Spiro indolone pyrrolidine compound as well as preparation method and application thereof

Abstract

The invention discloses a synthesis method and application of a spiro indolone-containing pyrrolidine compound, and belongs to the field of medicine synthesis. According to the invention, asymmetric synthesis of a pyrrolidine derivative with a spiro indolone structure is realized through a 1, 3-dipolar cycloaddition reaction of isatin, 4-nitrochalcone and a sarcosine derivative, and an in-vitro anti-inflammatory activity test is carried out on the prepared spiro indolone pyrrolidine analogue. An in-vitro anti-inflammatory activity test shows that the prepared spiro indolone pyrrolidine analogue has a remarkable inhibition effect on generation of nitric oxide of LPS-induced mouse macrophages RAW264.7 cells, and particularly, the inhibition activity of a compound 1f is equivalent to that of positive control ammonium pyrrolidine dithioformate (PDTC).

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a spirocyclic indole ketone pyrrolidine compound, a preparation method thereof and an application thereof. Background Art

[0002] Spiroindole derivatives have a variety of biological activities and are widely used in the medical field. Spiroindole pyrrolidine compounds are an important structural framework of spiroindole alkaloids. The characteristics of this type of compound are that a spiro ring is connected to the C3 position of the oxidized indole ring, and there are different substituents on the pyrrolidine and oxidized indole rings. Among many biologically active spiroindole natural products, spiroindole pyrrolidine is its core structure.

[0003] Inflammation is a complex defense reaction of the body's tissues to pathogenic factors. It is also an immune response process of the human body. It manifests as redness, swelling, heat, pain and dysfunction, accompanied by varying degrees of enhanced metabolism and leukocytosis. It is a very common disease in clinical practice. At present, anti-inflammatory drugs have become the second largest category of drugs in clinical use, second only to anti-infective drugs. Currently, the most widely used anti-inflammatory drugs in clinical practice are non-steroidal anti-inflammatory drugs (NSAIDS) and adrenocortical hormones. However, these drugs have their own side effects, especially gastrointestinal irritation and cardiovascular damage, which to a certain extent limit their clinical application. Therefore, it is of great significance to find new, efficient and low-toxic anti-inflammatory drugs. Summary of the invention

[0004] In view of the shortcomings of the prior art described above, the object of the present invention is to provide a spiroindolone pyrrolidine compound to solve the problems in the prior art. At the same time, the present invention will also provide a method for preparing a spiroindolone pyrrolidine compound; in addition, the present invention will also provide a new use of a spiroindolone pyrrolidine compound.

[0005] To achieve the above purposes and other related purposes,

[0006] In the first aspect of the present invention, a spirocyclic indole pyrrolidine compound of formula (I) is provided, or a tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof is provided:

[0007]

[0008] in:

[0009] X1 and X2 are each independently selected from C, N, O or S;

[0010] R1 and R2 are each independently selected from hydrogen, halogen, cyano, C1-6 Alkyl or C 1-6 Haloalkyl;

[0011] R3 is selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0012] R4 and R5 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 haloalkyl or phenyl; or

[0013] R4 and R5 and the atoms to which they are attached form a 4-8 membered ring;

[0014] m, n, and r are each independently selected from 0, 1, 2, 3, 4, 5, and 6.

[0015] In order to solve the problem of the insufficiency of the prior art, the purpose of the present invention is to provide a preparation method and use of spirocyclic indole pyrrolidine analogs. Such compounds have a significant inhibitory effect on inflammatory cells.

[0016] In one embodiment of the present invention, the spiroindolone pyrrolidine compound, or its tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, is selected from the compound represented by general formula (II):

[0017]

[0018] in:

[0019] R1 and R2 are each independently selected from hydrogen, halogen, cyano, C 1-6 alkyl;

[0020] R3 is selected from hydrogen, halogen, cyano, nitro, C 1-6 alkyl;

[0021] R4 and R5 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl or phenyl; or

[0022] R4 and R5 and the atoms to which they are attached form a 4-6 membered heterocyclic ring;

[0023] m, n, and r are each independently selected from 0, 1, 2, and 3.

