Preparation and Application of Pyrimido[4,5-d]thiazine-2,4(1H,3H)-dione Inhibitors of KRAS G12C Mutant Protein

Abstract

The present invention relates to pyrimido[4,5-d]thiazine-2,4-dione inhibitors of KRAS G12C mutant protein and their uses. Specifically, the present invention provides a compound represented by formula (I), wherein the definitions of each substituent are as described in the specification. In addition, it also relates to compositions of the inhibitor and their applications. The compounds of the present invention have good activities in inhibiting tumor growth and have good safety profiles.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and particularly relates to a novel KRAS G12C inhibitor and its preparation method and use. Background Art

[0002] The present invention generally relates to novel compounds and their preparation methods and uses as KRAS G12C inhibitors (for example, for the treatment of cancer).

[0003] RAS represents a group of closely related monomeric globular proteins of 189 amino acids (molecular weight 21 kDa), which are associated with the plasma membrane and bind GDP or GTP. RAS acts as a molecular switch. When RAS contains bound GDP, it is in a resting or closed state and is in an "inactive state". In response to a cell's exposure to certain growth-promoting stimuli, RAS is induced to convert its bound GDP into GTP. After binding to GTP, RAS is "turned on" and is able to interact with other proteins (its "downstream targets") and activate other proteins. The RAS protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP, thus keeping itself in the off state. Turning off RAS requires extrinsic proteins called GTPase-activating proteins (GAPs), which interact with RAS and greatly accelerate the conversion of GTP to GDP. Any mutation in RAS that affects its interaction with GAP or its ability to convert GTP back to GDP will result in an extended activation time of the protein, leading to extended cell signaling and allowing it to continue growing and dividing. Since these signals cause cell growth and division, overactive RAS signaling may ultimately lead to cancer.

[0004] Structurally, the RAS protein contains a G domain that is responsible for the enzymatic activity of RAS - guanine nucleotide binding and hydrolysis (the GTPase reaction). It also contains a C - terminal extension called the CAAX box, which undergoes post - translational modification and is responsible for targeting the protein to the membrane. The G domain is approximately 21 - 25 kDa in size and it contains a phosphate - binding loop (P - loop). The P - loop is the pocket for nucleotide binding in the protein and is a rigid part of the domain with conserved amino acid residues ((glycine 12, threonine 26, and lysine 16)), which is crucial for nucleotide binding and hydrolysis. The G domain also contains the so - called Switch I (residues 30 - 40) and Switch II (residues 60 - 76) regions, both of which are dynamic parts of the protein and are often referred to as the "spring - loaded" mechanism because they are able to switch between a resting and a loaded state. The key interaction is a hydrogen bond formed between threonine 35 and glycine 60 with the γ - phosphate of GTP, which keeps the Switch1 and Switch2 regions in their active conformations respectively. After GTP hydrolysis and the release of phosphate, these two relax to the inactive GDP conformation.

[0005] The best - known members of the RAS subfamily are HRAS, KRAS, and NRAS, mainly because they are associated with multiple types of cancer. Mutations in any of the three major isoform (HRAS, NRAS, or KRAS) genes of RAS are among the most common in human tumorigenesis. It is found that approximately 30% of human tumors carry RAS gene mutations. Notably, KRAS mutations are detected in 25 - 30% of tumors. In contrast, the rate of oncogenic mutations occurring in NRAS and HRAS family members is much lower (8% and 3% respectively). The most common KRAS mutations are found at residues G12 and G13 in the P - loop and at residue Q61. G12C is a frequent mutation in the KRAS gene (glycine 12 mutated to cysteine). This mutation has been found in approximately 13% of cancers, approximately 43% of lung cancers, and approximately 100% of MYH - associated polyposis (familial colorectal cancer syndrome).

[0006] As a front-line target, the KRAS G12C mutant protein has received extensive attention. Araxes (a subsidiary of Wellspring) developed ARS-853 and ARST620 compounds in 2013 and 2016 respectively. In recent years, it has also applied for a number of patents for KRAS G12C inhibitors, such as W02016164675 and W02016168540. The MRS-853 compound showed good cell viability, but their pharmacokinetic properties were very poor, which was not suitable for evaluating the pharmacodynamics in animal models in vivo. Ars-1620 has high efficiency and selectivity for KRAS G12C, and can achieve rapid and continuous target engagement in vivo, thereby inducing tumor regression. The in vivo evidence provided by this study indicates that ARS-1620 represents a new generation of KRAS G12C-specific inhibitors with great therapeutic potential. Wellspring announced that the FDA has approved the IND application of ARS-3248. Other candidate KRAS G12C inhibitors include MRTX-849 from Mirati and BI-2852 from Boehringer Ingelheim, etc. Therefore, although progress has been made in this field, there is still a need for improved compounds and methods for treating cancer in this field, such as treating cancer by inhibiting KRAS, HRAS or NRAS. The present invention meets this need and provides other related advantages.

