Preparation and application of KRAS G12C mutant protein pyrimido-thiapyran diketone inhibitor

Abstract

The invention relates to a KRAS G12C mutant protein pyrimido-thiapyran diketone inhibitor and application thereof, in particular to a compound shown in a formula (I), and the definition of each substitution in the formula is described in the specification. In addition, the invention also relates to a composition of the inhibitor and application thereof. The compound provided by the invention has good activity of inhibiting tumor growth. And the safety is good.

Description

Technical Field

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

[0002] The present invention generally relates to novel compounds and methods for their preparation and use 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) that are associated with the plasma membrane and bind to either GDP or GTP. RAS acts as a molecular switch. When RAS contains bound GDP, it is in a resting, or closed, state and "inactive." In response to exposure of cells to certain growth-promoting stimuli, RAS is induced to convert its bound GDP into GTP. Once bound to GTP, RAS is "switched on" and able to interact with and activate other proteins (their "downstream targets"). RAS proteins themselves have a very low intrinsic capacity and are unable to hydrolyze GTP back to GDP, thus maintaining their closed state. Turning off RAS requires external 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 ability to interact with GAPs or convert GTP back to GDP results in prolonged activation of the protein, leading to prolonged cellular signaling that allows cells to continue growing and dividing. Because these signals drive cell growth and division, overactive RAS signaling may ultimately lead to cancer.

[0004] Structurally, the RAS protein contains a G domain, which is responsible for the enzymatic activity of RAS - guanine nucleotide binding and hydrolysis (GTPase reaction). It also contains a C-terminal extension called the CAAX box, which can be post-translationally modified and is responsible for targeting the protein to the membrane. The G domain is approximately 21-25 kDa in size and contains a phosphate-binding loop (P-loop). The P-loop is the pocket where nucleotides bind in the protein. This is a rigid part of the domain with conserved amino acid residues (glycine 12, threonine 26, and lysine 16) and 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 a "spring-loaded" mechanism due to their ability to switch between resting and loaded states. The key interaction is a hydrogen bond formed by threonine 35 and glycine 60 with the γ-phosphate of GTP, which holds the Switch1 and Switch2 regions, respectively, in their active conformations. Upon GTP hydrolysis and release of the phosphates, the two relax to the inactive GDP conformation.

[0005] The best-known members of the RAS subfamily are HRAS, KRAS, and NRAS, primarily due to their association with various types of cancer. Mutations in any of the three major RAS isoforms (HRAS, NRAS, or KRAS) are the most common in human tumorigenesis. Approximately 30% of human tumors are found to harbor RAS gene mutations. Notably, KRAS mutations are detected in 25-30% of tumors. In contrast, the prevalence of oncogenic mutations 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 of the P-loop and residue Q61. G12C is a frequent mutation in the KRAS gene (glycine 12 to cysteine). This mutation has been found in approximately 13% of cancers, approximately 43% of lung cancers, and approximately 100% of cases of MYH-associated polyposis (a familial colon cancer syndrome).

[0006] As a cutting-edge target, KRAS G12C mutant protein has received widespread 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 KRASG12C inhibitors, such as W02016164675 and W02016168540. The MRS-853 compound showed good cell viability, but their pharmacokinetic performance was poor, which is not suitable for evaluating the pharmacodynamics of animal models in vivo. Ars-1620 has high efficiency and selectivity for KRASG12C, and can achieve rapid and sustained target effects in vivo, thereby inducing tumor regression. The in vivo evidence provided by this study shows that ARS-1620 represents a new generation of KRASG12C-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. Thus, despite progress in this field, there remains a need in the art for improved compounds and methods for treating cancer, such as by inhibiting KRAS, HRAS, or NRAS. The present invention addresses 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 stereoisomers, pharmaceutically acceptable salts, tautomers and prodrugs thereof. In some cases, the compound acts as an electrophilic agent capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS, HRAS or NRAS G12C mutant protein. Methods of using such compounds to treat various diseases or conditions such as cancer are also provided. Summary of the Invention

