Pyrazolopyridine derivatives with glp-1 receptor agonist action

Abstract

The present invention provides a compound represented by formula (I), wherein the indole ring or the pyrrolo[2,3-b]pyridine ring and the pyrazolopyridine skeleton are bonded by a substituent, or a salt of the compound; a solvate thereof; And a preventive or therapeutic agent for non-insulin-dependent diabetes (type 2 diabetes), obesity, etc., wherein the compound, salt or solvate is used as an active ingredient. (In this formula, X, Y, Q 1 , Q 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , n1, n2, Z 1 and Z 2 Indicates substances indicated in this manual)

Description

[0001] field of invention

[0002] The present invention relates to a GLP-1 receptor agonist compound, a salt thereof, or a solvate of the compound or the salt of the compound, which has an action similar to that of GLP-1. The present invention further relates to a preventive or therapeutic agent for non-insulin-dependent diabetes (type 2 diabetes) or obesity comprising the compound, salt or solvate as an active ingredient. Background technique

[0003] Glucagon-like peptide-1 (GLP-1) is an incretin secreted by L cells of the small intestine when nutrients pass through the digestive tract, and GLP-1 is known to exhibit various actions through the GLP-1 receptor, such as Promote glucose-dependent insulin secretion, inhibit glucagon secretion, delay gastric emptying, and inhibit food intake. Although GLP-1 analogs have been commercialized as diabetes therapeutics and are regarded as one of the most effective diabetes therapeutics due to their potent effects of HbA1c lowering an...

Examples

Embodiment 1

[0410] 3-[(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl) )- 2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridine - 4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2, 4 - Synthesis of Oxadiazol-5-one (Compound 1)

[0411] [chemical formula 17]

[0412]

[0413]

[0414] [(5-cyano-1,2,3,6-tetrahydropyridin-4-yl)amide] potassium (compound 1b)

[0415] To a solution of 3-(2-cyanoethylamino)propionitrile (compound 1a, 22.0 g, 179 mmol) in tetrahydrofuran (THF) (179 mL) was added a 1M solution of potassium tert-butoxide in THF (179 mL), and the mixture was dissolved in Stir at room temperature for 1 hour. The reaction mixture was filtered, washed with THF (50 mL), and the filtrate was dried under reduced pressure to give the title compound 1b (23.8 g, 83% yield) as a light brown solid.

[0416] LC / MS mass spectrum: m / z 124 ([M+H] + ).

[0417] LC / MS retention time: 0.14 minutes (analysis conditions:...

Embodiment 2

[0469]

[0470] Apply the combination of the 2-oxoimidazole compound shown in Table 2-2 and the halogen compound shown in the following Table 2-3, and an appropriate solvent, carry out the operation similar to Example 1 step 1-11, and pass The following reactions gave Example compounds 2 to 50 shown in Table 2-1.

[0471] [chemical formula 18]

[0472]

[0473] [table 2-1]

[0474] Table 2-1. Obtained embodiment compounds 2 to 50

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500] The compounds in Table 2-1 have rotamers, and as an example, the compound of Example 2 has 1 H-NMR is shown below.

[0501] Rotamer A

[0502] 1 H-NMR (600MHz, CDCl 3 )δ:11.29(1H,s),8.40(1H,d,J=5.2Hz), 7.93(1H,s),7.74(1H,d,J=1.5Hz),7.70(1...

Embodiment 51 to 53

[0954] By the following reaction, 3-[(1S,2S)-1-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1 -Methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole- 1-yl]-2-methylcyclopropyl]-4H-1,2,4- Oxadiazol-5-one (compound 51d), substituted morpholine and appropriate reagents, followed by a similar operation to Step 7-1 of Example 7, to obtain Example compounds 51 to 53 represented in Table 2-4.

[0955] [chemical formula 48]

[0956]

[0957] [Table 2-4]

[0958] Table 2-4. Obtained example compounds 51 to 53

[0959]

[0960]

[0961] Compound 51d was synthesized as follows.

