Preparation method for spiro compound, and intermediate thereof

Abstract

The present invention relates to a key intermediate for synthesis of a KRAS inhibitor, and a preparation method therefor. Specifically, the present invention provides intermediate compounds as shown in formula I and formula II, and a preparation method therefor, and a method for using the intermediate compound to prepare 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-1-(2-fluoroacroloyl)piperazin-2-yl)acetonitrile and an analogous compound thereof.

Description

Process for the preparation of spiro compounds and intermediates thereof TECHNICAL FIELD

[0001] The present invention relates to the field of pharmaceutical synthesis, in particular, the present invention relates to chemical intermediates for the preparation of KRAS inhibitors and processes for their preparation. BACKGROUND

[0002] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRAS”) is a Guanosine triphosphate (GTP)ase and is one of the members of the RAS oncogene family. KRAS acts as a molecular switch that cycles between an inactive (Guanosine diphosphate (GDP)-bound) and active (GTP-bound) state to transduce upstream cellular signals received from a variety of tyrosine kinases to downstream effectors to regulate a variety of processes, including cell proliferation (Current Opin Pharmcol. 2013 (13): 394-401).

[0003] KRAS is one of the most common mutations in cancer. Approximately 22% of cancer patients have KRAS mutations, especially in pancreatic cancer (68%), cholangiocarcinoma (27%), and lung cancer (17%). Among them, KRAS G12C accounts for 48%, 10%, and 1% in non-small cell lung cancer, colorectal cancer, and pancreatic cancer, respectively. KRAS protein lacks an ideal small molecule binding pocket, and it has a high affinity for the abundant GTP in cells, which makes it challenging to design specific small molecule drugs. Among different known mutations, KRAS G12C mutation is considered the most likely drug target. Currently, some covalent inhibitors targeting KRAS G12C are in clinical trials, such as AMG 510 by Amgen and MRTX849 by Mirati Therapeutics. These compounds all covalently bind to KRAS G12C at cysteine residue 12, keeping KRAS G12C in an inactive GDP-bound state and inhibiting KRAS-dependent signaling.

[0004] A series of KRAS G12C inhibitors with spirocyclic structure are disclosed in WO2022135546, in which the compounds shown in the table below all have good antitumor activity. In this patent, the synthesis route of such compounds is long, difficult to operate and requires chiral resolution.

[0005] A similar structure of pan-KRAS inhibitors is also disclosed in WO2023154766, wherein the inhibitory activity of compound 65 on the ERK phosphorylation level of AGS cells is 0.01 μM < IC 50 <0.1 μM. However, there are also problems such as long route and difficult operation. In view of the above reasons, it is urgent to develop a method for preparing such compounds which is simple to operate, mild in reaction conditions and suitable for industrial production.

[0006] The structure of the compound 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[inden-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-1-(2-fluorovinylcarbonyl)piperazin-2-yl)acetonitrile disclosed in the patent PCT / CN2021 / 140991 and the preparation method thereof are taken as examples. The compound irreversibly inhibits KRAS G12C protein by forming a covalent bond with cysteine residue 12. In the patent, 7-fluoro-1-indanone is used as a raw material, and compound SM (i.e. compound 8-5) is synthesized through 9 steps, and then a pair of diastereoisomers of the compound is obtained through 5 steps, and finally the compound Example 28 is obtained by chiral supercritical fluid chromatography resolution. The entire route involves a total of 14 chemical reactions, and involves two steps of low-temperature reaction (synthesis of compounds 6-4 and 6-9), one step of sealed tube reaction (synthesis of compound 6-7) and chiral chromatography resolution, which is not suitable for industrial production.

[0007] In view of the above reasons, it is urgent to develop a method for preparing 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[inden-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-1-(2-fluorovinylcarbonyl)piperazin-2-yl)acetonitrile, also known as compound 28, which is simple to operate, mild in reaction conditions and suitable for industrial production. SUMMARY

[0008] An object of the present application is to provide a key intermediate compound for synthesizing KRAS inhibitors.

[0009] Another object of the present application is to provide a preparation method of a key intermediate compound for synthesizing KRAS inhibitors.

[0010] It is another object of the present application to provide a method for preparing KRAS G12C inhibitor 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[indeno-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-1-(2-fluorovinylcarbonyl)piperazin-2-yl)acetonitrile and its analogues.

[0011] In a first aspect of the present application, there is provided a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, or deuterated form thereof,

[0012] wherein,

[0013] R 1 and R 2 each independently is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, phenyl, 5-6 membered heteroaryl, C1-C4 alkyl-S(O)-, C1-C4 alkyl-S(O)2-, C1-C4 haloalkyl-S(O)2-, phenyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, wherein the phenyl, heteroaryl is unsubstituted or optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl;

[0014] R 3 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 carbocyclyl;

[0015] r represents the number of methylene groups, r is 1 or 2;

[0016] Ring B is a substituted or unsubstituted C6-10 aryl ring, or a substituted or unsubstituted 5-10 membered heteroaryl ring; wherein the substitution means one or more hydrogens on the group are replaced with R 4 substituents;

[0017] and each R 4 is independently selected from the group consisting of halogen, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 carbocyclyl, C1-C3 alkoxy, haloC1-C3 alkoxy, allyloxy, benzyloxy, and benzylamine, wherein the allyloxy, benzyloxy, or benzylamine is optionally substituted with halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro.

[0018] In another preferred embodiment, R 1 and R 2each independently selected from the group consisting of: C1-C4alkyl, C1-C4haloalkyl.

[0019] In another preferred embodiment, R 3 is selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl.

[0020] In another preferred embodiment, ring B is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-6 membered heteroaromatic ring; wherein the substitution means that one or more hydrogens (e.g., 1, 2, 3, or 4 hydrogens) on the group are replaced with R 4 substituted; halogen, C1-C4alkyl, C1-C4haloalkyl, hydroxyl, amino, benzyloxy, and benzylamino.

[0021] In another preferred embodiment, the compound is selected from the group consisting of:

[0022] In a second aspect of the application, there is provided a compound of formula II,

[0023] wherein,

[0024] R 5 is selected from the group consisting of H, C1-C6alkyl, C3-C6carbocyclyl, phenyl, 5-6 membered heteroaryl, C1-C6alkyl-S(O)-, haloC1-C6alkyl-S(O)-, C1-C6alkyl-S(O)2-, C1-C6haloalkyl-S(O)2-, phenyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, wherein the alkyl, carbocyclyl, phenyl, heteroaryl are unsubstituted or optionally substituted with one or more substituents selected from the group consisting of phenyl, oxo, halogen, nitro, cyano, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, benzyloxy;

[0025] R 1 , R 2 , ring B and r are as defined in the first aspect of the application.

[0026] In another preferred embodiment, R 5 is selected from the group consisting of C1-C6alkyl, C1-C4alkyl-S(O)-, haloC1-C4alkyl-S(O)-, C1-C4alkyl-S(O)2-, C1-C4haloalkyl-S(O)2-, phenyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-; preferably C1-C4alkyl-S(O)-.

[0027] In another preferred embodiment, the compound is selected from the group consisting of:

[0028] In a third aspect of the present application, a method for preparing a compound of formula SM1 is provided, comprising the following steps:

[0029] wherein, ring B, R 1 , R 2 , r are as described in the first aspect of the present application;

[0030] X 1 and X 2 are each independently halogen, mesylate, triflate, besylate, tosylate, nosylate, or p-nitrophenoxy;

[0031] (1) condensation reaction of compound SM1-1 and (R)-tert-butylsulfonamide in the presence of a Lewis acid in a solvent to obtain compound SM1-2;

[0032] (2) nucleophilic addition reaction of compound SM1-2 and compound SM1-3 in the presence of a strong base reagent, with or without a ligand, in a solvent to obtain compound SM1-4;

[0033] (3) one-step deprotection / Mannich reaction / reductive amination reaction of compound SM1-4 in the presence of paraformaldehyde and formic acid, and chiral acid refinement to obtain compound SM1-5;

[0034] (4) hydrolysis reaction of compound SM1-5 in the presence of an acid in a solvent to obtain compound SM1-6;

[0035] (5) reaction of compound SM1-6 in the presence of a halogenating reagent or a sulfonylating reagent or p-nitrofluorobenzene or p-nitrochlorobenzene, with or without a basic reagent to obtain compound SM1.

[0036] In another preferred embodiment, in step (2), the strong base reagent is an organometallic reagent.

[0037] In another preferred embodiment, in step (1), one or more of the following characteristics are present:

[0038] the Lewis acid is selected from the group consisting of p-toluenesulfonic acid, magnesium sulfate, tetraethyl titanate, and tetraisopropyl titanate;

[0039] the solvent is selected from C2-6 ether solvents and / or aromatic hydrocarbon solvents, preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, m-xylene;

[0040] The reaction temperature is 60-140°C, preferably 95-105°C;

[0041] The molar ratio of (R)-tert-butylsulfinamide to the compound SM1-1 is (1-2): 1, preferably 1.05:1; and / or

[0042] The molar ratio of Lewis acid to the compound SM1-1 is (1-3): 1, preferably 2:1.

[0043] In another preferred embodiment, in step (2), one or more of the following characteristics is present:

[0044] The strong base is selected from lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS), n-butyllithium (n-BuLi), sec-butyllithium (s-BuLi) and tert-butyllithium (t-BuLi);

[0045] The ligand is selected from ethylenediamine ligands, preferably N,N,N',N'-tetramethylethylenediamine;

[0046] The solvent is selected from C2-6 ether solvents, preferably tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether or a combination thereof;

[0047] The reaction temperature is -70 to 0°C, preferably -70 to -50°C;

[0048] The molar ratio of the compound SM1-3 to the compound SM1-2 is (1-2): 1, preferably 1.4:1;

[0049] The molar ratio of the strong base to the compound SM1-2 is (1-2): 1, preferably 1.4:1; and / or

[0050] The molar ratio of the ligand to the compound SM1-2 is (1-2): 1, preferably 1.4:1.

[0051] In another preferred embodiment, in step (3), one or more of the following characteristics is present:

[0052] The molar ratio of the paraformaldehyde to the compound SM1-4 is (10-40): 1, preferably (10-20): 1; more preferably 10:1;

[0053] The reaction temperature is 75-100°C, preferably 75-85°C; and / or

[0054] The chiral acid is selected from tartaric acid, malic acid, camphoric acid, camphorsulfonic acid, diacetone-L-gulonic acid, mandelic acid, phenoxypropionic acid, hydroatromic acid and derivatives of the aforementioned acids, preferably tartaric acid and derivatives thereof or camphorsulfonic acid and derivatives thereof.

[0055] In another preferred embodiment, in step (4), one or more of the following features apply:

[0056] The acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, aluminum trichloride, aluminum tribromide, trimethylsilyl iodide, and boron tribromide, preferably hydrochloric acid;

[0057] The reaction temperature is 40-100°C, preferably 75-85°C; and / or

[0058] The solvent is selected from one or more of the group consisting of C1-6alcohols, C2-6nitriles, water, C2-6ethers, C1-6hydrocarbons, C1-6haloalkanes, and acids, preferably one or more of ethanol, water, acetonitrile, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, and acetic acid.

[0059] In another preferred embodiment, in step (5), one or more of the following features apply:

[0060] The halogenating reagent is selected from one or more of the group consisting of phosphorus oxyhalides, phosphorus halides, dichlorosulfoxide, and chlorophenylphosphonic acid; and / or

[0061] The sulfonylating reagent is selected from the group consisting of methanesulfonyl chloride, trifluoromethylsulfonyl anhydride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride; and / or

[0062] The basic reagent is selected from one or more of the group consisting of triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline, and 4-dimethylaminopyridine (DMAP).

