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WO2007081901A2 - Derives de pyrimidinone comme inhibiteurs de proteines kinases - Google Patents

Derives de pyrimidinone comme inhibiteurs de proteines kinases Download PDF

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Publication number
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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WO2007081901A3 (fr
Inventor
Congxin Liang
Marcel Koenig
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Scripps Research Institute
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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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés de pyrimidinone qui possèdent de façon inattendue des propriétés thérapeutiques accrues d'inhibiteurs de protéines kinases et sont utiles pour traiter des troubles liés à des activités anormales de protéines kinases telles que des maladies inflammatoires et certains types de cancer.
PCT/US2007/000441 2006-01-05 2007-01-05 Derives de pyrimidinone comme inhibiteurs de proteines kinases Ceased WO2007081901A2 (fr)

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US75695006P 2006-01-05 2006-01-05
US60/756,950 2006-01-05

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101827525A (zh) * 2007-06-06 2010-09-08 蒂罗格内克斯公司 激酶抑制剂化合物
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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7183287B2 (en) * 2003-04-03 2007-02-27 Pharmacia Corporation Substituted pyrimidinones

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101827525A (zh) * 2007-06-06 2010-09-08 蒂罗格内克斯公司 激酶抑制剂化合物
EP2166857A4 (fr) * 2007-06-06 2011-03-30 Xcovery Inc Composés d'inhibiteur de kinase
US8198276B2 (en) 2007-06-06 2012-06-12 Xcovery Holding Company Llc Kinase inhibitor compounds
US9365546B2 (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
US9365547B2 (en) 2010-12-06 2016-06-14 Confluence Life Sciences Inc. Substituted pyridinone-pyridinyl compounds
US8507499B2 (en) 2010-12-06 2013-08-13 Confluence Life Sciences, Inc. Substituted indole/indazole-pyrimidinyl compounds
EP3469907A1 (fr) 2010-12-06 2019-04-17 Aclaris Therapeutics, Inc. Composés pyridinone-pyridinyl substitués
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
EP3845529A1 (fr) 2013-06-07 2021-07-07 Aclaris Therapeutics, Inc. Composés de pyridinone-pyridinyle substitués avec méthyle/fluoro-pyridinyle-méthoxy et des composés de pyridinone-pyridinyle substitués avec fluoro-pyrimidinyl-méthoxy
US11844801B2 (en) 2020-03-27 2023-12-19 Aclaris Therapeutics, Inc. Oral compositions of MK2 pathway inhibitor for treatment of immune conditions
US12370195B2 (en) 2020-03-27 2025-07-29 Aclaris Therapeutics, Inc. Oral compositions of MK2 pathway inhibitor for treatment of immune conditions

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