Quinoline compounds and their uses

Abstract

The quinoline compound and its use. The quinoline compound is a compound represented by formula (I), formula (II), or formula (III), a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, or an isotope thereof.

Description

Detailed Description of the Invention

[0001] This application claims priority to Chinese patent application No. 2022101147120, filed on January 30, 2022, claims priority to Chinese patent application No. 2022106541481, filed on June 9, 2022, claims priority to Chinese patent application No. 2022108381203, filed on July 17, 2022, claims priority to Chinese patent application No. 2022111251811, filed on September 15, 2022, and claims priority to Chinese patent application No. 2022112045597, filed on September 29, 2022. This application cites the above Chinese patent applications in their entirety.

[0002] [Technical Field] The present invention relates to quinoline compounds and their uses.

[0003] [Background technology] RAS represents a group of closely related monomeric globular proteins of 189 amino acids (molecular mass 21 kDa) that associate with the plasma membrane and bind either GDP or GTP. RAS acts as a molecular switch. When RAS has bound GDP, it is in a resting, or off, state and is "inactive." In response to exposure of cells to a given growth-promoting stimulus, RAS is induced to exchange bound GDP for GTP. Upon GTP binding, RAS is "switched on" and can interact with and activate other proteins (its "downstream targets"). RAS proteins themselves have very little intrinsic ability to hydrolyze GTP back to GDP, thereby turning themselves off. To switch off RAS, an exogenous protein called a GTPase-activating protein (GAP) is required, which interacts with RAS and greatly promotes the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAP or convert GTP back to GDP prolongs the activation of the protein, thereby prolonging the signals that tell cells to continue growing and dividing. Because these signals cause cells to grow and divide, overactive RAS signaling can ultimately lead to cancer.

[0004] Structurally, RAS proteins contain a G domain responsible for the enzymatic activity of RAS—guanine nucleotide binding and hydrolysis (GTPase reaction). RAS proteins also contain a C-terminal extension known as the CAAX box, which can be post-translationally modified and is responsible for membrane targeting of RAS proteins. The G domain is approximately 21–25 kDa in size and contains a phosphate-binding loop (P-loop). The P-loop represents the nucleotide-binding pocket in RAS proteins and is the anchor portion of the domain, containing conserved amino acid residues (glycine 12, threonine 26, and lysine 16) essential for nucleotide binding and hydrolysis. The G domain also contains the so-called switch I region (residues 30–40) and switch II region (residues 60–76), which together are dynamic portions of the protein often referred to as a "spring-loaded" mechanism due to their ability to switch between resting and loaded states. The key interactions are hydrogen bonds formed by threonine-35 and glycine-60 with the γ-phosphate of GTP, maintaining the switch 1 and switch 2 regions, respectively, in their active conformations. After GTP hydrolysis and phosphate release, the two relax to the inactive GDP conformation.

[0005] The most prominent members of the RAS subfamily are HRAS, KRAS, and NRAS, which are primarily involved in many types of cancer, but there are many other members: DIRAS1, DIRAS2, DIRAS3, ERAS, GEM, MRAS, NKIRAS1, NKIRAS2, NRAS, RALA, RALB, RAP1A, RAP1B, RAP2A, RAP2B, RAP2C, RASD1, RASD2, RASL10A, RASL10B, RASL11A, RASL11B, RASL12, REM1, REM2, RERG, RERGL, RRAD, RRAS, and RRAS2.

[0006] Mutations in any one of the three major isoforms of the RAS gene (HRAS, NRAS, or KRAS) are the most common event in human tumor development. Approximately 30% of all human tumors have been found to harbor several mutations in RAS genes. Surprisingly, KRAS mutations have been detected in 25-30% of tumors. In contrast, the rates of oncogenic mutations occurring in NRAS and HRAS family members are much lower (8% and 3%, respectively). The most common KRAS mutations are found at residues G12 and G13 in the P-loop and residue Q61. Among tumor-associated KRAS G12 mutations, the KRAS G12D mutation accounts for the highest proportion, approximately 40%.

[0007] Based on the importance of aberrant KRAS activation in cancer progression and the ubiquity of KRAS gene mutations in human cancers, KRAS has long been of interest to drug developers. Although progress has been made in this field, the art remains in need of improved KRAS G12D mutation inhibitors.

[0008] Summary of the Invention The technical problem to be solved by the present invention is to provide a quinazoline compound and its use, which overcomes the drawback of the limited variety of KRAS G12D mutant protein inhibitors in the prior art. The quinazoline compound provided by the present invention has good inhibitory effect on KRAS G12D mutant protein.

[0009] The present invention solves the above technical problems through the following technical solutions.

[0010] The present invention provides a compound represented by Formula I, Formula II, Formula III or Formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof. [ka] However, Formula I, II, or III satisfies the following condition 1 or condition 2. Situation 1: X is N, O or S; each n1 and n4 is independently 1, 2, 3, or 4; Each L is independently -O-(CR L-1 R L-2 ) n2 - * , -(CR L-3 R L-4 ) n3 - * or [ka] and; * is R 1 represents one end connected to n2 and n3 each independently represent 0, 1, 2, 3, or 4; Each R L-1 , R L-2 , R L-3 and R L-4 are each independently H, C1-C6 alkyl, C1-C6 alkoxy, one or more R L-1-1 C1-C6 alkyl or halogen substituted by Each R L-1-1 are each independently halogen or C1-C6 alkoxy, Each R 1 is one or more R 1-1 and wherein one or more R 1-1 the heteroatoms in the 4-10-membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 1-1 are each independently a halogen, R 2 and R 13 are each independently H or halogen; R 3 and R 14 are C6 to C 10 Aryl, "one or more R3-1 C6 to C substituted by 10 aryl," 5- to 10-membered heteroaryl, or "one or more R 3-2 "5- to 10-membered heteroaryl substituted with one or more R 3-2 The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 and R 3-2 are each independently OH, halogen, C1-C6 alkyl, one or more R 3-1-1 C1-C6 alkyl, C2-C6 alkynyl, 3-8 membered cycloalkyl, -SC(R 3-1-2 )3, -S(R 3-1-3 ) 5, amino, C1-C6 alkyl or 5-10 membered heteroaryl; Or, any two adjacent R 3-1 together with the carbon atoms to which they are attached form a 5- to 10-membered heteroaryl, or "one or more R 3-1-4 and forming a 5- to 10-membered heteroaryl substituted with one or more R 3-1-4 The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 3-1-1 are each independently oxo (=O), OH, C1-C6 alkoxy, or halogen, Each R 3-1-2 and each R 3-1-3 are each independently a halogen, Each R 3-1-4 are each independently C1-C6 alkyl, R 4 is H, OH, C1-C6 alkyl, C1-C6 alkoxy, "one or more R 4-1 C1-C6 alkyl substituted by , cyano or halogen; Each R 4-1 are each independently a halogen, X 1 is C(R 1a R 1b ) or O, X 2 is C(R 2a R 2b ) or O, X 3 is C(R 3a R 3b ) or O, R 1a , R 1b , R 2a , R 2b , R 3a and R 3b are each independently H, C1-C6 alkyl, or halogen, R 5 is H or OH, R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, 3- to 8-membered cycloalkyl, halogen, or one or more R 6-1 C1-C6 alkyl substituted with Each R 6-1 are independently halogens, R 7 and R 8 are linked to form ring A, and ring A is a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R 7-1 a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring carbocyclic ring substituted by one or more R 7-2 "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl having 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S" substituted by Each R 7-1 and R 7-2 are each independently C1 to C6 alkyl, oxy, or halogen, R 9 , R 10 , R 11 , R12 , R 15 and R 16 are each independently H, C1-C6 alkyl, or halogen, Situation 2: X is N, O or S; n1 and n4 are independently 1, 2, 3, or 4; Each L is independently -O-(CR L-1 R L-2 ) n2 - * , -(CR L-3 R L-4 ) n3 - * or [ka] and * is R 1 represents one end connected to n2 and n3 each independently represent 0, 1, 2, 3, or 4; R L-1 , R L-2 , R L-3 and R L-4 are each independently H, C1-C6 alkyl, C1-C6 alkoxy, one or more R L-1-1 C1-C6 alkyl or halogen substituted by Each R L-1-1 are each independently halogen or C1-C6 alkoxy, Each R 1 is one or more R 1-1 and wherein one or more R 1-1 The heteroatoms in the 4-10 membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 1-1 are each independently halogen, hydroxy, —O—C1-C6 alkyl, C1-C6 alkyl, or one or more R 1-1-1 C1-C6 alkyl substituted with Each R1-1-1 are each independently hydroxy, —O—C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or one or more R 1-1-1-1 wherein the 4- to 10-membered heterocycloalkyl and the one or more R 1-1-1-1 The heteroatoms in the 4- to 10-membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 1-1-1-1 are each independently C1-C6 alkyl, R 2 and R 13 are each independently H or halogen; R 3 teeth [ka] and R 3 but [ka] If R 4 is F, R 14 are C6 to C 10 Aryl, "one or more R 3-1 C6 to C substituted by 10 aryl," 5- to 10-membered heteroaryl, or "one or more R 3-2 "5- to 10-membered heteroaryl substituted with one or more R 3-2 The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 and R 3-2 are each independently OH, halogen, C1-C6 alkyl, one or more R 3-1-1 C1-C6 alkyl, C2-C6 alkynyl, 3-8 membered cycloalkyl, -SC(R3-1-2 )3, -S(R 3-1-3 ) 5, amino, C1-C6 alkyl, 5-10 membered heteroaryl, one or more R 3-1-4 and the 5- to 10-membered heteroaryl and the "one or more R 3-1-4 The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Or, any two adjacent R 3-1 together with the carbon atoms connected thereto form a 5- to 6-membered carbocyclic ring, one or more R 3-1-4 a 5- to 6-membered carbocycle, a 5- to 6-membered heterocyclyl, or one or more R 3-1-4 and forming a 5- to 6-membered heterocyclyl substituted by said 5- to 6-membered heterocyclyl and said "one or more R 3-1-4 The heteroatoms of the 5- to 6-membered heterocyclyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 3-1-1 are each independently oxo (=O), OH, C1-C6 alkoxy, or halogen, Each R 3-1-2 and R 3-1-3 are each independently a halogen, Each R 3-1-4 are each independently C1-C6 alkyl, R 4 is H, OH, C1-C6 alkyl, C1-C6 alkoxy, "one or more R 4-1 C1-C6 alkyl substituted by ", cyano or F; Each R 4-1 are each independently a halogen, X 1 is C(R 1a R 1b ) or O, X 2 is C(R 2a R 2b ) or O, X 3 is C(R3a R 3b ) or O, R 1a , R 1b , R 2a , R 2b , R 3a and R 3b are each independently H, C1-C6 alkyl, or halogen, R 5 is H or OH, R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, 3- to 8-membered cycloalkyl, halogen, or one or more R 6-1 C1-C6 alkyl substituted with Each R 6-1 are independently halogens, R 7 and R 8 are linked to form ring A, and ring A is a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R 7-1 a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring carbocyclic ring substituted by one or more R, "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocyclyl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three" 7-2 "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocyclyl having 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S" substituted by Each R 7-1 and R 7-2 are each independently C1 to C6 alkyl, oxo, or halogen, R 9 , R 10 , R 11 , R 12 , R 15 and R 16 are each independently H, C1-C6 alkyl, or halogen, In formula IV, X is N, O or S; each n1 is independently 1, 2, 3, or 4; Each L is independently -O-(CR L-1 R L-2 ) n2 - * , -(CR L-3 R L-4 ) n3 - * or [ka] and * is R 1 represents one end connected to n2 and n3 each independently represent 0, 1, 2, 3, or 4; Each R L-1 , R L-2 , R L-3 and R L-4 are each independently H, C1-C6 alkyl, C1-C6 alkoxy, one or more R L-1-1 C1-C6 alkyl or halogen substituted by Each R L-1-1 are each independently halogen or C1-C6 alkoxy, Each R 1 is one or more R 1-1 and wherein one or more R 1-1 The heteroatoms in the 4-10 membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 1-1 are each independently halogen, hydroxy, —O—C1-C6 alkyl, C1-C6 alkyl, or one or more R 1-1-1 C1-C6 alkyl substituted with Each R 1-1-1 are each independently hydroxy, —O—C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or one or more R 1-1-1-1 wherein the 4- to 10-membered heterocycloalkyl and the one or more R 1-1-1-1The heteroatoms in the 4- to 10-membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 1-1-1-1 are each independently C1-C6 alkyl, Each R 2 and R 13 are each independently H or halogen; R 3X is a 5- to 10-membered heteroaryl, or "one or more R 3X-1 "5- to 10-membered heteroaryl substituted with one or more R 3X-1 The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 3X-1 are each independently C1-C6 alkyl, amino, or C1-C6 alkyl substituted with one or more halogens, Each R 9 , each R 10 are each independently H, C1-C6 alkyl or halogen.

[0011] In some embodiments, in situation 1, each R 1 may further include one or more R 1-1 and wherein said one or more R 1-1 The heteroatoms in the 11-membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3.

[0012] In some embodiments, in situation 1, each R 1-1 may further each independently be hydroxy, —O—C1-C6 alkyl, C1-C6 alkyl, or one or more R 1-1-1 C1-C6 alkyl substituted with Each R 1-1-1are each independently hydroxy, —O—C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or one or more R 1-1-1-1 wherein the 4- to 10-membered heterocycloalkyl and the one or more R 1-1-1-1 The heteroatoms in the 4- to 10-membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 1-1-1-1 are each independently C1 to C6 alkyl.

[0013] In some embodiments, in situation 1, each R 3-1 and R 3-2 further independently represent one or more R 3-1-4 and the "one or more R 3-1-4 The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Or, any two adjacent R 3-1 together with the carbon atoms connected thereto form a 5- to 6-membered carbocyclic ring, one or more R 3-1-4 a 5- to 6-membered carbocycle, a 5- to 6-membered heterocyclyl, or one or more R 3-1-4 and forming a 5-6 heterocyclyl substituted by the "5-6 heterocyclyl" and the "one or more R 3-1-4 The heteroatoms of the "5-6 heterocyclyl substituted by" are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3.

[0014] In some embodiments, X is O.

[0015] In some embodiments, n1 is 1 or 2.

[0016] In some embodiments, n1 is 1.

[0017] In some embodiments, n2 and n3 are each independently 1 or 2.

[0018] In some embodiments, R L-1 , R L-2 , R L-3 and R L-4 are each independently H, one or more R L-1-1 or halogen, preferably H.

[0019] In some embodiments, each R L-1-1 are each independently C1 to C6 alkoxy.

[0020] In some embodiments, R 2 is a halogen.

[0021] In some embodiments, R 3 means "one or more R 3-1 C6 to C substituted by 10 aryl,” or “one or more R 3-2 and "5-10 membered heteroaryl substituted by."

[0022] In some embodiments, R 3 means "one or more R 3-1 C6 to C substituted by 10 "aryl".

[0023] In some embodiments, each R 3-1 are each independently 5-10 membered heteroaryl, —O—C1-C6 alkyl, one or more R 3-1-1 C1-C6 alkyl, 3- to 8-membered cycloalkyl, OH, halogen, C1-C6 alkyl or C2-C6 alkynyl substituted by

[0024] In some embodiments, each R 3-1 are each independently OH, halogen, C1-C6 alkyl, or C2-C6 alkynyl.

[0025] In some embodiments, R 4 is H, halogen, cyano, OH, C1-C6 alkoxy, or one or more R 4-1 and preferably H or halogen.

[0026] In some embodiments, X 1 is C(R 1a R 1b )

[0027] In some embodiments, X 2 is C(R 2a R 2b )

[0028] In some embodiments, X 3 is C(R 3a R 3b )

[0029] In some embodiments, R 1a , R 1b , R 2a , R 2b , R 3a and R 3b are each independently H or halogen, preferably H.

[0030] In some embodiments, R 5 is OH.

[0031] In some embodiments, R 6 is H, halogen, C1-C6 alkyl, one or more R 6-1 and is preferably a C1-C6 alkyl or 3- to 8-membered cycloalkyl substituted by, preferably a halogen.

[0032] In some embodiments, ring A is a 5-6 membered saturated or unsaturated monocyclic, spirocyclic, or fused ring carbocyclic ring, 7-1or "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl in which the heteroatom is one, two or three selected from N, O and S and the number of heteroatoms is one, two or three", preferably a 5- to 6-membered saturated or unsaturated monocyclic carbocycle.

[0033] In some embodiments, R 9 , R 10 , R 11 and R 12 are each independently H or C1-C6 alkyl, preferably H.

[0034] In some embodiments, each R 3-2 are each independently C1-C6 alkyl, amino, halogen, or one or more R 3-1-1 is a C1-C6 alkyl substituted by

[0035] In some embodiments, each R 3-1-1 are each independently C1 to C6 alkoxy or halogen.

[0036] In some embodiments, X is O, n1 is 1, R 1 is one or more R 1-1 is a 4- to 10-membered heterocycloalkyl substituted by Each R 1-1 are each independently a halogen, R 2 is a halogen, R 4 is H or a halogen, R 3 means "one or more R 3-1 C6 to C substituted by 10 aryl" Each R 3-1 are each independently OH, halogen, C1-C6 alkyl, or C2-C6 alkynyl, L is -O-(CR L-1R L-2 ) n2 - * and R L-1 or R L-2 are each independently H, n2 is 1, R 9 and R 10 are each independently H.

[0037] In some embodiments, X 1 is C(R 1a R 1b ) or O, X 2 is C(R 2a R 2b ) or O, X 3 is C(R 3a R 3b ) or O, R 1a , R 1b , R 2a , R 2b , R 3a and R 3b are each independently H or halogen; L is -O-(CR L-1 R L-2 ) n2 - * , -(CR L-3 R L-4 ) n3 - * or [ka] and * is R 1 represents one end connected to n2 and n3 each independently represent 1 or 2; R L-1 , R L-2 , R L-3 and R L-4 are each independently H, one or more R L-1-1 C1-C6 alkyl or halogen substituted by Each R L-1-1are each independently C1-C6 alkoxy, R 1 is one or more R 1-1 is a 4- to 10-membered heterocycloalkyl substituted by Each R 1-1 are each independently a halogen, R 5 is H or OH, R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, 3- to 8-membered cycloalkyl, halogen, or one or more R 6-1 C1-C6 alkyl substituted with Each R 6-1 are each independently a halogen, R 7 and R 8 are linked to form ring A, and ring A is a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R 7-1 or "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring carbocyclic ring in which the heteroatom is one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," Each R 7-1 are each independently C1-C6 alkyl, oxo (=O) or halogen, R 11 and R 12 are each independently H, C1-C6 alkyl or halogen.

[0038] In some embodiments, X 1 is C(R 1a R 1b ) and X 2 is C(R 2a R 2b ) and X 3 is C(R 3a R 3b ) and R 1a , R 1b , R 2a , R2b , R 3a and R 3b are each independently H or halogen; R 1 is one or more R 1-1 is a 4- to 10-membered heterocycloalkyl substituted by Each R 1-1 are each independently a halogen, L is -O-(CR L-1 R L-2 ) n2 - * and R L-1 or R L-2 are each independently H, n2 is 1, R 5 is OH, R 6 is a halogen, Ring A is a 5-membered saturated monocyclic carbocyclic ring; R 11 and R 12 are each independently H.

[0039] In some embodiments, R 1 Among them, the "one or more R 1-1 The "4- to 10-membered heterocycloalkyl" in "4- to 10-membered heterocycloalkyl substituted by" is an 8- to 10-membered heterocycloalkyl containing an N atom, and may further be a bicyclo[3.3.0]octaheterocycloalkyl containing an N atom, for example, [ka] is.

[0040] In some embodiments, R 1-1-1 Among these, the 4- to 10-membered heterocycloalkyl and the "one or more R 1-1-1-1The 4- to 10-membered heterocycloalkyl of "4- to 10-membered heterocycloalkyl substituted by" is independently a 5- to 6-membered monocyclic heterocycloalkyl, the heteroatom is N and / or O, the number is 1 or 2, and may further be piperidinyl, piperazine or morpholinyl, and further [ka] may be.

