Tetrahydropyridopyrimidine compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to tetrahydropyridopyrimidine compounds as well as a preparation method and application thereof, in particular to tetrahydropyridopyrimidine compounds or pharmaceutically acceptable salts thereof as well as a preparation method and application thereof in preparation of antitumor drugs. The structure of the tetrahydropyridopyrimidine compound or the pharmaceutically acceptable salt thereof is as shown in a general formula (I), and R1-R4 are as shown in the specification and claims. The compound provided by the invention can be used for preparing a KRAS G12C inhibitor, is used for inhibiting G12C mutation of KRAS, has an obvious inhibiting effect on lung cancer, pancreatic cancer or colon cancer, and can be used for preparing antitumor drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and relates to tetrahydropyrido-pyrimidine compounds and preparation methods and applications thereof, and specifically to tetrahydropyrido-pyrimidine compounds or pharmaceutically acceptable salts thereof and preparation methods thereof, and applications thereof in the preparation of anti-tumor drugs. Background Art

[0002] RAS is the abbreviation of rat sarcoma viral oncogene homolog. In 1964, Jennifer Harvey discovered that leukemia viruses from leukemia mice can induce tumor formation in rodents. In 1967, Kirsten also obtained a similar type of virus by serially propagating leukemia mice. These two retroviruses that can induce sarcoma in mice were named Harvey sarcoma virus (Ha-SV) and Kirsten sarcoma virus (Ki-SV). In the early 1980s, homologs of the gene sequences of these two viruses were found in the human genome. Corresponding to the names of the viruses, they were called HRAS and KRAS, respectively. RAS thus became the first oncogene discovered. Subsequently, the third member of the RAS family, NRAS, was also found in neuroblastoma. N stands for "New" or "Neuroblastoma".

[0003] RAS plays the role of a switch in cell signal transduction, and exists in two states: RAS-GTP and RAS-GDP. Normally, the inherent GTP hydrolysis activity and guanine nucleotide exchange activity of RAS are both low. GTPase-activating proteins (GAPs), such as p120GAP or neurofibromin 1 (NF1), bind to RAS-GTP, increase the hydrolysis rate, promote the conversion of RAS-GTP to RAS-GDP, and inactivate (close) the switch. In contrast, guanine nucleotide exchange factors (GEFs), such as RASGRF or SOS1, bind to RAS-GDP, increase the nucleotide exchange rate, promote RAS to excrete GDP and bind to GTP, and activate (open) the switch. The activated RAS then binds to downstream effectors, such as PI3K and RAF, to transmit the signal downstream.

[0004] As the most susceptible RAS subtype to mutation, the population of cancer patients carrying KRAS mutations is huge, so KRAS has always been an important target for drug development. However, due to the relatively small size of the KRAS protein and its smooth surface lacking the binding pockets required for small molecule drugs, KRAS has a strong affinity for its own substrate GTP, and it is difficult for general drugs to compete with high concentrations of GTP. The biochemical characteristics of the various mutants (such as G12C, G12D, G12V, G13D, Q61H) vary greatly, and other factors, this target was once considered difficult to drug.

[0005] KRAS mutations are common in many cancers, including colorectal cancer (CRC), lung adenocarcinoma (LUAD), pancreatic ductal adenocarcinoma (PDAC), etc. Among the three subtypes, KRAS mutation frequency is the highest, followed by NRAS mutation, and HRAS mutation frequency is relatively low. KRAS mutations most commonly occur at codons 12, 13, and 61, among which the main mutation types at codon 12 are G12C, G12D, G12R, G12V, etc., and the main mutation types at codon 61 are Q61R, Q61K, Q61L, etc.

[0006] In summary, based on the urgent clinical needs, it is particularly necessary to research and develop KRAS inhibitors. Using KRAS inhibitors to prepare anti-tumor drugs will inevitably expand the clinical application scope of anti-tumor drugs and provide more drugs for cancer patients. Summary of the invention

[0007] In order to overcome the defects of the prior art, the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] in,

[0010] R 1 is a substituted or unsubstituted 6-10 membered aryl or heteroaryl group;

[0011] The heteroaryl group contains 1-3 heteroatoms of N, O or S;

[0012] The substituent is a C1-C6 alkyl group or a C1-C6 alkoxy group;

[0013] R 2 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, OH, amino, cyano, halogen;

[0014] R 3is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, OH, amino, cyano, halogen;

[0015] R 4 is C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 5-10 membered heterocyclic group; the substituent is C1-C6 alkyl, C1-C6 alkoxy, halogen;

[0016] The heterocyclic group contains 1-3 N, O or S heteroatoms.

