Cathepsin K inhibitors and application thereof

[0190] Example 1

[0191] (S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4-(4' -(2-oxopyrrolidin-1-yl)-1',3'-dihydrospiro[cyclopentane-1,2'-indene]-7'-yl)phenyl)ethyl)amino)pentan Amide

[0192]

[0193] Step 1: 4'-(2-oxopyrrolidin-1-yl)-1',3'-dihydrospiro[cyclopentane-1,2'-indene]-7'-yltrifluoromethanesulfonic acid ester

[0194] Add 4'-iodine-1',3'-dihydrospiro[cyclopentane-1,2'-indene]-7'-yl trifluoromethanesulfonate (522mg, 1.77) to a pressure-resistant glass test tube mmol) [refer to patent WO 2014082379 for synthesis method, the synthetic route of intermediate 1-8 on page 113-115], 2-pyrrolidone (151mg, 1.77mmol), potassium phosphate (0.75g, 3.54mmol), cuprous iodide ( 17mg, 0.09mmol) and anhydrous toluene (10mL), N,N'-dimethylethylenediamine (8.0mg, 0.09mmol) was added under nitrogen flow, sealed and heated to 130°C to react overnight. After the reaction was completed, it was cooled to room temperature, quenched with water, extracted with ethyl acetate (30 mL×2), the organic phase was washed with saturated brine (10 mL), and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 5:1) to obtain the title compound (606 mg, 85%) as a pale yellow oil. MS(ESI,pos.ion)m/z:404.1(M+1).

[0195] Step 2: (S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4- (4'-(2-oxopyrrolidin-1-yl)-1',3'-dihydrospiro[cyclopentane-1,2'-indene]-7'-yl)phenyl)ethyl) Amino) pentane

[0196] Add 4'-(2-oxopyrrolidin-1-yl)-1',3'-dihydrospiro[cyclopentane-1,2'-indene]-7'-yltrifluoro Methanesulfonate (430mg, 1.00mmol), (S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2- Trifluoro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)amino)pentanamide (497mg ,1.00mmol), (1,1'-bis(diphenylphosphine)ferrocene)dichloropalladium dichloromethane complex (67mg, 0.08mmol), potassium carbonate aqueous solution (1.5mL, 2mmol/L) And DMF (10mL), under the protection of nitrogen, heat to 85°C and react for 3 hours. After the reaction was completed, it was cooled to room temperature, quenched with water, and extracted with ethyl acetate (60 mL×2). The organic phase was washed with water (60 mL×2) and saturated brine (60 mL) successively, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane: ethyl acetate (V/V)=1:1) to obtain the title compound (0.42 g, 68%) as a white solid.

[0197] MS(ESI,pos.ion)m/z:625.3(M+1);

[0198] 1 H NMR(400MHz, CDCl 3 )δ(ppm)7.49(s,1H),7.46(d,J=8.2Hz,2H), 7.40(d,J=8.2Hz,2H), 7.23(d,J=8.1Hz,1H), 7.14( d,J=8.1Hz,1H), 4.18–4.10(m,1H), 3.84(t,J=6.9Hz,2H), 3.71–3.64(m,1H), 2.95(s,2H), 2.84(s ,2H), 2.63(t,J=8.0Hz,2H),2.30–2.20(m,2H),1.71–1.57(m,8H),1.51(d,J=12.3Hz,3H),1.45(d, J = 12.8Hz, 3H), 1.31-1.25 (m, 2H), 1.07-0.92 (m, 2H).

[0199] Example 2

[0200] (2S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((1S)-2,2,2-trifluoro-1-(4-(8- (2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydro-1,4-monaphth-5-yl)phenyl)ethyl)amino)pentaneamide

[0201]

[0202] Step 1: 5-Methoxy-1,4-dihydro-1,4-methylponphthalene

[0203] Add magnesium chips (600mg, 24.9mmol), a small piece of elemental iodine and anhydrous tetrahydrofuran (10mL) to the dry reaction flask. Install the reflux condenser and protect it with nitrogen. Add 2-bromo-1-fluoro-3 first -Methoxybenzene (0.5g) initiates the reaction, and then another 2-bromo-1-fluoro-3-methoxybenzene (2.5g, 12.2mmol) and freshly distilled 1,3-cyclopentadiene (1.05g.17.56mmol) was dissolved in anhydrous tetrahydrofuran (20mL), then placed in a constant pressure dropping funnel and slowly added dropwise, keeping the reaction system slightly refluxed. After the addition was completed, the reaction system continued to be heated and refluxed for 1 hour. After the reaction was cooled, it was quenched with saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (60 mL×2), the organic phase was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluted with petroleum ether) to obtain the title compound (1.43 g, 56%) as a colorless liquid.