[0008] A compound represented by general formula (I), its stereoisomers, pharmaceutically acceptable salts, polymorphs or isomers, wherein the compound represented by general formula (I) has the following structure:

[0009]

[0010] in,

[0011] Each X1 is independently selected at each occurrence from N, CR4;

[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 condensed alkyl, 5-12 membered condensed heterocyclic group, 5-12 membered spirocyclic group, 5-12 membered spiro heterocyclic group wherein the cycloalkyl, heterocycloalkyl, spirocyclic group, condensed cyclic group, condensed heterocyclic group, spiro heterocyclic group is replaced by one or more G 1 replaced by;

[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 does not exist or select C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spirocyclyl, 5-12 membered spiro heterocyclyl, aromatic or heteroaromatic, wherein the cycloalkyl, heterocycloalkyl, spirocyclyl, fused cyclyl, fused heterocyclyl, spiro heterocyclyl, aromatic or heteroaromatic is optionally substituted by one or more G 2 replaced by;

[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 are each independently selected from H, deuterium, cyano, halogen, C 1-6 Alkyl, C 3-6 wherein the alkyl, cycloalkyl and heterocyclic groups are optionally substituted by one or more G 3 replaced by;

[0020] R a and R b or R b and R c Optionally, together with the carbon atoms to which they are attached, they form a 3-6 membered ring which optionally contains heteroatoms;

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

[0022] R 10 Independently selected from H, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the alkyl, cycloalkyl and heterocyclic group are optionally substituted by one or more G 5 replaced by;

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

[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 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaromatic, -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 Each 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 group;

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

[0027] In some embodiments, the compound of formula (I), its pharmaceutically acceptable salt or stereoisomer thereof, 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 isomer, solvate or precursor, or pharmaceutically acceptable salt thereof is selected from the following compounds, its isomer, solvate or precursor, or pharmaceutically acceptable salt thereof:

[0030] 1. A compound represented by general formula (I), its stereoisomers, pharmaceutically acceptable salts, polymorphs or isomers, wherein the compound represented by general formula (I) has the following structure:

[0031]

[0032] in,

[0033] Each X1 is independently selected at each occurrence from N, CR4;

[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 condensed alkyl, 5-12 membered condensed heterocyclic group, 5-12 membered spirocyclic group, 5-12 membered spiro heterocyclic group wherein the cycloalkyl, heterocycloalkyl, spirocyclic group, condensed cyclic group, condensed heterocyclic group, spiro heterocyclic group is replaced by one or more G 1 replaced by;

[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 does not exist or select C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spirocyclyl, 5-12 membered spiro heterocyclyl, aromatic or heteroaromatic, wherein the cycloalkyl, heterocycloalkyl, spirocyclyl, fused cyclyl, fused heterocyclyl, spiro heterocyclyl, aromatic or heteroaromatic is optionally substituted by one or more G 2 replaced by;

[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 wherein the alkyl, cycloalkyl and heterocyclic groups are optionally substituted by one or more G 3 replaced by;

[0042] R a and R b or R b and R c Optionally, together with the carbon atoms to which they are attached, they form a 3-6 membered ring which optionally contains heteroatoms;

[0043] When bond c is a triple bond, R a and R c Does not exist, R b independently selected from H, deuterium, cyano, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group is replaced by one or more G 4 replaced by;

[0044] R 10 Independently selected from H, deuterium, C 1-6 Alkyl, C 3-6Cycloalkyl or 3-6 membered heterocyclic group, wherein the alkyl, cycloalkyl and heterocyclic group are optionally substituted by one or more G 5 replaced by;

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

[0046] 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 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaromatic, -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 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)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 substituted by a substituent;

[0047] R 8 、R 9 、R 11 、R 12 、R 13 、R 14 and R 15 Each 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 group;

[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 its prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, polymorph or isomer, and mixtures thereof, selected from the following compounds:

[0054]

[0055]

[0056]

[0057] In some embodiments, the compound of formula (I) or its isomers, solvates or precursors, or pharmaceutically acceptable salts thereof are selected from the following compounds, their isomers, solvates or precursors, or pharmaceutically acceptable salts thereof:

[0058]

[0059]

[0060] On the other hand, the present invention also provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0061] In another aspect, the present invention relates to a method for treating KRAS G12C-associated diseases in mammals, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0062] In another aspect, the present invention relates to use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in a drug for preventing or treating KRASG12C-related diseases.