[0017] The present invention preferably comprises the following compounds or pharmaceutically acceptable salts thereof:

[0018] in,

[0019] R 1 is a substituted or unsubstituted 6-10 membered aryl or heteroaryl group;

[0020] The heteroaryl group contains 1 heteroatom of O or S;

[0021] R 2 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, OH, amino, cyano, halogen;

[0022] R 3 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, OH, amino, cyano, halogen;

[0023] R 4 is a substituted or unsubstituted 5-10 membered heterocyclic group; the substituent is a C1-C4 alkyl, a C1-C4 alkoxy, or a halogen;

[0024] The heterocyclic group contains 1 to 3 N heteroatoms.

[0025] The present invention preferably comprises the following compounds or pharmaceutically acceptable salts thereof:

[0026] in,

[0027] R 1 Substituted or unsubstituted The substituent is a C1-C4 alkyl group or a C1-C4 alkoxy group;

[0028] R 2 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen;

[0029] R 3 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen;

[0030] R 4 Substituted or unsubstituted The substituent is C1-C4 alkyl, C1-C4 alkoxy, or halogen.

[0031] The present invention preferably comprises the following compounds or pharmaceutically acceptable salts thereof:

[0032] in,

[0033] R 1 for:

[0034]

[0035] R 2 Selected from hydrogen, methyl, halogen.

[0036] R 3 Selected from hydrogen and methyl.

[0037] R 4 for: The present invention preferably comprises the following compounds or pharmaceutically acceptable salts thereof:

[0038]

[0039]

[0040] The present invention provides a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0041]

[0042] Among them, R 1 -R 4 As mentioned before.

[0043] The present invention provides an intermediate for preparing a compound of general formula (I):

[0044]

[0045] R 1 , R 4 As mentioned before.

[0046] The compounds of the present invention also include pharmaceutically acceptable salts thereof. The compounds of the present invention are alkalis, wherein the desired salt form can be prepared by suitable methods known in the art, including treating the free alkali with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or treating the free alkali with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidic acid (e.g., glucuronic acid or galacturonic acid), α-hydroxy acids (e.g., citric acid or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid or cinnamic acid), sulfonic acids (e.g., toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), etc.

[0047] The pharmaceutically acceptable salts of the present invention include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propionates, oxalates, malonates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, mandelates and sulfonates, xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates and naphthalene-2-sulfonates.

[0048] The present invention provides a pharmaceutical composition, which comprises the tetrahydropyridopyrimidine compound or a pharmaceutically acceptable salt thereof.

[0049] The present invention also provides use of the tetrahydropyridopyrimidine compound or a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof in the preparation of a KRAS G12C inhibitor.

[0050] The KRAS G12C inhibitor can inhibit the KRAS mutation of G12C.

[0051] The present invention also provides the use of the tetrahydropyridopyrimidine compound or its pharmaceutically acceptable salt and their pharmaceutical composition in the preparation of anti-tumor drugs.

[0052] The tumor is lung cancer, pancreatic cancer, colon cancer, etc. accompanied by KRAS G12C mutation. DETAILED DESCRIPTION

[0053] The present invention is further described and explained below in conjunction with specific examples, but these examples are not intended to limit the scope of the present invention.

[0054] The experimental methods in the examples of the present invention that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0055] Example 1 Preparation of target molecules

[0056] The technical solution adopted by the present invention is as follows:

[0057]

[0058] Preparation of intermediate 4

[0059] 9.0 g 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (2, 30.7 mmol), 6.92 g 3 (30.7 mmol), 20.6 mL DIPEA (122.8 mmol) were added to a 100 mL single-mouth bottle in sequence and stirred at room temperature for 8 h. The reaction was detected by TLC, and the solvent was concentrated under reduced pressure. The obtained product was dispersed in dichloromethane, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography (DCM / MeOH=15 / 1, containing 1% triethylamine) to obtain 9.6 g of a white solid with a yield of 81.7%.

[0060] Preparation of intermediates 6a-c

[0061] Under argon protection, 5.2 g of tert-butyl 4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(nitrilemethyl)piperazine-1-carboxylate (4, 9.87 mmol), R 4 -OH (5a-c, 19.7mmol), 0.22g palladium acetate (0.99mmol), 0.92g RuPhos (1.97mmol), 9.65g cesium carbonate (29.6mmol), reflux reaction for 10h. After TLC detection, the reaction was cooled to room temperature, filtered with diatomaceous earth, and the filtrate was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated in sequence. The obtained product was purified by column chromatography to obtain off-white solid products 6a-c with a yield of 45-55%.

[0062] Preparation of intermediates 7a-c

[0063] 6a-c (6.4 mmol), 0.90 g palladium carbon (water content 55%, palladium content 5%), and 30 mL ethanol were added to a 50 mL single-mouth bottle in sequence, and refluxed for 12 h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature, the palladium carbon was filtered out, and the filtrate was concentrated to obtain white loose solid 7a-c, with a yield of about 100%.