[0063] In another preferred embodiment, the method of preparation comprises the following steps:

[0064] wherein X 1 and X 2 each independently is halogen, mesylate, triflate, besylate, tosylate, nosylate, or p-nitrophenoxy;

[0065] (1) Compound S1-1 and (R)-tert-butylsulfmide are condensed in the presence of a Lewis acid in a solvent to obtain compound S1-2;

[0066] (2) Compound S1-2 and compound S1-3 undergo a nucleophilic addition reaction in the presence of an organometallic reagent, with or without a ligand, in a solvent to obtain compound S1-4;

[0067] (3) Compound S1-4 undergoes a deprotection / Mannich reaction / reductive amination reaction in one step in the presence of paraformaldehyde and formic acid, and is refined by chiral acid to obtain compound S1-5;

[0068] (4) Compound S1-5 is subjected to hydrolysis reaction under the action of an acid in a solvent to obtain compound S1-6;

[0069] (5) Compound S1-6 is subjected to reaction in the presence of a halogenating reagent or a sulfonylating reagent or p-nitrofluorobenzene or p-nitrochlorobenzene with or without a basic reagent to obtain compound SM.

[0070] In another preferred embodiment, in step (1), one or more of the following characteristics are present:

[0071] The Lewis acid is selected from the group consisting of p-toluenesulfonic acid, magnesium sulfate, tetraethyl titanate and tetraisopropyl titanate;

[0072] The solvent is selected from C2-6 ether solvents and / or aromatic hydrocarbon solvents, preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, m-xylene;

[0073] The reaction temperature is 60-140°C, preferably 95-105°C;

[0074] The molar ratio of (R)-tert-butylsulfinamide to compound S1-1 is (1-2):1, preferably 1.05:1; and / or

[0075] The molar ratio of the Lewis acid to compound S1-1 is (1-3):1, preferably 2:1.

[0076] In another preferred embodiment, in step (2), one or more of the following characteristics are present:

[0077] The strong base is selected from lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS), n-butyllithium (n-BuLi), sec-butyllithium (s-BuLi) and tert-butyllithium (t-BuLi);

[0078] The ligand is selected from ethylenediamine ligands, preferably N,N,N',N'-tetramethylethylenediamine;

[0079] The solvent is selected from C2-6 ether solvents, preferably tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether or a combination thereof;

[0080] The reaction temperature is -70 to 0°C, preferably -70 to -50°C;

[0081] The molar ratio of compound S1-3 to compound S1-2 is (1-2):1, preferably 1.4:1;

[0082] The molar ratio of the strong base to compound S1-2 is (1-2):1, preferably 1.4:1; and / or

[0083] The molar ratio of the ligand to compound S1-2 is (1-2): 1, preferably 1.4: 1.

[0084] In another preferred embodiment, in step (3), one or more of the following features is present:

[0085] The molar ratio of the paraformaldehyde to compound S1-4 is (10-40): 1, preferably (10-20): 1; more preferably 10: 1;

[0086] The reaction temperature is 75-100°C, preferably 75-85°C; and / or

[0087] The chiral acid is selected from tartaric acid, malic acid, camphoric acid, camphorsulfonic acid, diacetone-L- glutaric acid, mandelic acid, phenoxypropionic acid, hydroatromic acid, and derivatives of the above acids, preferably tartaric acid and derivatives thereof or camphorsulfonic acid and derivatives thereof.

[0088] In another preferred embodiment, in step (4), one or more of the following features is present:

[0089] The acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, aluminum trichloride, aluminum tribromide, trimethylsilyl iodide, and boron tribromide, preferably hydrochloric acid;

[0090] The reaction temperature is 40-100°C, preferably 75-85°C; and / or

[0091] The solvent is selected from one or more of C1-6alcohols, C2-6nitriles, water, C2-6ethers, C1-6hydrocarbons, C1-6haloalkanes, and acids, preferably one or more of ethanol, water, acetonitrile, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, and acetic acid.

[0092] In another preferred embodiment, in step (5), one or more of the following features is present:

[0093] The halogenating reagent is selected from one or more of phosphorus oxyhalide, phosphorus halide, dichlorosulfoxide, and phenylphosphonic chloride;

[0094] The sulfonylating reagent is selected from methanesulfonyl chloride, trifluoromethylsulfonyl anhydride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride; and / or

[0095] The basic reagent is selected from one or more of triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline, and 4-dimethylaminopyridine (DMAP).

[0096] In a fourth aspect of the present application, a method for preparing a compound of formula V is provided, comprising the following steps: In a fourth aspect of the present application, a method for preparing a compound of formula V is provided, comprising the following steps:

[0097] wherein

[0098] Ring B is as defined in the first aspect of the application;

[0099] X 1 and X 2 as defined in the third aspect of the application;

[0100] r represents the number of methylene groups, r is 1 or 2;

[0101] R 6 is selected from hydrogen, optionally substituted C1-C4 alkyl, optionally substituted saturated or unsaturated 3-8 membered carbocyclyl, optionally substituted saturated or unsaturated 4-12 membered heterocyclyl, optionally substituted saturated or unsaturated 3-8 membered carbocyclyl-fused 6-10 membered aryl, optionally substituted saturated or unsaturated 3-8 membered carbocyclyl-fused 5-10 membered heteroaryl, optionally substituted saturated or unsaturated 3-8 membered heterocyclyl-fused 6-10 membered aryl, optionally substituted saturated or unsaturated 3-8 membered heterocyclyl-fused 5-10 membered heteroaryl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; wherein R 2 the optionally substituted substituents described in the above groups are selected from: deuterium, halogen, hydroxyl, cyano, oxo, C1-C3 alkoxy, -NR c R d , -CO2R m , -CONR e R f , C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, -SO2NR g R h , optionally substituted 3-8 membered saturated or unsaturated carbocyclyl, and optionally substituted 4-8 membered saturated or unsaturated heterocyclyl;

[0102] R c and R d are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 4-8 membered heterocyclyl, or R c and R d together with the N to which they are attached form an optionally substituted 4-8 membered heterocyclic ring;

[0103] R e and R f are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 4-8 membered heterocyclyl, or R e and R f together with the N to which they are attached form an optionally substituted 4-8 membered heterocyclic ring;

[0104] R g and R hEach is independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 4-8 membered heterocyclic groups, or R g With R h Together with the attached N, it forms an optionally substituted 4-8 membered heterocycle;

[0105] R m It is hydrogen or an optional substituted C1-C4 alkyl group;

[0106] R 7 yes

[0107] in,

[0108] R a It is hydrogen, halogen, optionally substituted C1-C3 alkyl, -N(R) 5 2. Optionally substituted 4-6 membered saturated heterocyclic groups, C1-C3 alkoxy groups, C1-C3 alkylthio groups, or acetyl groups, wherein R a The optional substituents described herein are selected from the group consisting of: methyl, ethyl, -N(R) n 2. Halogens, C1-C3 alkoxy groups, 4-6 membered saturated heterocyclic groups;

[0109] Each R n Each is independently hydrogen or C1-C3 alkyl;

[0110] R a’ R b Each is independently hydrogen, halogen, or C1-C3 alkyl;

[0111] Compound SM1 is prepared by the method described in the third aspect of this invention.

[0112] (a) Compounds SM1 and SM-2A under basic conditions undergo nucleophilic substitution reaction and are protected with protecting group PG to give compound I-1;

[0113] Alternatively, in a solvent, compound SM-1 and compound SM-2B undergo a nucleophilic substitution reaction in a basic reagent to give compound I-1;

[0114] (b) Compound I-1 and Compound R 6 -OH undergoes a Buchwald coupling reaction in a palladium catalyst, ligand, basic reagent, and solvent, followed by deprotection to yield compound I-2;

[0115] (c) Compound I-2 and Compound R 7 -OH undergoes a condensation reaction in a condensing agent, a basic reagent, and a solvent, with or without the addition of a condensing agent or activator, to give the compound shown in formula V;

[0116] In another preferred embodiment, step (a) has one or more of the following characteristics:

[0117] (a-1) the basic reagent is selected from one or more of carbonates, triethylamine and diisopropylethylamine;

[0118] (a-2) the solvent is selected from one or more of amide solvents, C3-6 ketone solvents, halogenated C1-6 hydrocarbon solvents and C1-6 hydrocarbon solvents, preferably one or more of dichloromethane, chloroform, acetone, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone;

[0119] (a-3) the reaction temperature of the nucleophilic substitution reaction is 0-30 °C, preferably 0-20 °C;

[0120] (a-4) the protecting group PG is selected from tert-butyloxycarbonyl (Boc) and carbobenzyloxy (Cbz), and the reaction temperature for the protecting group PG protection is 20-30 °C;

[0121] (a-5) the molar ratio of compound SM-2A or SM-2B to compound SM-1 is (1-2):1, preferably (1-1.5):1, more preferably 1.2:1;

[0122] (a-6) the molar ratio of the basic reagent to compound SM1 is (2-6):1, preferably 4.0:1; and / or

[0123] (a-7) the molar ratio of the protecting group reagent to compound SM1 is (1-2):1, preferably 1.5:1.

[0124] In another preferred embodiment, step (b) has one or more of the following characteristics:

[0125] (b-1) the palladium catalyst is selected from one or more of palladium acetate, tris(dibenzylideneacetone)dipalladium, RuPhos Pd G3 (CAS: 1445085-77-7);

[0126] (b-2) the ligand is selected from one or more of 1,1'-binaphthalene-2,2'-bis- diphenylphosphine (BINAP, CAS: 98327-87-8), tri-tert-butylphosphine (P(t-Bu)3, CAS: 13716-12-6), tri-o-tolylphosphine (P(o-tolyl)3, CAS: 6163-58-2), BrettPhos (CAS: 1070663-78-3), RuPhos (CAS: 787618-22-8), XPhos (CAS: 564483-18-7), tBuXPhos (CAS: 564483-19-8), Me4tBuXPhos (CAS: 857356-94-6), tBuBrettPhos (CAS: 1160861-53-9), SPhos (CAS: 657408-07-6), DavePhos (CAS: 213697-53-1), JohnPhos (CAS: 224311-51-7), JackiePhos (CAS: 1160861-60-8);

[0127] (b-3) the basic reagent is selected from one or more of cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium phosphate and diisopropylethylamine;

[0128] (b-4) the solvent is selected from one or more of aromatic hydrocarbon solvents, ether solvents, preferably one or more of toluene, xylene, tetrahydrofuran, dioxane;

[0129] (b-5) the reaction temperature is from 80 to 110 °C, preferably from 95 to 105 °C;

[0130] (b-6) the compound R 6 the molar ratio of -OH to compound I-1 is (1 to 2): 1, preferably 1.5: 1;

[0131] (b-7) the molar ratio of palladium catalyst to compound I-1 is (0.01 to 0.1): 1, preferably 0.05: 1;

[0132] (b-8) the molar ratio of ligand to palladium catalyst is (1 to 4): 1, preferably (2 to 3): 1, more preferably 2.8: 1; and / or

[0133] (b-9) the molar ratio of basic reagent to compound I-1 is (1 to 4): 1, preferably (2 to 3): 1, more preferably 2.5: 1.