[0204] MS(ESI,pos.ion)m/z:173.1(M+1).

[0205] Step 2: 5-Methoxy-1,2,3,4-tetrahydro-1,4-methylponphthalene

[0206] Add 5-methoxy-1,4-dihydro-1,4-methylponphthalene (0.82g, 0.47mmol), p-toluenesulfonyl hydrazide (5.25g, 2.82mmol) and sodium acetate (3.82g, 2.82mmol) to the reaction flask g, 2.82 mmol), tetrahydrofuran (30 mL) was added, and the reaction mixture was heated to reflux overnight under a nitrogen atmosphere. After the completion of the reaction, it was cooled to room temperature, the solids were filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluted with petroleum ether) to obtain the title compound (0.65 g, 80%) as a colorless liquid.

[0207] MS(ESI,pos.ion)m/z:175.1(M+1).

[0208] Step 3: 5-Bromo-8-methoxy-1,2,3,4-tetrahydro-1,4-methylponphthalene

[0209] Dissolve 5-methoxy-1,2,3,4-tetrahydro-1,4-methylponphthalene (0.85g, 0.48mmol) in anhydrous acetonitrile (20mL), and then add NBS in portions at room temperature ( 0.93g, 0.52mmol), after the addition, react at room temperature for 3 hours. Water (20 mL) was added and extracted with dichloromethane (80 mL×2), the organic phase was washed with saturated brine (30 mL), and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluted with petroleum ether) to obtain the title compound (0.96 g, 83%) as a pale yellow liquid.

[0210] MS(ESI,pos.ion)m/z:254.0(M+2).

[0211] Step 4: 1-(8-Methoxy-1,2,3,4-tetrahydro-1,4-maptonaphth-5-yl)pyrrolidin-2-one

[0212] Combine 5-bromo-8-methoxy-1,2,3,4-tetrahydro-1,4-methylponaphthalene (0.50g, 1.97mmol), pyrrolidin-2-one (0.37g, 3.95mmol) , Cuprous iodide (0.037g, 0.20mmol) and potassium carbonate (0.54g, 3.95mmol) were mixed with anhydrous toluene (8mL), the reaction flask was protected with nitrogen, and then N,N'-dimethyl-1, 2-Ethylenediamine (0.070g, 0.79mmol), the reaction mixture was heated to 120°C for 15 hours. After the completion of the reaction, it was cooled to room temperature, ethyl acetate (80 mL) was added, washed with saturated brine (30 mL×2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 2/1) to obtain the title compound (0.42 g, 82%) as a pale yellow oil.

[0213] MS(ESI,pos.ion)m/z:258.1(M+1).

[0214] Step 5: 1-(8-Hydroxy-1,2,3,4-tetrahydro-1,4-maptonaphth-5-yl)pyrrolidin-2-one

[0215] Add 1-(8-methoxy-1,2,3,4-tetrahydro-1,4-methanenaphth-5-yl)pyrrolidin-2-one (0.42g, 1.63mmol) to the two-neck flask ) And dichloromethane (20mL), under nitrogen protection, the reaction mixture was cooled to -20°C, and a dichloromethane solution of boron tribromide (3.3mL, 3.3mmol, 1mol/L) was slowly added dropwise. After the addition, The reaction mixture continued to react for 2.5 hours. Water (10 mL) was carefully added to quench the reaction, and extracted with dichloromethane (30 mL×2), the organic phase was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 1/1) to obtain the title compound (0.41 g, 98%) as a pale yellow liquid.

[0216] MS(ESI,pos.ion)m/z:244.1(M+1).

[0217] Step 6: 8-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydro-1,4-methanenaphthalene-5-yl trifluoromethanesulfonate

[0218] Add 1-(8-Hydroxy-1,2,3,4-tetrahydro-1,4-methylaphthalen-5-yl)pyrrolidin-2-one (0.20g, 0.82mmol) into the two-neck flask, Pyridine (0.066mL, 1.64mmol) and anhydrous dichloromethane (15mL), protected by nitrogen, cooled to 0°C, trifluoromethanesulfonic anhydride (0.28g, 0.98mmol) was added dropwise, and then warmed to room temperature to react for 1 hour. Water (10 mL) was added to quench the reaction, and extracted with dichloromethane (30 mL×2), the organic phase was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 1/1) to obtain the title compound (0.22 g, 71%) as a pale yellow liquid.

[0219] MS(ESI,pos.ion)m/z:376.1(M+1).