[0064] Preparation of intermediates 9a-p

[0065] Under argon protection, 7a-c (0.64 mmol), bromine substituted R 1 -Br(8a~c, 0.82mmol), 200mg Pd 2 (dba) 3 (0.13mmol), 50mg RuPhos (0.13mmol), 0.63g cesium carbonate (1.28mmol), reflux reaction for 12h. After the reaction is completed by TLC detection, cool to room temperature, filter with diatomaceous earth, wash the filtrate with water, wash with saturated sodium chloride, dry with anhydrous sodium sulfate and concentrate, and purify the obtained product by column chromatography to obtain a white solid with a yield of 45-55%. Add the product of the previous step and 2.0M HCl / ethyl acetate solution (10.0eq) into a 50mL single-mouth bottle and stir at room temperature for 6h. After the reaction is completed by TLC detection, the reaction solution is cooled to room temperature and poured into an ice-water solution of 4M sodium hydroxide under stirring. The organic layer is separated and washed with a saturated sodium carbonate aqueous solution, a saturated sodium chloride solution, anhydrous sodium sulfate and concentrated to obtain a white solid with a yield of 85-90%. Preparation of compounds of general formula (I):

[0066] 9a-p (0.414 mmol), 189 mg HATU (0.497 mmol), 107 mg DIPEA (0.818 mmol), 10a-c (0.497 mmol), and 10 mL dichloromethane were added to a 25 mL single-mouth bottle and reacted at room temperature for 12 h. The reaction was completed by TLC detection, and the reaction solution was concentrated and purified by column chromatography to obtain a white powdery solid with a yield of 70-76%.

[0067] The compound of general formula (I) was synthesized according to the above method, and the NMR HR MS data are as follows:

[0068] MZ3:

[0069]

[0070] 1 H NMR (400 MHz, CDCl 3)δ7.35(d,J=1.5Hz,1H),7.24-7.15(m,2H),6.86(dd,J=6.9,1.7Hz,1H),6.56(d,J=12.6Hz,1H),6.38(dd,J=16.7,1.7Hz,1H),5.82(d,J=10.5Hz,1H),5.06(s,1H),4.40(dd,J=10.6,5.1Hz,1H),4.23-4.06(m,4H),4.02-3.84(m,1H),3.57(s,1H),3.47-3.26(m,3H),3.22-3.03(m,2H),3.03-2.60(m,6H),2.50(s,3H),2.40(d,J=1.3Hz,3H),2.35-2.25(m,1H),2.10-2.02(m,1H),1.89-1.70(m,1H). 13 C NMR(101MHz,CDCl 3 )δ166.65,166.19,165.89,162.82,157.00,146.98,141.51,129.97,126.74,124.67,123.07,115.52,112.47,109.27,107.96,69.84,64.23,57.95,57.76,51.20,47.91,41.86,29.38,29.18,26.13,23.06.HRMS(ESI)for C 31 H 38 N 7 O 3 + [M+H] + calcd:556.3036,found:556.3029.

[0071] MZ3F:

[0072]

[0073] 1 H NMR(400MHz,CDCl 3)δ7.34(d,J=1.3Hz,1H),7.25-7.14(m,2H),6.85(dd,J=6.8,1.8Hz,1H),5.48-5.32(m,1H),5.24(dd,J=16.9,3.7Hz,1H),4.86(s,1H),4.39(dd,J=10.6,5.1Hz,1H),4.30-4.04(m,4H),4.02-3.87(m,1H),3.52-3.25(m,4H),3.16-2.65(m,8H),2.49(s,3H),2.39(d,J=1.4Hz,3H),2.30(td,J=9.5,7.2Hz,1H),2.14-1.99(m,1H),1.88-1.69(m,3H).13C NMR(101MHz,CDCl3)δ166.60,166.02,162.88,161.89,161.58,158.12,157.02,155.43,146.96,141.51,124.66,123.08,116.82,115.50,112.50,109.29,107.97,101.40,69.95,64.20,57.97,57.73,51.18,48.93,47.98,41.82,29.19,26.08,23.06,19.00.HRMS(ESI)forC 31 H 37 N 7 O 3 F + [M+H] + calcd:574.2942,found:574.2939.

[0074] MZ4:

[0075]

[0076] 1 H NMR(400MHz,CDCl 3)δ7.19-7.05(m,2H),6.82(dd,J=7.4,1.4Hz,1H),6.56(d,J=11.8Hz,1H),6.38(dd,J=16.7,1.8Hz,1H),6.01-5.69(m,1H),5.06(s,1H),4.37(dd,J=10.6,4.9Hz,1H),4.23-4.04(m,4H),3.96(d,J=12.6Hz,1H),3.56(s,1H),3.38-3.21(m,3H),3.15-3.01(m,2H),3.00-2.57(m,6H),2.47(s,2H),2.35(s,2H),2.32(s,1H),2.29-2.22(m,1H),2.11-1.98(m,1H),1.93-1.63(m,3H).13C NMR(101MHz,CDCl3)δ166.68,166.19,166.05,162.90,155.27,150.37,146.03,129.86,126.80,124.32,123.42,112.46,109.51,109.32,107.20,70.12,64.09,58.03,57.77,51.06,47.94,41.87,29.31,26.08,23.12,11.85,9.97.HRMS(ESI)forC 32 H 40 N 7 O 3 + [M+H] + calcd:570.3193,found:570.3186.