[0041] In some embodiments, R 4 , R 6 , R 3-1 , R L-1 , R L-2 , R L-3 , R L-4 , R 7-1 , R 7-2 , R 9 , R 10 , R 11 and R 12 Among these, the "C1-C6 alkyl" and "one or more R 4-1 "C1-C6 alkyl substituted with," "one or more R 3-1-1 "C1-C6 alkyl substituted with one or more R L-1-1 Each of the "C1 to C6 alkyl" in the "C1 to C6 alkyl substituted by" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, and preferably methyl or ethyl.

[0042] In some embodiments, R 1-1 Among these, the C1-C6 alkyl of the —O—C1-C6 alkyl, C1-C6 alkyl, and one or more R 1-1-1 The C1-C6 alkyl in the C1-C6 alkyl substituted by is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, and preferably methyl or ethyl.

[0043] In some embodiments, R 3-1 and R 3-2Among these, the C1 to C6 alkyls in the —O—C1 to C6 alkyl are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, and preferably methyl or ethyl.

[0044] In some embodiments, R 1-1-1 , R 1-1-1-1 , R 3-1-4 , R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 15 , R 16 , R 3X-1 and R 3-2 Among these, the "C1-C6 alkyl" and "one or more R 3-1-1 "C1-C6 alkyl substituted by," "-O-C1-C6 alkyl," "one or more R 1-1-1 The "C1-C6 alkyl" in "C1-C6 alkyl substituted by" and "C1-C6 alkyl substituted by one or more halogens" is each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, and preferably methyl or ethyl.

[0045] In some embodiments, R 1-1-1 In the formula, two R 1-1-1 and the carbon atoms connected thereto together form a 3- to 8-membered cycloalkyl, which is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0046] In some embodiments, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 1-1 , R 2 , R 4 , R 6 , R 3-1 , R 3-1-1 , R 3-1-2, R 3-1-3 , R 4-1 , R 6-1 , R L-1 , R L-2 , R L-3 , R L-4 , R L-1-1 , R 7-1 , R 7-2 , R 9 , R 10 , R 11 and R 12 In the formula (I), the halogens are each independently fluorine, chlorine, bromine or iodine, and preferably fluorine or chlorine.

[0047] In some embodiments, R 13 , R 3-2 , R 15 , R 16 and R 3X-1 In the formula (I), the halogens are each independently fluorine, chlorine, bromine or iodine, and preferably fluorine or chlorine.

[0048] In some embodiments, R 4 , R 6 , R 3-1-1 , R L-1 , R L-2 , R L-3 , R L-4 and R L-1-1 Among these, the "C1 to C6 alkoxy" is each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, and preferably methoxy or ethoxy.

[0049] In some embodiments, R 6 and R 3-1 Among these, the 3- to 8-membered cycloalkyls are each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and preferably cyclopropyl or cyclobutyl.

[0050] In some embodiments, R 3-2Among these, the 3- to 8-membered cycloalkyls are each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and preferably cyclopropyl or cyclobutyl.

[0051] In some embodiments, R 3-1 Among these, the "C2-C6 alkynyl" is C2-C4 alkynyl, and preferably ethynyl.

[0052] In some embodiments, R 3-2 Among these, the "C2-C6 alkynyl" is C2-C4 alkynyl, and preferably ethynyl.

[0053] In some embodiments, R 14 Among them, the above "C6~C 10 aryl," and "one or more R 3-1 C6 to C substituted by 10 Aryl "C6~C 10 Each "aryl" is independently phenyl or naphthyl, preferably naphthyl.

[0054] In some embodiments, R 3 Among them, the above "C6~C 10 aryl," and "one or more R 3-1 C6 to C substituted by 10 Aryl "C6~C 10 Each "aryl" is independently phenyl or naphthyl, preferably naphthyl.

[0055] In some embodiments, R 3 Among these, the "5- to 10-membered heteroaryl" is a 9- to 10-membered heteroaryl.

[0056] In some embodiments, R 3-1 , R 3-2 and R 1 Among these, the "5- to 10-membered heteroaryl", the "5- to 10-membered heteroaryl substituted with C1-C6 alkyl", and "one or more R3-2 Each "5- to 10-membered heteroaryl" in "5- to 10-membered heteroaryl substituted by" is independently a 9- to 10-membered heteroaryl.

[0057] In some embodiments, R 3X Among these, the "5- to 10-membered heteroaryl" and the "one or more R 3a-1 Each "5- to 10-membered heteroaryl" in "5- to 10-membered heteroaryl substituted by" is independently pyridine.

[0058] In some embodiments, R 3 and R 14 Each independently represents "one or more R 3-1 C6 to C substituted by 10 aryl" and any two adjacent R 3-1 together with the carbon atom to which they are attached form a 5- to 10-membered heteroaryl, or "one or more R 3-1-4 When forming "5- to 10-membered heteroaryl substituted by R 3 and R 14 are each independently [ka] is.

[0059] In some embodiments, -LR 1 teeth [ka] and preferably [ka] and more preferably, [ka] is.

[0060] In some embodiments, R 2 is fluorine.

[0061] In some embodiments, R 3 teeth [ka] and preferably [ka] is.

[0062] In some embodiments, R 4 is H, fluorine, chlorine, cyano, trifluoromethyl, hydroxy, methoxy or ethoxy, preferably hydrogen or fluorine.

[0063] In some embodiments, R 9 , R 10 , R 11 and R 12 are each independently H or methyl, preferably H.

[0064] In some embodiments, X 1 , X 2 , X 3 are each independently CH2, O, CHF or CF2, preferably CH2.

[0065] In some embodiments, R 5 is OH or H, preferably OH.

[0066] In some embodiments, R 6 is H, chlorine, fluorine, methyl, trifluoromethyl or cyclopropyl, preferably chlorine.

[0067] In some embodiments, ring A is [ka] And ( [ka] represents a bond to the benzene ring on which R5 is located), preferably [ka] For example, [ka] (* is X 1 , X 2 and X 3 represents the position where the ring is bonded to.

[0068] In some embodiments, R 13 is fluorine.

[0069] In some embodiments, R 14 teeth [ka] is.

[0070] In some embodiments, R 3X teeth [ka] is.

[0071] In some embodiments, the compound of formula I, formula II, or formula III, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, or an isotopic compound thereof, where X is N, O or S; n1 and n4 are independently 1, 2, 3, or 4; Each L is independently -O-(CR L-1R L-2 ) n2 - * , -(CR L-3 R L-4 ) n3 - * or [ka] and * is R 1 represents one end connected to n2 and n3 each independently represent 0, 1, 2, 3, or 4; R L-1 , R L-2 , R L-3 and R L-4 are each independently H, C1-C6 alkyl, C1-C6 alkoxy, one or more R L-1-1 C1-C6 alkyl or halogen substituted by Each R L-1-1 are each independently halogen or C1-C6 alkoxy, Each R 1 is one or more R 1-1 and wherein one or more R 1-1 the heteroatoms in the 4-10-membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 1-1 are each independently a halogen, R 2 and R 13 are each independently H or halogen; R 3 and R 14 are C6 to C 10 Aryl, "one or more R 3-1 C6 to C substituted by 10 aryl," 5- to 10-membered heteroaryl, or "one or more R 3-2 "5- to 10-membered heteroaryl substituted with one or more R3-2 The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 and R 3-2 are each independently OH, halogen, C1-C6 alkyl, one or more R 3-1-1 C1-C6 alkyl, C2-C6 alkynyl, 3-8 membered cycloalkyl, -SC(R 3-1-2 )3, -S(R 3-1-3 ) 5, amino, C1-C6 alkyl or 5-10 membered heteroaryl; Or, any two adjacent R 3-1 together with the carbon atoms to which they are attached form a 5- to 10-membered heteroaryl, or "one or more R 3-1-4 and forming a 5- to 10-membered heteroaryl substituted with one or more R 3-1-4 The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 3-1-1 are each independently oxo (=O), OH, C1-C6 alkoxy, or halogen, Each R 3-1-2 and R 3-1-3 are each independently a halogen, Each R 3-1-4 are each independently C1-C6 alkyl, R 4 is H, OH, C1-C6 alkyl, C1-C6 alkoxy, "one or more R 4-1 C1-C6 alkyl substituted by , cyano or halogen; Each R 4-1 are each independently a halogen, X 1 is C(R 1a R 1b ) or O, X 2 is C(R 2a R 2b ) or O, X3 is C(R 3a R 3b ) or O, R 1a , R 1b , R 2a , R 2b , R 3a and R 3b are each independently H, C1-C6 alkyl, or halogen, R 5 is H or OH, R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, 3- to 8-membered cycloalkyl, halogen, or one or more R 6-1 C1-C6 alkyl substituted with Each R 6-1 are independently halogens, R 7 and R 8 are linked to form ring A, and ring A is a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R 7-1 a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring carbocyclic ring, "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl in which the heteroatom is one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one or more R 7-2 "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl having 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S" substituted by Each R 7-1 and R 7-2 are each independently C1 to C6 alkyl, oxo, or halogen, R 9 , R 10 , R 11 , R 12 , R 15 and R 16 are each independently H, C1-C6 alkyl or halogen.

[0072] In some embodiments, the compound of formula I, formula II or formula III, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, or an isotopic compound thereof, In the compounds of formula I, II or III, X is N, O or S; n1 and n4 are independently 1, 2, 3, or 4; Each L is independently -O-(CR L-1 R L-2 ) n2 - * , -(CR L-3 R L-4 ) n3 - * or [ka] and * is R 1 represents one end connected to n2 and n3 each independently represent 0, 1, 2, 3, or 4; R L-1 , R L-2 , R L-3 and R L-4 are each independently H, C1-C6 alkyl, C1-C6 alkoxy, one or more R L-1-1 C1-C6 alkyl or halogen substituted by Each R L-1-1 are each independently halogen or C1-C6 alkoxy, Each R 1 is one or more R 1-1 and wherein one or more R 1-1 The heteroatoms in the 4-10 membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 1-1 are each independently a halogen, R 2 and R 13are each independently H or halogen; R 3 and R 14 are C6 to C 10 Aryl, "one or more R 3-1 C6 to C substituted by 10 aryl," 5- to 10-membered heteroaryl, or "one or more R 3-2 "5- to 10-membered heteroaryl substituted with one or more R 3-2 The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 and R 3-2 are each independently OH, halogen, C1-C6 alkyl, one or more R 3-1-1 C1-C6 alkyl, C2-C6 alkynyl, 3-8 membered cycloalkyl, -SC(R 3-1-2 )3, -S(R 3-1-3 ) 5 or amino; Or, any two adjacent R 3-1 together with the carbon atoms to which they are attached form a 5- to 10-membered heteroaryl, or "one or more R 3-1-4 and forming a 5- to 10-membered heteroaryl substituted with one or more R 3-1-4 The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 3-1-1 are each independently oxo (=O), OH, C1-C6 alkoxy, or halogen, Each R 3-1-2 and R 3-1-3 are each independently a halogen, Each R 3-1-4 are each independently C1-C6 alkyl, R 4 is H, OH, C1-C6 alkyl, C1-C6 alkoxy, "one or more R 4-1C1-C6 alkyl substituted by , cyano or halogen; Each R 4-1 are each independently a halogen, X 1 is C(R 1a R 1b ) or O, X 2 is C(R 2a R 2b ) or O, X 3 is C(R 3a R 3b ) or O, R 1a , R 1b , R 2a , R 2b , R 3a and R 3b are each independently H, C1-C6 alkyl, or halogen, R 5 is H or OH, R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, 3- to 8-membered cycloalkyl, halogen, or one or more R 6-1 C1-C6 alkyl substituted with Each R 6-1 are independently halogens, R 7 and R 8 are linked to form ring A, and ring A is a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R 7-1 a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring carbocyclic ring, "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl in which the heteroatom is one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one or more R 7-2 "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl having 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S" substituted by Each R 7-1 and R 7-2are each independently C1 to C6 alkyl, oxo, or halogen, R 9 , R 10 , R 11 , R 12 , R 15 and R 16 are each independently H, C1-C6 alkyl or halogen.

[0073] In some embodiments, the compound is a compound represented by Formula I or Formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, or an isotope thereof. [ka] where X is N, O or S; n1 is 1, 2, 3 or 4; L is -O-(CR L-1 R L-2 ) n2 - * , -(CR L-3 R L-4 ) n3 - * or [ka] and * is R 1 represents one end connected to n2 and n3 each independently represent 0, 1, 2, 3, or 4; R L-1 , R L-2 , R L-3 and R L-4 are each independently H, C1-C6 alkyl, C1-C6 alkoxy, one or more R L-1-1 C1-C6 alkyl or halogen substituted by Each R L-1-1 are each independently halogen or C1-C6 alkoxy, R 1 is one or more R 1-1and wherein one or more R 1-1 The heteroatoms in the 4-10 membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 1-1 are each independently a halogen, R 2 is H or a halogen, R 3 is C6~C 10 Aryl, "one or more R 3-1 C6 to C substituted by 10 aryl" or 5- to 10-membered heteroaryl, wherein the heteroatoms of the 5- to 10-membered heteroaryl are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 are each independently OH, halogen, C1-C6 alkyl, one or more R 3-1-1 C1-C6 alkyl, C2-C6 alkynyl, 3-8 membered cycloalkyl, -SC(R 3-1-2 )3 or -S(R 3-1-3 )5, Each R 3-1-1 are each independently oxo (=O), OH, C1-C6 alkoxy, or halogen, Each R 3-1-2 and R 3-1-3 are each independently a halogen, R 4 is H, OH, C1-C6 alkyl, C1-C6 alkoxy, "one or more R 4-1 C1-C6 alkyl substituted by , cyano or halogen; Each R 4-1 are each independently a halogen, X 1 is C(R 1a R 1b ) or O, X 2 is C(R 2a R 2b ) or O, X 3 is C(R 3a R 3b ) or O, R 1a , R 1b , R 2a , R 2b , R 3a and R 3b are each independently H, C1-C6 alkyl, or halogen, R 5 is H or OH, R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, 3- to 8-membered cycloalkyl, halogen, or one or more R 6-1 C1-C6 alkyl substituted with Each R 6-1 are independently halogens, R 7 and R 8 are linked to form ring A, and ring A is a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R 7-1 a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring carbocyclic ring, "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl in which the heteroatom is one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one or more R 7-2 "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl having 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S" substituted by Each R 7-1 and R 7-2 are each independently C1-C6 alkyl, oxo (=O) or halogen, R 9 , R 10 , R 11 and R 12 are each independently H, C1-C6 alkyl or halogen.

[0074] In some embodiments, X is N, O, or S; n1 is 1, 2, 3 or 4; L is -O-(CR L-1 R L-2 ) n2 - * , -(CR L-3 R L-4 ) n3 - * or [ka] and * is R 1 represents one end connected to n2 and n3 each independently represent 0, 1, 2, 3, or 4; R L-1 , R L-2 , R L-3 and R L-4 are each independently H, C1-C6 alkyl, C1-C6 alkoxy, one or more R L-1-1 C1-C6 alkyl or halogen substituted by Each R L-1-1 are each independently halogen or C1-C6 alkoxy, R 1 is one or more R 1-1 and wherein one or more R 1-1 The heteroatoms in the 4-10 membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 1-1 are each independently a halogen, R 2 is H or a halogen, R 3 is C6~C 10 Aryl, "one or more R 3-1 C6 to C substituted by 10 aryl" or 5- to 10-membered heteroaryl, wherein the heteroatoms of the 5- to 10-membered heteroaryl are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 are each independently OH, halogen, C1-C6 alkyl, one or more R 3-1-1 C1-C6 alkyl, C2-C6 alkynyl, 3-8 membered cycloalkyl, -SC(R 3-1-2 )3 or -S(R 3-1-3 )5, Each R 3-1-1 are each independently oxo (=O), OH, C1-C6 alkoxy, or halogen, Each R 3-1-2 and R 3-1-3 are each independently a halogen, R 4 is H, OH, C1-C6 alkyl, C1-C6 alkoxy, "one or more R 4-1 C1-C6 alkyl substituted by , cyano or halogen; Each R 4-1 are each independently a halogen, X 1 is C(R 1a R 1b ) or O, X 2 is C(R 2a R 2b ) or O, X 3 is C(R 3a R 3b ) or O, R 1a , R 1b , R 2a , R 2b , R 3a and R 3b are each independently H, C1-C6 alkyl, or halogen, R 5 is H or OH, R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, 3- to 8-membered cycloalkyl, halogen, or one or more R 6-1 C1-C6 alkyl substituted with Each R 6-1 are independently halogens, R 7 and R 8are linked to form ring A, and ring A is a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R 7-1 a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring carbocyclic ring, "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl in which the heteroatom is one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one or more R 7-2 "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl having 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S" substituted by Each R 7-1 and R 7-2 are each independently C1 to C6 alkyl or halogen, R 9 , R 10 , R 11 and R 12 are each independently H, C1-C6 alkyl or halogen.

[0075] In some embodiments, the compound of Formula I, Formula II, Formula III, or Formula IV is any of the following compounds: [ka] JPEG2025504041000029.jpg219169 JPEG2025504041000030.jpg231169 JPEG2025504041000031.jpg41169

[0076] In some embodiments, the stereoisomer of the compound of Formula I, Formula II, Formula III, or Formula IV is any of the following compounds: [ka] JPEG2025504041000033.jpg69169 [Table 1] [ka] JPEG2025504041000036.jpg195169 JPEG2025504041000037.jpg245169 JPEG2025504041000038.jpg229169 JPEG2025504041000039.jpg227169 JPEG2025504041000040.jpg185169

[0077] Preferably, The retention time is 1.275 minutes under the following conditions: [ka] The compound obtained was prepared using one stereoisomer of Optichiral C9-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% phase B within 1.8 min; detector: UV 220 nm.

[0078] Alternatively, the retention time is 1.082 min under the following conditions: [ka] The compound obtained was prepared using one stereoisomer of Optichiral C9-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% phase B within 1.8 min; detector: UV 220 nm.

[0079] Alternatively, the retention time is 5.009 min under the following conditions: [ka] The compound obtained was prepared using one stereoisomer of (S,S)-Whelk-O1, 4.6 × 100 mm, 3.5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 40% phase B within 6.5 min; detector: UV 220 nm.

[0080] Alternatively, the retention time is 4.193 min under the following conditions: [ka] The compound obtained was prepared using one stereoisomer of (S,S)-Whelk-O1, 4.6 × 100 mm, 3.5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 40% phase B within 6.5 min; detector: UV 220 nm.

[0081] Alternatively, the retention time is 0.836 min under the following conditions: [ka] One stereoisomer of was determined using: Column: Optichiral C9-3, 3 x 100 mm, 3 μm; Mobile phase A: supercritical carbon dioxide fluid; Mobile phase B: methanol (20 mmol / L ammonia); Flow rate: 2 mL / min; Isogradient elution with 50% B phase within 2 min; Detector: UV 230 nm.

[0082] Alternatively, the retention time is 1.233 min under the following conditions: [ka] One stereoisomer of was analyzed using: Column: Optichiral C9-3, 3 x 100 mm, 3 μm; Mobile phase A: supercritical carbon dioxide fluid; Mobile phase B: methanol (20 mmol / L ammonia); Flow rate: 2 mL / min; Elution with an isocratic gradient of 50% B phase within 2 min; Detector: UV 230 nm.

[0083] Alternatively, the retention time is 3.304 min under the following conditions: [ka] The compound obtained was prepared using one stereoisomer of N-CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 3.0 × 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% of phase B within 12 min; detector: UV 220 nm.

[0084] Or, under the following conditions, the retention time is 2.199 min. [ka] The compound obtained was prepared using one stereoisomer of N-CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 3.0 × 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% of phase B within 12 min; detector: UV 220 nm.

[0085] Alternatively, the retention time is 3.795 min under the following conditions: [ka] The compound obtained was prepared using one stereoisomer of N-CHIRALPAK IC-3 (Lot No. IC30CS-VF008), 4.6 × 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% B phase within 6 min; detector: UV 220 nm.