[0007] In short, the present invention provides compounds capable of modulating G12C mutant KRAS, HRAS and / or NRAS proteins, including their stereoisomers, pharmaceutically acceptable salts, tautomers and prodrugs. In some cases, the compounds act as electrophiles capable of forming covalent bonds with cysteine residues at position 12 of the KRAS, HRAS or NRAS G12C mutant proteins. Also provided are methods of using such compounds to treat various diseases or conditions such as cancer. SUMMARY OF THE INVENTION

[0008] A compound having the formula (I), its stereoisomers, pharmaceutically acceptable salts, polymorphs or isomers, wherein the structure of the compound having the formula (I) is as follows:

[0009]

[0010] Wherein,

[0011] Each X1 is independently selected from N, CR4 each time it appears;

[0012] L1 is independently selected from -C 0-4 alkyl-, -CR8R9-, -C 1-2 alkyl (R 8)(OH)-, -C(O)-, -CR8R9O-, -OCR8R9-, -SCR8R9-, -CR8R9S-, -NR8-, -NR8C(O)-, -C(O)NR8-, -NR8C(O)NR9-, -CF2-, -O-, -S-, -S(O) m -, -NR8S(O) m -, -S(O) m NR8-;

[0013] R1 is independently selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclic group, 5-12 membered spiro group, 5-12 membered spiroheterocyclic group, wherein the cycloalkyl, heterocycloalkyl, spiro group, fused ring group, fused heterocyclic group, spiroheterocyclic group is substituted by one or more G 1 substituted;

[0014] R4 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, COOH, NHCOH, CONH2, OH or NH2;

[0015] U is independently selected from -C 0-4 alkyl-, -CR8R9-, -C 1-2 alkyl(R 8 )(OH)-, -C(O)-, -CR8R9O-, -OCR8R9-, -SCR8R9-, -CR8R9S-, -NR8-, -NR8C(O)-, -C(O)NR8-, -NR8C(O)NR9-, -CF2-, -O-, -S-, -S(O) m -, -NR8S(O) m -, -S(O) m NR8-;

[0016] Y is absent or selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclic group, 5-12 membered spiro group, 5-12 membered spiroheterocyclic group, aryl or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, spiro group, fused ring group, fused heterocyclic group, spiroheterocyclic group, aryl or heteroaryl is optionally substituted by one or more G 2 substituted;

[0017] Z is independently selected from cyano, -NR 10 CN,

[0018] Bond c is a double bond or a triple bond;

[0019] When c is a double bond, R a , R band R c each independently selected from H, deuterium, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclic group. Wherein said alkyl, cycloalkyl and heterocyclic group are optionally substituted by one or more G 3 ;

[0020] R a and R b or R b and R c optionally together with the carbon atom to which they are attached form an optionally heteroatom-containing 3- to 6-membered ring;

[0021] When bond c is a triple bond, R a and R c do not exist, and R b is independently selected from H, deuterium, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclic group substituted by one or more G 4 ;

[0022] R 10 is independently selected from H, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclic group, wherein said alkyl, cycloalkyl and heterocyclic group are optionally substituted by one or more G 5 ;

[0023] Each Ar, each occurrence independently, is selected from 5- to 12-membered heteroaryl, and the heteroaryl, each occurrence independently, contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S, wherein said heteroaryl is optionally substituted by one or more G 6 ;

[0024] G 1 、G 2 、G 3 、G 4 、G 5 and G 6 each independently selected from deuterium, cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -OR 11 、-OC(O)NR 11 R 12 、-C(O)OR 11 、-C(O)NR 11 R 12 、-C(O)R11 、-NR 11 R 12 、-NR 11 C(O)R 12 、-NR 11 C(O)NR 12 R 13 、-S(O) m R 11 or -NR 11 S(O) m R 12 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with one or more deuterium, cyano, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaromatic, -OR 14 、-OC(O)NR 14 R 15 、-C(O)OR 14 、-C(O)NR 14 R 15 、-C(O)R 14 、-NR 14 R 15 、-NR 14 C(O)R 15 、-NR 14 C(O)NR 15 R 16 、-S(O) m R 14 or -NR 14 S(O) n R 15 substituted by a substituent;

[0025] R 8 , R 9 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered monocyclic heterocyclic group, monocyclic heteroaromatic group or phenyl;

[0026] And m, n are 1 or 2.

