tert-Butyl 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylate

10L three bottles into 810g (2.91mol) Compound B, 3.9LTHF, purged with nitrogen and evacuated three times, 20 stirred for 30 minutes and slowly dropping 1.2L isopropyl chloride (2.0Min THF) to the system, 20 incubated for 1 hour, the system was charged with 770g (2.25mol) compounds of the C, vacuum purged with nitrogen three times, and slowly added dropwise isopropylmagnesium chloride 1.2L (2.0MinTHF) to the system, after completion of the dropwise addition, temperature was raised to 70 The reaction was stirred , TLC monitoring of the reaction process. After completion of the reaction was added to the reaction solution and 1.3L of acetic acid 1.3LTHF (THF) mixture, solid precipitated, suction filtered, the filter cake were washed with acetone, water, acetone beating once, 50 blast drying, solid was constant weight 1338g, a pale yellow solid, yield 99.9percent.A dry, nitrogen purged reactor was charged with tetrahydrofuran (900 ml_, 15 ml_/g). The batch temperature was set at 20°C and agitation at 250 RPM was started. The reactor was charged with 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (63.4g, 0.2278 moles, 1.3 equiv.) and the mixture held at 20°C for 30 min to dissolve the starting material. The reactor was charged with isopropylmagnesium chloride (93.9 g, 0.193 moles, 1 st charge 1.1 eq) (2.0M in THF, 1.1 equiv.) by pump over 30 min. The batch was maintained at 20°C for 40 min. The reactor was charged with 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8/-/-pyrido[2, 3- c]pyrimidin-7-one (60.1g, 0.1755 moles, 1 eq.) all at once and rinsed with THF (50 ml_ rinse). An additional charge of isopropylmagnesium chloride (93.9g, 0.193 moles, 1.1 eq - 2nd charge (2.0M in THF, 1.1 equiv.) was added by pump over 30 min. The batch was held at 20°C for 90 min. and then heated from 20°C to 60°C.After reaction, a mixture of THF (2.86 vol) and HOAc (1 equiv.) was used to quench the reaction. The batch was then seeded with 0.5 wt/wtpercent of 4-{6-[6-bromo-8-cyclopentyl-5-methyl-7- oxo-7, 8-dihydro-pyrido[2, 3-c]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert- butyl ester and a mixture of THF (1.14 vol) and HOAc (0.4 equiv.) was charged to complete the precipitation. After cooling to 20°C, the batch was filtered, washed with acetone (4 vol), water (6 vol) and acetone (4 vol).The wet cake was dried under vacuum at 65°C to a constant weight to give 4-{6-[6- bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido[2, 3-c]pyrimidin-2-ylamino]-pyridin-3-yl}- piperazine-1-carboxylic acid te/f-butyl ester in 93percent yield.A mixture of B1 (30.62 g, 110 mmol) and N, N-dimethylformamide (170 mL) was added to the three-necked flask and the mixture was stirred Cold to 0 ~ 5 , Adding lithium hexamethylsilaneTetrahydrofuran solution(1.0 M, 120 mL, 120 mmol)After stirring at a low temperature for 20 to 30 minutes, compound 5 (34.26 g, 100 mmol) was added dropwise, and the mixture was allowed to stand at room temperature 20 to 25C for 6 to 8 hours. Reaction end plus The mixture was extracted with ethyl acetate (170 mL) and extracted three times with the organic phase saturated brine (170 mL), dried over anhydrous sodium sulfate. After concentration, the compound 10 was separated by a dichloromethane ethyl acetate mixed solvent column chromatography. (53.81 g, 92percent)Step c): synthesis