[0024] In one embodiment of the present invention, the spirocyclic indolinone pyrrolidine compound, or its tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, wherein:

[0025] R1 and R2 are each independently selected from hydrogen, halogen, C1-4 alkyl;

[0026] R3 is selected from hydrogen, halogen, nitro, C 1-4 alkyl;

[0027] R4 and R5 are each independently selected from hydrogen, C 1-4 Alkyl; or

[0028] R4 and R5 and the atoms to which they are connected form a 4-6 membered saturated heterocyclic ring;

[0029] m, n, and r are each independently selected from 0, 1, and 2.

[0030] In one embodiment of the present invention, the spirocyclic indolinone pyrrolidine compound, or its tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, wherein:

[0031] R1 is selected from hydrogen, halogen, C 1-4 alkyl;

[0032] R2 is selected from hydrogen, halogen;

[0033] R3 is selected from nitro;

[0034] R4 and R5 are each independently selected from hydrogen, C 1-4 Alkyl or phenyl; or

[0035] R4 and R5 and the atoms to which they are connected form a 5-membered saturated heterocyclic ring;

[0036] m, n, and r are each independently selected from 0, 1, and 2.

[0037] In one embodiment of the present invention, the spiroindolone pyrrolidine compound, or its tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, is selected from the following compounds:

[0038]

[0039] The second aspect of the present invention provides a method for preparing a spirocyclic indole ketone pyrrolidine compound represented by formula (III), comprising the following steps:

[0040]

[0041] The compound of formula (III-1) and the compound of formula (III-2) are reacted in a reaction solvent to prepare a compound of formula (III);

[0042] in:

[0043] C is selected from

[0044] X1 is each independently selected from C, N, O or S;

[0045] R1 and R2 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0046] R3 is selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0047] R4 is selected from H, methyl or phenyl;

[0048] R5 is selected from hydrogen, methyl; or

[0049] R4 and R5 and the atoms they are connected to form

[0050] m, n, and r are each independently selected from 0, 1, 2, 3, 4, 5, and 6.

[0051] The present invention uses isatin, 4-nitrochalcone and sarcosine derivatives to design and synthesize a series of spirocyclic indole pyrrolidine compounds through 1,3-dipolar cycloaddition reaction. The anti-inflammatory cell activity is tested in vitro, and the in vitro test results show that the compounds have a significant inhibitory effect on the production of NO in RAW264.7 cells induced by LPS.

[0052] In one embodiment of the present invention, wherein:

[0053] C is selected from

[0054] X1 is each independently selected from N;

[0055] R1 is selected from hydrogen, halogen, C 1-4 alkyl;

[0056] R2 is selected from hydrogen, halogen;

[0057] R3 is selected from nitro;

[0058] R4 is selected from H, methyl or phenyl;

[0059] R5 is selected from hydrogen, methyl; or

[0060] R4 and R5 and the atoms connected thereto form

[0061] m, n, and r are each independently selected from 0, 1, and 2.

[0062] The third aspect of the present invention provides the use of spirocyclic indole pyrrolidine compounds in the preparation of anti-inflammatory drugs.

[0063] As described above, the spirocyclic indole ketone pyrrolidine compounds and the preparation method and application thereof of the present invention have the following beneficial effects:

[0064] 1. Spiroindolone pyrrolidine analogs were tested for in vitro anti-inflammatory activity. The in vitro anti-inflammatory activity test showed that the prepared spiroindolone pyrrolidine analogs had a significant inhibitory effect on the production of nitric oxide in LPS-induced mouse macrophage RAW264.7 cells, especially the inhibitory activity of compound 1f was comparable to that of the positive control ammonium pyrrolidine dithiocarboxylate (PDTC). The application of the compounds of the present invention in anti-inflammatory aspects has not been reported, and they have broad application prospects in the field of anti-inflammatory drugs. Therefore, the present invention effectively overcomes the various shortcomings of the prior art and has a high industrial utilization value.