[0027] In some embodiments, the compound of general formula (I), its pharmaceutically acceptable salts or its stereoisomers, and general formula (I) is further represented by (II-A), (II-B), (II-C) or (II-D)

[0028]

[0029] In some embodiments, the compound of formula (I) or its isomers, solvates or precursors, or their pharmaceutically acceptable salts are selected from the following compounds, their isomers, solvates or precursors, or their pharmaceutically acceptable salts:

[0030] 1. A compound of general formula (I), its stereoisomers, pharmaceutically acceptable salts, polymorphs or isomers, wherein the structure of the compound of general formula (I) is as follows:

[0031]

[0032] Wherein,

[0033] Each X1 is independently selected from N, CR4 each time it appears;

[0034] L1 is independently selected from -C 0-4 alkyl-, -CR8R9-, -C 1-2 alkyl(R 8 )(OH)-, -C(O)-, -CR8R9O-, -OCR8R9-, -SCR8R9-, -CR8R9S-, -NR8-, -NR8C(O)-, -C(O)NR8-, -NR8C(O)NR9-, -CF2-, -O-, -S-, -S(O) m -, -NR8S(O) m -, -S(O) m NR8-;

[0035] R1 is independently selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclic group, 5-12 membered spirocyclic group, 5-12 membered spiroheterocyclic group, wherein the cycloalkyl, heterocycloalkyl, spirocyclic group, fused ring group, fused heterocyclic group, spiroheterocyclic group is substituted by one or more G 1 substituted;

[0036] R4 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, COOH, NHCOH, CONH2, OH or NH2;

[0037] U is independently selected from -C 0-4 alkyl-, -CR8R9-, -C 1-2 alkyl(R8 )(OH)-, -C(O)-, -CR8R9O-, -OCR8R9-, -SCR8R9-, -CR8R9S-, -NR8-, -NR8C(O)-, -C(O)NR8-, -NR8C(O)NR9-, -CF2-, -O-, -S-, -S(O) m -, -NR8S(O) m -, -S(O) m NR8-;

[0038] Y is absent or is C 3-8 cycloalkyl, 3- to 8-membered heteroalkyl, 5- to 12-membered fused alkyl, 5- to 12-membered fused heteroaryl, 5- to 12-membered spiroalkyl, 5- to 12-membered spiroheteroaryl, aryl or heteroaryl, wherein the cycloalkyl, heteroalkyl, spiroalkyl, fused ring alkyl, fused heteroaryl, spiroheteroaryl, aryl or heteroaryl is optionally substituted with one or more G 2 substituted;

[0039] Z is independently selected from cyano, -NR 10 CN,

[0040] bond c is a double bond or a triple bond;

[0041] When c is a double bond, R a 、 R b and R c are each independently selected from H, deuterium, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heteroaryl. Wherein the alkyl, cycloalkyl and heteroaryl are optionally substituted with one or more G 3 substituted;

[0042] R a and R b or R b and R c optionally together with the carbon atom to which they are attached form an optionally heteroatom-containing 3- to 6-membered ring;

[0043] When bond c is a triple bond, R a and R c are absent, R b is independently selected from H, deuterium, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heteroaryl substituted with one or more G 4 substituted;

[0044] R 10 is independently selected from H, deuterium, C 1-6 alkyl, C 3-6A cycloalkyl group or a 3- to 6-membered heterocyclic group, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally substituted by one or more G 5 ;

[0045] Each Ar, each occurrence independently, is selected from 5- to 12-membered heteroaryl groups, and each occurrence of the heteroaryl group independently contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S, wherein the heteroaryl group is optionally substituted by one or more G 6 ;

[0046] G 1 , G 2 , G 3 , G 4 , G 5 and G 6 are each independently selected from deuterium, cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -OR 11 , -OC(O)NR 11 R 12 , -C(O)OR 11 , -C(O)NR 11 R 12 , -C(O)R 11 , -NR 11 R 12 , -NR 11 C(O)R 12 , -NR 11 C(O)NR 12 R 13 , -S(O) m R 11 or -NR 11 S(O) m R 12 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted by one or more deuterium, cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -OR 14 , -OC(O)NR 14 R 15 , -C(O)OR 14 , -C(O)NR 14 R 15 , -C(O)R14 、 -NR 14 R 15 、 -NR 14 C(O)R 15 、 -NR 14 C(O)NR 15 R 16 、 -S(O) m R 14 or -NR 14 S(O) n R 15 is substituted by a substituent of;

[0047] R 8 、R 9 、R 11 、R 12 、R 13 、R 14 and R 15 are each independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 3-8 cycloalkyl or 3 - 8 membered monocyclic heterocyclic group, monocyclic heteroaryl or phenyl;

[0048] and m, n are 1 or 2.

[0049] 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (II - A), (II - B), (II - C) or (II - D):

[0050]

[0051] 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is selected from:

[0052]

[0053] 4. The compound according to claim 1 or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, polymorph or isomer thereof and mixtures thereof, which is selected from the following compounds:

[0054]

[0055]

[0056] In some embodiments, the compound of formula (I) or its stereoisomers, solvates or precursors, or pharmaceutically acceptable salts thereof are selected from the following compounds, their isomers, solvates or precursors, or pharmaceutically acceptable salts thereof:

[0057]

[0058]

[0059] On the other hand, the present invention also provides a pharmaceutical composition, which comprises the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0060] On the other hand, the present invention relates to a method for treating a disease associated with KRAS G12C in a mammal, which comprises administering to a mammal in need of such treatment, preferably a human, a therapeutically effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0061] On the other hand, the present invention relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a KRAS G12C-related disease.