of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro- pyrido[2, 3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert- butyl ester (formula 6) Step c): A 2 L 3-necked RBF was charged with 54.60 g of 4-(6-Amino-pyridin-3-yl)- piperazine-1 -carboxylic acid tert-butyl ester (0.196 mol, 2.1 eq.) and 360 ml toluene. The mixture was cooled to 10°C then 196 ml of LiHMDS solution (1 M in THF, 0.196 mol, 2.1 eq.) was added dropwise, under argon, within 10 min. After stirring for 10 min at Ι Ο ', a slurry of 32.00 g aryl chloride 6-bromo-2-chloro-8-cyclopentyl-5- methyl-8H-pyrido[2, 3-d]pyrimidin-7-one in 250 ml toluene was added dropwise within 10 min. After 15 min, the cooling bath was removed, the mixture stirred at RT for 1 .5 h then quenched with 375 ml of sodium hydrogen carbonate saturated aqueous solution. After 1 h, the precipitated solid was collected by filtration, washed with toluene (240 ml), acetone/water 1 /1 (240 ml), acetone (320 ml) then dried at RT/20 mbar for 6 h to give 50.10 g of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido[2, 3- d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1 -carboxylic acid tert-butyl ester (formula 6) (91 .8percent yield) as yellow solid.HPLC (Method 1 ): 9.06 min (97.2percent) (254 nm).Compound A cast material 304g (1.1mol), Compound B (250 g, 0.73 mol)Dry THF solvent 4000mL, N2 protection, Stirring to dissolve, cooling to 0 ~ 10 or so, 1120 mL (2.19 mol) of isopropylmagnesium chloride was added dropwise, Slower temperature increase, the control drop temperature 0 ~ 10 , Dropping the end of stirring 20min, warming to room temperature 25 ~ 30 or so, The reaction was stirred overnight. Point board shows the reaction of raw materials, the reaction liquid cooling, Dropping 4000mL ammonium chloride solution, stirring for 1 hour, filtered, The filter cake was washed twice with 1000mL water, filtered and dried, Filter cake with 1000mL methyl tert-butyl methyl ether beating beating, 1000mL acetone washing cake, drying weighed 366g. Yield 85percent.5)Synthesis of Compound 18: 490mg 4-(6-amino-pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester was added to 15ml of anhydroustoluene. The system was cooled to 0 °C. 1.05eq LiHMDS was added dropwise. Aftercompletion of the dropwise addition, reaction was continued for 30min at roomtemperature. After the completion of the reaction, the system was cooled to 0 °C. A solution of 5ml toluene containing 300mg ofCompound 17 was added dropwise. After the completion of the dropwise addition, the reaction was warmed to room temperature and reacted for 40min. After thecompletion of the reaction, the system was cooled to 0 °C, and saturated NH36 g of Compound A was added to 250 ml of tetrahydrofuran, Cool the system to 0 ° C;Under nitrogen protection, A solution of 240 mL of isopropylmagnesium chloride (1 M) in tetrahydrofuran was slowly added dropwise, After dripping, The system was warmed to room temperature and continued to react for 1 h;Then 35 g of compound B was added, Continue to react overnightThe reaction was quenched by the addition of saturated NH4Cl solution, Extracted three times with ethyl acetate, Combined organic phase, Dry, concentrated, To obtain 44 g of the compound represented by the formula (IV)Take 36g of compound A into 250mL of tetrahydrofuran, the system was cooled to 0 ;Under nitrogen protection, Slowly add 240 mL of isopropylmagnesium chloride (1 M)Tetrahydrofuran