[0962] [chemical formula 49]

[0963]

[0964]

[0965] 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4, 3-c] tert-butyl pyridine-5-carboxylate (compound 51a)

[0966] Add triethylamine (0.936mL, 6.72mmol), di-tert-butyl dicarbonate (0.425mL , 1.85 mmol), and the suspension was stirred at room temperatu...

[0001] field of invention

[0002] The present invention relates to a GLP-1 receptor agonist compound, a salt thereof, or a solvate of the compound or the salt of the compound, which has an action similar to that of GLP-1. The present invention further relates to a preventive or therapeutic agent for non-insulin-dependent diabetes (type 2 diabetes) or obesity comprising the compound, salt or solvate as an active ingredient. Background technique

[0003] Glucagon-like peptide-1 (GLP-1) is an incretin secreted by L cells of the small intestine when nutrients pass through the digestive tract, and GLP-1 is known to exhibit various actions through the GLP-1 receptor, such as Promote glucose-dependent insulin secretion, inhibit glucagon secretion, delay gastric emptying, and inhibit food intake. Although GLP-1 analogs have been commercialized as diabetes therapeutics and are regarded as one of the most effective diabetes therapeutics due to their potent effects of HbA1c lowering an...

Examples

Embodiment 1

[0410] 3-[(1S,2S)-1-[2-[2-(3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl) )- 2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(2-ethyl-3-methylpyridine - 4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2, 4 - Synthesis of Oxadiazol-5-one (Compound 1)

[0411] [chemical formula 17]

[0412]

[0413]

[0414] [(5-cyano-1,2,3,6-tetrahydropyridin-4-yl)amide] potassium (compound 1b)

[0415] To a solution of 3-(2-cyanoethylamino)propionitrile (compound 1a, 22.0 g, 179 mmol) in tetrahydrofuran (THF) (179 mL) was added a 1M solution of potassium tert-butoxide in THF (179 mL), and the mixture was dissolved in Stir at room temperature for 1 hour. The reaction mixture was filtered, washed with THF (50 mL), and the filtrate was dried under reduced pressure to give the title compound 1b (23.8 g, 83% yield) as a light brown solid.

[0416] LC / MS mass spectrum: m / z 124 ([M+H] + ).

[0417] LC / MS retention time: 0.14 minutes (analysis conditions:...

Embodiment 2

[0469]

[0470] Apply the combination of the 2-oxoimidazole compound shown in Table 2-2 and the halogen compound shown in the following Table 2-3, and an appropriate solvent, carry out the operation similar to Example 1 step 1-11, and pass The following reactions gave Example compounds 2 to 50 shown in Table 2-1.

[0471] [chemical formula 18]

[0472]

[0473] [table 2-1]

[0474] Table 2-1. Obtained embodiment compounds 2 to 50

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500] The compounds in Table 2-1 have rotamers, and as an example, the compound of Example 2 has 1 H-NMR is shown below.

[0501] Rotamer A

[0502] 1 H-NMR (600MHz, CDCl 3 )δ:11.29(1H,s),8.40(1H,d,J=5.2Hz), 7.93(1H,s),7.74(1H,d,J=1.5Hz),7.70(1...

Embodiment 51 to 53

[0954] By the following reaction, 3-[(1S,2S)-1-[5-bromo-2-[2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1 -Methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole- 1-yl]-2-methylcyclopropyl]-4H-1,2,4- Oxadiazol-5-one (compound 51d), substituted morpholine and appropriate reagents, followed by a similar operation to Step 7-1 of Example 7, to obtain Example compounds 51 to 53 represented in Table 2-4.

[0955] [chemical formula 48]

[0956]

[0957] [Table 2-4]

[0958] Table 2-4. Obtained example compounds 51 to 53

[0959]

[0960]

[0961] Compound 51d was synthesized as follows.

[0962] [chemical formula 49]

[0963]

[0964]

[0965] 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4, 3-c] tert-butyl pyridine-5-carboxylate (compound 51a)

[0966] Add triethylamine (0.936mL, 6.72mmol), di-tert-butyl dicarbonate (0.425mL , 1.85 mmol), and the suspension was stirred at room temperatu...

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