[0077] MZ5:

[0078]

[0079] 1 H NMR(400MHz,CDCl 3)δ7.40(d,J=1.5Hz,1H),7.21-7.08(m,2H),6.80(dd,J=7.2,1.8Hz,1H),6.67-6.47(m,1H),6.38(dd,J=16.8,1.8Hz,1H),5.81(d,J=10.5Hz,1H),5.07(s,1H),4.54-4.33(m,3H),4.17(dd,J=10.6,6.7Hz,1H),4.06(d,J=13.8Hz,1H),3.94(d,J=12.5Hz,1H),3.86-3.72(m,1H),3.64-3.43(m,2H),3.29(d,J=13.8Hz,1H),3.18-2.64(m,8H),2.50(s,3H),2.35-2.27(m,1H),2.24(d,J=1.3Hz,3H),2.09-2.01(m,1H),1.89-1.66(m,3H).13C NMR(101MHz,CDCl3)δ165.57,165.07,164.32,161.76,145.69,139.57,134.86,129.34,128.69,125.70,122.15,114.99,111.54,109.98,108.30,68.87,63.05,56.64,53.20,46.85,46.51,40.73,28.09,25.39,21.96,6.98.HRMS(ESI)forC 31 H 38 N 7 O 3 + [M+H] + calcd:556.3036,found:556.3031.

[0080] MZ6:

[0081]

[0082] 1 H NMR(400MHz,CDCl 3)δ7.61(d,J=8.7Hz,1H),7.36(d,J=2.2Hz,1H),7.12(dd,J=8.9,2.3Hz,1H),6.86(s,1H),6.65-6.50(m,1H),6.41-6.33(m,1H),5.81(d,J=10.5Hz,1H),5.06(s,1H),4.46-4.24(m,3H),4.18(dd,J=10.6,6.6Hz,1H),4.06(d,J=13.7Hz,1H),3.92(d,J=12.6Hz,1H),3.69-3.36(m,3H),3.28(d,J=13.3Hz,1H),3.17-2.58(m,8H),2.50(s,3H),2.39(s,3H),2.34-2.25(m,1H),2.10-2.02(m,1H),1.90-1.68(m,3H).13CNMR(101MHz,CDCl3)δ166.54,166.09,165.20,162.87,147.27,142.00,133.33,131.77,129.79,126.69,122.27,118.65,114.79,109.24,108.29,69.95,64.08,57.68,54.26,47.85,47.41,41.78,29.10,26.21,22.99,13.95.HRMS(ESI)for C 31 H 38 N 7 O 2 S + [M+H] + calcd:572.2808,found:572.2803.

[0083] MZ7:

[0084]

[0085] 1 H NMR(400MHz,CDCl 3)δ7.63(d,J=7.2Hz,1H),7.37-7.29(m,1H),7.07(dd,J=22.4,7.5Hz,1H),7.00(s,1H),6.58(t,J=13.8Hz,1H),6.39(dd,J=16.7,1.8Hz,1H),5.82(d,J=11.3Hz,1H),5.06(s,1H),4.39(dd,J=10.6,4.9Hz,1H),4.35-3.82(m,6H),3.55-2.67(m,11H),2.64(s,3H),2.48(s,3H),2.36-2.24(m,1H),2.12-1.99(m,1H),1.90-1.67(m,3H).HRMS(ESI)for C 31 H 38 N 7 O 2 S + [M+H] + calcd:572.2808,found:572.2804.

[0086] MZ8:

[0087]

[0088] 1 H NMR(400MHz,CDCl 3 )δ7.13(t,J=7.7Hz,1H),7.05(dd,J=7.7,1.1Hz,1H),6.74(dd,J=7.7,1.1Hz,1H),6.56(d,J=12.8Hz,1H),6.38(dd,J=16.7,1.8Hz,1H),6.02-5.62(m,1H),5.07(s,1H),4.54-4.29(m,3H),4.17(dd,J=10.6,6.7Hz,1H),4.06(d,J=13.8Hz,1H),3.94(d,J=12.6Hz,1H),3.86-3.69(m,1H),3.64-3.41(m,2H),3.29(d,J=13.5Hz,1H),3.20-2.66(m,8H),2.50(s,3H),2.40(s,3H),2.31(td,J=9.2,7.0Hz,1H),2.14(s,3H),2.09-2.02(m,1H),1.91-1.71(m,3H). 13C NMR(101MHz,CDCl3)δ166.70,166.22,165.66,162.89,150.06,145.32,135.32,131.91,129.85,126.84,122.97,112.27,110.59,110.20,109.43,70.01,64.22,57.79,54.54,48.00,47.60,41.89,29.25,26.37,23.11,12.06,8.19.HRMS(ESI)for C 32 H 40 N 7 O 3 + [M+H] + calcd:570.3193,found:570.3184.