[0062] On the other hand, the present invention relates to the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a KRAS G12C-related disease. Specific implementation methods

[0063] The present invention also provides a method for preparing the compound. The preparation of the compound represented by the general formula (I) of the present invention can be completed by the following exemplary methods and examples, but these methods and examples should not be considered as limiting the scope of the present invention in any way. The compounds of the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or by combining the methods known in the art and the methods of the present invention. The product obtained in each step should be obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be synthesized or purchased conventionally according to the literature (Reaxys).

[0064] Unless otherwise specified, the temperature is in degrees Celsius. The reagents are purchased from commercial suppliers such as Xianghui Pharmaceutical or Macklin, and these reagents can be used directly without further purification, unless otherwise specified.

[0065] Unless otherwise specified, the following reactions are carried out at room temperature, in an anhydrous solvent, under a positive pressure of nitrogen or argon, or using a drying tube; the glassware is dried by baking and / or heating.

[0066] Unless otherwise specified, column chromatography purification uses silica gel with a mesh size of 200-300 from Qingdao Ocean Chemical Factory; preparative thin-layer chromatography uses prefabricated thin-layer chromatography silica gel plates (HSGF254) produced by Yantai Chemical Industry Research Institute; the determination of MS is carried out using a Thermo LCD Fleet type (ESI) liquid chromatography-mass spectrometry instrument.

[0067] Nuclear magnetic data (1H NMR) was obtained using a Bruker Avance-400 MHz or Varian Oxford-400 Hz nuclear magnetic resonance spectrometer. Solvents used for nuclear magnetic data included CDCl3, CD3OD, D2O, DMS-d6, etc. Tetramethylsilane (0.000 ppm) or residual solvent was used as the reference (CDCl3: 7.26 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm). When indicating the multiplicity of peaks, the following abbreviations were used to represent different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (doublet of doublets), dt (doublet of triplets). If coupling constants were given, they were in Hertz (Hz).

[0068] Intermediate synthesis

[0069] Preparation of A1

[0070]

[0071] Step A

[0072] In a dry 2 L three-necked flask, sodium hydride (0.8 g, 19 mmol) was added to N,N-dimethylformamide (10 mL). The reaction system was heterogeneous and gray. The temperature was lowered to 0 °C, and a solution of compound A1-1 (1 g, 8 mmol) in N,N-dimethylformamide (200 mL) was added dropwise under nitrogen protection. The reaction was continued at 0 °C for 0.5 h. Then, p-methoxybenzyl chloride (2.75 g, 17 mmol, 2.4 mL) was added, and the temperature was slowly raised to 20 °C, and stirring was continued for 7.5 h under nitrogen protection. The reaction solution was slowly added to 10 mL of saturated ammonium chloride, extracted with methyl tert-butyl ether (10 mL × 2), the combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain compound A1-2. LC-MS (ESI): m / z = 365.45 [M + H] + 。

[0073] Step B

[0074] 2,2,6,6 - Tetramethylpiperidine (1.14 g, 8.21 mmol) was added to anhydrous tetrahydrofuran (300 mL). The temperature was lowered to -5 °C, and n-butyllithium (2.5 M, 4 mL) was added dropwise. The reaction was carried out at -5 to 0 °C for 15 minutes. Then the temperature was lowered to -60 °C, and a solution of compound A1-2 (0.98 g, 2.7 mmol) in tetrahydrofuran (3 mL) was added. The reaction was carried out at -60 °C for 0.5 hour. N,N-Dimethylformamide (4 g, 0.05 mol) was quickly added, and the reaction mixture was stirred at -60 °C for an additional 10 minutes. 20 mL of saturated ammonium chloride was added to the reaction mixture, and the mixture was extracted with methyl tert-butyl ether (10 mL × 2). The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvents were removed under reduced pressure. The resulting crude product was slurried in a solvent for 0.5 hour, filtered, and the filter cake was dried. The filtrate was concentrated and then purified by silica gel column chromatography. The filter cake and the column chromatography fractions were combined to obtain compound A1-3. LC-MS (ESI): m / z = 393.5 [M+H] + 。

[0075] Step C

[0076] Compound A1-3 (0.98 g, 2.5 mmol) was added to 10 mL of N,N-dimethylformamide, and N-bromosuccinimide (0.45 g, 2.5 mmol) was added. The reaction mixture was stirred at 20 °C for an additional 20 minutes. The reaction mixture was added to 15 mL of water, and the mixture was extracted with methyl tert-butyl ether (8 mL × 2). The combined organic phases were washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the organic solvents were removed under reduced pressure. The resulting crude product was slurried in a mixed solvent for 0.5 hour, filtered, and the filter cake was dried to obtain compound A1-4. LC-MS (ESI): m / z = 472.4 [M+H] + 。

