sciences, Inc. Substituted indole/indazole-pyrimidinyl compounds
US9365546B2 (en) 2010-12-06 2016-06-14 Confluence Life Sciences Inc. Substituted pyridinone-pyridinyl compounds
EP3469907A1 (en) 2010-12-06 2019-04-17 Aclaris Therapeutics, Inc. Substituted pyridinone-pyridinyl compounds
US9056110B2 (en) 2011-12-06 2015-06-16 Confluence Life Sciences, Inc. Substituted pyrimidinone-phenyl-pyrimidinyl compounds
US9115089B2 (en) 2013-06-07 2015-08-25 Confluence Life Sciences, Inc. Methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
US9636333B2 (en) 2013-06-07 2017-05-02 Confluence Life Sciences, Inc. Methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
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US11844801B2 (en) 2020-03-27 2023-12-19 Aclaris Therapeutics, Inc. Oral compositions of MK2 pathway inhibitor for treatment of immune conditions

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