[0089] MZ9:

[0090]

[0091] 1 H NMR(400MHz,CDCl 3 )δ7.63(d,J=7.8Hz,1H),7.37-7.28(m,1H),7.17-6.84(m,3H),6.27(d,J=15.0Hz,1H),5.03(s,1H),4.49-4.35(m,1H),4.33-3.78(m,6H),3.45(d,J=25.3Hz,2H),3.27-2.92(m,5H),2.88-2.45(m,10H),2.41-2.27(m,1H),2.15-2.02(m,1H),1.96-1.69(m,6H).HRMS(ESI)for C 32 H 40 N 7 O 2 S + [M+H] + calcd:586.2964,found:586.3234.MZ10:

[0092]

[0093] 1H NMR(400MHz,DMSO-d6)δ7.72(d,J=7.9Hz,1H),7.51-7.26(m,2H),7.26-7.08(m,1H),5.28(s,1H),5.10(s,1H),4.24(dd,J=10.8,4.9Hz,1H),4.14-3.70(m,6H),3.38(s,1H),3.23-2.66(m,8H),2.59(s,3H),2.34(s,3H),2.25(t,J=6.7Hz,1H),2.21-2.14(m,1H),1.91(s,4H),1.81-1.56(m,5H).HRMS(ESI)for C 32 H 40 N 7 O 2 S + [M+H] + calcd:586.2964,found:586.3234.

[0094] MZ11:

[0095]

[0096] 1 H NMR(400MHz,CDCl 3 )δ7.52(s,1H),7.21-7.08(m,1H),7.11-6.92(m,1H),6.58(s,1H),6.38(d,J=16.7Hz,1H),5.82(d,J=10.7Hz,1H),4.62-3.69(m,7H),3.47(s,2H),3.28-2.89(m,4H),2.89-2.19(m,14H),2.05(s,1H),1.97-1.56(m,4H).HRMS(ESI)forC 32 H 40 N 7 O 2 S + [M+H] + calcd:586.2964,found:586.3234.

[0097] MZ11F:

[0098]

[0099] 1 H NMR(600MHz,CDCl 3)δ7.53(t,J=9.2Hz,1H),7.35-7.17(m,1H),7.03(dd,J=35.2,7.7Hz,1H),5.41(d,J=47.4Hz,1H),5.25(d,J=16.7Hz,1H),4.89(s,1H),4.47-3.81(m,7H),3.72-3.34(m,3H),3.27-2.91(m,5H),2.92-2.35(m,12H),2.28(s,1H),2.16-1.96(m,1H),1.87-1.60(m,3H).HRMS(ESI)for C 32 H 39 FN 7 O 2 S + [M+H] + calcd:604.2859,found:604.2870.MZ12:

[0100]

[0101] 1 H NMR(400MHz,CDCl 3 )δ7.33(s,1H),6.91(s,1H),6.58(s,1H),6.38(d,J=16.6Hz,1H),5.81(d,J=10.4Hz,1H),5.08(s,1H),4.73-3.81(m,7H),3.77-3.52(m,1H),3.51-3.20(m,2H),3.21-2.61(m,7H),2.53-2.21(m,10H),2.14-1.94(m,1H),1.93-1.59(m,4H). 13 C NMR(101MHz,CDCl 3 )δ166.62,166.11,165.73,162.79,145.36,142.66,133.40,131.52,129.68,127.92,126.76,125.04,116.48,112.57,109.38,69.89,64.09,57.65,55.23,48.86,47.93,41.99,41.73,29.14,27.02,26.71,25.01,22.97,13.70,11.61.HRMS(ESI)for C 32 H 40 N 7 O 2 S + [M+H]+ calcd:586.2964,found:586.3234.

[0102] MZ13:

[0103]

[0104] 1 H NMR(600MHz,CDCl 3 )δ7.45(d,J=7.9Hz,1H),7.37(m,1H),7.06(s,1H),6.97(d,J=7.6Hz,1H),6.57(s,1H),6.38(d,J=16.7Hz,1H),5.81(d,J=10.6Hz,1H),5.08(s,1H),4.42(dd,J=10.8,5.1Hz,1H),4.34(d,J=8.3Hz,1H),4.18(dd,J=10.7,6.5Hz,1H),4.14-4.04(m,1H),3.95(d,J=13.0Hz,1H),3.70-3.61(m,1H),3.58(s,1H),3.45-3.22(m,2H),3.13(t,J=8.3Hz,1H),3.08(s,1H),3.01-2.68(m,7H),2.51(s,3H),2.44(s,3H),2.32(q,J=8.7Hz,1H),2.10-2.04(m,1H),1.89-1.73(m,3H).HRMS(ESI)for C 31 H 38 N 7 O 2 S + [M+H] + calcd:572.2808,found:572.3077.