[0063] On the other hand, the present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating KRAS G12C-related diseases. Specific implementation methods

[0064] The present invention also provides a method for preparing the compound. The preparation of the compound described in 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 to limit the scope of the present invention in any way. The compound described in the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and the method described in the present invention can be used. The product obtained in each step is 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 conventionally synthesized or purchased according to the literature.

[0065] Unless otherwise stated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Xianghui Pharmaceuticals or Maclean and were used directly without further purification unless otherwise stated.

[0066] Unless otherwise stated, the following reactions were performed at room temperature in anhydrous solvents under a positive pressure of nitrogen or CO or using a drying tube; glassware was oven-dried and / or heat-dried.

[0067] Unless otherwise specified, column chromatography purification used 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; preparative thin-layer chromatography silica gel precast plates (HSGF254) produced by Yantai Institute of Chemical Industry; and MS determination was performed using a ThernoLCD Fleet (ESI) liquid chromatography-mass spectrometer.

[0068] Nuclear magnetic resonance data (1H NMR) were obtained using a Bruker Avance-400MHz or Varian Oxford-400Hz NMR spectrometer. The solvents used for the NMR data included CDCl3, CD3OD, D2O, DMS-d6, etc., and the relative humidity was calculated based on tetramethylsilane (0.000ppm) or residual solvent (CDCl 3: When peak diversity is indicated, the following abbreviations are used to denote the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (double of doublets), dt (double of triplets). Coupling constants, if given, are in Hertz (Hz).

[0069] Intermediate synthesis

[0070] Preparation of A1

[0071]

[0072] Step A

[0073] In a dry 2L three-necked flask, sodium hydride (0.8 g, 19 mmol) was added to N,N-dimethylformamide (10 mL). The reaction system was a heterogeneous gray. The temperature was cooled to 0°C. Under nitrogen, a solution of compound A1-1 (1 g, 8 mmol) in N,N-dimethylformamide (200 mL) was added dropwise. The reaction was continued at 0°C for 0.5 hours. p-Methoxybenzyl chloride (2.75 g, 17 mmol, 2.4 mL) was added, the temperature was slowly raised to 20°C, and stirring was continued under nitrogen for 7.5 hours. The reaction solution was slowly added to 10 mL of saturated ammonium chloride and extracted with methyl tert-butyl ether (10 mL x 2). The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography to yield compound A1-2. LC-MS (ESI): m / z = 365.45 [M+H] + .

[0074] Step B

[0075] 2,2.6,6-Tetramethylpiperidine (1.14 g, 8.21 mmol) was added to anhydrous tetrahydrofuran (300 mL), cooled to -5°C, n-butyllithium (2.5 M, 4 mL) was added dropwise, and the mixture was reacted at -5 to 0°C for 15 minutes. The mixture was cooled to -60°C, and a solution of compound A1-2 (0.98 g, 2.7 mmol) in tetrahydrofuran (3 mL) was added. The mixture was reacted at -60°C for 0.5 hours. N,N-dimethylformamide (4 g, 0.05 mol) was quickly added, and the reaction solution was stirred at -60°C for 10 minutes. 20 mL of saturated ammonium chloride was added to the reaction solution, and the mixture was extracted with methyl tert-butyl ether (10 mL x 2). The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The resulting crude product was slurried with the solvent for 0.5 hours, filtered, and the filter cake dried. The filtrate was concentrated and purified by silica gel column chromatography. The filter cake and column chromatography were combined to obtain compound A1-3. LC-MS (ESI): m / z = 393.5 [M+H] + .