[0065] 2. The present invention uses commercially available indigo carmine, 4-nitrochalcone and sarcosine derivatives to design and synthesize a series of spiroindolone pyrrolidine compounds through 1,3-dipolar cycloaddition reaction, with an overall yield of 55% to 80%, mainly in a single configuration, to achieve asymmetric synthesis of pyrrolidine derivatives with a spiroindolone structure. The preparation method of the present invention is simple and easy to operate, can be achieved through a one-step reaction, does not involve extreme reactions of high temperature, high pressure and strong acid and strong base, and the reaction raw materials and solvents are all commercially available and easy to obtain. In general, the synthesis route is short, the yield is high, and the material utilization rate is high. DETAILED DESCRIPTION

[0066] The following is a description of the implementation of the present invention by means of specific embodiments. Those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0067] The present invention provides a method for preparing a spirocyclic indole pyrrolidine compound, which can be selected from the following synthetic routes:

[0068] It consists of the following steps:

[0069] Scheme1

[0070]

[0071] In Scheme 1, R1 is selected from hydrogen, halogen, and methyl; in Scheme 1, R2 is selected from hydrogen and halogen; in Scheme 1, R3 is selected from hydrogen, phenyl, and thiazolyl.

[0072] Example 1

[0073] The preparation method of 1a of the present invention:

[0074]

[0075] 6-Chloroindigo red (181 mg, 1.0 mmol), 4-nitrochalcone (278 mg, 1.1 mmol), sarcosine (98 mg, 1.1 mmol) and 5 mL of anhydrous methanol were added to a round-bottom flask and heated and stirred at 65°C for 6 h. After the reaction was completed, the methanol was removed by vacuum concentration and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1, V / V) to obtain 1a as a brown solid (434 mg) with a yield of 78%.

[0076] Product identification: mp205-207℃;

[0077] 1 HNMR (600MHz, CDCl3) δ (ppm): 8.17 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7. 41(d,J=7.2Hz,2H),7.35(t,J=7.4Hz,1H),7.18(t,J=7.6Hz,2H),7.02(d,J=8. 1Hz,1H),6.91(dd,J=8.2,1.8Hz,1H),6.52(d,J=1.8Hz,1H),4.66-4.57(m,1H) ,4.48(d,J=9.2Hz,1H),3.65(t,J=9.2Hz,1H),3.52-3.45(m,1H),2.21(s,3H).

[0078] 13 CNMR (150MHz, CDCl3) δ (ppm): 196.73, 179.79, 149.15, 147.01, 141.53, 136.66, 135.14, 133.32, 129.13, 129.13, 128.38, 128.38 ,127.70,127.64,127.64,125.02,123.99,123.99,123.17,110.09,73.11,62.81,59.91,44.21,34.84.ESI-MSm / z:484.0[M+Na] + ,Formula:C 25 H 20 ClN3O4.

[0079] Example 2

[0080] The preparation method of 1b of the present invention:

[0081]

[0082] Preparation method: Same as Example 1, 6-bromoisidine (226 mg, 1.0 mmol), 4-nitrochalcone (278 mg, 1.1 mmol), sarcosine (98 mg, 1.1 mmol) and 5 mL of anhydrous methanol were added to a round-bottom flask, and heated and stirred at 65°C for 6 h. After the reaction was completed, the methanol was removed by vacuum concentration and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain 1b as a light yellow solid (433 mg) with a yield of 72%.

[0083] Product identification: mp221-223℃;

[0084] 1 HNMR (600MHz, CDCl3) δ (ppm): 8.02 (d, J = 8.8Hz, 2H), 7.74 (s, 1H), 7.54 (d, J = 8.7Hz ,2H),7.25(d,J=7.2Hz,2H),7.21(t,J=7.3Hz,1H),7.07–7.01(m,2H),6.92(dd,J=8 .0,1.7Hz,1H),6.81(d,J=8.0Hz,1H),6.50(d,J=1.7Hz,1H),4.48-4.41(m,1H),4.3 2(d,J=9.2Hz,1H),3.50(t,J=9.3Hz,1H),3.32(dd,J=9.1,7.2Hz,1H),2.06(s,3H).

[0085] 13 CNMR(150MHz, CDCl3)δ(ppm):196.83,179.57,149.18,147.13,141.69,136.77,133.43,129.25,129.25,128.49,128.49,128.1 5,127.75,127.75,126.22,125.72,124.10,124.10,123.13,112.89,73.21,62.93,60.02,44.35,34.95.HRMS(ESI):Calcd.ForC 25 H 21 BrN3O4.[M+H] + :506.0710;found:506.0694.