[0105] MZ14:

[0106]

[0107] 1 H NMR(400MHz,CDCl 3)δ7.68-7.58(m,1H),7.35-7.28(m,1H),7.07(dd,J=23.0,8.1Hz,1H),7.00(s,1H),5.41(d,J=47.7Hz,1H),5.24(dd,J=16.9,3.8Hz,1H),4.85(s,1H),4.47-3.81(m,7H),3.58-3.37(m,1H),3.21-3.04(m,5H),2.80(s,3H),2.70-2.55(m,5H),2.49(s,3H),2.40-2.25(m,1H),2.08-2.00(m,1H),1.87-1.67(m,3H).HRMS(ESI)forC 31 H 37 FN 7 O 2 S + [M+H] + calcd:590.2713,found:590.2984.

[0108] MF6:

[0109]

[0110] 1 H NMR(600MHz,CDCl 3 )δ7.61(dd,J=10.2,7.9Hz,1H),7.05(m,1H),6.98(s,1H),5.39(d,J=47.5Hz,1H),5.32-5.12(m,2H),4.91(br,1H),4.33-4.19(m,4H),4.18-3.82(m,6H),3.57-2.69(m,13H),2.64-2.54(m,4H),2.27-2.18(m,1H),2.14-2.07(m,1H),1.98-1.76(m,3H).HRMS(ESI)for C 33 H 38 F 2 N 7 O 2 S + [M+H] + calcd:634.2776,found:634.2759.

[0111] MF7:

[0112]

[0113] 1H NMR(600MHz,CDCl 3 )δ7.70-7.49(m,1H),7.05(dd,J=35.4,7.6Hz,1H),6.99(d,J=4.2Hz,1H),6.64-6.50(m,1H),6.38(d,J=16.7Hz,1H),5.81(d,J=10.6Hz,1H),5.30(s,0.5H),5.21(s,0.5H),5.06(m,0.5H),4.58(m,0.5H),4.38-4.16(m,1H),4.14-3.83(m,6H),3.53-3.36(m,2H),3.34-2.89(m,9H),2.84-2.56(m,6H),2.34-2.18(m,1H),2.16-2.10(m,1H),1.96-1.77(m,3H).HRMS(ESI)for C 33 H 39 FN 7 O 2 S + [M+H] + calcd:616.2870,found:616.2855.MF8:

[0114]

[0115] 1 H NMR(600MHz,DMSO-d6)δ7.40-7.24(m,2H),6.97(d,J=7.1Hz,1H),5.39(dd,J=17.9,4.1Hz,1H),5.31(s,0.5H),5.22(s,0.5H),4.87(br,1H),4.19(d,J=3.8Hz,2H),4.08-3.83(m,5H),3.68-3.44(m,1H),3.22-2.94(m,9H),2.85-2.72(m,3H),2.46(s,3H),2.27(s,3H),2.16-1.91(m,3H),1.89-1.65(m,3H).HRMS(ESI)for C 34 H 40 F 2 N 7 O 2 S + [M+H] + calcd:648.2932,found:648.2915.

[0116] MF9:

[0117]

[0118] 1 H NMR(600MHz,CDCl 3 )δ7.53(t,J=8.9Hz,1H),7.23-7.13(m,1H),7.01(dd,J=35.0,7.7Hz,1H),5.41(d,J=47.6Hz,1H),5.32-5.17(m,2H),4.89(br,1H),4.37-3.82(m,7H),3.60-2.72(m,13H),2.67-2.38(m,7H),2.30-2.19(m,1H),2.19-2.07(m,1H),2.02-1.81(m,3H).HRMS(ESI)for C 34 H 40 F 2 N 7 O 2 S + [M+H] + calcd:648.2932,found:648.2932.

[0119] MF10:

[0120]

[0121] 1 H NMR(600MHz,DMSO-d 6 )δ7.44-7.23(m,1H),6.98(d,J=7.1Hz,1H),6.92-6.79(m,1HF),6.19(d,J=16.6Hz,1H),5.78(d,J=10.5Hz,1H),5.26(d,J=54.4Hz,1H),4.98(s,0.5H),4.76(s,0.5H),4.29-4.10(m,2H),4.09-3.77(m,5H),3.52(s,1H),3.19-2.92(m,7H),2.88-2.74(m,4H),2.47(s,3H),2.34-2.21(m,4H),2.16-1.92(m,3H),1.87-1.67(m,3H).HRMS(ESI)for C 34 H 41 FN 7 O 2 S + [M+H] + calcd:630.3026,found:630.3012.