[0076] Step C

[0077] Compound A1-3 (0.98 g, 2.5 mmol) was added to 10 mL of N,N-dimethylformamide, and bromosuccinimide (0.45 g, 2.5 mmol) was added. The reaction solution was stirred at 20°C for 20 minutes. The reaction solution was added to 15 mL of water and 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 solvent was removed under reduced pressure. The resulting crude product was slurried in a mixed solvent for 0.5 hours, filtered, and the filter cake was dried to obtain compound A1-4. LC-MS (ESI): m / z = 472.4 [M+H] + .

[0078] Step D

[0079] Compound A1-4 (0.97 g, 2.04 mmol) was added to N,N-dimethylformamide (9.5 mL). Cuprous iodide (0.78 g, 4.1 mmol) and methyl fluorosulfonyldifluoroacetate (2 g, 10 mmol) were added to the reaction solution under nitrogen. The reaction solution was heated to 100°C and stirred for 1 hour. After cooling, the reaction solution was filtered through celite. The filtrate was added to 15 mL of water and 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 solvent was removed under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain compound A1-5. LC-MS (ESI): m / z = 461.5 [M+H] + .

[0080] Step E

[0081] Anhydrous tetrahydrofuran (50 mL) and sodium hydride (0.3 g, 7.3 mmol) were added to a dry three-necked flask, cooled to 0°C, and ethyl acetate (0.85 g, 7.3 mmol, 0.8 mL) was added dropwise under nitrogen. The reaction solution was stirred at 0°C for 0.5 hours. n-Butyl lithium (2.5 M, 3 mL) was added dropwise, and the reaction solution was stirred under these conditions for 0.5 hours. The temperature was then cooled to -60°C, and a solution of compound A1-5 (1.15 g, 2.5 mmol) in tetrahydrofuran (5 mL) was added dropwise. The reaction solution was stirred at -60°C for 0.5 hours. 25 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with 10 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain compound A1-6. LC-MS (ESI): m / z = 531.6 [M+H] + .

[0082] Step F

[0083] Compound A1-6 (1 g, 1.9 mmol) was added to dichloromethane (10 mL), followed by ethyl 3-mercaptopropionate (0.3 g, 2.3 mmol) and titanium tetrachloride. The mixture was stirred at room temperature for 48 hours. The mixture was filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound A1-7. LC-MS (ESI): m / z = 665.7 [M+H] +

[0084] Step G

[0085] Compound A1-7 (0.80 g, 1.2 mmol) and sodium ethoxide (0.57 mg, 1.9 mmol) were dissolved in 10 mL of THF and stirred at room temperature for 24 hours. Filter and dry to obtain A1-8. LC-MS (ESI): m / z = 619.7 [M+H] + .

[0086] Step H

[0087] To a suspension of A1-8 (3.3 g, 5.3 mmol) in water (10 mL) were added S-methylisothiourea sulfate (1.7 g, 6.2 mmol) and potassium carbonate (1.6 g, 11.7 mmol) at room temperature. The reaction mixture was stirred for 20 hours. The precipitate was collected, washed with water (twice) and isopropyl ether, and dried to give A1-9; LC-MS (ESI): m / z = 645.7 [M+H] + .

[0088] Step I

[0089] Compound A1-9 (1 g, 1.6 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (0.6 g, 4.8 mmol) was added. The temperature was lowered to 0-10°C, and trifluoromethanesulfonic anhydride (0.7 g, 2.4 mmol, 400 μL) was slowly added to the reaction solution. The reaction was allowed to react at this temperature for 15 minutes. The reaction solution was poured into saturated aqueous ammonium chloride (8 mL), and the layers were separated. The aqueous phase was extracted with dichloromethane (5 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was slurried, filtered, and the filter cake was dried to obtain A1. LC-MS (ESI): m / z = 777.8 [M+H] + .