[0220] Step 7: (2S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((1S)-2,2,2-trifluoro-1-(4- (8-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydro-1,4-methanenaphthyl-5-yl)phenyl)ethyl)amino)pentanamide

[0221] Add 8-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydro-1,4-methanenaphthalene-5-yl trifluoromethanesulfonate ( 375mg, 1.00mmol), (S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1- (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)amino)pentaneamide (497mg, 1.00mmol), (1,1'-bis(diphenylphosphine)ferrocene)dichloropalladium dichloromethane complex (67mg, 0.08mmol), potassium carbonate aqueous solution (1.5mL, 2mmol/L) and DMF (10mL) , Under the protection of nitrogen, heat to 85°C for 3 hours. After the reaction was completed, it was cooled to room temperature, quenched with water, and extracted with ethyl acetate (60 mL×2). The organic phase was washed with water (60 mL×2) and saturated brine (60 mL) successively, and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/ethyl acetate (V/V)=1/1) to obtain the title compound (0.39 g, 65%) as a white solid.

[0222] MS(ESI,pos.ion)m/z:597.2(M+1);

[0223] 1 H NMR(400MHz, CDCl 3 )δ(ppm)7.49(s,1H),7.46(d,J=8.2Hz,2H), 7.40(d,J=8.2Hz,2H), 7.23(d,J=8.1Hz,1H), 7.14( d,J=8.1Hz,1H), 4.18–4.10(m,1H), 3.84(s,3H), 3.83–3.79(m,1H), 3.77–3.69(m,2H), 3.62(s,1H) ,3.33(s,1H),2.60(t,J=8.1Hz,2H),2.30–2.15(m,2H),1.92(dd,J=7.8,3.6Hz,2H),1.51(d,J=12.3 Hz, 3H), 1.45 (d, J = 12.8 Hz, 3H), 1.33-1.22 (m, 6H), 1.07-0.92 (m, 2H).

[0224] Example 3

[0225] (S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4-(4' -(2-oxopyrrolidin-1-yl)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-7-yl)phenyl)ethyl)amino)pentanamide

[0226]

[0227] Step 1: 7-Methoxy-1-methylene-2,3-dihydro-1H-indene

[0228] Add potassium tert-butoxide (3.50g, 30.86mmol), methyltriphenylphosphonium iodide (13.7g, 33.9mmol) and anhydrous tetrahydrofuran (200mL) into the reaction flask, protect with nitrogen, and react at room temperature for 1 hour . Then 7-methoxy-2,3-dihydro-1H-inden-1-one (5.0g, 30.86mmol) in anhydrous tetrahydrofuran (20mL) solution was added dropwise to the reaction flask, the addition was completed, the reaction mixture Stir overnight at room temperature. The reaction was completed, quenched with water (80 mL), extracted with ethyl acetate (80 mL×3), the organic phase was washed with saturated brine (60 mL), and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/petroleum ether (V/V)=1/100) to obtain the title compound (3.80 g, 77%) as a colorless liquid.

[0229] MS(ESI,pos.ion)m/z:161.1(M+1).

[0230] Step 2: 7'-Methoxy-2',3'-dihydrospiro[cyclopropane-1,1'-indene]

[0231] To the dry reaction flask, add anhydrous DCM (80mL) and diethyl zinc (71.3mL, 71.28mmol, 1.0mol/L), the reaction system is cooled to -20 ℃, dropwise add trifluoroacetic acid (5.2mL, 71.28 mmol). After the addition was completed, the reaction mixture was stirred and reacted for 1 hour, and diiodomethane (5.8 mL, 71.28 mmol) was added dropwise at 0°C. After the addition, the reaction was continued at 0°C for 40 minutes. The 7-methoxy-1-methylene A solution of phenyl-2,3-dihydro-1H-indene (3.8 g, 23.76 mmol) in anhydrous dichloromethane (20 mL) was added dropwise to the reaction flask, and the reaction mixture was raised to room temperature and stirred for 3 hours. After the reaction is complete, add saturated NH to the reaction mixture 4 The Cl solution (50 mL) was extracted with dichloromethane (80 mL×3), washed with saturated brine (80 mL×2), and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate under reduced pressure, the crude product was purified by column chromatography (petroleum ether/dichloromethane (V/V)=100/1) to obtain the title compound (8.3 g, 67%) as a pale yellow liquid.

[0232] MS(ESI, pos.ion)m/z:175.1(M+1).

[0233] Step 3: 4'-bromo-7'-methoxy-2',3'-dihydrospiro[cyclopropane-1,1'-indene]

[0234] Dissolve 7'-methoxy-2',3'-dihydrospiro[cyclopropane-1,1'-indene] (2.5g, 14.35mmol) in anhydrous acetonitrile (30mL), and then batch at room temperature Add NBS (2.76g, 15.5mmol), and react at room temperature for 3 hours after addition. Water (40 mL) was added and extracted with dichloromethane (80 mL×2), the organic phase was washed with saturated brine (30 mL), and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluted with petroleum ether) to obtain the title compound (2.9 g, 80%) as a pale yellow liquid.