[0122] MH4:

[0123]

[0124] 1 H NMR(600MHz,CDCl 3 )δ7.32(s,2H),6.89(s,1H),5.54-5.14(m,3H),4.92(br,1H),4.37-4.26(m,2H),4.13(s,3H),3.97(d,J=12.7Hz,1H),3.63(s,1H),3.42-3.30(m,2H),3.20(s,2H),3.10(s,1H),3.02-2.93(m,1H),2.90-2.75(m,3H),2.67(s,2H),2.49(s,3H),2.30(s,3H),2.11(s,2H),1.89(s,4H),1.79-1.65(m,2H).HRMS(ESI)for C 34 H 41 FN 7 O 2 S + [M+H] + calcd:630.3026,found:630.3012.

[0125] MH5:

[0126]

[0127] 1 H NMR(600MHz,CDCl 3 )δ7.68-7.50(m,1H),7.13-6.92(m,2H),5.40(d,J=48.0Hz,1H),5.24(d,J=16.7Hz,1H),4.88(br,0.5H),4.35-3.79(m,6H),3.47(s,2H),3.27-2.96(m,5H),2.86-2.46(m,11H),2.14-2.04(m,2H),1.96-1.79(m,4H),1.79-1.59(m,2H).HRMS(ESI)for C 33 H 39 FN 7 O 2 S + [M+H] + calcd:616.2870,found:616.2859.

[0128] MH6:

[0129]

[0130] 1 H NMR(600MHz,CDCl 3 )δ7.52(t,J=8.8Hz,1H),7.22-7.14(m,1H),7.07-6.91(m,1H),5.40(d,J=47.9Hz,1H),5.25(d,J=16.5Hz,1H),4.90(s,0.5H),4.53(s,0.5H),4.36-3.80(m,7H),3.59-3.34(m,2H),3.23-2.82(m,7H),2.72-2.37(m,10H),2.13-2.06(m,2H),1.92-1.83(m,4H),1.73-1.66(m,2H).HRMS(ESI)for C 34 H 41 FN 7 O 2 S + [M+H] + calcd:630.3026,found:630.3014..

[0131] MH7:

[0132]

[0133] 1 H NMR(600MHz,CDCl 3 )δ7.52(t,J=8.8Hz,1H),7.20-7.13(m,1H),7.07-6.94(m,1H),6.58(s,1H),6.38(d,J=16.7Hz,1H),5.82(d,J=10.3Hz,1H),5.04(s,0.5H),4.66-4.59(s,0.5H),4.46-3.79(m,7H),3.61-3.02(m,8H),2.90-2.38(m,11H),2.18-2.01(m,2H),1.89(s,4H),1.76-1.66(m,2H).HRMS(ESI)for C 34 H 42 N 7 O 2 S + [M+H] + calcd:612.3121,found:612.3106.

[0134] MH8:

[0135]

[0136] 1 H NMR(600MHz,DMSO-d6)δ7.72(d,J=7.9Hz,1H),7.31(s,2H),7.22-7.09(m,1H) ,6.96-6.72(m,1H),6.18(d,J=16.6Hz,1H),5.77(d,J=10.5Hz,1H),4.97(s,0. 5H),4.77(s,0.5H),4.25-3.76(m,7H),3.38(s,1H),3.26-2.68(m,10H),2.59( s,3H),2.56-2.52(m,2H),1.87-1.68(m,6H),1.61-1.45(m,2H).HRMS(ESI)for C 33 H 40 N 7 O 2 S + [M+H] + calcd:598.2964,found:598.2951.

[0137] Example 2 Inhibitory activity of the compounds of the present invention on H358 (KRAS G12C) proliferation

[0138] (1) Cell type and selection: H358 cells (with KRAS G12C mutation).

[0139] (2) Cell inoculation: Collect cells in the logarithmic growth phase and adjust the cell suspension concentration to 4×10 per well. 3 Each well was inoculated with 100 μL of cells into a 96-well plate, with 3 replicate wells set up for each group (the edge wells were filled with sterile PBS).

[0140] (3) Cell culture: After cell inoculation, the control group was cultured with 10% FBS RPMI-1640, and the experimental groups were given different concentration gradients of the target compound (0.001-5 μmol / L) at 37°C and 5% CO 2 The cells were cultured in the incubator for 72 h.

[0141] (4) Color development: After 72 h of culture, 10 μL of CCK-8 solution (5 mg / ml) was added to the two groups of cells respectively. The culture was terminated after 4 h and the cells were shaken on a shaker for 10 min.

[0142] (5) Colorimetry: The photometric value (OD value) of each well was measured on an enzyme-linked immunosorbent assay (ELISA) at a wavelength of 450 nm. The blank well without cells, i.e., RPMI-1640 culture medium, was used as the zero value, and the absorbance value of each well was measured.