[0090] Preparation of B1

[0091]

[0092] Compound B1 was obtained using a similar preparation method to Intermediate A1 (the starting material was replaced with 6-bromo-4-methylpyridin-2-amine). LC / MS (ESI): m / z = 760.8 [M+H] + .

[0093] Example 1

[0094] 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)

[0095]

[0096] Step A

[0097] Compound A1 (82 mg, 105.02 μmol) and 8-tert-butyloxycarbonyl-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. The reaction mixture was heated to 100°C and stirred for 1 hour. After cooling, the organic solvent was removed under reduced pressure. The crude product was separated and purified by preparative thin-layer chromatography to obtain compound 1-1. LC / MS (ESI): m / z = 828 [M+H]. + .

[0098] Step B

[0099] Compound 1-1 (71 mg, 84.96 μmol) was dissolved in dichloromethane (2 mL), and m-chloroperbenzoic acid (34.50 mg, 169.92 μmol) was added. The reaction mixture was stirred at 20°C for 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] + .

[0100] Step C

[0101] In an ice-water bath, compound ((2R,7AS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (12.09 mg, 75.94 μmol) was dissolved in anhydrous toluene (1 mL). Sodium tert-butoxide (7.30 mg, 75.94 μmol) was added, and the reaction solution was stirred for 30 minutes. A solution of compound 1-2 (53 mg, 58.42 μmol) in toluene (1 mL) was added, and the reaction solution was stirred for 2 hours in an ice-water bath. 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] + .

[0102] Step D

[0103] Compound 1-3 (42 mg, 42.78 μmol) was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at 20°C for 2 hours. The solvent was removed under reduced pressure, and the resulting crude product was separated and purified by HPLC to obtain compound 1-4. LC / MS (ESI): m / z = 630.7 [M+H] + .

[0104] Step E

[0105] 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 stirred at -78 ° C for 25 minutes. The reaction was quenched with water and extracted with dichloromethane. The organic layers were mixed together. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. 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)δ6.73-6.87(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,2 H),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).

[0106] Example 2

[0107] 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-thiopyrano[4,3-d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)prop-2-en-1-one (Compound 1A)

[0108] 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-thiopyrano[4,3-d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)prop-2-en-1-one (Compound 1B)

[0109]

[0110] Compound 1 was separated and purified by HPLC to obtain 1A and 2A (column: Chiralpak IG-3: 3 μm, 0.46 cm × 5 cm; mobile phase: A (CO2) and B (EtOH, containing 0.1% isopropylamine); gradient: B% = 5 to -50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 nm; LC / MS (ESI): m / z = 684.7 [M+H] + .

[0111] Example 3

[0112] 1-((3S)-4-(7-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-2-(((2R,7AS)-2- fluorotetrahydro-1 H-pyrrozine-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyran[4,3- d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)-2-fluoroprop-2-en-1-one (Compound 2)

[0113]

[0114] Compound 2 was obtained using a similar preparation method as Step E in Example 1. LC / MS (ESI): m / z = 702.7 [M+H] + .

[0115] Example 4

[0116] 1-((3S)-4-((7S)-7-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-2-(((2R,7AS)-2- fluorotetrahydro-1 H-pyrrozine-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyran[4,3- d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)-2-fluoroprop-2-en-1-one (2A)

[0117] 1-((3S)-4-((7R)-7-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-2-(((2R,7AS)-2- fluorotetrahydro-1 H-pyrrozine-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyran[4,3- d]pyrimidin-4-yl)-3-methylpyrazin-1-yl)-2-fluoroprop-2-en-1-one (2B)

[0118]

[0119] Compound 3A, 3B were obtained using a similar preparation method as Compound 1A, 1B in Example 2 (the starting material was changed to Compound 2). LC / MS (ESI): m / z = 702.7 [M+H] + .

[0120] Example 5

[0121] 2-((2S)-1-acryloyl-4-(7-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-2-(((2R,7AS)- 2-fluorotetrahydro-1 H-pyrrozine-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyran[4,3- d]pyrimidin-4-yl)pyrazin-2-yl)acetonitrile (Compound 3)

[0122]

[0123] Compound 3 was obtained using a similar preparation method as for compound 1 in Example 1. LC / MS (ESI): m / z = 709.7 [M+H] + . 1 H-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).

[0124] Example 6

[0125] 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-thiopyran[4,3-d]pyrimidin-4-yl)pyrazin-2-yl)acetonitrile (Compound 3A)

[0126] 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-thiopyran[4,3-d]pyrimidin-4-yl)pyrazin-2-yl)acetonitrile (Compound 3B)

[0127]

[0128] Compound 3A, 3B were obtained using a similar preparation method as for compounds 1A, 1B in Example 2 (starting material was changed to compound 3). LC / MS (ESI): m / z = 709.7 [M+H] + .

[0129] Example 7

[0130] 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-thiopyrano[4,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)pyrazin-2-yl)acetonitrile (Compound 4)

[0131]

[0132] Compound 4 was obtained using a similar preparation method to that in Step E of Example 1. LC / MS (ESI): m / z = 727.7 [M+H] + . 1 H-NMR(CD3OD)δ6.72-6.84(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).

[0133] Example 8

[0134] 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-thiopyrano[4,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)pyrazin-2-yl)acetonitrile (Compound 4A)

[0135] 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-thiopyrano[4,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)pyrazin-2-yl)acetonitrile (Compound 4B)

[0136]

[0137] Compounds 4A and 4B were obtained using a similar preparation method to that of compounds 1A and 1B in Example 2 (the starting material was replaced with compound 4). LC / MS (ESI): m / z = 727.7 [M+H] + .

[0138] Example 9

[0139] 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)

[0140]

[0141] Compound 5 was obtained by a similar preparation method to that of compound 1 in Example 1 (the starting material was replaced with B1). LC / MS (ESI): m / z = 6677 [M+H] + .

[0142] Example 10

[0143] 1-((3S)-4-((7S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7AS)-2-fluorotetrahydro-1H-pyrrolidin-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)

[0144] 1-((3S)-4-((7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7AS)-2-fluorotetrahydro-1H-pyrrolidin-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)

[0145]

[0146] Compounds 5A and 5B were prepared using a similar method to that of compounds 1A and 1B in Example 2 (the starting material was replaced with compound 5). LC / MS (ESI): m / z = 667.7 [M+H] + .

[0147] Example 11

[0148] 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)-2-fluoroprop-2-en-1-one (Compound 6)

[0149]

[0150] Compound 6 was obtained by a similar preparation method to that in Step E of Example 1. LC / MS (ESI): m / z = 685.7 [M+H] + .

[0151] Example 12

[0152] 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)-2-fluoroprop-2-en-1-one (Compound 6A)

[0153] 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)-2-fluoroprop-2-en-1-one (Compound 6B)

[0154]

[0155] Compounds 6A and 6B were obtained using a similar preparation method to that of compounds 1A and 1B in Example 2 (the starting material was replaced with compound 6). LC / MS (ESI): m / z = 685.7 [M+H] + .

[0156] Example 13

[0157] 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-thiopyrano[4,3-d]pyrimidin-4-yl)-1-(acryloyl)pyrazin-2-yl)acetonitrile (Compound 7)

[0158]

[0159] Compound 7 was obtained by a similar preparation method to that of compound 1 in Example 1 (the starting material was replaced with B1). LC / MS (ESI): m / z = 692.7 [M+H] + .

[0160] Example 14

[0161] 2-((2S)-4-((7S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7AS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)-1-(acryloyl)pyrazin-2-yl)acetonitrile (Compound 7A)

[0162] 2-((2S)-4-((7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7AS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)-1-(acryloyl)pyrazin-2-yl)acetonitrile (Compound 7B)

[0163]

[0164] Compounds 7A and 7B were prepared using a similar method to that of compounds 1A and 1B in Example 2 (the starting material was replaced with compound 7). LC / MS (ESI): m / z = 692.7 [M+H] + .