[0086] Example 3

[0087] The preparation method of 1c of the present invention:

[0088]

[0089] Preparation method: Same as Example 1, 5-methyl isatin (161 mg, 1.0 mmol), 4-nitrochalcone (278 mg, 1.1 mmol), sarcosine (98 mg, 1.1 mmol) and 5 mL of anhydrous methanol were added to a round-bottom flask, and heated and stirred at 65 ° C for 6 h. After the reaction was completed, the methanol was removed by vacuum concentration and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain 1c as a brown-yellow solid 375 mg, with a yield of 70%.

[0090] Product identification: mp187-189℃;

[0091] 1 HNMR (600MHz, CDCl3) δ (ppm): 8.17 (d, J = 8.7Hz, 2H), 7.73 (d, J = 8.7Hz, 2H), 7.38 (d, J = 7.4Hz, 2H), 7.29 (t, J = 7.3Hz, 1H), 7.14 (t, J = 7.8Hz, 2H), 6.90 ( s,1H),6.79(d,J=7.9Hz,1H),6.38(d,J=7.7Hz,1H),4.70-4.61(m,1H),4. 47(d,J=9.1Hz,1H),3.66(t,J=9.3Hz,1H),3.56–3.45(m,1H),2.23(s,6H).

[0092] 13 CNMR(150MHz, CDCl3)δ(ppm):197.03,179.83,149.69,147.04,138.09,137.03,133.01,132.81,129.79,129.30,129.30,128.26,1 28.26,128.26,127.74,127.74,127.33,124.03,124.03,109.27,73.60,62.87,60.10,44.21,35.04,21.10.HRMS(ESI):Calcd.ForC 26 H 24 N3O4.[M+H] + :442.1761;found:442.1748.

[0093] Example 4

[0094] The preparation method of 1d of the present invention:

[0095]

[0096] Preparation method: Same as Example 1. Add 6-chloroindigo red (181 mg, 1.0 mmol), 3,4-dichloro-4-nitrochalcone (322 mg, 1.0 mmol), sarcosine (98 mg, 1.1 mmol) and 5 mL of anhydrous methanol into a round-bottom flask and heat and stir at 65 ° C for 6 h. After the reaction is completed, vacuum concentration is performed to remove methanol, and purification is performed by silica gel column chromatography (eluent: dichloromethane: methanol = 30:1, V / V) to obtain 1d as a light yellow solid 330 mg, with a yield of 55%.

[0097] Product identification: mp234-236℃;

[0098] 1 HNMR (600MHz, DMSO-d6) δ (ppm): 10.74 (s, 1H), 8.20 (d, J = 8.7Hz, 2H), 7.75 (d ,J=8.7Hz,2H),7.55(d,J=8.4Hz,1H),7.45(d,J=2.0Hz,1H),7.32(dd,J=8.4, 1.9Hz,1H),6.96–6.87(m,2H),6.48(d,J=1.8Hz,1H),4.51(d,J=8.5Hz,1H), 4.49-4.42(m,1H),3.44(t,J=9.0Hz,1H),3.40(t,J=9.0Hz,1H),2.05(s,3H).

[0099] 13 CNMR(150MHz,DMSO-d6)δ(ppm):195.54,178.19,149.08,146.47,143.57,136.56,135.81,133.83,131.35,130.53,129.40,129. 40,129.29,127.30,127.19,125.18,123.68,123.68,121.68,109.33,72.27,61.83,59.59,43.30,34.44.HRMS(ESI):Calcd.ForC 25 H 19 Cl3N3O4.[M+H] + :530.0436;found:530.0414.

[0100] Example 5

[0101] The preparation method of 1e of the present invention:

[0102]

[0103] Preparation method: Same as Example 1, 6-chloroindigo red (181 mg, 1.0 mmol), 4-nitrochalcone (278 mg, 1.1 mmol), D-(-)-α-phenylglycine (166 mg, 1.1 mmol) and 5 mL of anhydrous methanol were added to a round-bottom flask, and heated and stirred at 65°C for 6 h. After the reaction was completed, the methanol was removed by vacuum concentration and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, V / V) to obtain 1e as a light yellow solid 375 mg, with a yield of 60%.