[0143] (6) Record the results: cell growth inhibition rate = (absorbance value of the control group - absorbance value of the experimental group) / absorbance value of the control group × 100%, cell proliferation rate = (absorbance value of the experimental group / absorbance value of the control group) × 100%.

[0144] (7) Plotting cell growth curves: Plot inhibitor concentrations in GraphPad Prism software to estimate IC 50 .

[0145] The results of the cell proliferation inhibitory activity evaluation are shown in Table 1.

[0146] Table 1. Results of the study on the inhibitory activity of the target compounds on H358 cell proliferation ( nM )

[0147] serial number <![CDATA[IC 50 ]]> serial number <![CDATA[IC 50 ]]> serial number <![CDATA[IC 50 ]]> serial number <![CDATA[IC 50 ]]> MZ3 4.51 MZ9 8.66 MH7 0.71 <![CDATA[ Adagrasib ]]> 1.28 MZ4 5.68 MZ11 2.27 MH6 11.06 Sotorasib 0.91 MZ5 64.0 MZ11F 37.7 MH4 29.07 MZ8 119.11 MZ6 184 MF7 0.68 MP3 1.61 MZ13 5.45 MF6 0.48 MZ7 0.97 MZ12 18.39 MF8 19.81 MZ14 2.45 MH8 0.35 MF10 1.86 MZ10 2339 MH5 0.42 MF9 3.72

[0148] As shown in Table 1, the synthesized compounds showed significant proliferation inhibitory activity on H358 cells, and some of the compounds were more active than the positive control drugs Adagrasib and Sotorasib.

[0149] Example 3 Inhibitory activity of target compounds on KRAS G12C

[0150] The results of the evaluation of KRAS G12C inhibitory activity are shown in Table 2.

[0151] Table 2. Results of the study on the inhibitory activity of the target compounds on KRAS G12C ( nM )

[0152] serial number Adagrasib Sotorasib MH5 MF6 MF9 MZ14 <![CDATA[IC 50 ]]> 35.64 27.10 43.18 32.26 63.21 33.91

[0153] Compounds with different structural types and strong cell proliferation inhibitory activity were selected for KRAS G12C activity testing. The results are shown in Table 2. MF6 showed strong KRAS G12C inhibitory activity, which was better than the positive control drug Adagrasib, and the activities of the remaining compounds were comparable to the control drug.

[0154] The activity test results of Examples 2-3 show that all the compounds of the present invention exhibit potent proliferation inhibition activity against H358 cells with KRAS G12C, and some of the target compounds have IC 50The value was lower than 1 nM, and some compounds were more active than the reference drug. The selected compounds showed KRAS G12C inhibitory activity comparable to that of the positive drug and had potential medicinal value.

[0155] In summary, the compounds of the present invention have profound potential significance for treating diseases caused by KRAS G12C, especially for treating lung cancer, pancreatic cancer, colon cancer, etc. associated with KRAS G12C, indicating that such molecules have the potential to be developed into new and highly effective KRAS G12C inhibitors.

[0156] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in, R1 is a substituted or unsubstituted 6-10 membered aryl or heteroaryl group; The heteroaryl group contains 1-3 heteroatoms of N, O or S; The substituent is a C1-C6 alkyl group or a C1-C6 alkoxy group; R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, OH, amino, cyano, halogen; R3 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, OH, amino, cyano, halogen; R4 is C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 5-10 membered heterocyclic group; the substituent is C1-C6 alkyl, C1-C6 alkoxy, halogen; The heterocyclic group contains 1-3 N, O or S heteroatoms.

2. The compound represented by the general formula (I) of claim 1 or a pharmaceutically acceptable salt thereof: in, R1 is a substituted or unsubstituted 6-10 membered aryl or heteroaryl group, wherein the heteroaryl group contains one heteroatom of O or S, and the substituent is a C1-C6 alkyl group or a C1-C6 alkoxy group; Preferably substituted or unsubstituted The substituent is C1-C4 alkyl, C1-C4 alkoxy; more preferably:

3. A compound represented by the general formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof: in, R2 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or halogen; R3 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or halogen.

4. A compound represented by general formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof: in, R4 is substituted or unsubstituted The substituent is C1-C4 alkyl, C1-C4 alkoxy, halogen; preferably, R4 is:

5. The following compound or a pharmaceutically acceptable salt thereof:

6. A pharmaceutical composition comprising the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. A method for preparing the compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that:

8. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 6 in the preparation of a KRAS G12C inhibitor.

9. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 6 in the preparation of an anti-tumor drug.

10. The use according to claim 9, characterized in that: The tumor is lung cancer, pancreatic cancer or colon cancer accompanied by KRAS G12C mutation.

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