[0077] Step D

[0078] Compound A1-4 (0.97 g, 2.04 mmol) was added to N,N-dimethylformamide (9.5 mL). Under nitrogen, cuprous iodide (0.78 g, 4.1 mmol) and methyl fluorosulfonyldifluoroacetate (2 g, 10 mmol) were added to the reaction mixture. The reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling, the reaction mixture was filtered through diatomaceous earth. The filtrate was added to 15 mL of water, and the mixture was extracted with methyl tert-butyl ether (7.5 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the organic solvents were removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain compound A1-5. LC-MS (ESI): m / z = 461.5 [M+H] + 。

[0079] Step E

[0080] Add anhydrous tetrahydrofuran (50 mL) and sodium hydride (0.3 g, 7.3 mmol) to a dry three-necked flask, cool to 0 °C, and dropwise add ethyl acetate (0.85 g, 7.3 mmol, 0.8 mL) under nitrogen protection. Stir the reaction mixture at 0 °C for an additional 0.5 h, then dropwise add n-butyllithium (2.5 M, 3 mL). Stir the reaction mixture under these conditions for 0.5 h, then cool to -60 °C and dropwise add a solution of compound A1-5 (1.15 g, 2.5 mmol) in tetrahydrofuran (5 mL). Stir the reaction mixture at -60 °C for 0.5 h. Add 25 mL of saturated ammonium chloride solution to the reaction mixture, extract with 10 mL of ethyl acetate, wash the organic phase with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and remove the organic solvent under reduced pressure. The resulting crude product is separated and purified by silica gel column chromatography to obtain compound A1-6. LC-MS (ESI): m / z = 531.6 [M+H] + 。

[0081] Step F

[0082] Add compound A1-6 (1 g, 1.9 mmol) to dichloromethane (10 mL), add ethyl 3-mercaptopropionate (0.3 g, 2.3 mmol) and titanium tetrachloride, and stir the reaction at room temperature for 48 h. Filter, remove the organic solvent under reduced pressure, and separate and purify the resulting crude product by silica gel column chromatography to obtain compound A1-7. LC-MS (ESI): m / z = 665.7 [M+H] +

[0083] Step G

[0084] Dissolve compound A1-7 (0.80 g, 1.2 mmol) and sodium ethoxide (0.57 mg, 1.9 mmol) in 10 mL of THF, and stir the reaction at room temperature for 24 h. Filter and dry to obtain A1-8. LC-MS (ESI): m / z = 619.7 [M+H] + 。

[0085] Step H

[0086] To a suspension of A1-8 (3.3 g, 5.3 mmol) in water (10 mL), add S-methylisothiourea sulfate (1.7 g, 6.2 mmol) and potassium carbonate (1.6 g, 11.7 mmol) at room temperature. Stir the reaction mixture for 20 h. Collect the precipitate, wash with water (twice) and isopropyl ether, and dry to obtain A1-9; LC-MS (ESI): m / z = 645.7 [M+H] + 。

[0087] Step I

[0088] Compound A1-9 (1 g, 1.6 mmol) was dissolved in dichloromethane (10 mL). N,N-Diisopropylethylamine (0.6 g, 4.8 mmol) was added, and the temperature was lowered to 0 - 10 °C. Trifluoromethanesulfonic anhydride (0.7 g, 2.4 mmol, 400 μL) was slowly added to the reaction solution, and the reaction was carried out at this temperature for 15 minutes. The reaction solution was poured into saturated ammonium chloride aqueous solution (8 mL), and liquid separation was performed. The aqueous phase was extracted with dichloromethane (5 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the organic solvents were removed under reduced pressure. The obtained crude product was slurried, filtered, and the filter cake was dried to obtain A1. LC-MS (ESI): m / z = 777.8 [M+H] + 。

[0089] Preparation of B1

[0090]

[0091] Compound B1 was obtained by a preparation method similar to that of intermediate A1 (with the raw material changed to 6-bromo-4-methylpyridin-2-amine). LC / MS (ESI): m / z = 760.8 [M+H] + 。

[0092] Example 1

[0093] 1-((3S)-4-(7-(3-Amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)prop-2-en-1-one (Compound 1)

[0094]

[0095] Step A

[0096] Compound A1 (82 mg, 105.02 μmol) and 8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane (26.63 mg, 126.03 μmol) were dissolved in N,N-dimethylformamide (2 mL). Diisopropylethylamine (40.72 mg, 315.07 μmol) was added, and the reaction solution was heated to 100 °C and stirred for an additional 1 hour. After cooling, the organic solvents were removed under reduced pressure. The obtained crude product was separated and purified by a preparative thin-layer chromatography plate to obtain Compound 1-1. LC / MS (ESI): m / z = 828 [M+H] + 。