[0235] MS(ESI, pos.ion)m/z:254.0(M+2).

[0236] Step 4: 1-(7'-Methoxy-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-4'-yl)pyrrolidin-2-one

[0237] 4'-bromo-7'-methoxy-2',3'-dihydrospiro[cyclopropane-1,1'-indene] (0.50g, 2.0mmol), pyrrolidin-2-one (0.37g , 3.95mmol), cuprous iodide (0.037g, 0.20mmol) and potassium carbonate (0.54g, 3.95mmol) mixed with anhydrous toluene (8mL), the reaction flask is protected with nitrogen, and then N,N'-dimethyl Benzyl-1,2-ethylenediamine (0.070g, 0.79mmol), the reaction mixture was heated to 120°C for 15 hours. After the completion of the reaction, it was cooled to room temperature, ethyl acetate (80 mL) was added, washed with saturated brine (30 mL×2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 2/1) to obtain the title compound (0.43 g, 85%) as a pale yellow oil. MS(ESI,pos.ion)m/z:258.1(M+1).

[0238] Step 5: 1-(7'-hydroxy-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-4'-yl)pyrrolidin-2-one

[0239] Add 1-(7'-methoxy-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-4'-yl)pyrrolidin-2-one (0.43 g, 1.63mmol) and dichloromethane (20mL), protected by nitrogen, the reaction mixture is cooled to -20°C, and a dichloromethane solution of boron tribromide (3.3mL, 3.3mmol, 1mol/L) is slowly added dropwise. After the addition, the reaction mixture continued to react for 2.5 hours. Water (10 mL) was carefully added to quench the reaction and extracted with dichloromethane (30 mL×2). The organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 1/1) to obtain the title compound (0.41 g, 98%) as a pale yellow liquid.

[0240] MS(ESI,pos.ion)m/z:244.1(M+1).

[0241] Step 6: 4'-(2-oxopyrrolidin-1-yl)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-7'-yl trifluoromethanesulfonate

[0242] Add 1-(7'-hydroxy-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-4'-yl)pyrrolidin-2-one (0.40g, 1.64mmol), pyridine (0.132mL, 3.3mmol) and anhydrous dichloromethane (15mL), protected by nitrogen, cooled to 0℃, added dropwise trifluoromethanesulfonic anhydride (0.56g, 2.0mmol), then warmed to room temperature for reaction 1 hour. Water (10 mL) was added to quench the reaction, and extracted with dichloromethane (30 mL×2), the organic phase was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V)=1/1) to obtain the title compound (0.43 g, 70%) as a pale yellow liquid.

[0243] MS (ESI, pos.ion) m/z: 376.1 (M+1);

[0244] Step 7: (S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4- (4'-(2-oxopyrrolidin-1-yl)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-7-yl)phenyl)ethyl)amino) Valeramide

[0245] Add 4'-(2-oxopyrrolidin-1-yl)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-7'-yltrifluoromethane to the two-neck flask Sulfonate (375mg, 1.00mmol), (S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-tri Fluoro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)amino)pentanamide (497mg, 1.00mmol), (1,1'-bis(diphenylphosphine)ferrocene) palladium dichloride dichloromethane complex (67mg, 0.08mmol), potassium carbonate aqueous solution (1.5mL, 2mmol/L) and DMF (10 mL) was heated to 85°C for 3 hours under the protection of nitrogen. After the reaction was completed, it was cooled to room temperature, quenched with water, and extracted with ethyl acetate (60 mL×2). The organic phase was washed with water (60 mL×2) and saturated brine (60 mL) successively, and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/ethyl acetate (V/V)=1/1) to obtain the title compound (0.4 g, 68%) as a white solid.

[0246] MS(ESI,pos.ion)m/z:597.2(M+1);

[0247] 1 H NMR(400MHz, CDCl 3 )δ(ppm)7.49(s,1H),7.46(d,J=8.2Hz,2H), 7.40(d,J=8.2Hz,2H), 7.23(d,J=8.1Hz,1H), 7.14( d,J=8.1Hz,1H), 4.18–4.10(m,1H), 3.84(s,3H), 3.83–3.79(m,1H), 3.77–3.69(m,2H), 3.62(s,1H) ,3.33(s,1H),2.60(t,J=8.1Hz,2H),2.45(t,J=8.1Hz,2H),2.10–1.96(m,4H),1.92(dd,J=7.8,3.6 Hz, 2H), 1.07-0.92 (m, 2H), 1.14-1.08 (m, 2H), 0.73-0.68 (m, 2H), 0.56-0.48 (m, 2H).