solution, after the addition was completed, The system was warmed to room temperature and continued to react for 1 h;Then 35 g of compound B was added, The reaction was continued overnight, and saturated saturated NH4Cl solution was addedThe reaction was quenched, extracted three times with ethyl acetate, the organic phases combined, dried, concentrated, To 44 g of compound DP-1;The procedure for synthesizing the compound of formula DP-1 in this step refers to the preparation method in the patent document (CN 104447739 A).105gm 6-Bromo-2-chloro-8-cyclopentyl-5 -methylpyrido[2, 3 -dl pyrimidin-7(8H)-one (Ill) was added in 13 volume of THF, cooled at 10-16°C, followed by addition of 225.0 ml of cyclohexyl magnesium chloride slowly under nitrogen over a period of 60 to 90 minutes, maintaining the temperature of reaction material to 10-1 5°C. The mixture was stirred for3 Ominutes at 10-15°C. Further, 100gm of 4-(6-aminopyridin-3 -yl)piperazine- 1 -carboxylic acid tert-butyl ester (VI) was added lot wise at 10-16°C followed by addition of 225 ml cyclohexyl magnesium chloride at 10-16°C under nitrogen in time interval of 60-90 minutes. The material was stirred for 120 to 180 minutes at 10-16°C and checked for completion ofreaction. On completion of reaction, a mixture of 300 ml of THF and 24 ml of acetic acid was added at 5-15°C. The product thus obtained was stirred for 240 minutes at 25-35°C, cooled to 10±5°C, stirred for 120 minutes at 5-10°C, followed by filtration and washed with S volume of acetone, S volume of hot water (SO-S S°C) and S volume of acetone. The crude material was dried at S0±S°C under vacuum for 8 hours to get 88 gm of 4-[6-(6-Bromo-8-cyclopentyl-S -methyl-7-oxo-7, 8-dihydropyrido [2, 3 -d]pyrimidin-2-ylamino)-pyridin-3 -yl]piperazine-1-carboxylic acid tert-butyl ester (V).‘H NIVIR (300 MHz, CDC13): ö 8.79 (s, 1H), 8.16-8.19 (d, 1H), 8.03-8.04 (m, 2H), 7.31-7.35 (dd, 1H), 5.92-6.04 (q, 1H), 3.60-3.63 (m, 4H), 3.10-3.14 (m, 4H), 2.61 (s, 3H), 1.62-1.76 & 2.03-2.18 (m, 4H), 1.81-1.97 &2.24-2.41 (m, 4H), 1.49 (s, 9H).Preparation of 4-R6- (6-BROMO-8-CVCLOPENTVL-5-METHYL-7-OXO-7, 8-DIHVDRO-PYRIDO [2 3- DPVRIMIDIN-2-VLAMINO)-PVRIDIN-3-VLL-PIPERAZINE-1-CARBOXVLIC acid TERT-BUTYL ester A suspension of 6-BROMO-8-CYCLOPENTYL-2-METHANSULFINYL-5-METHYL-8H-PYRIDO [2, 3- OGPYRIMIDIN-7-ONE (10.00 G, 0.027 mol, prepared as in Example 6 of WO 01/707041, which is incorporated herein by reference) and 10. 37 g (0.0373 mol) of 4-(6-amino-pyridin-3-yl)- piperazine-1-carboxylic acid tert-butyl ester in toluene (100 mL) was heated under nitrogen in an oil bath for 7 hours. Thin layer CHROMATOGRAPHY (SIOS, 10 percent MEOH/DCM) INDICATED THE presence of both starting materials. The suspension was heated under reflux for an additional 18 hours. The resulting suspension was cooled to RT and filtered to give 4- [6- (6- BROMO-8-CYCLOPENTYL-5-METHYL-7-OXO-7, 8-DIHYDRO-PYRIDO [2, 3-D] PYRIMIDIN-2-YLAMINO)-PYRIDIN-3- YLJ-PIPERAZINE-1-CARBOXYLIC acid tert-butyl ester (5. 