[0165] Example 15

[0166] 2-((2S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7AS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)pyrazin-2-yl)acetonitrile (Compound 8)

[0167]

[0168] Compound 8 was obtained by a similar preparation method to that in Step E of Example 1. LC / MS (ESI): m / z = 710.7 [M+H] + .

[0169] Example 16

[0170] 2-((2S)-4-((7S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7AS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)pyrazin-2-yl)acetonitrile (Compound 8A)

[0171] 2-((2S)-4-((7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((2R,7AS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6,6-dioxo-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)pyrazin-2-yl)acetonitrile (Compound 8B)

[0172]

[0173] Compounds 8A and 8B were prepared using a similar method to that of compounds 1A and 1B in Example 2 (the starting material was replaced with compound 8). LC / MS (ESI): m / z = 710.7 [M+H] + .

[0174] Example 17 Biological Activity Test

[0175] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0176] 1. Tumor Cell Proliferation Inhibition Experiment

[0177] 1. Experimental methods

[0178] Cell density was determined using a Scepter automated cell counter after digestion and centrifugation of H358 (KRAS G12C mutant) cells, and cells were diluted to a solution containing 44,000 cells per milliliter. The adjusted density solution was added to a 96-well plate at 90 microliters per well. The 96-well plate was placed in a 37°C, 5% CO2 incubator, and after 24 hours of cell culture, different concentrations of test compounds were added to the cells in the presence of 10% fetal bovine serum, and the cells were incubated with the compounds for 72 hours. Cell growth inhibition was assessed by measuring the amount of ATP using the CellTiter-Glo Luminescent Cell Viability Assay Kit (see manufacturer's instructions). Briefly, 30 microliters of Cell Titer-Glo reagent was added to each well, and the plate was shaken for 10 minutes to induce cell lysis. Fluorescence was measured using a Fluoroskan Ascent FL (Thermo), and the maximum signal was obtained from cells treated with dimethyl sulfoxide for 72 hours. The minimum signal was obtained from media alone (zero cells), and the % inhibition was calculated as (maximum signal - compound signal) / (maximum signal - minimum signal) x 100%. Data were analyzed using Graphpad Prism 5 software. IC 50 values were calculated by fitting the S-shaped dose response curve. 50 where "A" indicates IC 50 ≤ 100 nM; "C" indicates 100 < IC 50 ≤ 1000 nM; "D" indicates 1000 nM < IC 50

[0179] 2. Experimental Results

[0180] The IC 50 values of each compound in the above experiment were calculated, and the results are shown in Table 1 below.

[0181] Table 1. Inhibitory activity of compounds against tumor cell proliferation IC 50 (nM).

[0182]

[0183]

[0184] In vitro kinase activity showed that the designed compounds have strong inhibitory activity against KRAS G12C mutants.

[0185] Although the present application has been described in detail, those skilled in the art understand that various modifications and changes can be made to the present application without departing from the spirit and scope of the present application. The scope of the present application is not limited to the detailed description above, but is defined by the claims.

Claims

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

2. The compound according to any one of claims 1, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates, characterized in that: The pharmaceutically acceptable salt is selected from the group consisting of potassium salt, sodium salt, magnesium salt, calcium salt, sulfate, hydrochloride, phosphate, sulfonate, or carbonate.

3. A pharmaceutical composition, characterized in that Comprising the compound according to any one of claims 1, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.

4. Use of the compound according to any one of claims 1, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates, characterized in that: Used for preparing a pharmaceutical composition for treating diseases, disorders or conditions associated with KRas G12C activity or expression.

5. The use according to claim 4, characterized in that The disease, disorder or condition is selected from the following group: 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, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, polycythemia vera, multiple myeloma, myeloma and other solid tumors and blood tumors.

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