[0086] Alternatively, the retention time is 4.358 min under the following conditions: [ka] The compound obtained was prepared using one stereoisomer of N-CHIRALPAK IC-3 (Lot No. IC30CS-VF008), 4.6 × 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% B phase within 6 min; detector: UV 220 nm.

[0087] Alternatively, the retention time is 1.964 min under the following conditions: [ka] The compound obtained was prepared using one stereoisomer of: CHIRALPAK IG-3, 4.6 × 50 mm, 3 μm; mobile phase A: n-hexane (0.1% ethylenediamine); mobile phase B: ethanol; flow rate: 1.67 mL / min; isogradient elution with 30% B phase within 7 min; detector: UV 290 nm.

[0088] Alternatively, the retention time is 4.664 min under the following conditions: [ka] The compound obtained was prepared using one stereoisomer of: CHIRALPAK IG-3, 4.6 × 50 mm, 3 μm; mobile phase A: n-hexane (0.1% ethylenediamine); mobile phase B: ethanol; flow rate: 1.67 mL / min; isogradient elution with 30% B phase within 7 min; detector: UV 290 nm.

[0089] Alternatively, the retention time is 5.228 min under the following conditions: [ka] The compound obtained was prepared using one stereoisomer of: Lux Cellulose-2, 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (0.1% diethylamine); flow rate: 2 mL / min; isogradient elution with 50% phase B within 7.5 min; detector: UV 220 nm.

[0090] Alternatively, the retention time is 4.017 min under the following conditions: [ka] The compound obtained was prepared using one stereoisomer of: Lux Cellulose-2, 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (0.1% diethylamine); flow rate: 2 mL / min; isogradient elution with 50% phase B within 7.5 min; detector: UV 220 nm.

[0091] Here, the "*" mark indicates a carbon atom in the S configuration or a carbon atom in the R configuration, [ka] teeth [ka] or [ka] Represents.

[0092] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula I, Formula II, Formula III, or Formula IV can be the hydrochloride salt of the compound of Formula I, Formula II, or Formula III.

[0093] In some embodiments, there may be one, two, three, four, or five pharmaceutically acceptable salts of the compound of Formula I, Formula II, Formula III, or Formula IV.

[0094] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula I, Formula II, Formula III, or Formula IV is any one of the following compounds: [ka] JPEG2025504041000059.jpg128169

[0095] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula I, Formula II, Formula III, or Formula IV is any one of the following compounds: [ka] Preferably, The compound with a retention time of 1.275 min under the following conditions is [ka] One stereoisomer of Optichiral C9-3, 3.0 × 100 mm, 3 μm; Mobile phase A: supercritical carbon dioxide; Mobile phase B: methanol (20 mmol / L ammonia); Flow rate: 2 mL / min; Isogradient elution with 50% B phase within 1.8 min; Detector: UV 220 nm; Or, a compound with a retention time of 1.082 min under the following conditions: [ka] One stereoisomer of Optichiral C9-3, 3.0 × 100 mm, 3 μm; Mobile phase A: supercritical carbon dioxide; Mobile phase B: methanol (20 mmol / L ammonia); Flow rate: 2 mL / min; Isogradient elution with 50% B phase within 1.8 min; Detector: UV 220 nm; Or, a compound with a retention time of 5.009 min under the following conditions, which is [ka] One stereoisomer of (S,S)-Whelk-O1, 4.6 × 100 mm, 3.5 μm; Mobile phase A: supercritical carbon dioxide; Mobile phase B: methanol (20 mmol / L ammonia); Flow rate: 2 mL / min; Isogradient elution with 40% B phase within 6.5 min; Detector: UV 220 nm; Or, a compound with a retention time of 4.193 min under the following conditions: [ka] One stereoisomer of (S,S)-Whelk-O1, 4.6 × 100 mm, 3.5 μm; Mobile phase A: supercritical carbon dioxide; Mobile phase B: methanol (20 mmol / L ammonia); Flow rate: 2 mL / min; Isogradient elution with 40% B phase within 6.5 min; Detector: UV 220 nm; Alternatively, the retention time is 3.304 min under the following conditions: [ka] One stereoisomer of N-CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 3.0 × 100 mm, 3 μm; Mobile phase A: supercritical carbon dioxide fluid; Mobile phase B: methanol (20 mmol / L ammonia); Flow rate: 2 mL / min; Isogradient elution with 50% B phase within 12 min; Detector: UV 220 nm; Or, under the following conditions, the retention time is 2.199 min. [ka] One stereoisomer of N-CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 3.0 × 100 mm, 3 μm; Mobile phase A: supercritical carbon dioxide fluid; Mobile phase B: methanol (20 mmol / L ammonia); Flow rate: 2 mL / min; Isogradient elution with 50% B phase within 12 min; Detector: UV 220 nm; Alternatively, the retention time is 3.795 min under the following conditions: [ka] One stereoisomer of N-CHIRALPAK IC-3 (Lot No. IC30CS-VF008), 4.6 × 100 mm, 3 μm; Mobile phase A: supercritical carbon dioxide fluid; Mobile phase B: methanol (20 mmol / L ammonia); Flow rate: 2 mL / min; Isogradient elution with 50% B phase within 6 min; Detector: UV 220 nm; Alternatively, the retention time is 4.358 min under the following conditions: [ka] One stereoisomer of N-CHIRALPAK IC-3 (Lot No. IC30CS-VF008), 4.6 × 100 mm, 3 μm; Mobile phase A: supercritical carbon dioxide fluid; Mobile phase B: methanol (20 mmol / L ammonia); Flow rate: 2 mL / min; Isogradient elution with 50% B phase within 6 min; Detector: UV 220 nm; Alternatively, the retention time is 1.964 min under the following conditions: [ka] One stereoisomer of , CHIRALPAK IG-3, 4.6 × 50 mm, 3 μm; Mobile phase A: n-hexane (0.1% ethylenediamine); Mobile phase B: ethanol; Flow rate: 1.67 mL / min; Isogradient elution with 30% B phase within 7 min; Detector: UV 290 nm; Alternatively, the retention time is 4.664 min under the following conditions: [ka] One stereoisomer of , CHIRALPAK IG-3, 4.6 × 50 mm, 3 μm; Mobile phase A: n-hexane (0.1% ethylenediamine); Mobile phase B: ethanol; Flow rate: 1.67 mL / min; Isogradient elution with 30% B phase within 7 min; Detector: UV 290 nm; Alternatively, the retention time is 5.228 min under the following conditions: [ka] One stereoisomer of Lux Cellulose-2, 4.6 × 100 mm, 3 μm; Mobile phase A: supercritical carbon dioxide fluid; Mobile phase B: methanol (0.1% diethylamine); Flow rate: 2 mL / min; Isogradient elution with 50% B phase within 7.5 min; Detector: UV 220 nm; Alternatively, the retention time is 4.017 min under the following conditions: [ka] One stereoisomer of Lux Cellulose-2, 4.6 x 100 mm, 3 μm; Mobile phase A: supercritical carbon dioxide fluid; Mobile phase B: methanol (0.1% diethylamine); Flow rate: 2 mL / min; Isogradient elution with 50% B phase within 7.5 min; Detector: UV 220 nm.

[0096] [ka] JPEG2025504041000074.jpg39169 Here, the "*" mark indicates a carbon atom in the S configuration or a carbon atom in the R configuration, [ka] teeth [ka] or [ka] Represents.

[0097] The present invention further provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof: [ka] JPEG2025504041000079.jpg223169 JPEG2025504041000080.jpg211169 JPEG2025504041000081.jpg212169 JPEG2025504041000082.jpg237169 JPEG2025504041000083.jpg224169 JPEG2025504041000084.jpg232169 JPEG2025504041000085.jpg224169 JPEG2025504041000086.jpg237169 JPEG2025504041000087.jpg38169 Here, the "*" mark indicates a carbon atom in the S configuration or a carbon atom in the R configuration, [ka] teeth [ka] or [ka] Represents.

[0098] The present invention provides a pharmaceutical composition comprising a compound represented by formula I, II, III or IV, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof, and an excipient.

[0099] In the pharmaceutical composition, the compound represented by Formula I, Formula II, Formula III or Formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof may be administered in a therapeutically effective amount.

[0100] The present invention further provides use of a compound represented by formula I, formula II, formula III or formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, an isotope thereof or the pharmaceutical composition in the preparation of a KRAS mutant protein inhibitor.

[0101] In the above use, the KRAS mutant protein may be a KRAS G12D mutant protein, and the KRAS mutant protein inhibitor is used mainly for experimental purposes other than in vitro use, for example, to provide a comparison as a standard sample or control sample, or to prepare a kit according to conventional methods in the field to provide rapid detection of the inhibitory effect of KRAS G12D mutant protein.

[0102] The present invention further provides use of a compound represented by Formula I, Formula II, Formula III or Formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, an isotope thereof or the pharmaceutical composition thereof in the preparation of a medicament, wherein the medicament is used for the prevention or treatment of cancer mediated by KRAS mutation.

[0103] The KRAS mutant protein is preferably a KRAS G12D mutant protein.

[0104] The cancer mediated by the KRAS mutant protein may be a blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer, etc.

[0105] The present invention further provides use of a compound represented by Formula I, Formula II, Formula III or Formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, an isotope thereof or the pharmaceutical composition in the preparation of a medicament, wherein the medicament is used for the prevention or treatment of cancer.

[0106] The cancer may be, for example, a blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

[0107] The cancer is a cancer mediated by a KRAS mutation. The KRAS mutant protein may be a KRAS G12D mutant protein.

[0108] The present invention further provides a method for preventing or treating cancer mediated by KRAS mutation, which comprises administering to a patient a therapeutically effective amount of a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, an isotope thereof, or the pharmaceutical composition.

[0109] The cancer may be, for example, a blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

[0110] The KRAS mutant protein may be a KRAS G12D mutant protein.

[0111] The present invention further provides a method for preventing or treating cancer, which comprises administering to a patient a therapeutically effective amount of a compound represented by Formula I, Formula II, Formula III or Formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, an isotope compound thereof, or the pharmaceutical composition.

[0112] The cancer may be, for example, a blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

[0113] The present disclosure further relates to a method of treating a hyperproliferative disease in a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

[0114] Ras mutations include, but are not limited to, K-Ras, H-Ras, or N-Ras mutations identified in hematological cancers or malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, some embodiments relate to administering the disclosed compounds (e.g., in the form of a pharmaceutical composition) to a patient in need of treatment for a hematological cancer or malignancy.

[0115] In some specific embodiments, the present disclosure relates to a method for treating lung cancer, comprising administering an effective amount of any of the above compounds (or a pharmaceutical composition comprising said compounds) to a subject in need thereof.

[0116] In the present invention, the cancer or malignant tumor includes, but is not limited to, leukemia and lymphoma. In some embodiments, the blood disease is also, for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemia. In some embodiments, the lymphoma is, for example, any subtype of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0117] In some embodiments of the present invention, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell carcinoma, or large cell lung cancer. In other embodiments, the lung cancer is small cell lung cancer. Other lung cancers include, but are not limited to, adenoma, carcinoid, and undifferentiated carcinoma.

[0118] In some embodiments of the present invention, the cancer is, for example, acute myeloid leukemia, adolescent cancer, pediatric adrenocortical carcinoma, AIDS-related cancer (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratomas, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid, atypical teratomas, embryonal tumors, germ cell tumors, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia ( CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, central nervous system cancer, endometrial cancer, ependymoma, esophageal cancer, granulomatous neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumors, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart disease, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumors, pancreatic neuroendocrine tumors Urinary tract tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma, primary occult carcinoma, midline carcinoma, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasia tumors, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, osteosarcoma and malignant fibrous histiocytoma of bone, nasal cavity and paranasal sinuses, nasal cavity and paranasal sinus neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cancer cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, cancer of the paranasal sinuses and nasal cavity, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer or viral cancer.In some embodiments, the non-cancerous hyperproliferative disease is, for example, benign hyperplasia of the skin (eg, psoriasis), restenosis, or prostate (eg, benign prostatic hyperplasia (BPH)).

[0119] In some embodiments of the present invention, the cancer is brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, or glioblastoma, and is preferably selected from pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0120] [Definition of terms] The term "pharmaceutically acceptable salt" refers to salts, solvents, excipients, etc. that are generally non-toxic, safe, and suitable for use by a patient. The "patient" is preferably a mammal, more preferably a human.

[0121] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt, as defined herein, which possesses all the effects of the parent compound. Pharmaceutically acceptable salts can be prepared by adding the corresponding acid to an appropriate organic solvent of an organic base and treating according to conventional methods.

[0122] Example of salt formation: In the case of base addition salts, alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., aluminum, magnesium, calcium, zinc, or bismuth) salts are prepared by treating a compound of the present invention having a suitable acidic proton with an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g., ethylate or methoxide) or a suitable basic organic amine (e.g., diethanolamine, choline, or N-methyl-D-glucamine) in an aqueous medium.

[0123] Alternatively, in the case of acid addition salts, salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, 6-hydroxy-2-naphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, oxalic acid, pyruvic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, citric acid, cinnamic acid, p-toluenesulfonic acid, and trimethylacetic acid.

[0124] The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules of the solvate may be in an ordered or disordered arrangement. Such solvents include, but are not limited to, water, methanol, and ethanol.

[0125] The term "prodrug" refers to a compound that has no or little activity in vitro, obtained by modifying the chemical structure of a drug, and that exerts its effect by releasing the active drug through enzymatic or non-enzymatic conversion in vivo.

[0126] The term "metabolite" refers to intermediate and final products of metabolism.

[0127] The term "isotopic compound" refers to a compound in which one or more atoms may be present in an unnatural abundance. For example, for the hydrogen atom, its unnatural abundance refers to about 95% being deuterium.

[0128] The term "pharmaceutical excipient" may refer to an excipient widely used in the field of pharmaceutical manufacturing. Excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition, and may also provide a method for dissolving an active ingredient at a desired rate after administration to a subject or for promoting effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipient may be an inert filler, or may serve a specific function, such as stabilizing the overall pH value of the composition or preventing degradation of the active ingredient of the composition. The pharmaceutical excipient may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors, and sweeteners.

[0129] The pharmaceutical compositions of the present invention may be prepared in accordance with the present disclosure using any method known to one of skill in the art, such as, for example, conventional mixing, dissolving, granulating, emulsifying, pulverizing, encapsulating, embedding, or lyophilizing processes.

[0130] The pharmaceutical compositions described herein may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ophthalmic, rectal, topical, or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular). The pharmaceutical compositions of the present invention may also be in a controlled-release or delayed-release dosage form (e.g., liposomes or microspheres). Examples of solid oral dosage forms include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, detergents, drops, or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, injectable solutions, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, injectable suspensions, and injectable emulsions. Examples of other suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations; aerosols such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; lozenges and tablets.

[0131] "Treatment" means any treatment of a mammalian disease, including (1) preventing the disease, i.e., preventing the onset of clinical disease symptoms; (2) inhibiting the disease, i.e., preventing the onset of clinical symptoms; and (3) ameliorating the disease, i.e., causing the disappearance of clinical symptoms.

[0132] An "effective amount" refers to an amount of a compound that, when administered to a patient in need of treatment, is sufficient to (i) treat the relevant disease, (ii) alleviate, ameliorate, or eliminate one or more symptoms of a particular disease or disorder, or (iii) delay the onset of one or more symptoms of a particular disease or disorder described herein. The corresponding amount of the carbonyl heterocyclic compound represented by Formula II or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, may vary depending on factors such as the particular compound, the disease state and its severity, and the characteristics (e.g., body weight) of the patient requiring treatment, but can nevertheless be routinely determined by one of ordinary skill in the art.

[0133] "Methanol (20 mmol / L ammonia)" as used in the present invention means that 20 mmol of ammonia is contained per 1 L of methanol.

[0134] "Prevention" according to the present invention refers to reducing the risk of developing or occurring a disease or disorder.

[0135] The term "alkyl" refers to a straight or branched chain alkyl having a specified number of carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and similar alkyls, preferably methyl. Unless the substituent is specifically stated, the alkyl is unsubstituted.

[0136] The term "heterocycloalkyl" refers to a stable 4- to 10- or 11-membered saturated cyclic group consisting of 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, a heterocycloalkyl group can be a monocyclic ("monocyclic heterocycloalkyl"), or a bicyclic, tricyclic, or higher ring system, which can include fused (fused ring), bridged (bridged ring), or spiro (spirocyclic) ring systems (e.g., a bicyclic ring system ("bicyclic heterocycloalkyl")). Bicyclic ring systems of heterocycloalkyls can contain one or more heteroatoms in one or both rings and are saturated. Unless the substituents are otherwise specified, a heterocycloalkyl is unsubstituted.

[0137] The term "aryl" refers to phenyl or naphthyl.

[0138] The term "heteroaryl" refers to an aromatic group containing a heteroatom, preferably containing one, two, or three aromatic 5- to 10-membered monocyclic or bicyclic rings independently selected from nitrogen, oxygen, and sulfur, such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isothiazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl, isoquinolinyl, and the like.

[0139] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0140] The term "alkoxy" refers to -OR X refers to the group, where R X is alkyl as defined above.

[0141] The term "alkynyl" refers to a straight or branched chain hydrocarbon group having one or more triple bonds with a specified number of carbon atoms (e.g., C2-C6 alkynyl, also e.g., C2-C4 alkynyl). The one or more carbon-carbon triple bonds may be internal or terminal, for example, propynyl, where the triple bond is internal. [ka] Or propynyl, which has a terminal triple bond. [ka] is.

[0142] The term "carbocycle" refers to a cyclic, saturated or unsaturated ring having a specified number of carbon atoms (e.g., C3-C6) that is (1) attached to the rest of the molecule by two or more single bonds, or (2) shares two atoms and one bond with the rest of the molecule.

[0143] The term "heterocyclyl" refers to a cyclic, saturated, or unsaturated ring that (1) is attached to the rest of the molecule by two or more single bonds, or (2) shares two atoms and one bond with the rest of the molecule and has a specified number of ring atoms (e.g., 3-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S).

[0144] The term "cycloalkyl" refers to a cyclic, saturated monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C3 to C8). Cycloalkyl includes [ka] These include, but are not limited to:

[0145] The term "oxo" refers to the group "=O".

[0146] The term “-(CR L-3 R L-4 ) n3 - * " can be 0, 1, 2, 3 or 4 -(CR L-3 R L-4 ) n3 - refers to the fragments being concatenated, for example, if n3 is 2, then "-(CR L-3 R L-4 ) n3 - * " is -(CR L-3 R L-4 )-(CR L-3 R L-4 )- * where each R L-3 and R L-4 are the same or different.

[0147] In the present invention, when a compound or a salt thereof has a configuration due to a chiral axis or a chiral carbon, the configuration of the compound or a salt thereof is the same as that of the salt, for example, the configuration of compound 1a' is the same as that of salt 1a.

[0148] The above-mentioned preferable conditions can be arbitrarily combined to obtain a preferable example of the present invention, provided that it is not contrary to common knowledge in the art.

[0149] Positive and progressive effects of the present invention: The compounds of the present invention have good inhibitory effects on KRAS G12D mutant protein.

[0150] [Mode for Carrying Out the Invention] The present invention will be further described below with reference to examples, but the present invention is not limited to these examples. In the following examples, experimental methods for which no specific conditions are specified are selected according to conventional methods and conditions or product instructions.

[0151] In the present invention, when the compounds or salts thereof finally prepared in the following examples have a configuration resulting from a chiral axis or chiral carbon, the configuration resulting from the chiral carbon is the same as that of the intermediate containing the chiral axis or chiral carbon used in the preparation of these compounds. For example, when salts 1a and 1b of the compounds in Example 1 are prepared using intermediate 1-10a (intermediate 1-10b) containing a chiral carbon, the configuration resulting from the chiral carbon of salt 1a (1b) is the same as that of intermediate 1-10a (intermediate 1-10b). In other examples of the present invention, the configuration resulting from the chiral carbon or chiral axis is the same as that in Example 1.

[0152] Example 1 (S or R)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2'-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline] dihydrochloride 1a, (R or S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2'-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline] dihydrochloride 1b [ka] The synthetic route is as follows: [ka]

[0153] Step 1: [ka] A solution of methyltriphenylphosphonium bromide (136.7 g, 363.6 mmol, 1.2 eq) in anhydrous tetrahydrofuran (700 mL) was slowly added dropwise to a solution of n-butyllithium in n-hexane (2.5 mol / L, 145 mL, 363.6 mmol, 1.2 eq) at 0 °C under stirring under nitrogen gas protection. The mixture was reacted at 0 °C for 1 hour under stirring, and then a solution of 2-chloro-6-bromobenzaldehyde (70 g, 303.0 mmol, 1.0 eq) in anhydrous tetrahydrofuran (300 mL) was slowly added to the reaction solution at the same temperature. The resulting mixture was reacted at 25 °C under stirring for 2 hours, and the reaction progress was monitored by thin-layer chromatography. After completion of the reaction, the reaction system was quenched by adding saturated ammonium chloride solution (700 mL) at 0 °C. The mixture was extracted with ethyl acetate (700 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography, washed with petroleum ether, and the solvent was removed from the obtained fractions using a rotary evaporator under reduced pressure to give compound 1-1 (colorless liquid, 35 g, yield: 50%). 1 H NMR (300 MHz, CDCl3) δ 7.58 - 7.49 (m, 1H), 7.43 - 7.35 (m, 1H), 7.10 - 6.99 (m, 1H), 6.76 - 6.60 (m, 1H), 5.80 - 5.64 (m, 2H).

[0154] Step 2: [ka] To a mixture of compound 1-1 (20.7 g, 90.4 mmol, 1.0 eq), 2-cyclohexen-1-one-2-boronic acid pinacol ester (25.37 g, 108.5 mmol, 1.2 eq), and sodium carbonate (30.26 g, 271.25 mmol, 3 eq) in ethylene glycol dimethyl ether (150 mL) and water (30 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (3.88 g, 4.52 mmol, 0.05 eq) under stirring at 25 °C under nitrogen gas protection. The mixture was stirred at 90 °C for 2 h, and the reaction progress was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was cooled to room temperature. The reaction solution was diluted with water (200 mL) and then extracted with ethyl acetate (200 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 30% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 1-2 (pale yellow liquid, 20 g, yield: 82%). MS (ESI, m / z): 233.0 / 235.0 [M + H] + ; 1 H NMR (300 MHz, CDCl3) δ 7.46 - 7.36 (m, 1H), 7.30 - 7.18 (m, 1H), 7.13 - 7.03 (m, 1H), 6.98 - 6.82 (m, 1H), 6.17 - 6.10 (m, 1H), 5.60 - 5.45 (m, 2H), 2.60 - 2.42 (m, 4H), 2.15 - 2.02 (m, 2H).

[0155] Step 3: [ka] A solution of cuprous iodide (12.28 g, 61.2 mmol, 1.5 eq) and lithium chloride (2.73 g, 61.2 mmol, 1.5 eq) in anhydrous tetrahydrofuran (300 mL) was slowly added with vinylmagnesium bromide (1 mol / L, 122 mL, 122.46 mmol, 3 eq) in tetrahydrofuran at -78 °C under nitrogen gas protection. After stirring at -78 °C for 1 hour, a solution of compound 1-2 (10 g, 40.82 mmol, 1.0 eq) in anhydrous tetrahydrofuran (300 mL) was slowly added dropwise to the reaction solution at the same temperature. The mixture was stirred at -78 °C for 1 hour, then slowly warmed to room temperature and reacted for 0.5 hours. The reaction progress was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was quenched by adding saturated ammonium chloride solution (200 mL) at 0 °C. The mixture was extracted with ethyl acetate (200 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 10% ethyl acetate / petroleum ether. The solvent was removed from the obtained fractions on a rotary evaporator under reduced pressure to give compound 1-3 (pale yellow oil, 5.68 g, yield: 53%). MS (ESI, m / z): 261.0 / 263.0 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.39 - 7.33 (m, 1H), 7.31 - 7.27 (m, 1H), 7.19 - 7.13 (m, 1H), 6.83 - 6.72 (m, 1H), 5.97 - 5.88 (m, 1H), 5.64 - 5.58 (m, 1H), 5.38 - 5.30 (m, 1H), 5.20 - 5.14 (m, 1H), 4.98 - 4.90 (m, 1H), 2.79 (s, 2H), 2.75 - 2.65 (m, 1H), 2.35 - 2.26 (m, 2H), 2.06 - 1.96 (m, 1H), 1.91 - 1.79 (m, 1H), 1.67 - 1.59 (m, 1H).

[0156] Step 4: [ka] To a solution of compound 1-3 (5.68 g, 20.7 mmol, 1.0 eq) in dichloromethane (60 mL) was added 1,3-bis-(2,4,6-trimethylphenyl)-2-(imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (2.77 g, 3.10 mmol, 0.15 eq) at 25 °C under nitrogen gas protection and stirring. The mixture was stirred at 30 °C for 16 h, and the reaction process was monitored by thin-layer chromatography. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 10% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 1-4 (pale yellow oil, 3.8 g, yield: 74%). 1 H NMR (300 MHz, CDCl3) δ 7.30 - 7.14 (m, 3H), 6.93 - 6.86 (m, 1H), 6.57 - 6.52 (m, 1H), 2.77 - 2.69 (m, 1H), 2.63 - 2.55 (m, 2H), 2.36 - 2.24 (m, 1H), 2.22 - 2.14 (m, 1H), 2.14 - 1.94 (m, 2H), 1.75 - 1.64 (m, 1H).

[0157] Step 5: [ka] Platinum carbon (10% platinum content, 0.35 g) was added to a solution of compound 1-4 (3.5 g, 14.3 mmol, 1.0 eq) in ethyl acetate (50 mL) at 25 °C under stirring under nitrogen gas protection. The nitrogen gas was replaced with hydrogen gas by gas exchange. The mixture was reacted for 2 hours under stirring under a hydrogen gas atmosphere at 1 atmosphere pressure at 25 °C. The reaction process was monitored by thin-layer chromatography. After completion of the reaction, the mixture was filtered to remove insoluble materials. The cake was washed with ethyl acetate (70 mL x 3), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a 0% to 20% methyl tert-butyl ether / petroleum ether mobile phase. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 1-5 (colorless oil, 3.24 g, yield: 95%). 1 H NMR (300 MHz, CDCl3) δ 7.24 - 7.14 (m, 2H), 7.08 - 7.05 (m, 1H), 2.99 - 2.94 (m, 2H), 2.58 - 2.34 (m, 4H), 2.16 - 2.02 (m, 2H), 2.01 - 1.85 (m, 3H), 1.84 - 1.75 (m, 1H).

[0158] Step 6: [ka] To a solution of compound 1-5 (3.0 g, 12.14 mmol, 1.0 eq) in tetrahydrofuran (100 mL) was added sodium hydride (60%, 2.43 g, 60.7 mmol, 5.0 eq) under stirring at 25 °C under nitrogen gas protection. The mixture was stirred at 25 °C for 0.5 h, and then dimethyl carbonate (6.91 g, 72.85 mmol, 6.0 eq) was added to the reaction solution. The mixture was stirred at 70 °C for 2 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction was quenched by adding saturated ammonium chloride solution (100 mL) to the reaction system at 0 °C. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 20% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 1-6 (white solid, 3.7 g, yield: 98%). MS (ESI, m / z): 293.1 / 295.1 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 12.19 (s, 1H), 7.22 - 6.94 (m, 3H), 3.80 - 3.79 (m, 3H), 2.98 - 2.94 (m, 2H), 2.49 - 2.22 (m, 4H), 2.02 - 1.91 (m, 2H), 1.86 - 1.79 (m, 1H), 1.74 - 1.60 (m, 1H).

[0159] Step 7: [ka] Ammonium acetate (0.79 g, 9.73 mmol, 3.0 eq) was added to a solution of compound 1-6 (1.0 g, 3.24 mmol, 1.0 eq) in methanol (30 mL) under stirring at 25 °C. The mixture was stirred at 25 °C for 16 hours, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, water (70 mL) was added to dilute the reaction solution, and the mixture was extracted with dichloromethane (70 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. Trichloroacetyl isocyanate (0.84 g, 4.22 mmol, 1.3 eq) was added to a solution of the crude product in acetonitrile (20 mL) under stirring at 25 °C. The mixture was stirred at 25 °C for 0.5 hours, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the mixture was filtered to obtain the intermediate, which was then washed with acetonitrile (20 mL × 3). The intermediate was dissolved in ammonia in methanol (7 mol / L, 30 mL) under stirring at 25 °C, and the mixture was stirred at 70 °C for 2 hours, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the mixture was cooled to room temperature and filtered to obtain the solid. The cake was washed with methyl tert-butyl ether (10 mL × 3). The cake was dried to obtain compound 1-7 (white solid, 820 mg, yield: 81%). MS (ESI, m / z): 303.1 / 305.1 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.65 (s, 1H), 7.30 - 7.20 (m, 2H), 7.19 - 7.14 (m, 1H), 2.96 - 2.88 (m, 2H), 2.55 - 2.53 (m, 1H), 2.40 - 2.24 (m, 3H), 2.01 - 1.84 (m, 3H), 1.70 - 1.59 (m, 1H).

[0160] Step 8: [ka] N,N-Diisopropylethylamine (623 mg, 4.83 mmol, 2.0 eq) and N,N-dimethylformamide (28 mg, 0.384 mmol, 0.16 eq) were added to a solution of compound 1-7 (770 mg, 2.42 mmol, 1.0 eq) in phosphorus oxychloride (10 mL) at 25 °C under nitrogen gas protection. The mixture was stirred at 110 °C for 2 hours, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. 40 mL of saturated sodium bicarbonate was added to the mixture at 0 °C. The resulting mixture was extracted with ethyl acetate (60 mL × 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 20% ethyl acetate / petroleum ether. The solvent was removed from the obtained fractions using a rotary evaporator under reduced pressure to obtain compound 1-8 (white solid, 780 mg, yield: 93%). 1 H NMR (300 MHz, CDCl3) δ 7.29 - 7.13 (m, 2H), 6.93 - 6.87 (m, 1H), 3.07 - 2.98 (m, 4H), 2.95 - 2.78 (m, 2H), 2.18 - 1.89 (m, 4H).

[0161] Step 9: [ka] N,N-Diisopropylethylamine (831 mg, 6.44 mmol, 3.0 eq) was added to a solution of compound 1-8 (770 mg, 2.15 mmol, 1.0 eq) and 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (481 mg, 2.15 mmol, 1.0 eq) in dimethyl sulfoxide (12 mL) and 1,2-dichloroethane (3 mL) at 25 °C under nitrogen gas protection. The mixture was stirred at 55 °C for 1 hour, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was cooled to room temperature. Water (150 mL) was added to the mixture at 25 °C to dilute the reaction solution. The resulting mixture was extracted with ethyl acetate (80 mL x 3), and the combined organic phases were washed with saturated brine (150 mL). The organic phase was then dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 20% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to obtain compound 1-9 (white solid, 1 g, yield: 86%). MS (ESI, m / z): 515.0 / 517.0 / 519.0 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.23 - 7.18 (m, 1H), 7.16 - 7.09 (m, 1H), 6.95 - 6.87 (m, 1H), 4.44 - 4.20 (m, 2H), 3.96 - 3.86 (m, 1H), 3.78 - 3.69 (m, 1H), 3.38 - 3.26 (m, 1H), 3.25 - 3.17 (m, 1H), 3.06 - 2.95 (m, 2H), 2.94 - 2.89 (m, 2H), 2.74 - 2.49 (m, 2H), 2.10 - 2.01 (m, 2H), 1.99 - 1.88 (m, 4H), 1.85 - 1.70 (m, 2H), 1.49 (s, 9H).

[0162] Step 10: [ka] A solution of compound 1-9 (200 mg, 0.36 mmol, 1.0 eq) and (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-methanol (247 mg, 1.48 mmol, 4.0 eq) in 1,4-dioxane (5 mL) was added with potassium tert-butoxide in tetrahydrofuran (1 mol / L, 1.84 mL, 1.84 mmol, 5.0 eq) under stirring at 0 °C under nitrogen gas protection. The mixture was stirred at 100 °C for 2 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was cooled to room temperature. The reaction was quenched by adding water (30 mL) to the mixture at 0 °C. The resulting mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was filtered to remove the drying agent, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% methanol / dichloromethane. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 1-10 (white solid, 155 mg, yield: 64%). MS (ESI, m / z): 638.4 / 640.4 [M + H] + .

[0163] Step 11: [ka] Compound 1-10 (155 mg) obtained in step 10 was separated by preparative chiral HPLC (chiral column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol solution); mobile phase B: ethanol; flow rate: 20 mL / min; elution with 10% B phase within 10 min; detector: UV 222 / 288 nm). The product with the shorter retention time (6.2 min): compound 1-10a (white solid, 64.6 mg, recovery: 40%); MS (ESI, m / z): 638.4 / 640.4 [M + H]. + ;Product with longer retention time (7.9 min): Compound 1-10b (white solid, 57.5 mg, recovery: 35%), MS (ESI, m / z): 638.4 / 640.4 [M + H] + .

[0164] Step 12: [ka] A 1,4-dioxane solution of hydrogen chloride (4 mol / L, 2 mL) was slowly added to a methanol (2 mL) solution of compound 1-10a (58 mg, 0.088 mmol, 1.00 eq) at 0 °C under stirring. The reaction mixture was allowed to react for 1 h at 25 °C, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a reverse-phase chromatography column (C18 column) and eluted with a 0% to 95% acetonitrile / water mobile phase (0.1% hydrochloric acid) within 20 min. Detector: UV 254 / 220 nm. Compound 1a (white solid, 39.7 mg, yield: 73%) was obtained. MS (ESI, m / z): 538.2 / 540.2 [M + H] + ; 1H NMR (300 MHz, DMSO-d6) δ 12.18 - 11.99 (m, 1H), 10.20 - 10.07 (m, 1H), 9.88 - 9.71 (m, 1H), 7.34 - 7.19 (m, 3H), 5.73 - 5.47 (m, 1H), 4.72 - 4.57 (m, 4H), 4.41 - 4.26 (m, 1H), 4.18 - 4.00 (m, 2H), 3.97 - 3.62 (m, 5H), 3.32 - 3.19 (m, 1H), 3.01 - 2.79 (m, 5H), 2.67 - 2.56 (m, 1H), 2.48 - 2.37 (m, 1H), 2.30 - 1.89 (m, 10H), 1.87 - 1.70 (m, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -171.74. Chiral analytical conditions for compound 1a: Optichiral C9-3, 3.0 × 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isocratic elution with 50% B phase within 1.8 min; detector: UV 220 nm; retention time: 1.275 min; dr > 40:1.

[0165] Step 13: [ka] Compound 1b (white solid, 37.7 mg, yield: 69%) was obtained in the same manner as above. MS (ESI, m / z): 538.2 / 540.2 [M + H] + ; 1H NMR (300 MHz, DMSO-d6) δ 12.01 - 11.72 (m, 1H), 10.14 - 9.94 (m, 1H), 9.81 - 9.60 (m, 1H), 7.33 - 7.25 (m, 2H), 7.24 - 7.16 (m, 1H), 5.71 - 5.47 (m, 1H), 4.70 - 4.51 (m, 3H), 4.23 - 4.06 (m, 4H), 3.88 - 3.70 (m, 4H), 3.67 - 3.48 (m, 1H), 3.35 - 3.19 (m, 1H), 3.02 - 2.94 (m, 2H), 2.91 - 2.79 (m, 3H), 2.68 - 2.58 (m, 1H), 2.50 - 2.43 (m, 1H), 2.31 - 1.67 (m, 12H); 19 F NMR (282 MHz, DMSO-d6) δ -172.08. Chiral analytical conditions for compound 1b: Optichiral C9-3, 3.0 × 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isocratic elution with 50% B phase within 1.8 min; detector: UV 220 nm; retention time: 1.082 min; dr > 40:1.

[0166] Example 2 (S or R)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2'-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-6-ol Dihydrochloride 2a, (R or S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2'-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-6-ol dihydrochloride 2b [ka] The synthetic route is as follows: [ka]

[0167] Step 1: [ka] Compound 1-9 (300 mg, 0.553 mmol, 1.0 eq), bis(pinacolato)diboron (591 mg, 2.21 mmol, 4.0 eq), chloro-1,5-cyclooctadiene iridium(I) dimer (39 mg, 0.055 mmol, 0.1 eq), 4,4′-di-tert-butyl-2,2′-bipyridyl (31 mg, 0.111 mmol, 0.2 eq), and 1,4-dioxane (6 mL) were sequentially added to a reaction flask at 25 °C under stirring and nitrogen gas protection. The mixture was reacted at 120 °C for 3 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 20% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 2-1 (white solid, 280 mg, yield: 79%). MS (ESI, m / z): 641.2 / 643.2 / 645.2 [M + H] + .

[0168] Step 2: [ka] To a solution of compound 2-1 (280 mg, 0.415 mmol, 1 eq) in methanol (5 mL) was added hydrogen peroxide urea complex (287.44 mg, 2.905 mmol, 7 eq) under stirring at 25 °C. The mixture was stirred at 25 °C for 1 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 40% ethyl acetate / petroleum ether. The obtained fraction was subjected to rotary evaporation under reduced pressure to obtain compound 2-2 (white solid, 225 mg, yield: 96%). MS (ESI, m / z): 531.2 / 533.2 / 535.2 [M + H] + .

[0169] Step 3: [ka] To a solution of compound 2-2 (220 mg, 0.393 mmol, 1 eq) in dichloromethane (5 mL) was added dropwise N,N-diisopropylethylamine (160.50 mg, 1.179 mmol, 3.00 eq) and chloromethyl methyl ether (41.28 mg, 0.590 mmol, 1.50 eq) sequentially at 25 °C under nitrogen gas protection. The mixture was stirred at 25 °C for 2 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 40% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 2-3 (white solid, 170 mg, yield: 71%). MS (ESI, m / z): 575.2 / 577.2 / 579.2 [M + H] + .

[0170] Step 4: [ka] A solution of compound 2-3 (170 mg, 0.28 mmol, 1.0 eq) and (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-methanol (188 mg, 1.12 mmol, 4.0 eq) in 1,4-dioxane (5 mL) was added with potassium tert-butoxide in tetrahydrofuran (1 mol / L, 1.4 mL, 1.4 mmol, 5.0 eq) under stirring at 0 °C under nitrogen gas protection. The mixture was stirred at 90 °C for 1 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was cooled to room temperature. The reaction was quenched by adding water (30 mL) to the mixture at 0 °C. The resulting mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% methanol / dichloromethane. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 2-4 (white solid, 170 mg, yield: 82%). MS (ESI, m / z): 698.3 / 700.3 [M + H] + .

[0171] Step 5: [ka] Compounds 2-4 (170 mg) obtained in Step 4 were separated by preparative chiral HPLC (chiral column: (R,R)-WHELK-O1-Kromasil, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine); mobile phase B: isopropanol; flow rate: 40 mL / min; elution with 30% B phase within 79 min; detector: UV 210 / 259 nm). The product with the shorter retention time (42 min): compound 2-4a (white solid, 66 mg, recovery: 40%). MS (ESI, m / z): 698.3 / 700.3 [M + H]. +Product with longer retention time (63 min): Compound 2-4b (white solid, 64 mg, recovery: 39%), MS (ESI, m / z): 698.3 / 700.3 [M + H] + .

[0172] Step 6: [ka] A 1,4-dioxane solution of hydrogen chloride (4 mol / L, 2 mL) was slowly added dropwise to a methanol (2 mL) solution of compound 2-4a (66 mg, 0.094 mmol, 1.00 eq) at 0°C under stirring. The reaction mixture was allowed to react for 1.5 hours at 25°C, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a reverse-phase chromatography column (C18 column) with a gradient elution of 0% to 95% acetonitrile / water (0.1% hydrochloric acid) within 20 minutes. Compound 2a (white solid, 38.8 mg, yield: 63%) was obtained using a detector: UV 254 / 220 nm. MS (ESI, m / z): 554.1 / 556.1 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6+ D2O) δ 6.72 (d, J = 2.0 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H), 5.68 - 5.50 (m, 1H), 4.72 - 4.60 (m, 3H), 4.36 - 4.27 (m, 1H), 4.18 - 4.09 (m, 2H), 4.03 - 3.93 (m, 1H), 3.92 - 3.74 (m, 4H), 3.33 - 3.23 (m, 1H), 2.92 - 2.77 (m, 5H), 2.70 - 2.58 (m, 2H), 2.50 - 2.41 (m, 1H), 2.35 - 2.25 (m, 1H), 2.24 - 2.12 (m, 2H), 2.10 - 1.93 (m, 6H), 1.92 - 1.80 (m, 2H), 1.78 - 1.68 (m, 1H); 19F NMR (377 MHz, DMSO-d6) δ -171.82. Chiral analytical conditions for compound 2a: (S,S)-Whelk-O1, 4.6 × 100 mm, 3.5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isocratic elution with 40% B phase within 6.5 min; detector: UV 220 nm; retention time: 5.009 min; dr > 40:1.

[0173] Step 7: [ka] Compound 2b (white solid, 33.6 mg, yield: 57%) was obtained in the same manner as above. MS (ESI, m / z): 554.1 / 556.1 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.13 - 11.99 (m, 1H), 10.18 - 10.08 (m, 1H), 9.82 - 9.73 (m, 1H), 6.72 (d, J = 2.0 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 5.68 - 5.51 (m, 1H), 4.76 - 4.70 (m, 1H), 4.66 - 4.56 (m, 2H), 4.36 - 4.27 (m, 1H), 4.15 - 4.06 (m, 2H), 4.04 - 3.86 (m, 2H), 3.84 - 3.71 (m, 2H), 3.70 - 3.62 (m, 1H), 3.30 - 3.19 (m, 1H), 2.93 - 2.78 (m, 5H), 2.68 - 2.53 (m, 2H), 2.48 - 2.37 (m, 1H), 2.31 - 2.23 (m, 1H), 2.22 - 2.12 (m, 2H), 2.09 - 1.93 (m, 6H), 1.91 - 1.77 (m, 2H), 1.76 - 1.67 (m, 1H); 19F NMR (377 MHz, DMSO-d6) δ -171.76. Chiral analytical conditions for compound 2b: (S,S)-Whelk-O1, 4.6 × 100 mm, 3.5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isocratic elution with 40% B phase within 6.5 min; detector: UV 220 nm; retention time: 4.193 min; dr > 40:1.

[0174] Example 3 4-((5aS,6R,9S)-1-Fluoro-13-((R)-1-(2-fluoroethyl)pyrrolidin-2-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)naphthalen-2-ol dihydrochloride 3 [ka] The synthetic route is as follows: [ka]

[0175] Step 1: [ka] Compound 3-1 was synthesized with reference to patent (WO2019179515A1). A solution of compound 3-1 (1 g, 3.34 mmol, 1.0 eq) in anhydrous tetrahydrofuran (10 mL) was slowly added with a n-hexane solution of diisobutylaluminum hydride (1 mol / L, 13.36 mL, 13.36 mmol, 4 eq) at -40 °C under nitrogen gas protection. The mixture was stirred at -40 °C for 2 hours, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, saturated potassium sodium tartrate solution (50 mL) was added to the reaction solution at 0 °C to quench the reaction. The mixture was extracted with dichloromethane (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% ammonia-methanol (7 mol / L) / dichloromethane. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 3-2 (white solid, 500 mg, yield: 58%). MS (ESI, m / z): 243.3 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 4.20 - 3.94 (m, 2H), 3.59 - 3.55 (m, 1H), 3.45 - 3.40 (m, 1H), 3.10 - 2.93 (m, 2H), 2.74 - 2.70 (m, 1H), 1.96 - 1.82 (m, 2H), 1.79 - 1.70 (m, 2H), 1.47 (s, 9H).

[0176] Step 2: [ka] To a solution of compound 3-2 (420 mg, 1.647 mmol, 1.0 eq) and imidazole (141 mg, 1.976 mmol, 1.2 eq) in dichloromethane (5 mL) was slowly added tert-butyldimethylsilyl chloride (313 mg, 1.976 mmol, 1.2 eq) at 0 °C under stirring under nitrogen gas protection. The mixture was stirred at 25 °C for 2 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution with a 0% to 5% methanol / dichloromethane mobile phase. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 3-3 (white solid, 500 mg, yield: 81%). MS (ESI, m / z): 357.2 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 4.28 - 4.00 (m, 2H), 3.62 - 3.40 (m, 2H), 3.10 - 2.94 (m, 2H), 2.78 - 2.68 (m, 1H), 1.97 - 1.85 (m, 3H), 1.79 - 1.67 (m, 2H), 1.47 (s, 9H), 0.89 (s, 9H), 0.06 (s, 6H).

[0177] Step 3: [ka] N,N-Diisopropylethylamine (8.69 g, 66.57 mmol, 1.5 eq) and chloromethyl methyl ether (4.69 g, 57.69 mmol, 1.3 eq) were added to a solution of 1-bromo-3-hydroxynaphthalene (10 g, 44.38 mmol, 1.0 eq) in dichloromethane (100 mL) at 0 °C under nitrogen gas protection and stirring. The mixture was reacted at 25 °C for 3 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 10% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 3-4 (white solid, 10.5 g, yield: 87%). MS (ESI, m / z): 267.1 / 269.1 [M + H] + ; 1 H NMR (300 MHz, CDCl3) δ 8.16 - 8.11 (m, 1H), 7.75 - 7.71 (m, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.39 (d, J = 2.4 Hz, 1H), 5.28 (s, 2H), 3.52 (s, 3H).

[0178] Step 4: [ka] To a solution of compound 3-4 (10 g, 35.56 mmol, 1.0 eq) in 1,4-dioxane (100 mL) at 25 °C under nitrogen gas protection, potassium acetate (14.70 g, 142.26 mmol, 4.0 eq), bis(pinacolato)diboron (12.36 g, 46.23 mmol, 1.3 eq), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (3.05 g, 3.55 mmol, 0.1 eq) were added sequentially. The mixture was reacted under nitrogen gas at 100 °C for 1 hour, and the reaction progress was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was cooled to 25 °C and the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 20% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 3-5 (white solid, 10 g, yield: 85%). MS (ESI, m / z): 315.2 [M + H] + ; 1 H NMR (300 MHz, CDCl3) δ 8.72 - 8.66 (m, 1H), 7.82 (d, J = 2.7 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.51 (d, J = 2.7 Hz, 1H), 7.49 - 7.40 (m, 2H), 5.33 (s, 2H), 3.54 (s, 3H), 1.44 (s, 12H).

[0179] Step 5: [ka] Ammonium chloride (100.02 g, 1776.35 mmol, 5 eq) was added in batches to a solution of 3-bromo-2,5-difluoronitrobenzene (89.0 g, 355.27 mmol, 1.0 eq) and iron powder (104.42 g, 1776.35 mmol, 5 eq) in ethanol (1200 mL) / water (240 mL) under stirring at 25 °C. The mixture was reacted for 16 h under stirring at 25 °C, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the mixture was filtered to remove insoluble materials, and the cake was washed with ethanol (500 mL x 3). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 3-6 (orange oil, 44 g, yield: 56%). MS (ESI, m / z): 208.1 / 210.1 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 6.66 - 6.60 (m, 1H), 6.58 - 6.50 (m, 1H), 5.80 (s, 2H).

[0180] Step 6: [ka] To a mixture of compound 3-6 (44 g, 200.95 mmol, 1.0 eq) and chloral hydrate (38.48 g, 221.05 mmol, 1.1 eq) in sulfuric acid (220 mL) and water (924 mL) was added sodium sulfate (390.6 g, 2612.42 mmol, 13 eq) and hydroxylamine hydrochloride (44.1 g, 602.86 mmol, 3 eq) under stirring at 25 °C. The mixture was stirred at 70 °C for 16 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was cooled to room temperature. The mixture was filtered, and the cake was washed with water (500 mL × 3) to obtain crude compound 3-7 (orange solid, 54 g). The crude product was used directly in the next step without further purification. MS (ESI, m / z): 277.1 / 279.1 [M+H] - .

[0181] Step 7: [ka] Compound 3-7 (54 g, 172.23 mmol, 1.0 eq) was dissolved in sulfuric acid (475 mL) at 25 °C. The mixture was stirred at 90 °C for 1 hour, and the reaction process was monitored by thin-layer chromatography. After the reaction was completed, the mixture was cooled to room temperature. The mixture was quenched by pouring it into ice water. The mixture was filtered, and the cake was washed with water (500 mL × 3) to obtain crude product compound 3-8 (brown solid, 38 g). The crude product was used directly in the next step without further purification.

[0182] Step 8: [ka] Hydrogen peroxide (30%, 646 mL) was slowly added to compound 3-8 (38 g, 137.78 mmol, 1.0 eq) in aqueous sodium hydroxide (2 mol / L, 76 mL) at 25 °C under stirring. The mixture was reacted for 16 hours under stirring at 25 °C, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the pH of the reaction solution was adjusted to 7 with dilute hydrochloric acid, filtered, and the cake was washed with water (500 mL × 3). After combining, the filtrate was adjusted to pH 1 with dilute hydrochloric acid to precipitate a solid. The solid was filtered, and the cake was washed with water (500 mL × 3) to obtain crude compound 3-9 (gray solid, 20.4 g). The crude product was used directly in the next step without further purification. MS (ESI, m / z): 250.1 / 252.1 [M+H] - .

[0183] Step 9: [ka] Ethyl iodide (3.34 g, 20.35 mmol, 1.2 eq) was slowly added to a solution of compound 3-9 (4.5 g, 16.96 mmol, 1.0 eq) and cesium carbonate (11.64 g, 33.92 mmol, 2 eq) in N,N-dimethylformamide (45 mL) at 0 °C under nitrogen gas protection. The mixture was stirred at 25 °C for 4 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was diluted with water (400 mL). The resulting mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with saturated brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 50% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to give compound 3-10 (orange oil, 3.92 g, yield: 78%). MS (ESI, m / z): 280.1 / 282.2 [M + H] + ; 1H NMR (300 MHz, CDCl3) δ 6.62 - 6.53 (m, 1H), 4.49 - 4.34 (m, 2H), 1.52 - 1.32 (m, 3H).

[0184] Step 10: [ka] At 25 °C under nitrogen gas protection, trichloroacetyl isocyanate (3.96 g, 19.94 mmol, 1.5 eq) was slowly added to a solution of compound 3-10 (3.92 g, 13.29 mmol, 1.0 eq) in tetrahydrofuran (40 mL). The mixture was stirred at 25 °C for 0.5 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was slurried with methyl tert-butyl ether (500 mL) to obtain compound 3-11 (white solid, 6.5 g, yield: 99%). MS (ESI, m / z): 467.0 / 469.0 / 471.0 [M + H] + ; 1 H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 9.88 (s, 1H), 7.95 - 7.83 (m, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H).

[0185] Step 11: [ka] A solution of compound 3-11 (6.5 g, 13.18 mmol, 1.0 eq) in methanol (70 mL) was slowly added with ammonia methanol solution (7 mol / L, 7 mL) under stirring at 25 °C. The mixture was reacted for 1 hour under stirring at 25 °C, and the reaction process was monitored by liquid mass spectrometry and thin layer chromatography. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was slurried with methyl tert-butyl ether (200 mL) to obtain compound 3-12 (white solid, 3.92 g, yield: 99%). MS (ESI, m / z): 277.2 / 279.2 [M + H] + ; 1 H NMR (300 MHz, DMSO-d6) δ 11.67 - 11.41 (m, 2H), 7.47 - 7.36 (m, 1H).

[0186] Step 12: [ka] N,N-Diisopropylethylamine (5 mL, 27.2 mmol, 3.18 eq) was slowly added to a solution of compound 3-12 (2.5 g, 8.57 mmol, 1.0 eq) in phosphorus oxychloride (47.5 mL) under stirring at 0 °C. The mixture was stirred at 90 °C for 3 hours, and the reaction process was monitored by thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was dispersed in 50 mL of dichloromethane and concentrated to remove the solvent. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 10% ethyl acetate / petroleum ether. The solvent was removed from the obtained fractions on a rotary evaporator under reduced pressure to obtain compound 3-13 (white solid, 1 g, yield: 35%). 1 H NMR (400 MHz, CDCl3) δ 7.62 - 7.53 (m, 1H).

[0187] Step 13: [ka] To a dichloromethane (5 mL) solution of compound 3-13 (352 mg, 1.06 mmol, 1.0 eq) and compound 3-3 (400 mg, 1.06 mmol, 3.0 eq) was slowly added N,N-diisopropylethylamine (434 mg, 3.2 mmol, 3 eq) under stirring at 0 °C. The mixture was stirred at 25 °C for 1 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 20% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 3-14 (white solid, 550 mg, yield: 77%). MS (ESI, m / z): 633.2 / 635.2 / 637.2 [M + H] + .

[0188] Step 14: [ka] A solution of compound 3-14 (530 mg, 0.794 mmol, 1.0 eq) in anhydrous tetrahydrofuran (6 mL) was slowly added with tetra-n-butylammonium fluoride (1 mol / L, 1.75 mL, 1.75 mmol, 2.2 eq) in tetrahydrofuran under stirring at 25 °C. The mixture was reacted for 1 hour under stirring at 25 °C, then heated to 65 °C and stirred for 2 hours. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 20% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 3-15 (white solid, 120 mg, yield: 29%). MS (ESI, m / z): 483.0 / 485.0 [M + H] + ; 1H NMR (300 MHz, CDCl3) δ 7.12 (d, J = 5.8 Hz, 1H), 5.19 - 4.98 (m, 1H), 4.51 - 4.34 (m, 2H), 4.32 - 4.06 (m, 3H), 3.33 - 3.15 (m, 1H), 2.08 - 1.72 (m, 4H), 1.53 (s, 9H).

[0189] Step 15: [ka] Compound 3-15 (120 mg, 0.236 mmol, 1.0 eq), compound 3-5 (93 mg, 0.283 mmol, 1.2 eq), potassium phosphate (105 mg, 0.472 mmol, 2.0 eq), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole (16 mg, 0.047 mmol, 0.2 eq), tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.024 mmol, 0.1 eq), toluene (2 mL), and water (0.4 mL) were sequentially added to a three-neck flask at 25 °C under stirring and nitrogen gas protection. The mixture was reacted at 80 °C for 2 h, and the reaction progress was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 40% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 3-16 (white solid, 120 mg, yield: 29%). MS (ESI, m / z): 591.2 [M + H] + .

[0190] Step 16: [ka] Compound 3-16 (100 mg, 0.161 mmol, 1.0 eq), triethylenediamine (3.8 mg, 0.032 mmol, 0.2 eq), cesium carbonate (110 mg, 0.322 mmol, 2.0 eq), (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-methanol (40 mg, 0.241 mmol, 1.5 eq), and N,N-dimethylformamide (2 mL) were sequentially added to a reaction flask at 25 °C under stirring and nitrogen gas protection. The mixture was reacted at 100 °C for 6 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was diluted with 20 mL of water and then extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The organic phase was further washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution with a 0% to 10% methanol / dichloromethane mobile phase. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 3-17 (white solid, 60 mg, yield: 48%). MS (ESI, m / z): 730.1 [M + H] + .

[0191] Step 17: [ka] Compound 3-17 (50 mg, 0.065 mmol, 1.0 eq), methanol (1.0 mL), and a 1,4-dioxane solution of hydrochloric acid (4 mol / mL, 1.0 mL) were sequentially added to a reaction flask under stirring at 0 °C. The mixture was stirred at 25 °C for 2 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by high-performance liquid chromatography (chromatography column: XSelect CSH Prep C18 OBD, 19 × 150 mm, 5 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; flow rate: 25 mL / min, elution with 8% to 26% B phase, detector: UV 220 / 254 nm) to obtain compound 3 (yellow solid, 30 mg, yield: 69%). MS (ESI, m / z): 586.1 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.54 - 11.41 (m, 1H), 10.43 - 9.75 (m, 3H), 7.80 (d, J = 8.3 Hz, 1H), 7.48 - 7.35 (m, 2H), 7.31 - 7.20 (m, 2H), 7.16 - 7.09 (m, 1H), 6.91 (d, J = 6.0 Hz, 1H), 5.69 - 5.45 (m, 1H), 5.07 - 4.92 (m, 1H), 4.72 - 4.48 (m, 5H), 4.33 - 4.21 (m, 2H), 3.88 - 3.83 (m, 1H), 3.81 - 3.74 (m, 2H), 3.71 - 3.63 (m, 1H), 3.36 - 3.23 (m, 1H), 2.69 - 2.53 (m, 1H), 2.48 - 2.42 (m, 1H), 2.37 - 2.28 (m, 1H), 2.23 - 2.10 (m, 3H), 2.09 - 1.84 (m, 4H); 19 F NMR (377 MHz, DMSO-d6) δ -133.35, -133.54, -172.72.

[0192] Example 4 (S or R)-4-((5aS,6R,9S)-1,3-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 4a', (R or S)-4-((5aS,6R,9S)-1,3-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-ylmethoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 4b' [ka] The synthetic route is as follows: [ka]

[0193] Step 1: [ka] Compound 4-1 was synthesized with reference to Example 3. Compound 4-2 was synthesized with reference to a patent (WO2021041671). Compound 4-1 (240 mg, 0.455 mmol, 1.0 eq), compound 4-2 (294 mg, 0.546 mmol, 1.2 eq), potassium phosphate (203 mg, 0.91 mmol, 2.0 eq), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxaphosphole (31 mg, 0.091 mmol, 0.2 eq), tris(dibenzylideneacetone)dipalladium(0) (43 mg, 0.046 mmol, 0.1 eq), toluene (4 mL), and water (0.8 mL) were sequentially added to a three-neck flask at 25 °C under stirring and nitrogen gas protection. The resulting mixture was reacted at 80 °C for 1 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 40% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 4-3 (white solid, 300 mg, yield: 77%). MS (ESI, m / z): 807.3 [M + H] + .

[0194] Step 2: [ka] Compound 4-3 (270 mg, 0.318 mmol, 1.0 eq), triethylenediamine (7 mg, 0.064 mmol, 0.2 eq), cesium carbonate (218 mg, 0.636 mmol, 2.0 eq), (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-methanol (64 mg, 0.382 mmol, 1.2 eq), and N,N-dimethylformamide (3 mL) were sequentially added to a reaction flask at 25 °C under stirring and nitrogen gas protection. The mixture was reacted at 100 °C for 2 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was diluted with 30 mL of water and then extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The organic phase was further washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by high-performance liquid chromatography (chromatography column: XBridge Prep OBD C18, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium bicarbonate); mobile phase B: acetonitrile; flow rate: 60 mL / min, elution from 51% to 80% of B phase; detector: UV 220 / 254 nm) to obtain compound 4-4 (white solid, 70 mg, yield: 27%). MS (ESI, m / z): 790.3 [M + H] + .

[0195] Step 3: [ka] Compound 4-4 (70 mg) obtained in Step 2 was separated by preparative high-performance liquid chromatography (chiral column: (R,R)-WHELK-O1-Kromasil, 2.11 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol); mobile phase B: isopropanol; flow rate: 25 mL / min; elution with 50% B phase within 35 min; detector: UV 206 / 232 nm). The product with the shorter retention time (20.5 min): compound 4-4a (white solid, 23 mg, recovery: 32%); MS (ESI, m / z): 790.3 [M + H]. + Product with longer retention time (26 min): Compound 4-4b (white solid, 30 mg, recovery: 42%), MS (ESI, m / z): 790.3 [M + H] + .