93 G, 38 percent).Preparation 1 Mixture of compound 109 (500 mg, 1.35 mmol, 1.0 equiv) and compound 308-16 (524 mg, 1.62 mmol, 1.2 eq.) was dissolved in toluene was heated at reflux for 21 hours with stirring the reaction mixture was cooled and washed with toluene and filtered the yellow solid 4-(6-((6-bromo-8-cyclopentyl- 5-methyl-7-oxo-7, 8-dihydropyrido[2, 3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-carboxylic acid tert-butyl ester (209 mg, yield: 26.5percent).Comparative Example 1A: Preparation of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro- pyrido[2, 3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1 -carboxylic acid tert-butyl ester; A suspension of 6-bromo-8-cyclopentyl-2-methansulfinyl-5-methyl-8/-/-pyrido[2, 3-cdpyrimidin-7-one (10.00 g, 0.027 mol, prepared as in Example 6 of WO 01/707041 , which is incorporated herein by reference) and 10.37 g (0.0373 mol) of 4-(6-amino-pyhdin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester in toluene (100 ml.) was heated under nitrogen in an oil bath for 7 hours. Thin layer chromatography (SiOPreparation of 4-R6- (6-BROMO-8-CVCLOPENTVL-5-METHYL-7-OXO-7, 8-DIHVDRO-PYRIDO [2 3- DPVRIMIDIN-2-VLAMINO)-PVRIDIN-3-VLL-PIPERAZINE-1-CARBOXVLIC acid TERT-BUTYL ester A suspension of 6-BROMO-8-CYCLOPENTYL-2-METHANSULFINYL-5-METHYL-8H-PYRIDO [2, 3- OGPYRIMIDIN-7-ONE (10.00 G, 0.027 mol, prepared as in Example 6 of WO 01/707041, which is incorporated herein by reference) and 10. 37 g (0.0373 mol) of 4-(6-amino-pyridin-3-yl)- piperazine-1-carboxylic acid tert-butyl ester in toluene (100 mL) was heated under nitrogen in an oil bath for 7 hours. Thin layer CHROMATOGRAPHY (SIOS, 10 % MEOH/DCM) INDICATED THE presence of both starting materials. The suspension was heated under reflux for an additional 18 hours. The resulting suspension was cooled to RT and filtered to give 4- [6- (6- BROMO-8-CYCLOPENTYL-5-METHYL-7-OXO-7, 8-DIHYDRO-PYRIDO [2, 3-D] PYRIMIDIN-2-YLAMINO)-PYRIDIN-3- YLJ-PIPERAZINE-1-CARBOXYLIC acid tert-butyl ester (5. 93 G, 38 %).EXAMPLE 34 4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido[2, 3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic Acid Tert-butyl Ester. A suspension of 6-bromo-8-cyclopentyl-2-methansulfinyl-5-methyl-8H-pyrido[2, 3-d]pyrimidin-7-one (10.00 g, 0.027 mol, prepared as in Example 6 of WO 01/707041 which is incorporated here by reference) and 10.37 g (0.0373 mol) of 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester in toluene (100 mL) was heated under nitrogen in an oil bath for 7 hours. Thin layer chromatography (SiO2, 10% MeOH/DCM) indicated that both starting materials remained. The suspension was heated under reflux for a further 18 hours. The resulting suspension was cooled to room temperature and filtered to give 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido[2, 3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.93 g, 38%). mp>250 C. MS (APCI); M++1: Calc'd, 584.2, Found, 584.2Preparation 1 Preparation of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido[2, 3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester A suspension of 6-bromo-8-cyclopentyl-2-methansulfinyl-5-methyl-8H-pyrido[2, 3-d]pyrimidin-7-one (10.00 g, 0.027 mol, prepared as in Example 6 of WO 01/707041, which is incorporated herein by reference) and 10.37 g (0.0373 mol) of 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester in toluene (100 mL) was heated under nitrogen in an oil bath for 7 hours. Thin layer chromatography (SiO2, 10% MeOH/DCM) indicated the presence of both starting materials. The suspension was heated under reflux for an additional 18 hours. The resulting suspension was cooled to RT and filtered to give 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido[2, 3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.93 g, 38%). Melting point >250 C. MS (APCI) M++1: calc'd, 584.2, found, 584.2.Mixture of compound 109 (500 mg, 1.35 mmol, 1.0 equiv) and compound 308-16 (524 mg, 1.62 mmol, 1.2 eq.) was dissolved in toluene was heated at reflux for 21 hours with stirring the reaction mixture was cooled and washed with toluene and filtered the yellow solid 4-(6-((6-bromo-8-cyclopentyl- 5-methyl-7-oxo-7, 8-dihydropyrido[2, 3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-carboxylic acid tert-butyl ester (209 mg, yield: 26.5%).To a solution of 6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfinyl) pyrido[2, 3-d] pyrimidin-7(8H)-one (10, 9.80 g, 26.4 mmol) in dimethyl carbonate (100 mL), tertbutyl4-(6-aminopyridin-3-yl) piperazine-1-carboxylate(11.02 g, 39.6 mmol) was added under a nitrogen atmosphere.After completion of the addition, the reaction mixturewas stirred at 110 C for 25 h under nitrogen protection.After 25 h, the reaction solution was cooled to room temperature, diluted with water and then extracted with dichloromethaneand saturated NaHCO3solution. The combinedorganic phases were dried over MgSO4, filtered, and concentratedin vacuo. The residue was purified by passing theorganic extract through a silica gel column using DCM/MeOH (40:1) to give the product 11 (Toogood et al. 2005;VanderWel et al. 2005; Duan et al. 2016). Yellow solid;yield 47%; m.p. > 250 C; 1H NMR (300 MHz, CDCl3) delta8.82 (s, 1H), 8.43 (s, 1H), 8.21 (d, J = 9.0 Hz, 1H), 8.04(d, J = 2.5 Hz, 1H), 7.35 (dd, J = 9.1, 2.8 Hz, 1H), 5.99 (p, J = 8.7 Hz, 1H), 3.68-3.55 (m, 4H), 3.20-3.04 (m, 4H), 2.61 (s, 3H), 2.40-2.22 (m, 2H), 2.13 (t, J = 9.6 Hz, 2H), 1.95-1.84 (m, 2H), 1.74-1.64 (m, 2H), 1.49 (s, 9H); 13CNMR (75 MHz, CDCl3)delta 159.05, 157.84, 156.40, 154.96, 154.77, 145.59, 143.64, 143.49, 136.80, 127.04, 117.62, 113.67, 108.20, 80.26, 77.16, 55.29, 49.90, 43.62, 28.58, 28.44, 26.16, 18.19; HRMS ([M + H]+): m/z calcd for[(C27H34BrN7O3) + H]+: 586.19651, found 586.19626.After purging three times with nitrogen, 60 mmol of magnesium metal and 50 mL of dry tetrahydrofuran were added to the reaction flask, and heated to reflux. 50 mmol of the compound of the formula (IV) dissolved in 50 mL of dry tetrahydrofuran was dropped into the reaction flask, and then refluxed after the completion of the dropwise addition. 0.5h, stop heating, the reaction bottle was placed in an ice salt bath, the dry carbon dioxide gas was slowly introduced into the reaction system, the reaction temperature was controlled at about -10 C, and the reaction was continued for 1 h with carbon dioxide gas, and the ice salt bath was removed. Slowly rise to room temperature, and stir the reaction for 0.5 h, then place the reaction flask in an ice water bath, and add 50 mL of 1N hydrochloric acid into the reaction flask. After the completion of the dropwise addition, the mixture was stirred at room temperature for 30 min, and the organic layer was separated and washed three times with 120 mL of saturated brine. The organic layer was combined, dried over anhydrous sodium sulfate and evaporated evaporated. The solid is recrystallized from n-butanol and dried to give the compound of formula (V) in a yield of 88%.

Molecular Weight:584.5
XLogP3:4.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:8
Rotatable Bond Count:6
Exact Mass:583.19065
Monoisotopic Mass:583.19065
Topological Polar Surface Area:104
Heavy Atom Count:38
Complexity:911
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes