Spirotricyclic compound, its preparation method, and pharmaceutical composition containing it as well as application thereof

Abstract

The invention provides a spirotricyclic compound as shown in formula (I), and simultaneously discloses a preparation method of the compound and application thereof, as well as a pharmaceutical composition containing the spirotricyclic compound. Being an inhibitor of protein kinase, the compound in the invention can be used to treat diseases caused by abnormal protein kinase activity, such as tumors and the like.

Description

technical field

[0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular to a spirotricyclic compound, a preparation method thereof, a pharmaceutical composition containing the compound and an application thereof. Background technique

[0002] Cancer and cardiovascular disease are two major diseases that seriously threaten human health and life. In particular, the incidence and mortality of cancer have been rising rapidly in recent years, surpassing cardiovascular disease to become the number one killer of human health.

[0003] The proliferation, apoptosis, and metastasis of tumors are closely related to the abnormality of a certain link in a series of signal transduction pathways inside and outside cells. An important class of molecules in these signal transduction pathways are protein kinases. The abnormality of protein kinase activity is not only directly related to tumors, but also the main cause of a series of other human ...

Examples

Embodiment 1

[0289] 5-[1-(6-quinolinylmethyl)-1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl]spiro[indoline-3,4' Synthesis of -piperidin]-2-one

[0290]

[0291] Step 1: Synthesis of {2-oxyspiro[indoline-3,4'-piperidinyl]-5-yl}boronic acid pinacol ester

[0292]

[0293] Under nitrogen, add 5-bromospiro[indoline-3,4'-piperidin]-2-one (140.6mg or 0.5mmol), bipinacol borate (140mg or 0.55mmol) and potassium acetate (147mg or 1.5mmol) in DMSO solution (0.2ml) was added PdCl 2 (dppf).CH 2 Cl 2 (20.4 mg or 0.025 mmol), nitrogen was bubbled into the resulting solution for 2 minutes, and then stirred at 80° C. for 16 hours. LC-MS showed that the reaction was complete. After cooling to room temperature, 2 mL of water was added and extracted with DCM (5 mL was used for 3 extractions). Combine the organic phases with Na 2 SO 4 After drying and concentration, 162 mg of the target product was obtained (yield: 98.7%). Mass Spectrum m / z: 328.07 [M+H + ], 329.08[M+H + , 100%], 330.11 [M+H + ].

...

Embodiment 2

[0297] 6-[1-(6-quinolinylmethyl)-1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl]spiro[indoline-3,4' Synthesis of -piperidin]-2-one

[0298]

[0299] Step 1: Synthesis of {2-oxyspiro[indoline-3,4'-piperidinyl]-6-yl}boronic acid pinacol ester

[0300]

[0301] Referring to the method of Example 1, it was prepared from 6-bromospiro[indoline-3,4'-piperidin]-2-one, yield: 96.9%. Mass Spectrum m / z: 328.07 [M+H + ], 329.08[M+H + , 100%], 330.11 [M+H + ].

[0302] Step 2: 6-[1-(6-Quinolinylmethyl)-1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl]spiro[indoline-3 , Synthesis of 4'-piperidin]-2-one

[0303] Prepare with reference to the method of Example 1. Yield: 73%. Mass Spectrum m / z: 463.23 [M+H + ].

Embodiment 3

[0305]1'-Methyl-5-[1-(6-quinolylmethyl)-1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl]spiro[indole Synthesis of phen-3,4'-piperidin]-2-one

[0306]

[0307] Step 1: Synthesis of 5-bromo-1'-methylspiro[indoline-3,4'-piperidin]-2-one

[0308]

[0309] 5-Bromospiro[indoline-3,4'-piperidin]-2-one (1.686g or 6mmol) was suspended in 15mL THF, cooled to -78°C, and 1M NaN (SiMe 3 ) 2 THF solution (30mL or 30mmol). After the addition was complete, it was stirred at -78°C for 30 minutes, and then solid 2-chloro-N-(2-chloroethyl)-N-methylethylamine hydrochloride (1155 g or 6 mmol) was added. Stirring was continued for 30 minutes after the addition was complete, then raised to room temperature and stirred for two days. TLC showed that the reaction was complete, and 10 mL of 4M hydrochloric acid aqueous solution was carefully added to the pink suspension, then adjusted to pH ≈ 9 with concentrated ammonia water, and extracted with DCM (3 times with 80 mL for each extraction). Combine the ...

technical field

[0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular to a spirotricyclic compound, a preparation method thereof, a pharmaceutical composition containing the compound and an application thereof. Background technique

[0002] Cancer and cardiovascular disease are two major diseases that seriously threaten human health and life. In particular, the incidence and mortality of cancer have been rising rapidly in recent years, surpassing cardiovascular disease to become the number one killer of human health.

[0003] The proliferation, apoptosis, and metastasis of tumors are closely related to the abnormality of a certain link in a series of signal transduction pathways inside and outside cells. An important class of molecules in these signal transduction pathways are protein kinases. The abnormality of protein kinase activity is not only directly related to tumors, but also the main cause of a series of other human ...

Examples

Embodiment 1

[0289] 5-[1-(6-quinolinylmethyl)-1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl]spiro[indoline-3,4' Synthesis of -piperidin]-2-one

[0290]

[0291] Step 1: Synthesis of {2-oxyspiro[indoline-3,4'-piperidinyl]-5-yl}boronic acid pinacol ester

[0292]

[0293] Under nitrogen, add 5-bromospiro[indoline-3,4'-piperidin]-2-one (140.6mg or 0.5mmol), bipinacol borate (140mg or 0.55mmol) and potassium acetate (147mg or 1.5mmol) in DMSO solution (0.2ml) was added PdCl 2 (dppf).CH 2 Cl 2 (20.4 mg or 0.025 mmol), nitrogen was bubbled into the resulting solution for 2 minutes, and then stirred at 80° C. for 16 hours. LC-MS showed that the reaction was complete. After cooling to room temperature, 2 mL of water was added and extracted with DCM (5 mL was used for 3 extractions). Combine the organic phases with Na 2 SO 4 After drying and concentration, 162 mg of the target product was obtained (yield: 98.7%). Mass Spectrum m / z: 328.07 [M+H + ], 329.08[M+H + , 100%], 330.11 [M+H + ].

...

Embodiment 2

[0297] 6-[1-(6-quinolinylmethyl)-1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl]spiro[indoline-3,4' Synthesis of -piperidin]-2-one

[0298]

[0299] Step 1: Synthesis of {2-oxyspiro[indoline-3,4'-piperidinyl]-6-yl}boronic acid pinacol ester

[0300]

[0301] Referring to the method of Example 1, it was prepared from 6-bromospiro[indoline-3,4'-piperidin]-2-one, yield: 96.9%. Mass Spectrum m / z: 328.07 [M+H + ], 329.08[M+H + , 100%], 330.11 [M+H + ].

[0302] Step 2: 6-[1-(6-Quinolinylmethyl)-1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl]spiro[indoline-3 , Synthesis of 4'-piperidin]-2-one

[0303] Prepare with reference to the method of Example 1. Yield: 73%. Mass Spectrum m / z: 463.23 [M+H + ].

Embodiment 3

[0305]1'-Methyl-5-[1-(6-quinolylmethyl)-1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl]spiro[indole Synthesis of phen-3,4'-piperidin]-2-one

[0306]

[0307] Step 1: Synthesis of 5-bromo-1'-methylspiro[indoline-3,4'-piperidin]-2-one

[0308]

[0309] 5-Bromospiro[indoline-3,4'-piperidin]-2-one (1.686g or 6mmol) was suspended in 15mL THF, cooled to -78°C, and 1M NaN (SiMe 3 ) 2 THF solution (30mL or 30mmol). After the addition was complete, it was stirred at -78°C for 30 minutes, and then solid 2-chloro-N-(2-chloroethyl)-N-methylethylamine hydrochloride (1155 g or 6 mmol) was added. Stirring was continued for 30 minutes after the addition was complete, then raised to room temperature and stirred for two days. TLC showed that the reaction was complete, and 10 mL of 4M hydrochloric acid aqueous solution was carefully added to the pink suspension, then adjusted to pH ≈ 9 with concentrated ammonia water, and extracted with DCM (3 times with 80 mL for each extraction). Combine the ...

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