[0196] Step 4: [ka] Compound 4-4a (20 mg, 0.024 mmol, 1.0 eq), methanol (1.5 mL), and a 1,4-dioxane solution of hydrochloric acid (4 mol / mL, 1.5 mL) were sequentially added to the reaction flask under stirring at 0°C. The mixture was reacted for 2 hours under stirring at 0°C, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product. Ammonia-methanol solution (7 mol / L, 1 mL) was added to the crude product at 0 °C. The mixture was stirred at 0 °C for 10 minutes and then concentrated under reduced pressure to obtain the free crude product. The crude product was purified by reverse-phase chromatography (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% ammonium bicarbonate) within 25 minutes. Detector: UV 254 / 220 nm. Compound 4a' (white solid, 6 mg, yield: 38%) was obtained. MS (ESI, m / z): 646.0 [M + H] + ; 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.04 - 7.94 (m, 1H), 7.54 - 7.44 (m, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H), 5.41 - 5.17 (m, 1H), 4.78 - 4.69 (m, 1H), 4.62 - 4.53 (m, 1H), 4.44 - 4.32 (m, 1H), 4.11 - 4.02 (m, 2H), 4.01 - 3.92 (m, 2H), 3.64 - 3.54 (m, 1H), 3.52 - 3.44 (m, 1H), 3.18 - 2.97 (m, 4H), 2.90 - 2.71 (m, 1H), 2.20 - 1.95 (m, 3H), 1.92 - 1.50 (m, 7H); 19 F NMR (282 MHz, DMSO-d6) δ -110.18, -133.98, -141.52, -172.18. Chiral analysis conditions for compound 4a': Column: Optichiral C9-3, 3 × 100 mm, 3 μm; Mobile phase A: supercritical carbon dioxide fluid; Mobile phase B: methanol (20 mmol / L ammonia); Flow rate: 2 mL / min; Isogradient elution with 50% B phase within 2 min; Detector: UV 230 nm; Retention time: 0.836 min, dr > 40:1.

[0197] Step 5: [ka] Compound 4b' (white solid, 9.3 mg, yield: 32%) was obtained in the same manner as above. MS (ESI, m / z): 646.0 [M + H] + ; 1H NMR (300 MHz, DMSO-d6+ D2O) δ 8.02 - 7.94 (m, 1H), 7.53 - 7.45 (m, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.16 (d, J = 2.6 Hz, 1H), 5.69 - 5.43 (m, 1H), 5.13 - 5.02 (m, 1H), 4.77 - 4.67 (m, 1H), 4.61 - 4.40 (m, 4H), 4.31 - 4.20 (m, 2H), 4.07 - 4.02 (m, 1H), 3.88 - 3.72 (m, 3H), 3.54 - 3.43 (m, 1H), 3.36 - 3.23 (m, 1H), 2.62 - 2.54 (m, 1H), 2.47 - 2.41 (m, 1H), 2.38 - 2.26 (m, 1H), 2.25 - 1.87 (m, 7H); 19 F NMR (377 MHz, DMSO-d6) δ -110.00, -133.12, -139.43, -172.80. Chiral analytical conditions for compound 4b': Column: Optichiral C9-3, 3 × 100 mm, 3 μm; Mobile phase A: supercritical carbon dioxide fluid; Mobile phase B: methanol (20 mmol / L ammonia); Flow rate: 2 mL / min; Isogradient elution with 50% B phase within 2 min; Detector: UV 230 nm; Retention time: 1.233 min, dr > 13:1.

[0198] Example 5 (S or R)-4-((5aS,6S,9R)-1,3-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethyl-2-naphthol dihydrochloride 5a, (R or S)-4-((5aS,6S,9R)-1,3-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethyl-2-naphthol dihydrochloride 5a [ka] The synthetic route is as follows: [ka]

[0199] Step 1: [ka] Compound 4-1 (320 mg, 0.60 mmol, 1.0 eq), triethylenediamine (13.74 mg, 0.12 mmol, 0.2 eq), cesium carbonate (399.16 mg, 1.21 mmol, 2.0 eq), (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-methanol (121.9 mg, 0.728 mmol, 1.2 eq), and N,N-dimethylformamide (4 mL) were sequentially added to a reaction flask under stirring at 25 °C under nitrogen gas protection. The mixture was reacted at 60 °C for 16 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was concentrated, and the resulting crude product was purified by reverse-phase chromatography (C18 column). The product was eluted with a 10% to 90% acetonitrile / water mobile phase (0.1% ammonium bicarbonate) within 20 min. Detector: UV 254 / 220 nm. Compound 5-1 (white solid, 280 mg, yield: 68%) was obtained. MS (ESI, m / z): 640.0 / 642.0 [M + H] + .

[0200] Step 2: [ka] Compound 5-2 was synthesized with reference to patent (WO2019179515A1). Compound 5-1 (80 mg, 0.12 mmol, 1.0 eq), compound 5-2 (54.50 mg, 0.15 mmol, 1.2 eq), potassium phosphate (56.34 mg, 0.25 mmol, 2.0 eq), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxaphosphole (8.7 mg, 0.02 mmol, 0.2 eq), tris(dibenzylideneacetone)dipalladium(0) (12.15 mg, 0.01 mmol, 0.1 eq), toluene (1 mL), and water (0.2 mL) were sequentially added to a 25 mL Schreck tube under stirring at 25 °C under nitrogen gas protection. The resulting mixture was reacted at 80 °C for 16 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was cooled to room temperature and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 10% methanol / dichloromethane. The solvent was removed from the obtained fractions using a rotary evaporator under reduced pressure to obtain compound 5-3 (white solid, 100 mg, yield: 97%). MS (ESI, m / z): 776.3 [M + H] + .

[0201] Step 3: [ka] Compound 5-3 (100 mg) obtained in Step 2 was subjected to chiral separation by supercritical fluid chromatography (chiral column: NB_CHIRALPAK AD-H, 3 × 25 cm, 5 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol; flow rate: 75 mL / min; elution with 55% mobile phase B; detector: UV 224 / 292 nm) to obtain two products. The product with the shorter retention time (2.95 min): compound 5-3a (white solid, 40 mg, recovery: 40%), MS (ESI, m / z): 776.3 [M + H]. + Product with longer retention time (6.50 min): 5-3b (white solid, 40 mg, yield: 40%), MS (ESI, m / z): 776.3 [M + H]+ .

[0202] Step 4: [ka] A solution of compound 5-3a (40 mg, 0.04 mmol, 1.00 eq) in methanol (1 mL) was slowly added with hydrogen chloride in 1,4-dioxane (4 mol / L, 1 mL) under stirring at 0 °C. The mixture was reacted at 25 °C for 1 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified using a reverse-phase chromatography column (C18 column) and eluted with a 0% to 30% acetonitrile / water mobile phase (0.1% hydrochloric acid) within 20 min. Detector: UV 254 / 220 nm. Compound 5a (yellow solid, 30.0 mg, yield: 85%) was obtained. MS (ESI, m / z): 632.3 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6+ D2O) δ 7.74 - 7.65 (m, 1H), 7.44 - 7.38 (m, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.21 - 7.14 (m, 1H), 6.97 (d, J = 2.6 Hz, 1H), 5.70 - 5.47 (m, 1H), 5.12 - 5.02 (m, 1H), 4.78 - 4.67 (m, 1H), 4.66 - 4.45 (m, 4H), 4.37 - 4.24 (m, 2H), 3.91 - 3.84 (m, 1H), 3.83 - 3.76 (m, 2H), 3.62 - 3.54 (m, 1H), 3.37 - 3.24 (m, 1H), 2.67 - 2.55 (m, 1H), 2.51 - 2.29 (m, 4H), 2.26 - 1.86 (m, 7H), 0.95 - 0.81 (m, 3H); 19F NMR (377 MHz, DMSO-d) δ -132.33, -139.34, -172.64. Chiral analysis conditions for compound 5a: N-CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 3.0 × 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isocratic elution with 50% B phase within 12 min; detector: UV 220 nm; retention time: 3.304 min; dr > 40:1.

[0203] Step 5: [ka] Compound 5b (yellow solid, 32.0 mg, yield: 90%) was obtained in the same manner as in Step 4. MS (ESI, m / z): 632.3 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6+ D2O) δ 7.72 - 7.68 (m, 1H), 7.44 - 7.38 (m, 1H), 7.34 (d, J = 2.7 Hz, 1H), 7.19 - 7.14 (m, 1H), 6.98 (d, J = 2.6 Hz, 1H), 5.71 - 5.50 (m, 1H), 5.14 - 5.02 (m, 1H), 4.79 - 4.67 (m, 1H), 4.65 - 4.48 (m, 4H), 4.35 - 4.23 (m, 2H), 3.90 - 3.74 (m, 3H), 3.61 - 3.54 (m, 1H), 3.35 - 3.26 (m, 1H), 2.72 - 2.55 (m, 1H), 2.50 - 2.29 (m, 4H), 2.21 - 1.89 (m, 7H), 0.91 - 0.80 (m, 3H); 19F NMR (377 MHz, DMSO-d) δ -132.26, -139.60, -172.72. Chiral analysis conditions for compound 5b: N-CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 3.0 × 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isocratic elution with 50% B phase within 12 min; detector: UV 220 nm; retention time: 2.199 min; dr > 40:1.

[0204] Example 6 (S or R)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2'-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxy-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-3(2H)-one dihydrochloride 6a, (R or S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2'-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxy-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-3(2H)-one dihydrochloride 6b [ka] The synthetic route is as follows: [ka]

[0205] Step 1: [ka] Compound 2-3 (250 mg, 0.413 mmol, 1 eq), dichloromethane (4 mL), chromium trioxide (173.74 mg, 1.652 mmol, 4 eq), and tert-butyl hydroperoxide (70%, 2 mL) were sequentially added to a 25 mL single-neck flask under stirring at 0 °C. The mixture was stirred at 20 °C for 16 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the mixture was filtered, and the cake was washed with dichloromethane (15 mL × 3). After combining, the filtrate was washed with water (40 mL). The aqueous phase was further extracted with dichloromethane (30 mL × 3). All organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 60% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to give compound 6-1 (yellow solid, 140 mg, yield: 52%). MS (ESI, m / z): 589.0 / 591.0 / 593.0 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.07 - 7.04 (m, 1H), 6.93 - 6.88 (m, 1H), 5.24 - 5.17 (m, 2H), 4.42 - 4.23 (m, 2H), 4.16 - 4.06 (m, 1H), 3.72 - 3.64 (m, 1H), 3.50 - 3.44 (m, 4H), 3.22 - 3.11 (m, 2H), 2.96 - 2.87 (m, 1H), 2.76 - 2.55 (m, 5H), 2.01 - 1.91 (m, 5H), 1.49 (s, 9H).

[0206] Step 2: [ka] Compound 6-1 (135 mg, 0.218 mmol, 1 eq), [(2R,7aS)-2-fluoro-hexahydropyrrolidin-7a-yl]methanol (145.83 mg, 0.872 mmol, 1.2 eq), 1,4-dioxane (2 mL), and a solution of potassium tert-butoxide in tetrahydrofuran (1 mol / L, 1.09 mL, 1.09 mol, 1.5 eq) were sequentially added to a 250 mL three-neck flask at 25 °C under nitrogen gas protection. The mixture was reacted for 3 hours under nitrogen gas protection at 70 °C. The reaction system was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was quenched with water (25 mL). The resulting mixture was extracted with ethyl acetate (3 × 30 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase chromatography (C18 column) with a gradient elution of 20% to 95% acetonitrile / water (10 mmol / L ammonium bicarbonate) in 25 min. Detector: UV 254 / 220 nm. The resulting fraction was subjected to rotary evaporation under reduced pressure to obtain compound 6-2 (white solid, 73 mg, yield: 46%). MS (ESI, m / z): 712.2 / 714.2 [M + H]. + .

[0207] Step 3: [ka] Compound 6-2 (35 mg) obtained in Step 2 was chiral separated by preparative supercritical fluid chromatography (chiral column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 20 mL / min; elution with 20% B phase within 18 min; detector: UV 224 / 292 nm). The product with the shorter retention time (10.61 min): compound 6-2a (white solid, 14 mg, recovery: 39%), MS (ESI, m / z): 712.2 / 714.2 [M + H].+ Product with longer retention time (14.59 min): 6-2b (white solid, 12 mg, recovery: 34%), MS (ESI, m / z): 712.2 / 714.2 [M + H] + .

[0208] Step 4: [ka] Compound 6-2a (12 mg, 0.016 mmol, 1 eq), methanol (0.5 mL), and a solution of hydrochloric acid in 1,4-dioxane (4 mol / L, 0.5 mL) were sequentially added to a 25 mL single-neck flask at 0 °C with stirring. The reaction mixture was stirred at 25 °C for 1.5 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a reverse-phase chromatography column (C18 column) with mobile phase A: water (0.1% hydrochloric acid), mobile phase B: acetonitrile, and eluted with 5% to 95% B phase within 30 min. Detector: UV 220 / 254 nm. The resulting fraction was subjected to rotary evaporation under reduced pressure to obtain compound 6a (yellow solid, 3.4 mg, yield: 32%). MS(ESI,m / z): 568.1 / 569.9 [M+H] + ; 1H NMR (400 MHz, DMSO-d6+ D2O) δ 7.10 - 6.87 (m, 2H), 5.72 - 5.46 (m, 1H), 4.66 - 4.42 (m, 3H), 4.20 - 4.01 (m, 3H), 3.94 - 3.71 (m, 4H), 3.39 (s, 2H), 3.31 - 3.22 (m, 1H), 3.16 - 3.05 (m, 1H), 2.98 - 2.85 (m, 1H), 2.86 - 2.71 (m, 2H), 2.72 - 2.55 (m, 2H), 2.48 - 2.44 (m, 1H), 2.30 - 2.10 (m, 3H), 2.10 - 1.88 (m, 5H), 1.89 - 1.73 (m, 2H). Chiral analysis conditions for compound 6a: N-CHIRALPAK IC-3 (Lot No. IC30CS-VF008), 4.6 × 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isocratic elution with 50% B phase within 6 min; detector: UV 220 nm; retention time: 3.795 min; dr > 40:1.

[0209] Step 4: [ka] Compound 6b (yellow solid, 3.3 mg, yield: 31%) was obtained in the same manner as in Step 4. MS (ESI, m / z): 568.2 / 569.9 [M + H] + ; 1H NMR (400 MHz, DMSO-d6+ D2O) δ 7.06 - 6.96 (m, 1H), 6.96 - 6.88 (m, 1H), 5.71 - 5.47 (m, 1H), 4.64 - 4.37 (m, 3H), 4.19 - 4.00 (m, 3H), 3.94 - 3.73 (m, 4H), 3.40 - 3.37 (m, 2H), 3.32 - 3.22 (m, 1H), 3.14 - 3.05 (m, 1H), 2.97 - 2.85 (m, 1H), 2.85 - 2.71 (m, 2H), 2.72 - 2.56 (m, 2H), 2.48 - 2.37 (m, 1H), 2.31–2.09 (m, 3H), 2.09–1.88 (m, 5H), 1.88–1.74 (m, 2H). Chiral analytical conditions for compound 6b: N-CHIRALPAK IC-3 (Lot No. IC30CS-VF008), 4.6 × 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; isocratic elution with 50% B phase within 6 min; detector: UV 220 nm; retention time: 4.358 min; dr >40:1.

[0210] Example 7 (1R or 1S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2'-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-3-methyl-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-6-ol dihydrochloride 7a, (1R or 1S,3R or 3S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2'-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-3-methyl-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-6-ol dihydrochloride 7aa, (1R or 1S,3S or 3R)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2'-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-3-methyl-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-6-ol dihydrochloride 7ab [ka] The synthetic route is as follows: [ka]

[0211] Step 1: [ka] To a solution of compound 6-2a (50 mg, 0.067 mmol, 1 eq) in anhydrous tetrahydrofuran (0.8 mL) was slowly added a solution of lanthanum(III) chloride bis(lithium chloride) complex in tetrahydrofuran (0.6 mol / L, 111.15 μL, 0.067 mmol, 1 eq) at 0 °C under nitrogen gas protection and stirring. After reacting for 1 h, a solution of methylmagnesium bromide in 2-methyltetrahydrofuran (3 mol / L, 88.92 μL, 0.268 mmol, 4 eq) was added. After the addition was complete, the mixture was stirred at 0 °C under nitrogen gas protection for another 1 h. The reaction progress was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride (20 mL) at 0 °C. After quenching, the mixture was extracted with dichloromethane (3 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by reverse-phase chromatography (C18 column) and eluted with 50% to 95% methanol / water (10 mmol / L ammonium bicarbonate) within 20 min. Detector: UV 254 / 220 nm. Compound 7-1a (white solid, 49.0 mg, yield: 98%) was obtained. MS (ESI, m / z): 728.5 / 730.5 [M + H] + .

[0212] Step 2: [ka] Triethylsilane (20 mg, 0.165 mmol, 5 eq) was slowly added dropwise to a solution of compound 7-1a (25 mg, 0.033 mmol, 1 eq) in trifluoroacetic acid (0.5 mL) at 0 °C with stirring. The mixture was stirred at 25 °C for 2 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the solvent was removed using a rotary evaporator under reduced pressure to obtain the crude product. The crude product was purified on a reverse-phase chromatography column (C18 column) and eluted with 5% to 95% acetonitrile / water (0.1% hydrochloric acid) within 25 min. Compound 7a (white solid, 21.0 mg, yield: 98%) was obtained. MS (ESI, m / z): 568.2 / 570.2 [M+H] + , 1 H NMR (400 MHz, CD3OD) δ 6.74 - 6.63 (m, 1H), 6.63 - 6.51 (m, 1H), 5.72 - 5.48 (m, 1H), 4.80 - 4.64 (m, 2H), 4.58 - 4.37 (m, 1H), 4.31 - 4.13 (m, 2H), 4.04 - 3.89 (m, 2H), 3.90 - 3.76 (m, 2H), 3.66 - 3.51 (m, 1H), 3.50 - 3.35 (m, 2H), 3.09 - 2.58 (m, 6H), 2.53 - 1.70 (m, 13H), 1.48 - 1.34 (m, 3H); 19 F NMR (377 MHz, CD3OD) δ -174.27.

[0213] Step 3: [ka] Compound 7a (17 mg, 0.026 mmol) was separated by high-performance liquid chromatography (chiral column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia), mobile phase B: ethanol; flow rate: 25 mL / min; elution with 30% B within 33 min, detection: UV 210 / 290 nm) to give two products. The product with the shorter retention time (7.99 min) was further purified by reverse-phase chromatography (C18 column) with gradient elution from 5% to 95% acetonitrile / water (0.1% hydrochloric acid) within 10 min, detection: UV 220 / 254 nm to give product 7aa (white solid, 3.8 mg, yield: 22%). MS (ESI, m / z): 568.2 / 569.9 [M + H] + ; 1 H NMR (400 MHz, CD3OD) δ 6.72 - 6.67 (m, 1H), 6.62 - 6.54 (m, 1H), 5.75 - 5.47 (m, 1H), 5.14 - 4.98 (m, 1H), 4.82 - 4.66 (m, 2H), 4.65 - 4.47 (m, 1H), 4.38 - 4.12 (m, 2H), 4.03 - 3.78 (m, 4H), 3.75 - 3.55 (m, 1H), 3.52 - 3.35 (m, 2H), 3.19 - 2.86 (m, 3H), 2.84 - 2.54 (m, 3H), 2.54 - 1.91 (m, 10H), 1.91 - 1.70 (m, 2H), 1.49 - 1.32 (m, 3H), 19 F NMR (377 MHz, CD3OD) δ -174.26, -174.32. The product with a longer retention time (10.18 min) was also purified by reverse-phase chromatography (C18 column) with gradient elution from 5% to 95% acetonitrile / water (0.1% HCl) within 10 min. Detector: UV 220 / 254 nm. Product 7ab (white solid, 3.3 mg, 19% yield). MS (ESI, m / z): 568.2 / 567.0 [M + H] + ; 1H NMR (400 MHz, CD3OD) δ 6.71 - 6.65 (m, 1H), 6.60 - 6.52 (m, 1H), 5.69 - 5.50 (m, 1H), 4.85 - 4.68 (m, 3H), 4.67 - 4.46 (m, 1H), 4.39 - 4.11 (m, 2H), 4.09 - 3.76 (m, 4H), 3.76 - 3.55 (m, 1H), 3.55 - 3.35 (m, 2H), 3.09 - 2.55 (m, 6H), 2.54 - 2.00 (m, 10H), 2.00 - 1.76 (m, 2H), 1.50 - 1.36 (m, 3H); 19 F NMR (377 MHz, CD3OD) δ -174.25, -174.28. Chiral analysis conditions for compound 7aa: CHIRALPAK IG-3, 4.6 × 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine); mobile phase B: ethanol; flow rate: 1.67 mL / min; isocratic elution with 30% B phase over 7 min; detector: UV 290 nm; retention time: 1.964 min; dr > 40:1. Chiral analysis conditions for compound 7ab: CHIRALPAK IG-3, 4.6 × 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine); mobile phase B: ethanol; flow rate: 1.67 mL / min; isocratic elution with 30% B phase over 7 min; detector: UV 290 nm; retention time: 4.664 min; dr > 40:1.