[0134] (b-10) when PG is tert-butyloxycarbonyl (Boc), the deprotecting reagent is selected from the group consisting of trifluoroacetic acid, hydrochloric acid and trimethylsilyl iodide; when PG is benzyloxycarbonyl (Cbz), the deprotecting reagent is selected from the group consisting of palladium on carbon, palladium hydroxide on carbon, palladium chloride, hydrobromic acid / acetic acid and trimethylsilyl iodide.

[0135] In another preferred embodiment, step (c) has one or more of the following characteristics:

[0136] (c-1) the condensing reagent is selected from one or more of the group consisting of n-propylphosphonic anhydride (T3P), carbonyldiimidazole (CDI), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(5-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(N- succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TSTU), O-(N-endo-5-norbornene-2,3-dicarboxyimido)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TNTU), benzotriazol-1-yl oxytris(dimethylamino)phosphonium hexafluorophosphate (HOP), benzotriazol-1-yl oxytris(pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), 7-azabenzotriazol-1-yl oxytris(pyrrolidinyl)phosphonium hexafluorophosphate (PyAOP), dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCI);

[0137] (c-2) the condensing reagent activator is selected from one or more of the group consisting of 4-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine (4-PPY), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), N-hydroxyphthalimide (NHPI) and N-hydroxy-5-norbornene-2,3-dicarboxyimide (HONB);

[0138] (c-3) the basic reagent is selected from one or more of the group consisting of pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine;

[0139] (c-4) the solvent is selected from one or more of a Ci-6 hydrocarbon solvent, a Ci-6 halogenated hydrocarbon solvent, a ketone solvent, a C2-6 nitrile solvent, a C2-6 ether solvent, an amide solvent, and a sulfone solvent, preferably one or more of dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide;

[0140] (c-5) the molar ratio of the compound R 7 the molar ratio of -OH to compound I-2 is (1-2): 1, preferably (1-1.5): 1, more preferably 1.25: 1;

[0141] (c-6) the molar ratio of the condensing agent to compound I-2 is (1-2): 1, preferably 1.5: 1;

[0142] (c-7) the molar ratio of the base to compound I-2 is (2-4): 1, preferably (2-3): 1, more preferably 2.6; and / or

[0143] (c-8) the reaction temperature is 0-30 °C.

[0144] In another preferred embodiment, ring B is a substituted or unsubstituted phenyl ring, or a substituted or unsubstituted 5-6 membered heteroaromatic ring; wherein the substitution means one or more hydrogens on the group are replaced with R 4 , and each R 4 is independently selected from the group consisting of halogen, amino, hydroxyl, Ci-C6alkyl, Ci-C6haloalkyl, benzyloxy, benzylamino.

[0145] In another preferred embodiment, R 6 is selected from the group consisting of:

[0146] In another preferred embodiment, R 7 is selected from R a , R a` , and R b are as described above.

[0147] In another preferred embodiment, the present application provides a method of preparing the compound 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[indeno-l,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-l-(2-fluorovinyl)piperazin-2-yl)acetonitrile, comprising the steps of:

[0148] (a) the compound SM and the compound SM-2A are subjected to a nucleophilic substitution reaction under the condition of a basic reagent and are protected with a protecting group PG by a protecting group reagent to obtain the compound I-1a;

[0149] Alternatively, the compound SM and the compound SM-2B are subjected to a nucleophilic substitution reaction in a solvent under the condition of a basic reagent to obtain the compound I-1a;

[0150] (b) the compound I-1a and the compound SM-3 are subjected to a Buchwald coupling reaction in a palladium catalyst, a ligand, a basic reagent and a solvent, and after deprotection, the compound I-2a is obtained;

[0151] (c) the compound I-2a and the compound SM-4 are subjected to a condensation reaction in a condensing agent, a basic reagent and a solvent, with or without a condensing agent activator, to obtain the compound 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[indeno-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-1-(2-fluorovinyl)piperazin-2-yl)acetonitrile;

[0152] wherein the compound SM is prepared by the method of the third aspect of the present application.

[0153] In another preferred embodiment, step (a) has one or more of the following characteristics:

[0154] (a-1) the basic reagent is selected from one or more of carbonates, triethylamine and diisopropylethylamine;

[0155] (a-2) the solvent is selected from one or more of amide solvents, C3-6 ketone solvents, halogenated C1-6 hydrocarbon solvents and C1-6 hydrocarbon solvents, preferably one or more of dichloromethane, chloroform, acetone, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone;

[0156] (a-3) the reaction temperature of the nucleophilic substitution reaction is 0-30°C, preferably 0-20°C;

[0157] (a-4) the protecting group PG is selected from tert-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz), and the reaction temperature for the protection of the protecting group PG is 20-30°C;

[0158] (a-5) the molar ratio of the compound SM-2A or SM-2B to the compound SM is (1-2):1, preferably (1-1.5):1, more preferably 1.2:1;

[0159] (a-6) the molar ratio of the basic reagent to compound SM is (2-6): 1, preferably 4.0:1; and / or

[0160] (a-7) the molar ratio of the protecting group reagent to compound SM is (1-2): 1, preferably 1.5:1.

[0161] In another preferred embodiment, step (b) has one or more of the following characteristics:

[0162] (b-1) the palladium catalyst is selected from one or more of palladium acetate, tris(dibenzylideneacetone)dipalladium, RuPhos Pd G3 (CAS: 1445085-77-7);

[0163] (b-2) the ligand is selected from one or more of 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (BINAP, CAS: 98327-87-8), tri-tert-butylphosphine (P(t-Bu)3, CAS: 13716-12-6), tri-o-tolylphosphine (P(o-tolyl)3, CAS: 6163-58-2), BrettPhos (CAS: 1070663-78-3), RuPhos (CAS: 787618-22-8), XPhos (CAS: 564483-18-7), tBuXPhos (CAS: 564483-19-8), Me4tBuXPhos (CAS: 857356-94-6), tBuBrettPhos (CAS: 1160861-53-9), SPhos (CAS: 657408-07-6), DavePhos (CAS: 213697-53-1), JohnPhos (CAS: 224311-51-7), JackiePhos (CAS: 1160861-60-8);

[0164] (b-3) the basic reagent is selected from one or more of cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium phosphate, and diisopropylethylamine;

[0165] (b-4) the solvent is selected from one or more of aromatic hydrocarbon solvents, ether solvents, preferably one or more of toluene, xylene, tetrahydrofuran, dioxane;

[0166] (b-5) the reaction temperature is 80-110 °C, preferably 95-105 °C;

[0167] (b-6) the molar ratio of compound SM-3 to compound I-1a is (1-2): 1, preferably 1.5:1;

[0168] (b-7) the molar ratio of the palladium catalyst to compound I-1a is (0.01-0.1): 1, preferably 0.05:1;

[0169] (b-8) the molar ratio of the ligand to the palladium catalyst is (1-4): 1, preferably (2-3): 1, more preferably 2.8: 1;

[0170] (b-9) the molar ratio of the basic reagent to compound I-la is (1-4): 1, preferably (2-3): 1, more preferably 2.8: 1; and / or

[0171] (b-10) when PG is tert-butyloxycarbonyl (Boc), the deprotection reagent is selected from trifluoroacetic acid, hydrochloric acid and trimethylsilyl iodide; when PG is benzyloxycarbonyl (Cbz), the deprotection reagent is selected from palladium on carbon, palladium hydroxide on carbon, palladium chloride, hydrobromic acid / acetic acid and trimethylsilyl iodide.

[0172] In another preferred embodiment, step (c) has one or more of the following characteristics:

[0173] (c-1) the condensing agent is selected from one or more of n-propylphosphonic anhydride (T3P), carbonyldiimidazole (CDI), O-(7-azabenzotriazol-l-yl)-bis(dimethylamino)carbenium hexafluorophosphate (HATU), O-(benzotriazol-l-yl)-bis(dimethylamino)carbenium hexafluorophosphate (HBTU), O-(5-chlorobenzotriazol-l-yl)-bis(dimethylamino)carbenium hexafluorophosphate (HCTU), O-(benzotriazol-l-yl)-bis(dimethylamino)carbenium tetrafluoroborate (TBTU), O-(N-butyldiimide)-bis(dimethylamino)carbenium tetrafluoroborate (TSTU), O-(N-endo-5-norbornene-2,3-dicarboxyimide)-bis(dimethylamino)carbenium tetrafluoroborate (TNTU), benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (HOP), benzotriazol-l-yloxytris(pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), 7-azabenzotriazol-l-yloxytris(pyrrolidinyl)phosphonium hexafluorophosphate (PyAOP), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI);

[0174] (c-2) the condensing agent activator is selected from one or more of 4-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine (4-PPY), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), N-hydroxyphthalimide (NHPI) and N-hydroxy-5-norbornene-2,3-dicarboximide (HONB);

[0175] (c-3) the basic reagent is selected from one or more of pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine;

[0176] (c-4) the solvent is selected from one or more of Ci-6 hydrocarbon solvents, Ci-6 halogenated hydrocarbon solvents, ketone solvents, C2-6 nitrile solvents, C2-6 ether solvents, amide solvents, and sulfone solvents, preferably one or more of dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide;

[0177] (c-5) the molar ratio of the compound SM-4 to compound I-2a is (1-2): 1, preferably (1-1.5): 1, more preferably 1.25: 1;

[0178] (c-6) the molar ratio of the condensing agent to compound I-2a is (1-2): 1, preferably 1.5: 1;

[0179] (c-7) the molar ratio of the base to compound I-2a is (2-4): 1, preferably (2-3): 1, more preferably 2.6: 1; and / or

[0180] (c-8) the reaction temperature is 0-30 °C.

[0181] In a fifth aspect of the present application, there is provided a crystalline form of the compound 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[indene-l,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-l-(2-fluorovinyl)piperazin-2-yl)acetonitrile, Form I, having XRPD characteristic peaks 2Θ values selected from the group consisting of 9.0 ± 0.2°, 9.1 ± 0.2°, 13.2 ± 0.2°, 13.5 ± 0.2°, 15.4 ± 0.2°, 15.7 ± 0.2°, 16.0 ± 0.2°, 16.7 ± 0.2°, 17.7 ± 0.2°, 18.4 ± 0.2°, 19.5 ± 0.2°, 19.8 ± 0.2°, 20.8 ± 0.2°, 21.0 ± 0.2°, 21.9 ± 0.2°, 22.4 ± 0.2°, 24.0 ± 0.2°, 26.5 ± 0.2°, 27.7 ± 0.2°, 28.5 ± 0.2°.

[0182] In another preferred embodiment, the crystalline form Form I has XRPD peak 2Q values selected from the group consisting of: 16.69° ± 0.2°, 15.705° ± 0.2°, 9.132° ± 0.2°, 8.952° ± 0.2°, 18.438° ± 0.2°, 21.899° ± 0.2°, 24.038° ± 0.2°, 20.856° ± 0.2°.

[0183] In another preferred embodiment, the crystalline form Form I has XRPD peak 2Q values selected from the group consisting of: 8.952° ± 0.2°, 9.132° ± 0.2°, 12.021° ± 0.2°, 12.705° ± 0.2°, 13.15° ± 0.2°, 13.484° ± 0.2°, 14.563° ± 0.2°, 14.715° ± 0.2°, 15.047° ± 0.2°, 15.424° ± 0.2°, 15.705° ± 0.2°, 16.03° ± 0.2°, 16.69° ± 0.2°, 17.465° ± 0.2°, 17.727° ± 0.2°, 18.044° ± 0.2°, 18.438° ± 0.2°, 18.674° ± 0.2°, 19.485° ± 0.2°, 19.765° ± 0.2°, 20.262° ± 0.2°, 20.548° ± 0.2°, 20.856° ± 0.2°, 21.05° ± 0.2°, 21.899° ± 0.2°, 22.42° ± 0.2°, 22.785° ± 0.2°, 23.791° ± 0.2°, 24.038° ± 0.2°, 24.454° ± 0.2°, 24.696° ± 0.2°, 25.184° ± 0.2°, 25.727° ± 0.2°, 26.484° ± 0.2°, 26.823° ± 0.2°, 27.189° ± 0.2°, 27.726° ± 0.2°, 28.526° ± 0.2°, 28.931° ± 0.2°, 29.524° ± 0.2°, 29.983° ± 0.2°, 30.461° ± 0.2°, 31.016° ± 0.2°, 31.63° ± 0.2°, 31.971° ± 0.2°, 32.522° ± 0.2°, 33.151° ± 0.2°, 33.656° ± 0.2°, 34.848° ± 0.2°, 35.413° ± 0.2°, 35.92° ± 0.2°, 36.656° ± 0.2°, 36.963° ± 0.2°, 37.398° ± 0.2°, 37.825° ± 0.2°, 38.154° ± 0.2°, 38.68° ± 0.2°, 38.975° ± 0.2°.

[0184] In another preferred embodiment, the Form I has the XRPD characteristic peaks shown in Table 2.

[0185] In another preferred embodiment, the Form I has an XRPD pattern substantially as shown in Figure 1.

[0186] It should be understood that, within the scope of the present application, all the technical features of the present application described above and the technical features specifically described hereinafter (e.g. in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0187] Figure 1 shows the XRPD pattern of 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'- tetrahydro-6'H-spiro[indenno-l,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-l-(2- fluoropropenoyl)piperazin-2-yl)acetonitrile Form I. DETAILED DESCRIPTION

[0188] The inventors have made extensive and in-depth research and for the first time provided two brand-new intermediate compounds for preparing spiro KRAS inhibitors and a preparation method thereof. In addition, the present application also provides a preparation method of the KRAS G12C inhibitor 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[indenno-l,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-l-(2-fluoropropenoyl)piperazin-2-yl)acetonitrile. A new chiral center is induced by asymmetric induction of a chiral auxiliary; a one-pot method realizes deprotection / Mannich reaction / reductive amination reaction, greatly shortening the synthetic route; a tube sealing reaction is avoided, and a high-ee-value chemical intermediate is obtained by refining with a chiral acid. Based on this, the inventors have completed the present application.

[0189] TERMS

[0190] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0191] As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value can vary from the recited value by not more than 1%. For example, as used herein, the expression "about 100" includes all values between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0192] As used herein, the term "containing" or "including" can be open, semi-closed and closed. In other words, the term also includes "consisting essentially of or "consisting of.

[0193] When a substituent is described by a conventional chemical formula written from left to right, the substituent also equally includes a chemically equivalent substituent obtained by writing the chemical formula from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0194] The term "alkyl" means a monovalent saturated aliphatic hydrocarbon group having from 1 to 6 (preferably 1 to 4) carbon atoms, including straight chain and branched chain hydrocarbon groups such as methyl (i.e., CH3-), ethyl (i.e., CH3CH2-), n-propyl (i.e., CH3CH2CH2-), isopropyl (i.e., (CH3)2CH-), n-butyl (i.e., CH3CH2CH2CH2-), isobutyl (i.e., (CH3)2CHCH2-), sec-butyl (i.e., (CH3)(CH3CH2)CH-), t-butyl (i.e., (CH3)3C-), n-pentyl (i.e., CH3CH2CH2CH2CH2-), neopentyl (i.e., (CH3)3CCH2-).

[0195] In the present application, the term "C2-C6alkenyl" means a straight or branched chain alkenyl group having from 2 to 6 carbon atoms containing one double bond, including without limitation, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl, and the like.

[0196] In the present application, the term "C2-C6alkynyl" means a straight or branched chain alkynyl group having from 2 to 6 carbon atoms containing one triple bond, including without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl, and the like.

[0197] In the present application, the term "C1-C6alkoxy" means a straight or branched chain alkoxy group having from 1 to 6 carbon atoms, including without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy, and the like. Preferably, C1-C4alkoxy.

[0198] As used herein, the term "aryl" means a monovalent aromatic carbocyclic radical of six to fourteen (preferably six) carbon atoms having a single ring (e.g., phenyl) or a conjugated ring system (e.g., naphthyl or anthracyl), which can be non-aromatic (e.g., 2-benzoxazolone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like) if the point of attachment is on a non-aromatic carbon. Preferred aryl groups include phenyl and naphthyl.

[0199] As used herein, the term "carbocyclyl" refers to cyclic hydrocarbon groups having from 3 to 6 carbon atoms, the point of attachment being through a ring of the cyclic hydrocarbon group, and can include cycloalkenyl and cycloalkyl groups. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

[0200] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0201] As used herein, the term "heteroaryl" refers to an aromatic group having from 1 to 5 carbon atoms and from 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur within the ring, such heteroaryl groups can be monocyclic (such as pyridyl or furanyl) or fused ring (such as indolizinyl or benzothienyl), wherein the fused ring can be non-aromatic and / or contain one heteroatom, provided the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the ring atom nitrogen and / or sulfur of the heteroaryl group is optionally oxidized to an N-oxide (N-O), sulfinyl, or sulfonyl group. Preferably the heteroaryl group includes pyridyl, pyrrolyl, indolyl, thienyl, and furanyl. In one embodiment, heteroaryl refers to a 3-7 membered heteroaryl group, preferably a 5-6 membered heteroaryl group.

[0202] In the present application, the term "halogenating reagent" is a class of chemical reagents used in organic synthesis to introduce halogen (such as fluorine, chlorine, bromine, iodine) atoms. These reagents are generally highly reactive and can undergo substitution reactions with carbon-hydrogen bonds (C-H) or other functional groups, thereby introducing halogen atoms into organic molecules. Examples include phosphorus oxyhalides, phosphorus halides, thionyl chloride, and phenylphosphonic chloride.

[0203] In the present application, the term "carbocyclyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spiro ring systems, having from 3 to 15 carbon atoms, preferably having from 3 to 10 carbon atoms, more preferably having from 3 to 8 carbon atoms, and which is either saturated or unsaturated and can be attached to the remainder of the molecule via a single bond through any available carbon atom. Unless otherwise specifically noted in the specification, the carbon atoms in a carbocyclyl group can optionally be oxidized. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, indanyl, octahydro-4,7-methano-lH-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, lH-indenyl, 8,9-dihydro-7H-benzo-cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzo-cycloheptenyl, 5,6,7,8,9,10-hexahydro-benzo-cyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, and octahydro-2,5-methano-indenyl, and the like.

[0204] In the present application, the term "heterocyclyl" as a group or as part of a group means a stable 3- to 20-membered non-aromatic ring radical consisting of two to fourteen carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise particularly specified in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic, or more ring ring system, which can include fused ring systems, bridged ring systems, or spirocyclic ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical can optionally be oxidized; the nitrogen atoms can optionally be quaternized; and the heterocyclyl radical can be partially or fully saturated. The heterocyclyl radical can be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In a heterocyclyl radical comprising fused rings, one or more of the rings can be an aromatic carbocyclyl or heteroaromatic ring radical as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present application, the heterocyclyl radical is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic radical comprising one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic radical comprising one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heterocyclyl radicals include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolinyl, octahydroisoindolinyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.

[0205] In the present application, the term "aromatic ring radical" as a group or as part of a group means a conjugated hydrocarbon ring system radical having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present application, the aromatic ring radical can be a monocyclic, bicyclic, tricyclic, or more ring ring system, which can also be fused with a carbocyclyl or heterocyclyl radical as defined above, provided that the aromatic ring radical is attached to the remainder of the molecule via an atom on the aromatic ring by a single bond. Examples of aromatic ring radicals include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinonyl, 2H-1,4-benzoxazin-3(4H)-on-7-yl, and the like.

[0206] In the present application, the term "sulfonylating reagent" is a chemical reagent used to introduce a sulfonyl group in organic synthesis. Such reagents typically react with alcohols, amines to form sulfonates or sulfonamides. Examples include methanesulfonyl chloride, trifluoromethylsulfonyl anhydride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride. As used herein, the term "stereoisomer" refers to compounds which differ in the orientation of one or more chiral centers. Stereoisomers include enantiomers and diastereomers.

[0207] In the present application, the term "substituted" means that one or more hydrogen atoms on a particular group is replaced with a particular substituent. The particular substituent is a substituent described in the foregoing or a substituent appearing in the various embodiments. Unless otherwise specified, a substituted group can have at each substitutable position one substituent selected from a specified group, wherein the substituent can be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present application are those stable or chemically feasible combinations. The substituents are, for example, but not limited to, halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.

[0208] In the present application, the term 1-6 means 1, 2, 3, 4, 5, or 6. Other similar terms have similar meanings.

[0209] The term "solvate" means a complex of a compound of the present application with solvent molecules in a definite ratio.

[0210] Preparation methods

[0211] The preparation methods of the compounds of formula (I) of the present application are described in more detail below, but these specific methods do not constitute any limitation on the present application. The compounds of the present application can also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, which can be easily performed by those skilled in the art to which the present application belongs.

[0212] Typically, the preparation process of the compounds of the present application is shown in the examples of the present application, wherein the raw materials and reagents used, if not specifically stated, can be purchased through commercial channels.

[0213] The present application provides a preparation method of a key intermediate of a KRAS inhibitor, which specifically comprises the following steps:

[0214] wherein, ring B, R 1 , R2, r are described in the first aspect of the present application;

[0215] X 1 and X 2 each independently is halogen, mesylate, triflate, besylate, tosylate, nosylate, or nitrophenoxy;

[0216] (1) Compound SM1-1 and (R)-tert-butylsulfonamide are condensed in the presence of a Lewis acid in a solvent to obtain compound SM1-2;

[0217] (2) Compound SM1-2 and compound SM1-3 undergo a nucleophilic addition reaction in the presence of a strong base reagent, with or without a ligand, in a solvent to obtain compound SM1-4;

[0218] (3) Compound SM1-4 undergoes a deprotection / Mannich reaction / reductive amination reaction in the presence of paraformaldehyde and formic acid in one step, and is refined and separated by a chiral acid to obtain compound SM1-5;

[0219] (4) Compound SM1-5 undergoes a hydrolysis reaction in the presence of an acid in a solvent to obtain compound SM1-6;

[0220] (5) Compound SM1-6 undergoes a reaction in the presence of a halogenating reagent or a sulfonylation reagent or p-nitrofluorobenzene or p-nitrochlorobenzene, with or without a basic reagent to obtain compound SM1.

[0221] wherein the specific reaction conditions are as described above;

[0222] Unless otherwise specified, the reaction time and reaction temperature of each reaction step described above are not particularly limited, and can be specifically selected by a person of ordinary skill in the art according to the type of reaction, for example, the reaction time is 1-8h, preferably 1-4h; the reaction temperature is 0-40℃; preferably 0-30℃. The ratio between each reaction material is also not particularly limited, and is specifically selected as described above.

[0223] Further, the present application also provides a preparation method of a compound shown in formula V as a KRAS inhibitor, which specifically comprises the following steps:

[0224] (a) Compound SM1 and compound SM-2A undergo a nucleophilic substitution reaction in the presence of a basic reagent, and a protecting group PG is protected by a protecting group reagent to obtain compound I-1;

[0225] Alternatively, compound SM1 and compound SM-2B undergo a nucleophilic substitution reaction in the presence of a basic reagent in a solvent to obtain compound I-1;

[0226] (b) Compound I-1 and compound R6 The -OH is subjected to a Buchwald coupling reaction in a palladium catalyst, a ligand, a basic reagent and a solvent to obtain compound I-2 after deprotection;

[0227] (c) compound I-2 and compound R 7 The -OH is subjected to a condensation reaction in a condensing agent, a basic reagent and a solvent with or without a condensing agent activator to obtain a compound shown in formula V.

[0228] The compound SM-1 is prepared by the method as described above.

[0229] The specific reaction parameters and reaction conditions of each step are as described above.

[0230] Unless otherwise specified, the reaction time and reaction temperature of each reaction step described above are not particularly limited and can be specifically selected by those skilled in the art according to the reaction type, for example, the reaction time is 1-8h, preferably 1-4h. The ratio between the reaction materials is also not particularly limited and can be specifically selected as described above.

[0231] Specifically, the present application provides a preparation method of compound 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[inden-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-1-(2-fluorovinylcarbonyl)piperazin-2-yl)acetonitrile, comprising the following steps:

[0232] The reaction steps and reaction conditions are as described above.

[0233] The present application also provides a preparation method of a crystal form of compound 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[inden-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-1-(2-fluorovinylcarbonyl)piperazin-2-yl)acetonitrile, comprising the following steps:

[0234] The API of the above compound is dissolved in a C2-6 ketone solvent, stirred at 45-55°C for 1-3 hours, the internal temperature is controlled below 50°C, and concentrated under reduced pressure to 10-12X. Adjust the temperature to 45-55°C, and add the crystal seed. Control the temperature at 45-55°C, and stir for 1-3 hours; control the temperature at 35-45°C, and stir for 1-3 hours; control the temperature at 25-35°C, and stir for 1-3 hours; control the temperature at 15-25°C, and stir for 1-3 hours to obtain the crystal form, and the post-treatment further includes filtration and drying. The mass ratio of the API to the C2-6 ketone solvent is 1:50-70, preferably 1:60; and the C2-6 ketone solvent is preferably acetone;

[0235] The API is prepared by the method of the application.

[0236] Compared with the prior art, the main advantages of the application include:

[0237] (1) The one-pot method is used to realize the deprotection / Mannich reaction / reduction amination reaction, which greatly shortens the synthetic route.

[0238] (2) The intermediate provided by the application has few synthesis steps, is easy to operate, and has mild reaction conditions, does not need to be sealed, and is suitable for industrial production.

[0239] (3) The KRAS inhibitor obtained by the method of the application has a high ee value.

[0240] The application will be further described below in combination with specific examples. It should be understood that these examples are only used to illustrate the application and not to limit the scope of the application. The experimental methods in the following examples are not specified, and the conditions are generally described in the conventional conditions or the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are calculated by weight.

[0241] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In addition, any method and material similar or equivalent to those described herein can be used in the present application. The preferred methods and materials described herein are only used as examples.

[0242] Example 1: Synthesis of compound SM-1

[0243] First step:

[0244] Under nitrogen protection, control temperature 10-30℃, into the reactor dimethylbenzene (968.00 kg), stirring, add (R)-tert-butylsulfinamide (85.00 kg, 701.32 mol) and titanium acid tetraethyl ester (304.00 kg, 1332.75 mol). Increase temperature to 95-105℃, add S1-1 (100.00 kg, 666.22 mol) dimethylbenzene (322.00 kg) solution. Under nitrogen protection, 95-105℃, stirring 2.0-3.0 hours. Reaction is completed, the reaction system is cooled to 20-30℃, add water (60.00 kg) and stirring 0.5-1.0 hours. Add methyl tert-butyl ether (296.00 kg) and stirring 0.5-1.0 hours. Centrifugation, filter cake is washed with methyl tert-butyl ether (296.00 kg), combine all the filtrate. Combined filtrate is filtered through 100-200 mesh silica gel (100.00 kg), filter cake is washed with methyl tert-butyl ether (296.00 kg), combine all the filtrate. The combined filtrate is concentrated under reduced pressure to no distillate, to obtain S1-2 (151.62 kg) is directly used in the next step.

[0245] Second step:

[0246] Under nitrogen protection, into the low temperature reactor 2-methyltetrahydrofuran (688.00 kg) and S1-3 (68.00 kg, 440.98 mol). After stirring to dissolve, add N, N, N', N'-tetramethyl ethylenediamine (51.20 kg, 440.58 mol). The reaction system is cooled to -70--60℃, add 2.5M n-butyllithium (120.00 kg, 441.17 mol). -70--60℃, stirring 1-2 hours, then increase temperature to -60--55℃, continue to keep temperature and stirring 0.5-1 hour. Control temperature -60--55℃, drop S1-2 (80.00 kg, 315.83 mol) 2-methyltetrahydrofuran (344.00 kg) solution. At -60--55℃, nitrogen protection, keep temperature and stirring 1-2 hours. Reaction is completed, at -60--55℃, pump acetic acid (41.60 kg) into the low temperature reactor. The low temperature reactor is increased to 10-20℃, add water (800.00 kg), stirring 5-10 minutes, filter. The filtrate is layered, collect the organic phase. The organic phase is washed with 1M hydrochloric acid solution (973.60 kg) and 5% sodium hydroxide aqueous solution (420.00 kg) in turn, concentrated under reduced pressure to no distillate, to obtain crude S1-4 (30.00 kg).

[0247] Third step:

[0248] Into a reaction kettle, add formic acid (561.20 kg), S1-4 (46.00 kg, 112.88 mol) and polyformaldehyde (34.04 kg, 1134.67 mol) under nitrogen protection. After stirring and dissolving, react at 75-85 °C for 6-8 hours. Concentrate the reaction solution under reduced pressure to 2-3 V, dilute with water (230.00 kg), and filter through diatomite (23.00 kg). Extract the filtrate with methyl tert-butyl ether (136.16 kg). Adjust the pH of the water phase to 10-12 with 2M sodium hydroxide solution (49.68 kg), then extract with methyl tert-butyl ether (204.24 kg), and collect the organic phase. Concentrate the organic phase under reduced pressure to 3-4 V, then add ethanol (254.38 kg) and continue to concentrate to 3-4 V. Add ethanol (254.38 kg) and L-dibenzoyl tartaric acid (11.50 kg, 32 mol) to the concentrated residue, and react at 75-85 °C for 3.5-4.5 hours. Cool to 20-30 °C, and precipitate the solid. Filter, and collect the filter cake. Dissolve the filter cake with methyl tert-butyl ether (170.20 kg), then dilute with water (115.00 kg), and adjust the pH to 9-10 with 2M sodium hydroxide aqueous solution (49.68 kg). Separate the phases, and collect the organic phase. Extract the water phase with methyl tert-butyl ether (170.20 kg). Combine the organic phases. Concentrate the obtained product under reduced pressure to 3-4 V, then add ethanol (254.38 kg) and continue to concentrate to 3-4 V. Collect the product, weigh, and convert to S1-5 (17.50 kg, 53 mol) according to weight x purity.

[0249] Fourth step:

[0250] Into a reaction kettle, add ethanol (110.51 kg), S1-5 (21.50 kg, 65.3 mol) and 12M hydrochloric acid (25.16 kg, 262.5 mol) under nitrogen protection. Stir at 75-85 °C for 4-6 hours. After the reaction is complete, cool to 15-25 °C, and precipitate the solid. Filter, and collect the filter cake. Dry the filter cake to a moisture content of <3000 ppm to obtain S1-6 (13.10 kg).

[0251] Fifth step:

[0252] Into a reaction vessel was added phosphorous oxychloride (51.66 kg, 31.5 L) and S1-6 (10.50 kg, 28.15 mol) under nitrogen protection, and stirred at 95-105 °C for 8-10 hours. The reaction solution was concentrated under reduced pressure to 1.0-1.5 V, then acetonitrile (80.18 kg) was added to reduce the volume to 1.0-1.5 V, and then cooled to 15-25 °C. Dichloromethane (75.98 kg) was added to the concentrate, and after stirring to dissolve, the temperature was controlled at 0-10 °C, and then added dropwise to water (145.00 kg) for quenching. The pH was adjusted to 7-8 with 10% sodium bicarbonate solution. Extracted with dichloromethane (94.98 kg), and after standing to separate the layers, the organic phase was collected. The organic phase was washed with water (72.50 kg), and after standing to separate the layers, the organic phase was collected. The organic phase was filtered through a 100-200 mesh silica gel pad (20.00 kg), and the filtrate was concentrated under reduced pressure to a residue of 1-2 V, then n-heptane (150.00 kg) was added and the concentration was continued to 3-4 V. The temperature was cooled to 10-15 °C, and stirred for 3-5 hours. Centrifuged, and the filter cake was dried to obtain crude SM-1 (9.50 kg). The crude product was dissolved in dichloromethane (200 L), filtered through a 100-200 mesh silica gel pad (20.00 kg), and the filtrate was collected. The filtrate was concentrated to 2-3 V, isopropyl alcohol (50.0 L) was added, and the concentration was continued to 2-3 V. Centrifuged, and the filter cake was dried under vacuum to obtain the product SM-1 (6.80 kg).

[0253] Example 2: Synthesis of 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[inden-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-1-(2-fluorovinylcarbonyl)piperazin-2-yl)acetonitrile

[0254] First step:

[0255] Into a reaction kettle, N,N-dimethylformamide (12.00 kg), SM-1 (2.45 kg, 7.24 mol) were added, and the temperature was controlled at 0-15 °C. SM-2 (1.72 kg, 8.68 mol) was added into the reaction kettle in batches, and diisopropylethylamine (3.75 kg, 29.01 mol) was added dropwise. Stirring was performed at 0-15 °C for 12-24 hours. After the consumption of SM-1, carbonic acid di-tert-butyl ester (2.37 kg, 10.86 mol) was added into the reaction kettle at 0-15 °C, and stirring was performed at 20-30 °C for 12-24 hours. After the reaction was completed, the reaction liquid was slowly added into water (72.00 kg) dropwise, and the temperature was controlled at 20-30 °C. After the addition was completed, stirring was continued for 12-24 hours, and a solid was precipitated, which was filtered. The filter cake was rinsed with water (5.00 kg), and then dissolved in toluene (21.50 kg), stirred at 40-50 °C for 10-30 minutes, and then allowed to stand to separate into layers. The organic phase was washed with 10% sodium sulfate solution (7.50 kg x 2). The moisture of the organic phase was tested by Karl Fischer method, and the moisture was controlled to be ≤1.0%, which was directly used in the next step reaction.

[0256] Second step:

[0257] Into a reaction kettle was charged a solution of I-1 (3.80 kg, 7.21 mol) in toluene, followed by SM-3 (1.72 kg, 10.80 mol), cesium carbonate (5.90 kg, 18.11 mol), 1,1'-binaphthalene-2,2'-diphenylphosphine (0.55 kg, 0.88 mol), palladium acetate (70 g, 0.31 mol) at 20-30 °C, and the mixture was stirred at 95-105 °C for 12-24 h. The reaction mixture was cooled to room temperature and filtered through celite (2.00 kg). The filter cake was rinsed with dichloromethane (8.00 kg). The filtrate was concentrated under reduced pressure to 2-4 V, followed by the addition of dichloromethane (9.00 kg) and 2 M aqueous hydrochloric acid (30.00 kg, 60 mol) at 15-25 °C, and the mixture was stirred at 15-25 °C for 12-24 h. The mixture was filtered, and the filter cake was rinsed with dichloromethane (5.00 kg). The filtrate was partitioned. The aqueous phase was washed with dichloromethane (10.00 kg), followed by the addition of mercaptosilica gel (0.40 kg) at 15-25 °C, and the mixture was stirred for another 12-24 h. The mixture was filtered. To the filtrate was added dichloromethane (25.08 kg) and 20% aqueous sodium hydroxide (15.20 kg), and the mixture was stirred for 15-30 min. The mixture was allowed to stand to separate into layers. To the aqueous phase was added dichloromethane (10.00 kg), and the mixture was stirred at 15-25 °C for 15-35 min. The mixture was allowed to stand to separate into layers. The organic phases were combined and concentrated under reduced pressure to 2-4 V, followed by the addition of methyl tert-butyl ether (28.12 kg), and the mixture was concentrated under reduced pressure to 6-8 V. The temperature was controlled at 20-30 °C, and methyl tert-butyl ether (14.06 kg) was added to the reaction kettle, and the mixture was concentrated under reduced pressure to 6-8 V. The mixture was stirred at 55-65 °C for 2-4 h, at 20-30 °C for 12-24 h, and filtered. The filter cake was washed with methyl tert-butyl ether (2.96 kg) and dried under vacuum for 12-24 h to give crude I-2 (2.85 kg). Into a clean reaction kettle was charged ethanol (4.50 kg), crude I-2 (2.85 kg), and n-heptane (15.50 kg), and the mixture was slurried at 65-75 °C for 1-3 h, at 20-30 °C for 1-3 h, and the solid was precipitated. The mixture was filtered. The filter cake was washed with a mixture of ethanol and n-heptane (1:4 by volume, 2.00 kg). The mixture was dried under vacuum for 12-24 h to give 2.32 kg of I-2, in a yield of 58.5%.

[0258] Step 3:

[0259] Into a reaction kettle was charged tetrahydrofuran (10.35 kg), SM-4 (0.47 kg, 5.22 mol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.30 kg, 6.05 mol) was added at 0-10 °C, stirred for 15-35 min, then diisopropylethylamine (1.40 kg, 10.83 mol) was added, stirred for another 15-35 min, then I-2 (2.30 kg, 4.18 mol) was added. The reaction was stirred at 0-10 °C for 2-4 h. After the reaction was completed, water (10.35 kg) and ethyl acetate (10.35 kg) were added into the reaction kettle, stirred at 20-30 °C for 15-35 min, and then allowed to stand to separate into layers. The aqueous phase was extracted with ethyl acetate (10.35 kg). The organic phases were combined, 10% sodium sulfate aqueous solution (11.50 kg) was added, stirred for 15-35 min, and then allowed to stand to separate into layers. The organic phase was concentrated under reduced pressure to 2-4X. Acetone (3.8-4.2X) was added for three times for concentration.

[0260] The temperature was controlled at 45-55 °C and stirred for 1-3 h, and then stirred at 15-25 °C for 6-12 h. The solid was precipitated and filtered. The filter cake was washed with acetone (1.15 kg), transferred into a clean reaction kettle, and acetone (69.00 kg) was added. The temperature was controlled at 45-55 °C and stirred for 1-3 h, and the internal temperature was controlled below 50 °C. The mixture was concentrated under reduced pressure to 10-12X. The temperature was controlled at 45-55 °C, and seed crystals (0.02 kg) were added. The temperature was controlled at 45-55 °C and stirred for 1-3 h, at 35-45 °C and stirred for 1-3 h, at 25-35 °C and stirred for 1-3 h, and at 15-25 °C and stirred for 1-3 h. The mixture was filtered. The filter cake was washed with acetone (1.15 kg) and dried under vacuum to give 1.47 kg of 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[inden-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-1-(2-fluorovinylcarbonyl)piperazin-2-yl)acetonitrile in Form I.

[0261] Table 1 shows the XRPD test conditions of 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[inden-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-1-(2-fluorovinylcarbonyl)piperazin-2-yl)acetonitrile, and the XRPD pattern is shown in Figure 1. Table 2 shows the XRPD characteristic peak 2θ values and relative intensities of Form I crystals.

[0262] Table 1

[0263] Table 2

[0264] Example 3: Synthesis of compound 1

[0265] (1) To a solution of compound 1-1 (50.0 g, 308 mmol) in N,N-dimethylformamide (300 mL) was added benzyl bromide (58.0 g, 339 mmol, 40.2 mL), potassium carbonate (85.2 g, 616 mmol), and the reaction was stirred at 25 °C for 12 h under nitrogen. The reaction was poured into water (2000 mL) and filtered to give compound 1-2.

[0266] 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 2.8 Hz, 1H), 7.30-7.47 (m, 5H), 7.10-7.20 (m, 2H), 5.10 (s, 2H), 2.91 (t, J = 6.0 Hz, 2H), 2.61-2.68 (m, 2H), 2.09-2.15 (m, 2H).

[0267] (2) To compound 1-2 (16.3 g, 64.6 mmol) was added copper nitrate (20.0 g, 97.2 mmol), acetic anhydride (85.0 mL), and the reaction was stirred at 25 °C for 3 h under nitrogen. To the reaction was added ethyl acetate (1000 mL), washed with water (1000 mL x 1), and the organic phase was adjusted to pH 7 with aqueous sodium carbonate solution, washed with saturated brine (1500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to give compound 1-3.

[0268] 1 H NMR (400 MHz, CDCl3) δ 7.26-7.41 (m, 6H), 7.17-7.20 (m, 1H), 5.18 (s, 2H), 2.92 (t, J = 6.0 Hz, 2H), 2.63-2.69 (m, 2H), 2.12 (quin, J = 6.2 Hz, 2H).

[0269] (3) To a solution of compound 1-3 (5.00 g, 16.8 mmol) in methanol (75.0 mL) was added iron powder (4.70 g, 84.0 mmol), water (15.0 mL) and ammonium chloride (4.50 g, 84.0 mmol), and the reaction was stirred at 60 °C for 12 h under nitrogen. The reaction was filtered and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel (petroleum ether / ethyl acetate = 1:0 to 0:1) to give compound 1-4.

[0270] MS-ESI [M+H] 302.0, calc. 302.0, found 302.0. + , calculated value 268, found value 268.

[0271] 1 H NMR (400 MHz, CDCl3) δ 7.31-7.47 (m, 5H), 6.82 (d, J = 8.0 Hz, 1H), 6.36 (d, J = 8.0 Hz, 1H), 5.07 (s, 2H), 2.83 (t, J = 6.0 Hz, 2H), 2.58-2.64 (m, 2H), 2.02 (quin, J = 6.4 Hz, 2H).

[0272] (4) To a solution of compound 1-4 (2.00 g, 7.48 mmol) in acetonitrile (26.0 mL) was added a solution of N-chlorosuccinimide (999 mg, 7.48 mmol) in acetonitrile (5.0 mL), and the reaction was stirred at 60 °C for 1 h under nitrogen. To the reaction was added ethyl acetate (100 mL), washed with water (100 mL x 2), saturated brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel (petroleum ether / ethyl acetate = 1:0 to 0:1) to give compound 1-5.

[0273] MS-ESI [M+H] 302.0, calc. 302.0, found 302.0. + , calculated value 268, found value 268.

[0274] 1 H NMR (400 MHz, CDCl3) δ 7.31-7.47 (m, 5H), 6.82 (d, J = 8.0 Hz, 1H), 6.36 (d, J = 8.0 Hz, 1H), 5.07 (s, 2H), 2.83 (t, J = 6.0 Hz, 2H), 2.58-2.64 (m, 2H), 2.02 (quin, J = 6.4 Hz, 2H).

[0275] (5) To a tetrahydrofuran (15.0 mL) solution of compounds 1-5 (1.00 g, 3.31 mmol), add a solution of concentrated hydrochloric acid (12 mol / L, 2.50 mL) in water (10.0 mL) and a solution of sodium nitrite (251 mg, 3.65 mmol) in water (2.00 mL). The reaction mixture is stirred at 0 °C for 1 hour under nitrogen protection. Then, a solution of hypophosphoric acid (20.0 g, 307 mmol) in water (10.0 mL) is added, and the mixture is stirred at 25 °C for 12 hours under nitrogen protection. Ethyl acetate (100 mL) is added to the reaction mixture, and the mixture is washed with water (75 mL × 2). The organic phase is washed with saturated brine (75 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compounds 1-6.

[0276] MS-ESI[M+H] + Calculated value 287, measured value 287.

[0277] 1 H NMR(400MHz, CDCl3)δ7.58(d,J=2.8Hz,1H),7.31-7.44(m,5H),7.25(d,J=2.8Hz ,1H),5.09(s,2H),2.95(t,J=6.0Hz,2H),2.60-2.67(m,2H),2.10-2.18(m,2H).

[0278] (6) Compound 1-7 (399 mg, 3.30 mmol) and tetraethyl titanate (1.30 mL) were added to a toluene (13.5 mL) solution of compounds 1-6 (900 mg, 3.14 mmol). The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. Water (10.0 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was washed with ethyl acetate (50.0 mL × 2). The organic phases were combined, washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated into compounds 1-8 by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1).

[0279] MS-ESI[M+H] + Calculated value 390, measured value 390.

[0280] 1H NMR (400 MHz, CDC13) δ 7.67 (d, J = 2.4 Hz, 1H), 7.29 - 7.44 (m, 5H), 7.17 (d, J = 2.4 Hz, 1H), 5.08 (s, 2H), 3.21 (ddd, J = 17.2, 9.2, 4.4 Hz, 1H), 3.01 (ddd, J = 17.2, 7.6, 4.4 Hz, 1H), 2.77 - 2.94 (m, 2H), 1.87 - 2.04 (m, 2H), 1.28 (s, 9H).

[0281] (7) Compound 1-9 (249 mg, 1.62 mmol) was dissolved in tetrahydrofuran (5.0 mL), N,N,N',N'-tetramethylethylenediamine (187 mg, 1.62 mmol, 243 μL) was added, and n-butyllithium (2.5 mol / L, 243 μL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -78 °C. The reaction solution was stirred at -78 °C for 1 hour. Compound 1-8 (420 mg, 1.08 mmol) in tetrahydrofuran (2.0 mL) was added dropwise to the reaction solution, and stirring was continued at -78 °C for 3 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (50.0 mL), extracted with ethyl acetate (50.0 mL), and the organic phase was combined, washed with saturated water (50.0 mL x 1) and saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compound 1-10.

[0282] MS-ESI [M+H] + , calc 544, found 544.

[0283] 1 H NMR (400 MHz, CDC13) δ 7.31 - 7.40 (m, 5H), 7.10 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.15 (s, 1H), 5.00 (s, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 2.99 - 3.08 (m, 1H), 2.89 - 2.94 (m, 1H), 2.69 - 2.84 (m, 2H), 2.30 (t, J = 11.6 Hz, 1H), 1.95 - 2.04 (m, 1H), 1.86 - 1.95 (m, 1H), 1.70 - 1.81 (m, 1H), 1.27 (s, 9H).

[0284] (8) To a solution of compound 1-10 (330 mg, 606 μmol) in formic acid (4.0 mL) was added paraformaldehyde (182 mg), and the reaction was stirred at 80 °C for 4 h under nitrogen protection. To the reaction was added ethyl acetate (30.0 mL), washed with water (25 mL x 2), saturated brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 1.

[0285] MS-ESI [M+H] 466.2, calc. 466, found 466. + , calculated value 466, found value 466.

[0286] Example 4: Synthesis of compound 2

[0287] (1) To a solution of compound 2-1 (2.70 g, 9.42 mmol) in acetonitrile (60.0 mL) was added compound 2-2 (6.67 g, 18.8 mmol), and the reaction was stirred at 50 °C for 12 h under nitrogen protection. To the reaction was added dichloromethane (80.0 mL), washed with water (35.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to give compound 2-3.

[0288] MS-ESI [M+H] 466.2, calc. 466, found 466. + , calculated value 305, found value 305.

[0289] 1 H NMR (400 MHz, CDC13) δ 7.31-7.45 (m, 5H), 7.21 (d, J = 7.2 Hz, 1H), 5.13 (s, 2H), 2.93 (t, J = 6.4 Hz, 2H), 2.60-2.67 (m, 2H), 2.07-2.15 (m, 2H).

[0290] (2) To a solution of compound 2-3 (720 mg, 2.36 mmol) in toluene (12.0 mL) was added compound 2-4 (300 mg, 2.48 mmol), and titanium tetraethoxide (1.08 g, 4.73 mmol, 979 μL), and the reaction was stirred at 100 °C for 12 h under nitrogen protection. To the reaction was added water (10.0 mL), filtered, and the filter cake was washed with ethyl acetate (50.0 mL x 2), the combined organic phases were washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to give compound 2-5.

[0291] MS-ESI [M+H] 466.2, calc. 466, found 466. +, calculated 408, found 408.

[0292] 1 H NMR (400 MHz, CDC13) δ 7.37 - 7.45 (m, 5H), 7.13 (d, J = 7.2 Hz, 1H), 5.12 (s, 2H), 3.19 - 3.30 (m, 1H), 3.06 - 3.15 (m, 1H), 2.81 - 2.86 (m, 2H), 1.91 - 2.02 (m, 2H), 1.33 (s, 9H).

[0293] (3) Compound 2-5 (311 mg, 2.02 mmol) was dissolved in tetrahydrofuran (5.0 mL), N,N,N',N'-tetramethyl ethylenediamine (156 mg, 1.35 mmol, 203 μL) was added, and n-butyllithium (2.5 mol / L, 808 μL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -65 °C. The reaction solution was stirred at -65 °C for 1 hour. Compound 2-6 (550 mg, 1.35 mmol) in tetrahydrofuran (2.0 mL) was added dropwise to the reaction solution, and stirring was continued at -65 °C for 3 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (20.0 mL), extracted with ethyl acetate (20.0 mL), and the organic phase was combined, washed with saturated water (20.0 mL x 1) and saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 1:1) to obtain compound 2-7.

[0294] MS-ESI [M+H] + , calculated 562, found 562.

[0295] 1 H NMR (400 MHz, CDC13) δ 7.34 - 7.43 (m, 5H), 7.03 (d, J = 7.6 Hz, 1H), 6.20 (s, 1H), 5.58 (s, 1H), 5.08 (d, J = 3.2 Hz, 2H), 3.92 - 3.97 (m, 6H), 3.66 (d, J = 13.6 Hz, 1H), 3.09 (d, J = 14 Hz, 1H), 2.77 - 2.87 (m, 1H), 2.54 - 2.63 (m, 1H), 2.21 - 2.31 (m, 1H), 1.98 - 2.06 (m, 2H), 1.23 (s, 9H).

[0296] (4) To the solution of compound 2-7 (600 mg, 1.07 mmol) in formic acid (10.0 mL) was added paraformaldehyde (300 mg), and the reaction was stirred at 80 °C for 6 hours under nitrogen protection. To the reaction was added ethyl acetate (30.0 mL), washed with water (25 mL x 2), saturated brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 2.

[0297] MS-ESI [M+H] 484.2; Calculated 484.2. + , Calculated 484, Found 484.

[0298] All documents referred to in this disclosure are incorporated herein by reference as if each individual document were incorporated by reference. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that these equivalents ype within the scope of the appended claims.

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, or deuterated form thereof, wherein, R 1 and R 2 each independently is selected from the group consisting of C1-C4alkyl, C1-C4haloalkyl, phenyl, 5-6 membered heteroaryl, C1-C4alkyl-S(O)-, C1-C4alkyl-S(O)2-, C1-C4haloalkyl-S(O)2-, phenyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, wherein said phenyl, heteroaryl is unsubstituted or optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1-C4alkyl, C1-C4haloalkyl; R 3 is selected from: H, C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 carbocyclyl; r represents the number of methylene groups, r is 1 or 2; Ring B is a substituted or unsubstituted C6-10 aryl ring, or a substituted or unsubstituted 5-10 membered heteroaryl ring; wherein the substitution means that one or more hydrogens on the group are replaced with R 4 substitution; And each R 4 Each is independently selected from the group consisting of: halogen, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 carbocyclic, C1-C3 alkoxy, haloC1-C3 alkoxy, allyloxy, benzyloxy, and benzylamino, wherein the allyloxy, benzyloxy, or benzylamino may optionally be substituted with halogen, C1-C3 alkyl, C1-C3 alkoxy, or nitro.

2. The compound of claim 1, wherein R 1 and R 2 are each independently selected from the group consisting of: C1-C4alkyl, C1-C4haloalkyl; and / or, R 3 is selected from H, C1-C4alkyl, C1-C4haloalkyl; and / or, ring B is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-6 membered heteroaromatic ring; wherein the substitution means that one or more hydrogens on the group are replaced by R 4 ; and each R 4 is independently selected from the group consisting of: halogen, C1-C4alkyl, C1-C4haloalkyl, hydroxyl, amino, benzyloxy, and benzylamino.

3. The compound of claim 1, wherein The compounds are selected from the group consisting of:

4. A compound of Formula II, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, or deuterated form thereof, wherein, R 5 is selected from the group consisting of H, C1-C6alkyl, C3-C6carbocyclyl, phenyl, 5-6 membered heteroaryl, C1-C6alkyl-S(O)-, haloC1-C6alkyl-S(O)-, C1-C6alkyl-S(O)2-, C1-C6haloalkyl-S(O)2-, phenyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, wherein said alkyl, carbocyclyl, phenyl, heteroaryl are unsubstituted or optionally substituted with one or more substituents selected from the group consisting of phenyl, oxo, halogen, nitro, cyano, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, benzyloxy; R 1 , R 2 , ring B and r are as defined in claim 1.

5. The compound of claim 4, wherein The compounds are selected from the group consisting of:

6. A method of preparing a compound of formula SM1, characterized by, comprising the steps of: wherein ring B, R 1 , R 2 , r are as described in claim 1 ; X 1 and X 2 each independently is halogen, mesylate, triflate, besylate, tosylate, nosylate, or p-nitrophenoxy; (1) the condensation reaction of compound SM1-1 and (R)-tert-butylsulfinamide in the presence of a Lewis acid in a solvent to obtain compound SM1-2; (2) the nucleophilic addition reaction of compound SM1-2 and compound SM1-3 in the presence of a strong base reagent, with or without a ligand, in a solvent to obtain compound SM1-4; (3) the one-step deprotection / Mannich reaction / reductive amination reaction of compound SM1-4 in the presence of paraformaldehyde and formic acid, and the chiral acid refinement to obtain compound SM1-5; (4) the hydrolysis reaction of compound SM1-5 in the presence of an acid in a solvent to obtain compound SM1-6; (5) the reaction of compound SM1-6 in the presence of a halogenating reagent or a sulfonylating reagent or p-nitrofluorobenzene or p-nitrochlorobenzene, with or without a basic reagent to obtain compound SM1.

7. The method of claim 6, wherein, In step (1), one or more of the following characteristics are present: the Lewis acid is selected from the group consisting of p-toluenesulfonic acid, magnesium sulfate, tetraethyl titanate and tetraisopropyl titanate; the solvent is selected from C2-6 ether solvents and / or aromatic hydrocarbon solvents, preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, m-xylene; the reaction temperature is 60-140°C, preferably 95-105°C; the molar ratio of (R)-tert-butylsulfinamide to compound SM1-1 is (1-2):1, preferably 1.05:1; and / or the molar ratio of the Lewis acid to compound SM1-1 is (1-3):1, preferably 2:1; In step (2), one or more of the following characteristics are present: the strong base is selected from lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS), n-butyllithium (n-BuLi), sec-butyllithium (s-BuLi) and tert-butyllithium (t-BuLi); the ligand is selected from ethylenediamine ligands, preferably N,N,N',N'-tetramethylethylenediamine; the solvent is selected from C2-6 ether solvents, preferably tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether or a combination thereof; the reaction temperature is -70 to 0°C, preferably -70 to -50°C; the molar ratio of compound SM1-3 to compound SM1-2 is (1-2):1, preferably 1.4:1; the molar ratio of the strong base to compound SM1-2 is (1-2):1, preferably 1.4:1; and / or the molar ratio of the ligand to compound SM1-2 is (1-2):1, preferably 1.4:1; In step (3), one or more of the following characteristics are present: the molar ratio of paraformaldehyde to compound SM1-4 is (10-40):1, preferably (10-20):1; more preferably 10:1; the reaction temperature is 75-100°C, preferably 75-85°C; and / or the molar ratio of compound SM1-4 to compound SM1-5 is (1-2):1, preferably 1.05:1; and / or the molar ratio of the chiral acid to compound SM1-5 is (1-2):1, preferably 1.05:

1. The chiral acid is selected from tartaric acid, malic acid, camphoric acid, camphorsulfonic acid, diacetone-L-gulonic acid, mandelic acid, phenoxypropionic acid, hydroatromic acid and derivatives of the above acids, preferably tartaric acid and its derivatives or camphorsulfonic acid and its derivatives; In step (4), one or more of the following characteristics is present: The acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, aluminum trichloride, aluminum tribromide, trimethylsilyl iodide and boron tribromide, preferably hydrochloric acid; The reaction temperature is 40-100℃; and / or The solvent is selected from one or more of C1-6alcohol solvents, C2-6nitrile solvents, water, C2-6ether solvents, C1-6hydrocarbon solvents, C1-6halogenated alkane solvents and acids, preferably one or more of ethanol, water, acetonitrile, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran and acetic acid; In step (5), one or more of the following characteristics is present: The halogenating reagent is selected from one or more of phosphorus oxyhalide, phosphorus halide, thionyl chloride and phenylphosphonic chloride; The sulfonylating reagent is selected from methanesulfonyl chloride, trifluoromethylsulfonyl anhydride, benzenesulfonyl chloride, p-toluenesulfonyl chloride and p-nitrobenzenesulfonyl chloride; and / or The basic reagent is selected from one or more of triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline and 4-dimethylaminopyridine (DMAP).

8. A method for preparing a compound of formula SM, characterized by, comprising the steps of: wherein X 1 and X 2 each independently is halogen, mesylate, triflate, besylate, tosylate, nosylate, or p-nitrophenoxy; (1) Compound S1-1 and (R)-tert-butylsulfinamide are condensed in the presence of a Lewis acid in a solvent to obtain compound S1-2; (2) Compound S1-2 and compound S1-3 undergo nucleophilic addition reaction in the presence of an organometallic reagent, with or without a ligand, in a solvent to obtain compound S1-4; (3) Compound S1-4 is subjected to deprotection / Mannich reaction / reductive amination reaction in one step in the presence of paraformaldehyde and formic acid, and is refined and separated with a chiral acid to obtain compound S1-5; (4) Compound S1-5 is subjected to hydrolysis reaction in the presence of an acid in a solvent to obtain compound S1-6; (5) Compound S1-6 is subjected to reaction in the presence of a halogenating reagent or a sulfonylating reagent or p-nitrofluorobenzene or p-nitrochlorobenzene, with or without a basic reagent, to obtain compound SM.