[0097] Step B

[0098] Compound 1-1 (71 mg, 84.96 μmol) was dissolved in dichloromethane (2 mL), and m-chloroperoxybenzoic acid (34.50 mg, 169.92 μmol) was added. The reaction mixture was stirred at 20 °C for an additional 3 hours. The organic solvent was removed under reduced pressure, and the resulting crude product was separated and purified by preparative thin-layer chromatography to obtain Compound 1-2. LC / MS (ESI): m / z = 892 [M+H] + 。

[0099] Step C

[0100] Under an ice-water bath condition, ((2R,7aS)-2-fluoro-7a-hydro-1H-pyrrolizin-5(2H)-yl)methanol (12.09 mg, 75.94 μmol) was dissolved in anhydrous toluene (1 mL), and sodium tert-butoxide (7.30 mg, 75.94 μmol) was added. The reaction mixture was stirred for an additional 30 minutes, and a toluene (1 mL) solution of Compound 1-2 (53 mg, 58.42 μmol) was added. The reaction mixture was stirred at an ice-water bath for an additional 2 hours. The organic solvent was removed under reduced pressure, and the resulting crude product was separated and purified by preparative thin-layer chromatography to obtain Compound 1-3. LC / MS (ESI): m / z = 971.1 [M+H] + 。

[0101] Step D

[0102] Compound 1-3 (42 mg, 42.78 μmol) was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 20 °C for an additional 2 hours. The solvent was removed under reduced pressure, and the resulting crude product was separated and purified by high-performance liquid chromatography to obtain Compound 1-4. LC / MS (ESI): m / z = 630.7 [M+H] + 。

[0103] Step E

[0104] Compound 1-4 (0.46 g, 0.73 mmol) and N,N-diisopropylethylamine (0.48 g, 3.75 mmol) were dissolved in dichloromethane (20 mL). Acryloyl chloride (59.73 mg, 0.66 mmol) was added at -78 °C, and the mixture was stirred at -78 °C for 25 minutes. The reaction was quenched with water and extracted with dichloromethane. The organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was directly purified by reverse-phase chromatography to obtain Compound 1. LC-MS (ESI): m / z = 684.7 [M+H] + 。 1H-NMR (CD3OD) δ 6.73 - 6.87 (m, 1H), 6.68 (d, 1H), 6.25 (dd, 1H), 5.46 - 5.58 (m, 1H), 5.19 - 5.46 (m, 1H), 4.90 - 5.05 (m, 2H), 4.58 - 4.74 (m, 2H), 3.94 - 4.43 (m, 8H), 3.24 - 3.79 (m, 4H), 2.89 - 3.13 (m, 2H), 2.03 - 2.32 (9H), 1.31 - 1.42 (m, 3H).

[0105] Example 2

[0106] 1 - ((3S)-4 - ((7S)-7-(3 - amino - 2 - fluoro - 5 - methyl - 6 - (trifluoromethyl)phenyl)-2 - (((2R,7AS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-6,6 - dioxo - 7,8 - dihydro - 5H - thieno[4,3 - d]pyrimidin - 4 - yl)-3 - methylpyrazin - 1 - yl)prop - 2 - en - 1 - one (Compound 1A)

[0107] 1 - ((3S)-4 - ((7R)-7-(3 - amino - 2 - fluoro - 5 - methyl - 6 - (trifluoromethyl)phenyl)-2 - (((2R,7AS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-6,6 - dioxo - 7,8 - dihydro - 5H - thieno[4,3 - d]pyrimidin - 4 - yl)-3 - methylpyrazin - 1 - yl)prop - 2 - en - 1 - one (Compound 1B)

[0108]

[0109] Compound 1 was separated and purified by high - performance liquid chromatography column method to obtain 1A and 2A (Column: Chiralpak IG - 3: 3μm, 0.46 cm × 5 cm; Mobile phase: A (CO2) and B (EtOH, containing 0.1% isopropylamine); Gradient: B% = 5 - -50%, 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 n; Pressure: 1800, LC / MS (ESI): m / z = 684.7 [M + H] + .

[0110] Example 3

[0111] 1-((3S)-4-(7-(3-Amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)-2-fluoroprop-2-en-1-one (Compound 2)

[0112]

[0113] Compound 2 was obtained by a preparation method similar to Step E in Example 1. LC / MS (ESI): m / z = 702.7 [M+H] + 。

[0114] Example 4

[0115] 1-((3S)-4-((7S)-7-(3-Amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)-2-fluoroprop-2-en-1-one (2A)

[0116] 1-((3S)-4-((7R)-7-(3-Amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)-2-fluoroprop-2-en-1-one (2B)

[0117]

[0118] Compounds 3A and 3B were obtained by a preparation method similar to that of Compounds 1A and 1B in Example 2 (using Compound 2 as the raw material). LC / MS (ESI): m / z = 702.7 [M+H] + 。