[0214] Example 8 (1S or 1R,8'S or 8'R)-4'((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-8'-fluoro-2'((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-6-ol dihydrochloride 8a, (1R or 1S, 8'R or 8'S)-4'((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-8'-fluoro-2'((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-6-ol dihydrochloride 8b, (1S or 1R,8'R or 8'S)-4'((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-8'-fluoro-2'((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-6-ol dihydrochloride 8c, (1R or 1S,8'S or 8'R)-4'((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-8'-fluoro-2'((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-6-ol dihydrochloride 8d [ka] The synthetic route is as follows: [ka]

[0215] Step 1: [ka] A solution of compound 1-8 (1.5 g, 4.196 mmol, 1.0 eq) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to a solution of lithium diisopropylamide in tetrahydrofuran (1 mol / L, 5.96 mL, 5.958 mmol, 1.42 eq) at -78 °C under nitrogen gas protection. The mixture was stirred at -78 °C for 30 minutes, and then a solution of N-fluorobenzenesulfonimide (1.88 g, 5.665 mmol, 1.35 eq) in anhydrous tetrahydrofuran (5 mL) was slowly added to the reaction solution at the same temperature. The mixture was stirred at -78 °C for 5 minutes, then slowly warmed to -40 °C and reacted at this temperature for 1 hour. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction system was quenched by adding saturated sodium bicarbonate solution (20 mL) to the reaction solution. The resulting mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 25% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 8-1 (white solid, 1.4 g, yield: 90%). MS (ESI, m / z): 357.0 / 359.0 / 361.0 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.28 - 7.23 (m, 1H), 7.16 - 7.11 (m, 1H), 6.76 - 6.66 (m, 1H), 5.43- 5.27 (m, 1H), 3.15 - 3.00 (m, 2H), 2.97 - 2.76 (m, 2H), 2.38 - 2.29 (m, 1H), 2.18 - 2.02 (m, 3H).

[0216] Step 2: [ka] Compound 8-1 (789 mg, 2.096 mmol, 1.0 eq), 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (468.36 mg, 2.096 mmol, 1.0 eq), N,N-diisopropylethylamine (1.15 mL, 3.0 eq), and dimethyl sulfoxide (9 mL) were sequentially added to a reaction flask at 25 °C under stirring under nitrogen gas protection. The mixture was reacted at 25 °C for 1 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, saturated brine (10 mL) was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 20% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 8-2 (pale yellow solid, 987 mg, yield: 83%). MS (ESI, m / z): 533.2 / 535.2 / 537.2 [M + H] + .

[0217] Step 3: [ka] Compound 8-2 (985 mg, 1.754 mmol, 1.0 eq), chloro-1,5-cyclooctadiene iridium(I) dimer (124.02 mg, 0.175 mmol, 0.1 eq), 4,4′-di-tert-butyl-2,2′-bipyridyl (99.11 mg, 0.351 mmol, 0.2 eq), bis(pinacolato)diboron (1.88 g, 7.033 mmol, 4.0 eq), pinacolborane (107.16 μL, 0.702 mmol, 0.4 eq), and 1,4-dioxane (10 mL) were sequentially added to a 40 mL reaction flask at 25 °C under nitrogen gas protection and stirring. The mixture was reacted at 120 °C for 2 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was cooled to room temperature and the mixture was concentrated under reduced pressure to obtain a crude intermediate product. A methanol / tetrahydrofuran mixed solvent (1 / 1, 20 mL) was added to the crude intermediate product under stirring at 0 °C, and then urea peroxide (1.74 g, 17.57 mmol, 10.0 eq) was added in batches. The mixture was reacted at 25 °C for 2 hours, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified using a reverse-phase chromatography column (C18 column) and eluted with a 5% to 95% methanol / water mobile phase (0.1% ammonium bicarbonate) within 30 minutes. Detector: UV 254 / 220 nm. Compound 8-3 (light yellow solid, 564 mg, yield: 55%) was obtained. MS (ESI, m / z): 549.2 / 551.2 / 553.2 [M + H] + .

[0218] Step 4: [ka] Compound 8-3 (550 mg, 0.951 mmol, 1.0 eq), N,N-diisopropylethylamine (871.78 μL, 4.755 mmol, 5.0 eq), dichloromethane (7 mL), and chloromethyl methyl ether (188.33 μL, 2.853 mmol, 3.0 eq) were sequentially added to a reaction flask at 0 °C under nitrogen gas protection. The mixture was reacted at 20 °C for 1 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution with a 0% to 20% ethyl acetate / petroleum ether mobile phase. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 8-4 (white solid, 466 mg, yield: 78%). MS (ESI, m / z): 593.2 / 595.2 / 597.2 [M + H] + .

[0219] Step 5: [ka] A solution of compound 8-4 (440 mg, 0.704 mmol, 1.0 eq) and (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-methanol (590.12 mg, 3.521 mmol, 5.0 eq) in 1,4-dioxane (5 mL) was added with potassium tert-butoxide in tetrahydrofuran (1 mol / L, 3.52 mL, 3.520 mmol, 5.0 eq) at 0 °C under nitrogen gas protection. The mixture was reacted at 60 °C for 1 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, saturated brine (10 mL) was added to the reaction solution. The resulting mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution of 0% to 6% methanol / dichloromethane. The resulting fraction was then rotary evaporated under reduced pressure to give crude compound 8-5. The resulting crude product was further purified by reverse-phase chromatography (C18 column) using a 40% to 95% methanol / water mobile phase (10 mmol / L aqueous ammonia) in 30 min. Detector: UV254 / 220. The resulting fraction was then rotary evaporated under reduced pressure to give compound 8-5 (white solid, 231 mg, yield: 44%). MS (ESI, m / z): 716.3 / 718.3 [M + H] + .

[0220] Step 6: [ka] Compound 8-5 (231 mg) obtained in Step 5 was subjected to chiral separation twice by preparative chiral high-performance liquid chromatography to give four isomers. First chiral separation conditions: Chiral column: CHIRALPAK IE, 2 × 25 cm, 5 μm; Mobile phase A: n-hexane: methyl tert-butyl ether = 1:1 (0.5%, 2 mol / L, ammonia-methanol), Mobile phase B: ethanol; Flow rate: 20 mL / min; Elution with 20% Mobile phase B; Detector: UV 212 / 287 nm. The product corresponding to retention time RT1 = 7.165 min was identified as compound 8-5a (white solid, 40 mg, recovery: 17%), and MS (ESI, m / z): 716.3 / 718.3 [M + H]. + The product corresponding to a retention time of RT2 = 8.985 min was a mixture of compounds 8-5b and 8-5c (white solid, 100 mg), and the product corresponding to a retention time of RT3 = 14.34 min was compound 8-5d (white solid, 52 mg, yield: 23%). MS (ESI, m / z): 716.3 / 718.3 [M + H] + . A second chiral separation of a mixture of compounds 8-5b and 8-5c (100 mg) was performed using a chiral column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L, ammonia-methanol), mobile phase B: isopropanol; flow rate: 20 mL / min; elution with 10% mobile phase B; detector: UV 210 / 288 nm. The product with a shorter retention time (17.0 min): compound 8-5b (white solid, 35 mg, recovery: 15%). MS (ESI, m / z): 716.3 / 718.3 [M + H]. + Product with longer retention time (24.0 min): Compound 8-5c (white solid, 53 mg, yield: 23%), MS (ESI, m / z): 716.3 / 718.3 [M + H] + .

[0221] Step 7: [ka] Compound 8-5a (37 mg, 0.049 mmol, 1 eq), methanol (0.5 mL), and a 1,4-dioxane solution of hydrochloric acid (4 mol / L, 0.5 mL) were sequentially added to a 25 mL single-neck flask under stirring at 0 °C. The resulting mixture was reacted for 1.5 h under stirring at 25 °C. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was then purified using a reverse-phase chromatography column (C18 column). The crude product was eluted with a mobile phase of 5% to 95% acetonitrile / water (0.1% hydrochloric acid) within 20 min. Detector: UV 220 / 254 nm. The resulting fraction was subjected to rotary evaporation under reduced pressure to obtain compound 8a (white solid, 20.4 mg, yield: 64%). MS (ESI, m / z): 572.3 / 574.3 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6+ D2O) δ 6.79 - 6.69 (m, 1H), 6.59 - 6.48 (m, 1H), 5.67 - 5.45 (m, 1H), 5.42 - 5.24 (m, 1H), 4.54 - 4.43 (m, 2H), 4.17 - 4.06 (m, 3H), 4.02 - 3.93 (m, 1H), 3.86 - 3.70 (m, 3H), 3.60 - 3.53 (m, 1H), 3.44 - 3.41 (m, 1H), 3.33 - 3.20 (m, 1H), 2.89 - 2.73 (m, 3H), 2.61 - 2.52 (m, 2H), 2.47 - 2.42 (m, 1H), 2.35 - 2.11 (m, 4H), 2.10 - 1.78 (m, 8H); 19 F NMR (377 MHz, DMSO-d6+ D2O) δ -172.75, -184.78.

[0222] Step 8: [ka] Compound 8b (white solid, 17 mg, yield: 48%) was obtained by the method described in Step 7 of this example. MS (ESI, m / z): 572.3 / 574.3 [M + H] + ; 1 H NMR (400 MHz, CD3OD) δ 6.78 - 6.70 (m, 1H), 6.67 - 6.58 (m, 1H), 5.68 - 5.47 (m, 2H), 4.97 - 4.92 (m, 1H), 4.83 - 4.76 (m, 2H), 4.65 - 4.56 (m, 1H), 4.30 - 4.19 (m, 2H), 4.02 - 3.82 (m, 4H), 3.72 - 3.63 (m, 1H), 3.51 - 3.39 (m, 1H), 3.10 - 2.98 (m, 1H), 2.97 - 2.87 (m, 2H), 2.84 - 2.56 (m, 3H), 2.54 - 2.28 (m, 4H), 2.27 - 1.91 (m, 8H); 19 F NMR (377 MHz, CD3OD) δ -174.20, -193.42.

[0223] Step 9: [ka] Compound 8c (yellow solid, 25 mg, yield: 57%) was obtained by the method described in Step 7 of this example. MS (ESI, m / z): 572.3 / 574.3 [M + H] + ; 1H NMR (400 MHz, CD3OD) δ 6.75 - 6.73 (m, 1H), 6.65 - 6.62 (m, 1H), 5.71 - 5.51 (m, 1H), 5.25 - 5.07 (m, 1H), 5.05 - 4.98 (m, 1H), 4.92 - 4.90 (m, 1H), 4.79 - 4.71 (m, 1H), 4.58 - 4.46 (m, 1H), 4.33 - 4.20 (m, 2H), 4.02 - 3.90 (m, 3H), 3.89 - 3.83 (m, 1H), 3.68 - 3.59 (m, 1H), 3.51 - 3.41 (m, 1H), 3.05 - 2.91 (m, 3H), 2.86 - 2.59 (m, 3H), 2.52 - 2.42 (m, 1H), 2.41 - 2.02 (m, 10H), 1.94 - 1.84 (m, 1H); 19 F NMR (377 MHz, CD3OD) δ -174.02, -174.84.

[0224] Step 10: [ka] Compound 8d (yellow solid, 34.9 mg, yield: 83%) was obtained by the method described in Step 7 of this example. MS (ESI, m / z): 572.3 / 574.3 [M + H] + ; 1H NMR (400 MHz, DMSO-d6+ D2O) δ 6.78 - 6.73 (m, 1H), 6.67 - 6.58 (m, 1H), 5.66 - 5.49 (m, 1H), 5.08 - 4.91 (m, 1H), 4.56 - 4.43 (m, 2H), 4.39 - 4.26 (m, 1H), 4.17 - 4.06 (m, 2H), 4.00 - 3.90 (m, 1H), 3.87 - 3.82 (m, 1H), 3.81 - 3.72 (m, 2H), 3.70 - 3.64 (m, 1H), 3.45 - 3.36 (m, 1H), 3.34 - 3.22 (m, 1H), 2.96 - 2.76 (m, 3H), 2.72 - 2.55 (m, 2H), 2.48 - 2.44 (m, 1H), 2.34 - 2.25 (m, 1H), 2.24 - 1.96 (m, 8H), 1.95 - 1.84 (m, 2H), 1.79 - 1.68 (m, 1H); 19 F NMR (377 MHz, DMSO-d6+ D2O) δ -170.35, -172.72.

[0225] Example 9 (S or R)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-8',8'-difluoro-2'-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-6-ol dihydrochloride 9a, (R or S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-8',8'-difluoro-2'-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-6-ol dihydrochloride 9b [ka] The synthetic route is as follows: [ka]

[0226] Step 1: [ka] A solution of compound 8-1 (500 mg, 1.328 mmol, 1.0 eq) in anhydrous tetrahydrofuran (5 mL) was slowly added with a solution of lithium diisopropylamide in tetrahydrofuran (1.0 mol / L, 1.89 mL, 1.886 mmol, 1.42 eq) at -70 °C under stirring and nitrogen gas protection. The mixture was reacted at -70 °C under stirring and nitrogen gas protection for 0.5 hours. Then, a solution of N-fluorobenzenesulfonimide (595.16 mg, 1.793 mmol, 1.35 eq) in anhydrous tetrahydrofuran (5 mL) was slowly added dropwise to the mixture. The mixture was reacted at -40 °C under stirring and nitrogen gas protection for 1 hour. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was complete, the mixture was cooled to 0°C and quenched by adding 10 mL of saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was rotary evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 20% ethyl acetate / petroleum ether. The resulting fractions were rotary evaporated under reduced pressure to give compound 9-1 (yellow solid, 310 mg, yield: 59%). MS (ESI, m / z): 374.9 / 376.9 / 378.9 [M + H] + ; 1H NMR (300 MHz, CDCl3) δ 7.35 - 7.28 (m, 1H), 7.24 - 7.16 (m, 1H), 7.15 - 7.06 (m, 1H), 3.19 - 2.99 (m, 2H), 3.00 - 2.80 (m, 2H), 2.65 - 2.50 (m, 1H), 2.34 - 2.18 (m, 1H), 2.17 - 2.00 (m, 2H); 19 F NMR (282 MHz, CDCl3) δ -96.37, -97.36, -117.36, -118.36.

[0227] Step 2: [ka] Compound 9-1 (250 mg, 0.632 mmol, 1.0 eq), dimethyl sulfoxide (4 mL), N,N-diisopropylethylamine (258.07 g, 1.896 mmol, 3.0 eq), and 8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane (141.30 mg, 0.632 mmol, 1.0 eq) were sequentially added to a 25 mL Schreck tube at 25 °C under nitrogen gas protection and stirring. The mixture was reacted at 25 °C for 1 hour under nitrogen gas protection, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was cooled to 0 °C and quenched by adding ice water (30 mL). The mixture was extracted with ethyl acetate (3 × 20 mL), and the combined organic phases were washed with saturated brine and further dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 20% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to give compound 9-2 (white solid, 360 mg, yield: 98%). MS (ESI, m / z): 551.2 / 553.2 [M + H] + ; 1H NMR (400 MHz, CDCl3) δ 7.32 - 7.27 (m, 1H), 7.21 - 7.12 (m, 1H), 7.12 - 7.02 (m, 1H), 4.49 - 4.19 (m, 2H), 4.17 - 3.97 (m, 1H), 3.86 - 3.72 (m, 1H), 3.53 - 3.31 (m, 1H), 3.33 - 2.91 (m, 3H), 2.86 - 2.70 (m, 1H), 2.72 - 2.56 (m, 1H), 2.53 - 2.28 (m, 2H), 2.20 - 2.06 (m, 1H), 2.03 - 1.85 (m, 4H), 1.82 - 1.68 (m, 1H), 1.49 (s, 9H).

[0228] ステップ3:

change

[0229] Step 4: [ka] To a solution of compound 9-3 (170 mg, 0.285 mmol, 1.00 eq) in dichloromethane (2 mL) was added dropwise N,N-diisopropylethylamine (116.16 mg, 0.855 mmol, 3.0 eq) and chloromethyl methyl ether (39.83 mg, 0.570 mmol, 2.0 eq) sequentially at 0 °C under stirring under nitrogen gas protection. The mixture was reacted at 25 °C for 2 hours under stirring under nitrogen gas protection. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was cooled to 0 °C and quenched by adding 10 mL of water at 0 °C. The mixture was extracted with dichloromethane (3 × 10 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was evaporated under reduced pressure on a rotary evaporator to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 50% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 9-4 (white solid, 180 mg, yield: 98%). MS (ESI, m / z): 611.2 / 613.2 [M + H] + .

[0230] Step 5: [ka] To a solution of compound 9-4 (160 mg, 0.249 mmol, 1.00 eq) in 1,4-dioxane (2 mL) at 25 °C under stirring and nitrogen gas protection, (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-methanol (49.99 mg, 0.299 mmol, 1.2 eq) and a solution of potassium tert-butoxide in tetrahydrofuran (1 mol / L, 0.373 mL, 0.373 mmol, 1.5 eq) were added sequentially. The resulting mixture was stirred at 60 °C under nitrogen gas protection for 1 hour. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was cooled to 0 °C and quenched by adding 10 mL of water. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL) and further dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was then rotary evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% methanol / dichloromethane. The solvent was removed from the resulting fractions under reduced pressure on a rotary evaporator to give compound 9-5 (white solid, 125 mg, yield: 65%). MS (ESI, m / z): 734.3 / 736.3 [M + H] + .

[0231] Step 6: [ka] Compound 9-5 (120 mg) obtained in Step 5 was separated by preparative chiral HPLC (chiral column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2 mol / L ammonia in methanol), mobile phase B: ethanol; flow rate: 20 mL / min; elution with 20% mobile phase B for 9 min; detector: UV 212 / 288 nm). The product with the shorter retention time (3.95 min): compound 9-5a (white solid, 55 mg, recovery: 46%), MS (ESI, m / z): 734.3 / 736.3 [M + H]. + ;Product with longer retention time (5.99 min): Compound 9-5b (white solid, 50 mg, recovery: 42%), MS (ESI, m / z): 734.3 / 736.3 [M + H] + .

[0232] Step 7: [ka] A 1,4-dioxane solution of hydrochloric acid (4 mol / L, 1.5 mL) was added dropwise to a solution of compound 9-5a (55 mg, 0.071 mmol, 1.00 eq) in methanol (1.5 mL) under stirring at 0 °C. The mixture was stirred at room temperature for 1 hour, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase chromatography (C18 column) and eluted with a mobile phase of 5% to 95% acetonitrile / methanol (v / v = 1 / 1):water (0.1% hydrochloric acid) within 30 minutes. Detector: UV 254 / 220 nm. Compound 9a (white solid, 36.0 mg, yield: 75%) was obtained. MS (ESI, m / z): 590.2 / 591.5 [M + H] + , 1H NMR (400 MHz, DMSO-d6+ D2O) δ 6.79 (d, J = 2.0 Hz, 1H), 6.66 - 6.56 (m, 1H), 5.69 - 5.42 (m, 1H), 4.56 - 4.39 (m, 2H), 4.28 - 4.17 (m, 1H), 4.16 - 4.05 (m, 2H), 3.98 - 3.90 (m, 1H), 3.89 - 3.67 (m, 3H), 3.65 - 3.56 (m, 1H), 3.42 - 3.35 (m, 1H), 3.33 - 3.23 (m, 1H), 2.95 - 2.73 (m, 3H), 2.70 - 2.55 (m, 2H), 2.48 - 2.41 (m, 1H), 2.34 - 2.09 (m, 6H), 2.08 - 1.81 (m, 6H), 19 F NMR (377 MHz, DMSO-d6 + DO) δ -96.226, -96.957, -112.281, -113.042, -172.817, -172.858. Chiral analysis conditions for compound 9a: Lux Cellulose-2, 4.6 × 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (0.1% diethylamine); flow rate: 2 mL / min; isocratic elution with 50% B phase within 7.5 min; detector: UV 220 nm; retention time: 5.228 min; dr > 40:1.