9. A method for preparing a compound of formula V, characterized in that, wherein, Ring B is as defined in claim 1; X 1 and X 2 as defined in claim 6; r represents the number of methylene groups, and r is 1 or 2; R 6 selected from hydrogen, optionally substituted C1-C4alkyl, optionally substituted saturated or unsaturated 3-8 membered carbocyclyl, optionally substituted saturated or unsaturated 4-12 membered heterocyclyl, optionally substituted saturated or unsaturated 3-8 membered carbocyclyl fused to a 6-10 membered aromatic ring, optionally substituted saturated or unsaturated 3-8 membered carbocyclyl fused to a 5-10 membered heteroaromatic ring, optionally substituted saturated or unsaturated 3-8 membered heterocyclyl fused to a 6-10 membered aromatic ring, optionally substituted saturated or unsaturated 3-8 membered heterocyclyl fused to a 5-10 membered heteroaromatic ring, optionally substituted 6-10 membered aromatic ring, or optionally substituted 5-10 membered heteroaromatic ring; wherein the optional substituents of the optionally substituted substituents described in R 6 are selected from deuterium, halogen, hydroxyl, cyano, oxo, C1-C3alkoxy, -NR c R d , -CO2R m , -CONR e R f , C1-C4alkylsulfinyl, C1-C4alkylsulfonyl, -SO2NR g R h , optionally substituted 3-8 membered saturated or unsaturated carbocyclyl, and optionally substituted 4-8 membered saturated or unsaturated heterocyclyl; R c and R d are each independently selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 4-8 membered heterocyclyl, or R c and R d together with the N to which they are attached form an optionally substituted 4-8 membered heterocycle; R e and R f are each independently selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 4-8 membered heterocyclyl, or R e and R f together with the N to which they are attached form an optionally substituted 4-8 membered heterocycle; R g and R h are each independently selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 4-8 membered heterocyclyl, or R g and R h together with the N to which they are attached form an optionally substituted 4-8 membered heterocycle; R m is hydrogen or optionally substituted C1-C4alkyl; R 7 is wherein, R a is hydrogen, halogen, optionally substituted C1-C3alkyl, -N(R 5 )2, optionally substituted 4-6 membered saturated heterocyclyl, C1-C3alkoxy, C1-C3alkylsulfanyl, or acetyl, wherein the optional substituents in R a are selected from the group consisting of methyl, ethyl, -N(R n )2, halogen, C1-C3alkoxy, 4-6 membered saturated heterocyclyl; each R is independently hydrogen or C1-C3alkyl; n each independently is hydrogen or C1-C3alkyl; R a’ , R b are each independently hydrogen, halogen, or C1-C3alkyl; Compound SM1 is prepared by the method of claim 6; The method comprises the following steps: (a) Compound SM1 and compound SM-2A are subjected to nucleophilic substitution reaction in the presence of a basic reagent, and are protected with a protecting group PG by using a protecting group reagent, to obtain compound I-1; Alternatively, compound SM1 and compound SM-2B are subjected to nucleophilic substitution reaction in the presence of a basic reagent in a solvent to obtain compound I-1; (b) Compound I-1 and Compound R 6 -OH in the presence of a palladium catalyst, a ligand, a basic reagent and a solvent, followed by deprotection to give Compound I-2; (c) compound I-2 and compound R 7 The condensation reaction of -OH is carried out in a condensing agent, a basic reagent and a solvent, with or without a condensing agent activator, to obtain a compound shown in formula V.

10. The method of claim 9, wherein, Step (a) has one or more of the following characteristics: (a-1) The basic reagent is selected from one or more of carbonates, triethylamine and diisopropylethylamine; (a-2) the solvent is selected from one or more of amide solvents, C3-6 ketone solvents, halogenated C1-6 hydrocarbon solvents, and C1-6 hydrocarbon solvents, preferably one or more of dichloromethane, chloroform, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; (a-3) the reaction temperature of the nucleophilic substitution reaction is 0-30 °C, preferably 0-20 °C; (a-4) the protecting group PG is selected from tert-butyloxycarbonyl (Boc) and carbobenzyloxy (Cbz), and the reaction temperature for the protecting group PG protection is 20-30 °C; (a-5) the molar ratio of compound SM-2A or SM-2B to compound SM1 is (1-2):1, preferably (1-1.5):1, more preferably 1.2:1; (a-6) the molar ratio of the basic reagent to compound SM1 is (2-6):1, preferably 4.0:1; and / or (a-7) the molar ratio of the protecting group reagent to compound SM1 is (1-2):1, preferably 1.5:1; Step (b) has one or more of the following characteristics: (b-1) the palladium catalyst is selected from one or more of palladium acetate, tris(dibenzylideneacetone)dipalladium, RuPhos Pd G3 (CAS: 1445085-77-7); (b-2) the ligand is selected from one or more of 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (BINAP, CAS: 98327-87-8), tri-tert-butylphosphine (P(t-Bu)3, CAS: 13716-12-6), tri-o-tolylphosphine (P(o-tolyl)3, CAS: 6163-58-2), BrettPhos (CAS: 1070663-78-3), RuPhos (CAS: 787618-22-8), XPhos (CAS: 564483-18-7), tBuXPhos (CAS: 564483-19-8), Me4tBuXPhos (CAS: 857356-94-6), tBuBrettPhos (CAS: 1160861-53-9), SPhos (CAS: 657408-07-6), DavePhos (CAS: 213697-53-1), JohnPhos (CAS: 224311-51-7), JackiePhos (CAS: 1160861-60-8); (b-3) the basic reagent is selected from one or more of cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium phosphate, and diisopropylethylamine; (b-4) the solvent is selected from one or more of aromatic hydrocarbon solvents, ether solvents, preferably one or more of toluene, xylene, tetrahydrofuran, dioxane; (b-5) the reaction temperature is 80-110 °C, preferably 95-105 °C; (b-6) compound R 6 the molar ratio of -OH to compound I-1 is (1-2): 1, preferably 1.5:1; (b-7) the molar ratio of the palladium catalyst to compound I-1 is (0.01-0.1):1, preferably 0.05:1; (b-8) the molar ratio of the ligand to the palladium catalyst is (1-4): 1, preferably (2-3): 1, more preferably 2.8: 1; (b-9) the molar ratio of the basic reagent to compound I-1 is (1-4): 1, preferably (2-3): 1, more preferably 2.5: 1; and / or (b-10) when PG is tert-butyloxycarbonyl (Boc), the deprotecting reagent is selected from trifluoroacetic acid, hydrochloric acid and trimethylsilyl iodide; when PG is benzyloxycarbonyl (Cbz), the deprotecting reagent is selected from palladium on carbon, palladium hydroxide on carbon, palladium chloride, hydrobromic acid / acetic acid and trimethylsilyl iodide; step (c) has one or more of the following characteristics: (c-1) the condensing agent is selected from one or more of n-propylphosphonic anhydride (T3P), carbonyldiimidazole (CDI), O-(7-azabenzotriazol-1-yl)-di(dimethylamino)phosphonium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-di(dimethylamino)phosphonium hexafluorophosphate (HBTU), O-(5-chlorobenzotriazol-1-yl)-di(dimethylamino)phosphonium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-di(dimethylamino)phosphonium tetrafluoroborate (TBTU), O-(N-butyldiimide)-di(dimethylamino)phosphonium tetrafluoroborate (TSTU), O-(N-endo-5-norbornene-2,3-dicarboxyimide)-di(dimethylamino)phosphonium tetrafluoroborate (TNTU), benzotriazol-1-yl oxytris(dimethylamino)phosphonium hexafluorophosphate (HOP), benzotriazol-1-yl oxytris(pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), 7-azabenzotriazol-1-yl oxytris(pyrrolidinyl)phosphonium hexafluorophosphate (PyAOP), dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCI); (c-2) the condensing agent activator is selected from one or more of 4-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine (4-PPY), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), N-hydroxyphthalimide (NHPI) and N-hydroxy-5-norbornene-2,3-dicarboximide (HONB); (c-3) the basic reagent is selected from one or more of pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine; (c-4) the solvent is selected from one or more of C1-6 hydrocarbon solvents, C1-6 halogenated hydrocarbon solvents, ketone solvents, C2-6 nitrile solvents, C2-6 ether solvents, amide solvents and sulfone solvents, preferably one or more of dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone and dimethylsulfoxide; (c-5) the compound R 7 the molar ratio of -OH to compound I-2 is (1-2): 1, preferably (1-1.5): 1, more preferably 1.25:1; (c-6) the molar ratio of the condensing agent to compound I-2 is (1-2): 1, preferably 1.5: 1; (c-7) the molar ratio of the base to compound I-2 is (2-4): 1, preferably (2-3): 1, more preferably 2.6: 1; and / or (c-8) the reaction temperature is 0-30 °C.

11. The method of claim 9, wherein, Ring B is a substituted or unsubstituted phenyl ring, or a substituted or unsubstituted 5-6 membered heteroaromatic ring; wherein the substitution means one or more hydrogens on the group are replaced with R 4 substituted, and each R 4 is independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, benzyloxy, benzylamino; R 6 selected from the group consisting of: R 7 selected from R a , R a and R b as claimed in claim 9.

12. A method of preparing the compound 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'- tetrahydro-6'H-spiro[indeno-l,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-l-(2- fluoroallylidene)piperazin-2-yl)acetonitrile comprising the steps of: (a) compound SM and compound SM-2A are subjected to a nucleophilic substitution reaction under the condition of a basic reagent and protected with a protecting group PG by a protecting group reagent to obtain compound I-la; or, in a solvent, compound SM and compound SM-2B are subjected to a nucleophilic substitution reaction under the condition of a basic reagent to obtain compound I-la; (b) compound I-la and compound SM-3 are subjected to a Buchwald coupling reaction in a palladium catalyst, a ligand, a basic reagent and a solvent, and after deprotection, compound I-2a is obtained; (c) compound I-2a and compound SM-4 are subjected to a condensation reaction in a condensing agent, a basic reagent and a solvent, with or without a condensing agent activator to obtain the compound 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[indeno-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-1-(2-fluorovinylcarbonyl)piperazin-2-yl)acetonitrile; wherein Compound SM is prepared by the method of claim 8.

13. A crystalline form of the compound 2-((S)-4-((S)-7-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H-spiro[indeno-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-1-(2-fluorovinylcarbonyl)piperazin-2-yl)acetonitrile, Form I, characterized by, characteristic peaks 2Q values selected from the group consisting of: 9.0±0.2°, 9.1±0.2°, 13.2±0.2°, 13.5±0.2°, 15.4±0.2°, 15.7±0.2°, 16.0±0.2°, 16.7±0.2°, 17.7±0.2°, 18.4±0.2°, 19.5±0.2°, 19.8±0.2°, 20.8±0.2°, 21.0±0.2°, 21.9±0.2°, 22.4±0.2°, 24.0±0.2°, 26.5±0.2°, 27.7±0.2°, 28.5±0.2°.

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