[0119] Example 5

[0120] 2-((2S)-1-Acryloyl-4-(7-(3-Amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)pyrazin-2-yl)acetonitrile (Compound 3)

[0121]

[0122] Compound 3 was obtained by a preparation method similar to that of Compound 1 in Example 1. LC / MS (ESI): m / z = 709.7 [M+H] + 。 1 1H-NMR (CD3OD) δ 6.73 - 6.87 (m, 1H), 6.68 (d, 1H), 6.25 (dd, 1H), 5.46 - 5.58 (m, 1H), 5.19 - 5.46 (m, 1H), 4.90 - 5.05 (m, 2H), 4.58 - 4.74 (m, 2H), 3.94 - 4.43 (m, 8H), 3.24 - 3.79 (m, 4H), 2.89 - 3.13 (m, 2H), 2.16 - 2.82 (m, 9H).

[0123] Example 6

[0124] 2 - ((2S)-1 - acryloyl - 4 - ((7S)-7 - (3 - amino - 2 - fluoro - 5 - methyl - 6 - (trifluoromethyl)phenyl)-2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-6,6 - dioxo - 7,8 - dihydro - 5H - thieno[4,3 - d]pyrimidin - 4 - yl)pyrazin - 2 - yl)acetonitrile (Compound 3A)

[0125] 2 - ((2S)-1 - acryloyl - 4 - ((7R)-7 - (3 - amino - 2 - fluoro - 5 - methyl - 6 - (trifluoromethyl)phenyl)-2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-6,6 - dioxo - 7,8 - dihydro - 5H - thieno[4,3 - d]pyrimidin - 4 - yl)pyrazin - 2 - yl)acetonitrile (Compound 3B)

[0126]

[0127] Compound 3A and 3B were obtained by a preparation method similar to that of Compounds 1A and 1B in Example 2 (using Compound 3 as the raw material). LC / MS (ESI): m / z = 709.7 [M+H] + 。

[0128] Example 7

[0129] 2-((2S)-4-(7-(3-Amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)-1-(2-fluoropropenoyl)pyrazin-2-yl)acetonitrile (Compound 4)

[0130]

[0131] Compound 4 was obtained by a preparation method similar to that in Step E of Example 1. LC / MS (ESI): m / z = 727.7 [M+H] + 。 1 1H-NMR (CD3OD) δ 6.72 - 6.84 (m, 1H), 5.46 - 5.58 (m, 1H), 5.19 - 5.46 (m, 2H), 4.90 - 5.05 (m, 2H), 4.58 - 4.74 (m, 2H), 3.94 - 4.43 (m, 8H), 3.24 - 3.79 (m, 4H), 2.89 - 3.13 (m, 2H), 2.18 - 2.82 (m, 9H).

[0132] Example 8

[0133] 2-((2S)-4-((7S)-7-(3-Amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)-1-(2-fluoropropenoyl)pyrazin-2-yl)acetonitrile (Compound 4A)

[0134] 2-((2S)-4-((7R)-7-(3-Amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)-1-(2-fluoropropenoyl)pyrazin-2-yl)acetonitrile (Compound 4B)

[0135]

[0136] Compound 4A and 4B were obtained by a preparation method similar to that of Compounds 1A and 1B in Example 2 (using Compound 4 as the raw material). LC / MS (ESI): m / z = 727.7 [M+H] + 。

[0137] Example 9

[0138] 1-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)prop-2-en-1-one (Compound 5)

[0139]

[0140] Compound 5 was obtained by a preparation method similar to that of Compound 1 in Example 1 (with raw materials replaced by B1). LC / MS (ESI): m / z = 667.7 [M+H] + 。

[0141] Example 10

[0142] 1-((3S)-4-((7S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)prop-2-en-1-one (Compound 5A)

[0143] 1-((3S)-4-((7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)prop-2-en-1-one (Compound 5B)

[0144]

[0145] Compound 5A and 5B were obtained by a preparation method similar to that of Compounds 1A and 1B in Example 2 (with raw materials replaced by Compound 5). LC / MS (ESI): m / z = 667.7 [M+H] + 。

[0146] Example 11

[0147] 1-((3S)-4-(7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)-2-fluoroprop-2-en-1-one (Compound 6)

[0148]

[0149] Compound 6 was obtained by a preparation method similar to Step E in Example 1. LC / MS (ESI): m / z = 685.7 [M+H] + 。

[0150] Example 12

[0151] 1-((3S)-4-((7S)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)-2-fluoroprop-2-en-1-one (Compound 6A)

[0152] 1-((3S)-4-((7R)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)-2-fluoroprop-2-en-1-one (Compound 6B)

[0153]

[0154] Compound 6A and 6B were obtained by a preparation method similar to that of Compounds 1A and 1B in Example 2 (using Compound 6 as the raw material). LC / MS (ESI): m / z = 685.7 [M+H] + 。