[0104] Product identification: mp143-145℃;

[0105] 1 HNMR (600MHz, DMSO-d6) δ (ppm): 10.60 (s, 1H), 8.12 (d, J = 8.8Hz, 2H), 7.60 (m, J = 8.8Hz, 2H), 7 .48(t,J=7.2Hz,1H),7.40(d,J=7.2Hz,2H),7.35(d,J=7.2Hz,2H),7.31-7.23(m,4H),7.22–7 .19(m,1H),7.18(d,J=8.0Hz,1H),6.93(dd,J=8.0,1.9Hz,1H),6.42(d,J=1.9Hz,1H),5.02(d d,J=10.2,4.9Hz,1H),4.65(d,J=10.5Hz,1H),4.25(d,J=4.9Hz,1H),4.15(t,J=10.4Hz,1H).

[0106] 13 CNMR(150MHz,DMSO-d6)δ(ppm):197.18,181.96,147.66,146.95,143.46,1 41.04,136.75,133.83,133.50,130.13,130.13,129.32,129.32,128.86,12 8.69,128.69,128.14,127.80,127.80,127.80,127.73,127.73,124.09,12 4.09,121.82,109.52,67.59,67.35,62.15,55.39.ESI-MSm / z:546.9[M+Na] + ,Formula:C 30 H 22 ClN3O4.

[0107] Example 6

[0108] The preparation method of 1f of the present invention:

[0109]

[0110] Preparation method: Same as Example 1, 6-chloroindigo red (181 mg, 1.0 mmol), 4-nitrochalcone (278 mg, 1.1 mmol), L-thiazolidine-4-carboxylic acid (146 mg, 1.1 mmol) and 6 mL of anhydrous methanol were added to a round-bottom flask, and heated and stirred at 65 ° C for 6 h. After the reaction was completed, the methanol was removed by vacuum concentration and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1, V / V) to obtain 1f as a yellow solid 423 mg, with a yield of 70%.

[0111] Product identification: mp236-238℃;

[0112] 1 HNMR (600MHz, CDCl3) δ (ppm): 8.21 (d, J = 8.7Hz, 2H), 8.10 (s, 1H), 7.73 (d, J = 8.7Hz, 2H), 7.51 (d, J =8.2Hz,1H),7.39(t,J=7.4Hz,1H),7.37–7.32(m,2H),7.20(t,J=7.8Hz,2H),7.03(dd,J=8.1,1.9H z,1H),6.57(d,J=1.8Hz,1H),4.76(d,J=11.6Hz,1H),4.43-4.36(m,1H),4.03(t,J=9.7Hz,1H),3. 87(d,J=10.8Hz,1H), 3.48(d,J=10.7Hz,1H), 3.09(dd,J=12.0,6.5Hz,1H), 2.98(d,J=12.0Hz,1H).

[0113] 13 CNMR(150MHz, CDCl3)δ(ppm):195.88,179.98,147.49,146.56,141.72,136.46,136.19,133.63,129.70,129.70,129.48,128.51,1 28.51,127.91,127.91,124.31,124.31,122.83,121.21,110.68,74.50,74.16,62.74,54.86,51.40,36.75.ESI-MSm / z:504.1[MH] + ,Formula:C 26 H 20 ClN3O4S.

[0114] Example 7

[0115] Inhibitory test of spiroindolinone pyrrolidine compounds on LPS-induced nitric oxide production in RAW264.7 cells

[0116] Using ammonium pyrrolidine dithiocarboxylate (PDTC) as a positive control, an inflammation model was established by inducing RAW264.7 cells with LPS, and the anti-inflammatory activity of the compound was evaluated by the concentration of NO induced in the cell culture medium. The specific experimental steps are as follows:

[0117] 1. According to the experimental grouping, take RAW264.7 cells in the logarithmic growth phase and adjust the cell density to 4×10 5 / mL, inoculated into a 24-well culture plate, added 500μL to each well, and cultured for 12h.

[0118] 2. Dissolve the compound in DMSO and dilute it with culture medium to the experimental design concentration. Discard the old culture medium on the top of the 24-well plate and add 500 μL of fresh culture medium containing the drug (the model group adds the same amount of DMSO as the drug group). After continuing to culture for 2 hours, add 10 μL of 5 μg / mL LPS solution to each well of the model group and the drug group.

[0119] 3. After 12 hours of culture, aspirate 50 μL of the upper layer from the 24-well culture plate, add NO detection reagent (follow the instructions of the NO detection kit), use a multifunctional microplate reader to detect the optical density (OD) value of each well at a wavelength of 540 nm, and calculate the NO concentration in the culture medium using the standard curve method. Repeat three times and calculate the IC 50 The results are shown in Table 1.

[0120] Table 1 In vitro anti-inflammatory results of the compounds of the present invention

[0121]

[0122] As shown in Table 1, the compounds of the present invention have significant inhibitory activity on LPS-induced nitric oxide production in RAW264.7 cells, and the inhibitory activity of compounds 1e and 1f on nitric oxide production is better than that of the positive control ammonium pyrrolidine dithiocarboxylate (PDTC). These compounds are expected to be developed as new anti-inflammatory drugs. Therefore, the present invention effectively overcomes the various shortcomings of the prior art and has a high industrial utilization value.

[0123] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A spirocyclic indole pyrrolidine compound represented by formula (I), or its tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal: in: X1 and X2 are each independently selected from C, N, O or S; R1 and R2 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Haloalkyl; R3 is selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl or C 1-6 Haloalkyl; R4 and R5 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 haloalkyl or phenyl; or R4 and R5 and the atoms to which they are attached form a 4-8 membered ring; m, n, and r are each independently selected from 0, 1, 2, 3, 4, 5, and 6.

2. The spirocyclic indole pyrrolidine compound according to claim 1, or its tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compound represented by general formula (II): in: R1 and R2 are each independently selected from hydrogen, halogen, cyano, C 1-6 alkyl; R3 is selected from hydrogen, halogen, cyano, nitro, C 1-6 alkyl; R4 and R5 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl or phenyl; or R4 and R5 and the atoms to which they are attached form a 4-6 membered heterocyclic ring; m, n, and r are each independently selected from 0, 1, 2, and 3.

3. The spirocyclic indole one pyrrolidine compound according to claim 1, or its tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, wherein: R1 and R2 are each independently selected from hydrogen, halogen, C 1-4 alkyl; R3 is selected from hydrogen, halogen, nitro, C 1-4 alkyl; R4 and R5 are each independently selected from hydrogen, C 1-4 Alkyl; or R4 and R5 and the atoms to which they are connected form a 4-6 membered saturated heterocyclic ring; m, n, and r are each independently selected from 0, 1, and 2.

4. The spirocyclic indolinone pyrrolidine compound according to claim 1, or its tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, wherein: R1 is selected from hydrogen, halogen, C 1-4 alkyl; R2 is selected from hydrogen, halogen; R3 is selected from nitro; R4 and R5 are each independently selected from hydrogen, C 1-4 Alkyl or phenyl; or R4 and R5 and the atoms to which they are connected form a 5-membered saturated heterocyclic ring; m, n, and r are each independently selected from 0, 1, and 2.

5. The spiroindolone pyrrolidine compound according to claim 1, or its tautomer, stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, wherein the spiroindolone pyrrolidine compound is selected from the following compounds:

6. A method for preparing a spirocyclic indole ketone pyrrolidine compound represented by formula (III), characterized in that: The steps include: The compound of formula (III-1) and the compound of formula (III-2) are reacted in a reaction solvent to prepare a compound of formula (III); in: C is selected from X1 is each independently selected from C, N, O or S; R1 and R2 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Haloalkyl; R3 is selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl or C 1-6 Haloalkyl; R4 is selected from H, methyl or phenyl; R5 is selected from hydrogen, methyl; or R4 and R5 and the atoms connected thereto form m, n, and r are each independently selected from 0, 1, 2, 3, 4, 5, and 6.

7. The method for preparing the spirocyclic indole ketone pyrrolidine compound according to claim 6, characterized in that: in: C is selected from X1 is each independently selected from N; R1 is selected from hydrogen, halogen, C 1-4 alkyl; R2 is selected from hydrogen, halogen; R3 is selected from nitro; R4 is selected from H, methyl or phenyl; R5 is selected from hydrogen, methyl; or R4 and R5 and the atoms they are connected to form m, n, and r are each independently selected from 0, 1, and 2.

8. Use of the spiroindolinone pyrrolidine compound according to any one of claims 1 to 7 in the preparation of anti-inflammatory drugs.

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