[0155] Example 13

[0156] 2-((2S)-4-(7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)-1-(acryloyl)pyrazin-2-yl)acetonitrile (Compound 7)

[0157]

[0158] Compound 7 was obtained by a preparation method similar to that of Compound 1 in Example 1 (using B1 as the raw material). LC / MS (ESI): m / z = 692.7 [M+H] + 。

[0159] Example 14

[0160] 2-((2S)-4-((7S)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)-1-(acryloyl)pyrazin-2-yl)acetonitrile (Compound 7A)

[0161] 2-((2S)-4-((7R)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)-1-(acryloyl)pyrazin-2-yl)acetonitrile (Compound 7B)

[0162]

[0163] Compound 7A and 7B were obtained by a preparation method similar to that of Compounds 1A and 1B in Example 2 (using Compound 7 as the raw material). LC / MS (ESI): m / z = 692.7 [M+H] + 。

[0164] Example 15

[0165] 2-((2S)-4-(7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thieno[4,3-d]pyrimidin-4-yl)-1-(2-fluoropropenoyl)pyrazin-2-yl)acetonitrile (Compound 8)

[0166]

[0167] Compound 8 was obtained by a preparation method similar to that in Step E of Example 1. LC / MS (ESI): m / z = 710.7 [M+H] + 。

[0168] Example 16

[0169] 2-((2S)-4-((7S)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)-1-(2-fluoropropenoyl)pyrazin-2-yl)acetonitrile (Compound 8A)

[0170] 2-((2S)-4-((7R)-7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)-1-(2-fluoropropenoyl)pyrazin-2-yl)acetonitrile (Compound 8B)

[0171]

[0172] Compound 8A and 8B were obtained by a preparation method similar to that of Compounds 1A and 1B in Example 2 (using Compound 8 as the raw material). LC / MS (ESI): m / z = 710.7 [M+H] + 。

[0173] Biological Activity Test of Example 17

[0174] The present invention will be further described and explained below in combination with test examples, but these examples do not mean to limit the scope of the present invention.

[0175] I. Tumor Cell Proliferation Inhibition Experiment

[0176] 1. Experimental Method

[0177] After digesting, centrifuging, and resuspending H358 (KRAS G12C mutant) cells, the cell density was measured using a Scepter automated cell counter. The cells were diluted into a solution containing 44,000 cells per milliliter, and 90 μL of the adjusted cell solution was added to each well of a 96-well culture plate. The 96-well plate was placed in an incubator at 37 °C and 5% CO2. After 24 hours of cell culture, different concentrations of the test compound were added, and the cells were cultured with the compound for 72 hours in the presence of 10% fetal bovine serum. The CellTiter-Glo luminescent cell viability assay kit (see the manufacturer's instructions for details) was used to measure the ATP content to evaluate cell growth inhibition. Briefly, 30 μL of Cell Titer-Glo reagent was added to each well, the plate was shaken for 10 minutes to induce cell lysis, and the fluorescence signal was detected and recorded using a Fluoroskan Ascent FL (Thermo). The maximum signal value was obtained from cells treated with dimethyl sulfoxide for 72 hours. The minimum signal value was obtained from the separate medium (cell count = zero). The inhibition rate (%) = (maximum signal value - compound signal value) / (maximum signal value - minimum signal value) × 100%. The Graphpad prism 5 software was used to process the data. The IC 50 value was calculated by fitting an S-shaped dose-response curve. Among them, "A" represents IC 50 ≤ 10 nM; "B" represents 10 < IC 50 ≤ 100 nM; "C" represents 100 < IC 50 ≤ 1000 nM; "D" represents 1000 nM < IC 50

[0178] 2. Experimental results

[0179] The IC 50 of each compound in the above experiment was calculated, and the results are shown in Table 1 below

[0180] Table 1. Inhibitory activity of compounds on tumor cell proliferation IC 50 (nm).

[0181]

[0182]

[0183] In vitro kinase activity indicated that the designed compounds had strong inhibitory activity against KRAS G12C mutant strains.

[0184] Although the present invention has been described in detail above, those skilled in the art understand that various modifications and changes can be made to the present invention without departing from the spirit and scope of the present invention. The scope of the rights of the present invention is not limited to the detailed description above, but should be attributed to the claims.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, selected from any of the following:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salts are selected from the group consisting of: potassium salts, sodium salts, magnesium salts, calcium salts, sulfates, hydrochlorides, phosphates, sulfonates and carbonates.

3. A pharmaceutical composition, characterized in that, Comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier.

4. Use of the compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for the treatment of a disease, disorder or condition associated with KRas G12C activity or expression level.

5. The use according to claim 4, characterized in that, The disease, disorder or condition is selected from the group consisting of: pancreatic cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioblastoma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, acute myeloid leukemia, myelofibrosis, monocytic leukemia, myeloma.

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