[0233] Step 7: [ka] Compound 9b (white solid, 38.0 mg, yield: 88%) was obtained in the same manner as in Step 7. MS (ESI, m / z): 590.1 / 591.9 [M + H] + , 1H NMR (400 MHz, DMSO-d6+ D2O) δ 6.79 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 1.8 Hz, 1H), 5.70 - 5.43 (m, 1H), 4.57 - 4.39 (m, 2H), 4.26 - 4.16 (m, 1H), 4.16 - 4.05 (m, 2H), 4.00 - 3.90 (m, 1H), 3.90 - 3.67 (m, 3H), 3.67 - 3.56 (m, 1H), 3.46 - 3.46 (m, 1H), 3.36 - 3.20 (m, 1H), 2.95 - 2.74 (m, 3H), 2.71 - 2.55 (m, 2H), 2.49 - 2.42 (m, 1H), 2.37 - 2.09 (m, 6H), 2.09 - 1.81 (m, 6H), 19 F NMR (377 MHz, DMSO-d6 + DO) δ -96.640, -97.390, -111.876, -112.605, -172.779, -172.826. Chiral analytical conditions for compound 9b: Lux Cellulose-2, 4.6 × 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (0.1% diethylamine); flow rate: 2 mL / min; isocratic gradient elution of 50% B phase within 7.5 min; detector: UV 220 nm; retention time: 4.017 min; dr > 40:1.

[0234] Example 10 (S or R)-6-((5aS,6S,9R)-1,3-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiaminoazepino[2',1:3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine 10a', (R or S)-6-((5aS,6S,9R)-1,3-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiaminoazepino[2',1:3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine 10b' [ka] The synthetic route is as follows: [ka]

[0235] Step 1: [ka] Compound 10-1 was synthesized with reference to patent (WO2022035790A1). Compound 10-1 (1.2 g, 1 eq), hexamethyldistannane (1.8 eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (0.1 eq), and 1,4-dioxane (12 mL) were sequentially added to a reaction flask at 25 °C under stirring and nitrogen gas protection. The resulting mixture was reacted at 100 °C for 20 h under stirring and nitrogen gas protection. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the crude product was purified using a reverse-phase chromatography column (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% ammonium bicarbonate) within 25 min. Detector: UV 254 / 200 nm. Compound 10-2 (yellow oil, 280 mg, yield: 18%) was obtained. MS (ESI, m / z): 577.1 / 579.1 / 581.1 [M + H] + ; 1 H NMR (400 MHz, CD3OD) δ 7.00 - 6.88 (m, 4H), 6.72 - 6.60 (m, 4H), 6.14 (s, 1H), 4.56 (s, 4H), 3.57 (s, 6H), 2.13 - 2.02 (m, 3H), 0.07 (s, 9H); 19 F NMR (377 MHz, CD3OD) δ -56.55.

[0236] Step 2: [ka] Compound 10-2 (122 mg, 0.200 mmol, 1.5 eq), compound 5-1 (90 mg, 0.13 mmol, 1 eq), tetrakis(triphenylphosphine)palladium(0) (283 mg, 0.24 mmol, 0.5 eq), cuprous iodide (13 mg, 0.07 mmol, 0.5 eq), a solution of lithium chloride in tetrahydrofuran (0.67 mL, 0.33 mmol, 2.5 eq, 0.5 mol / L), and N,N-dimethylformamide (2 mL) were sequentially added to a reaction flask at 25 °C under stirring and nitrogen gas protection. The resulting mixture was reacted at 100 °C for 16 h under stirring and nitrogen gas protection. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the crude product was purified by reverse-phase chromatography (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% ammonium bicarbonate) within 25 min. Detector: UV 254 / 220 nm. Compound 10-3 (white solid, 68 mg, yield: 49%) was obtained. MS (ESI, m / z): 976.3 [M + H] + .

[0237] Step 3: [ka] Trifluoroacetic acid (2 mL) was added dropwise to a solution of 10-3 (68 mg, 0.07 mmol, 1 eq) in anisole (2 mL) under stirring at 0 °C. The resulting mixture was stirred at 100 °C for 1.5 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the solvent was removed using a rotary evaporator under reduced pressure to obtain the crude product. The resulting crude product was purified by high-performance liquid chromatography (chromatography column: YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution with 25% to 45% B phase within 13 min; detector: 220 nm). Among them, the compound with the shorter retention time (10.13 min): Compound 10a (11 mg, white solid, yield: 24%); MS (ESI, m / z): 636.2 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 6.87 (s, 2H), 6.49 (s, 1H), 5.39 - 5.16 (m, 1H), 4.87 - 4.77 (m, 1H), 4.62 - 4.50 (m, 1H), 4.34 - 4.24 (m, 1H), 4.08 - 3.98 (m, 2H), 3.98 - 3.91 (m, 1H), 3.62 - 3.54 (m, 1H), 3.47 - 3.42 (m, 1H), 3.14 - 2.97 (m, 4H), 2.86 - 2.66 (m, 2H), 2.40 - 2.32 (m, 3H), 2.14 - 1.94 (m, 3H), 1.89 - 1.61 (m, 6H), 1.59 - 1.47 (m, 1H); 19 F NMR (377 MHz, DMSO-d6) δ -53.51, -135.87, -143.64, -172.14. Compound with longer retention time (10.98 min): Compound 10b (5 mg, white solid, yield: 11%); MS (ESI, m / z): 636.2 [M + H] + ; 1H NMR (300 MHz, DMSO-d6) δ 6.87 (s, 2H), 6.50 (s, 1H), 5.42 - 5.16 (m, 1H), 4.78 - 4.69 (m, 1H), 4.60 - 4.47 (m, 1H), 4.42 - 4.29 (m, 1H), 4.14 - 4.04 (m, 1H), 4.00 - 3.89 (m, 2H), 3.65 - 3.56 (m, 1H), 3.50 - 3.44 (m, 1H), 3.13 - 2.98 (m, 4H), 2.89 - 2.65 (m, 2H), 2.44 - 2.32 (m, 3H), 2.17 - 2.10 (m, 1H), 2.09 - 1.93 (m, 2H), 1.88 - 1.52 (m, 7H); 19 F NMR (282 MHz, DMSO-d6) δ -53.51, -135.81, -143.67, -172.10.

[0238] Example 11 5-Cyclopropyl-4-(2R or 2S,5aS,6S,9R)-1,3-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1:3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)naphth-2-ol dihydrochloride 11a, 5-cyclopropyl-4-(2S or 2R,5aS,6S,9R)-1,3-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1:3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)naphth-2-ol dihydrochloride 11b [ka] The synthetic route is as follows: [ka]

[0239] Step 1: [ka] At 25 °C, under stirring and nitrogen gas protection, 1-bromo-8-iodonaphthalene (6.00 g, 17.119 mmol, 1 eq), cyclopropylboronic acid (1.55 g, 17.119 mmol, 1 eq), potassium phosphate (7.65 g, 34.238 mmol, 2 eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (1.47 g, 1.712 mmol, 0.1 eq), toluene (60 mL), and water (12 mL) were sequentially added to a reaction flask. The resulting mixture was stirred and under nitrogen gas protection at 60 °C for 6 hours, and the reaction process was monitored by thin-layer chromatography. After completion of the reaction, the reaction solution was cooled to room temperature and diluted with 20 mL of saturated aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% ethyl acetate / petroleum ether. The fractions were concentrated under reduced pressure to remove the solvent, giving compound 11-1 (pale yellow solid, 2.4 g, yield: 53%). 1 H NMR (300 MHz, CDCl3) δ 7.93 - 7.87 (m, 1H), 7.84 - 7.78 (m, 1H), 7.74 - 7.69 (m, 1H), 7.52 - 7.47 (m, 1H), 7.43 - 7.36 (m, 1H), 7.28 - 7.22 (m, 1H), 3.08 - 2.94 (m, 1H), 1.18 - 1.08 (m, 2H), 0.93 - 0.84 (m, 2H).

[0240] Step 2: [ka] To a solution of compound 11-1 (1.5 g, 5.776 mmol, 1 eq) in heptane (20 mL) was added bis(pinacolato)diboron (1.34 g, 7.496 mmol, 1.3 eq), 4,4'-di-tert-butyl-2,2'-bipyridyl (330 mg, 1.153 mmol, 0.2 eq), and chloro-1,5-cyclooctadiene iridium(I) dimer (410 mg, 0.577 mmol, 0.1 eq) sequentially at 25 °C under nitrogen gas protection. The mixture was stirred at 80 °C for 2 hours, and the reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the mixture was concentrated under reduced pressure to remove the solvent. The resulting mixture was dissolved in tetrahydrofuran (10 mL). Water (5 mL), acetic acid (30 mL), and hydrogen peroxide (30%, 15 mL) were added dropwise to the mixture at 0°C under stirring. The mixture was stirred at 0°C for 30 minutes, and the reaction process was monitored by thin-layer chromatography. After the reaction was completed, saturated sodium bicarbonate solution was added slowly to the reaction solution under stirring at 0°C to adjust the pH to 8. The mixture was extracted with ethyl acetate (100 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution of 0% to 20% methyl tert-butyl ether / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 11-2 (yellow oil, 700 mg, yield: 45%). 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 7.65 - 7.58 (m, 1H), 7.50 (d, J = 2.6 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.24 - 7.17 (m, 2H), 2.83 (m, 1H), 1.08 - 1.01 (m, 2H), 0.83 - 0.77 (m, 2H).

[0241] Step 3: [ka] To a solution of compound 11-2 (650 mg, 2.347 mmol, 1 eq) in dichloromethane (10 mL) was slowly added N,N-diisopropylethylamine (860.56 μL, 4.694 mmol, 2 eq) and chloromethyl methyl ether (298.32 mg, 3.521 mmol, 1.5 eq) at 0 °C under nitrogen gas protection. The mixture was stirred at 25 °C for 2 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution of 0% to 12% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 11-3 (yellow oil, 660 mg, yield: 88%). 1 H NMR (300 MHz, CDCl3) δ 7.68 (d, J = 2.6 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.36 - 7.31 (m, 2H), 5.28 (s, 2H), 3.53 (s, 3H), 2.99 - 2.90 (m, 1H), 1.16 - 1.07 (m, 2H), 0.94 - 0.83 (m, 2H).

[0242] Step 4: [ka] To a solution of compound 11-3 (300 mg, 0.928 mmol, 1 eq) in anhydrous tetrahydrofuran (4 mL) was slowly added a solution of n-butyllithium in n-hexane (2.5 mol / L, 0.59 mL, 1.485 mmol, 1.6 eq) dropwise at -78 °C under stirring and nitrogen gas protection. The mixture was reacted at -78 °C for 1 hour under stirring and nitrogen gas protection, and then a solution of pinacol isopropoxyboronate (327.07 mg, 1.670 mmol, 1.8 eq) in anhydrous tetrahydrofuran (1 mL) was slowly added dropwise at the same temperature. The mixture was reacted at -78 °C for 1 hour, then allowed to warm to room temperature and stirred at room temperature for 30 minutes. The reaction progress was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction was quenched by adding 50 mL of saturated aqueous ammonium chloride at 0 °C. The mixture was extracted with ethyl acetate (60 mL × 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 12% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to obtain compound 11-4 (colorless oily liquid, 290 mg, yield: 79%). MS (ESI, m / z): 355.1 [M + H] + ; 1 H NMR (400 MHz,CDCl3) δ 7.61 - 7.56 (m, 1H), 7.44 - 7.39 (m, 2H), 7.35 - 7.29 (m, 1H), 7.23 - 7.19 (m, 1H), 5.29 (s, 2H), 3.51 (s, 3H), 2.72 - 2.57 (m, 1H), 1.40 (s, 12H), 1.05 - 0.97 (m, 2H), 0.69 - 0.59 (m, 2H).

[0243] Step 5: [ka] Compound 5-1 (200 mg, 0.297 mmol, 1.0 eq), compound 11-4 (143.8 mg, 0.386 mmol, 1.3 eq), tris(dibenzylideneacetone)dipalladium(0) (28.59 mg, 0.03 mmol, 0.1 eq), 3-tert-butyl-4-(9-anthryl)-2,3-dihydro-1,3-benzoxaphosphole (20.63 mg, 0.06 mmol, 0.2 eq), potassium phosphate (132.56 mg, 0.594 mmol, 2.0 eq), toluene (4.0 mL), and water (0.8 mL) were sequentially added to a reaction flask at 25 °C under nitrogen gas protection. The mixture was stirred at 80 °C for 3 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was cooled to 25°C and concentrated under reduced pressure to remove excess solvent, yielding a crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a 0% to 10% methanol / dichloromethane mobile phase. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to yield compound 11-5 (white solid, 180 mg, yield: 73%). MS (ESI, m / z): 788.4 [M + H] + .

[0244] Step 6: [ka] Compound 11-5 (180 mg) obtained in Step 5 was chiral separated by supercritical fluid chromatography (chiral column: CHIRALPAK ID, 2 × 25 cm, 5 μm; mobile phase A: n-hexane / methyl tert-butyl ether (1 / 1) (0.5%, 2 mol / L ammonia / methanol); mobile phase B: ethanol; flow rate: 20 mL / min; elution with 30% mobile phase B; UV detection at 226 nm). The product with the shorter retention time (5.20 min): compound 11-5a (white solid, 62 mg, recovery: 44%). Compound 11-5a: MS (ESI, m / z): 788.4 [M + H] +Product with a longer retention time (8.19 min): 11-5b (white solid, 57 mg, yield: 44%), Compound 11-5b: MS (ESI, m / z): 788.4 [M + H] + .

[0245] Step 7: [ka] A 1,4-dioxane solution of hydrochloric acid (4 mol / L, 2 mL) was added dropwise to a methanol (2 mL) solution of compound 11-5a (67 mg, 0.081 mmol, 1.00 eq) at 0°C under stirring. The mixture was reacted at room temperature for 1.5 hours, and the reaction process was monitored by liquid mass spectrometry. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase flash chromatography (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% hydrochloric acid) within 25 minutes. Detector: UV 254 nm. Compound 11a (white solid, 41 mg, yield: 69%) was obtained. MS (ESI, m / z): 644.3 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 10.38 - 9.72 (m, 3H), 7.69 (d, J = 8.0 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.13 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 5.65 - 5.48 (m, 1H), 4.99 (d, J = 14.0 Hz, 1H), 4.75 - 4.68 (m, 1H), 4.65 - 4.54 (m, 4H), 4.30 - 4.22 (m, 2H), 3.80 - 3.70 (m, 3H), 3.65 (d, J = 14.0 Hz, 1H), 3.35 - 3.22 (m, 1H), 2.64 - 2.52 (m, 1H), 2.49 - 2.45 (m, 1H), 2.37 - 2.27 (m, 1H), 2.22 - 1.88 (m, 7H), 1.58 - 1.46 (m, 1H), 0.55 - 0.44 (m, 2H), 0.34 - 0.27 (m, 1H), 0.13 - 0.07 (m, 1H); 19 19F NMR (377 MHz, DMSO-d6) δ -132.06, -139.03, -172.75。

[0246] Step 8:

Chem.

[0247] Example 12 4-((2R or 2S,5aS,6S,9R)-1,3-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1:3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-(2-methoxyethyl)naphthalen-2-ol dihydrochloride 12a, 4-((2S or 2R,5aS,6S,9R)-1,3-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1:3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-(2-methoxyethyl)naphthalen-2-ol dihydrochloride 12b [ka] The synthetic route is as follows: [ka]

[0248] Step 1: [ka] A solution of 1,8-dibromonaphthalene (20 g, 66.441 mmol, 1.0 eq) in anhydrous tetrahydrofuran (200 mL) was slowly added dropwise to a solution of n-butyllithium in n-hexane (2.5 mol / L, 31.9 mL, 79.729 mmol, 1.2 eq) at -78 °C under stirring and nitrogen gas protection. The mixture was reacted at -78 °C under stirring and nitrogen gas protection for 0.5 hours. Then, a solution of ethylene oxide in anhydrous tetrahydrofuran (2.5 mol / L, 265.8 mL, 664.410 mmol, 10 eq) was slowly added dropwise to the mixture. The mixture was reacted at 0 °C under stirring and nitrogen gas protection for 0.5 hours. The reaction solution was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was quenched by adding water (500 mL) at 0 °C. The mixture was extracted with ethyl acetate (1 L × 3). The combined organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was rotary evaporated under reduced pressure to give the crude product. The crude product was purified by reverse-phase chromatography (C18 column) and eluted with a 40% to 95% acetonitrile / water mobile phase (10 mmol / L aqueous ammonium bicarbonate) within 30 min. The solvent was then removed by rotary evaporation under reduced pressure to give compound 12-1 (white solid, 9.5 g, yield: 54%). 1 H NMR (300 MHz, CDCl3) δ 7.91 - 7.76 (m, 3H), 7.51 - 7.40 (m, 2H), 7.29 - 7.24 (m, 1H), 4.10 - 3.99 (m, 2H), 3.94 - 3.83 (m, 2H).

[0249] Step 2: [ka] Sodium hydride (60%, 1.51 g, 37.83 mmol, 2.0 eq) was added in batches to a solution of 12-1 (5 g, 18.915 mmol, 1.0 eq) in anhydrous tetrahydrofuran (50 mL) at 0 °C under nitrogen gas protection and stirring. After the addition was complete, the mixture was stirred at 0 °C under nitrogen gas protection for 30 minutes, and then methyl iodide (4.24 g, 28.372 mmol, 1.5 eq) was added dropwise. After the addition was complete, the mixture was stirred at 25 °C under nitrogen gas protection for 1 hour. The reaction process was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was carefully poured into ice water (250 mL) to quench the reaction. Then, the mixture was extracted with ethyl acetate (250 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% ethyl acetate / petroleum ether. The obtained fraction was evaporated under reduced pressure on a rotary evaporator to obtain compound 12-2 (orange liquid, 5.1 g, yield: 97%). 1 H NMR (400 MHz, CDCl3) δ 7.88 - 7.72 (m, 3H), 7.48 - 7.37 (m, 2H), 7.25 - 7.18 (m, 1H), 3.89 - 3.82 (m, 2H), 3.79 - 3.72 (m, 2H), 3.39 (s, 3H).

[0250] Step 3: [ka] A 100 mL three-neck flask was charged with 12-2 (2.6 g, 9.315 mmol, 1.0 eq), n-hexane (26 mL), bis(pinacolato)diboron (3.24 g, 12.110 mmol, 1.3 eq), bis(1,5-cyclooctadiene)(methoxy)iridium(I) dimer (0.65 g, 0.931 mmol, 0.1 eq), and 4,4′-di-tert-butyl-2,2′-dipyridyl (0.53 g, 1.863 mmol, 0.2 eq) at 25 °C under stirring and nitrogen gas protection. The mixture was reacted at 60 °C for 2 h under stirring and nitrogen gas protection. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was concentrated. Tetrahydrofuran (8 mL), water (4 mL), acetic acid (12 mL), and hydrogen peroxide (6 mL) were added to the resulting mixture while stirring at 0°C for 0.5 hours. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, a saturated solution of sodium bicarbonate (100 mL) was added while stirring at 0°C. The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined extracts were dried and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution of 0% to 30% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to obtain compound 12-3 (white solid, 870 mg, yield: 32%). MS (ESI, m / z): 278.9 / 280.9 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.60 - 7.53 (m, 1H), 7.52 (d, J = 2.7 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.13 (d, J = 2.7 Hz, 1H), 3.83 - 3.77 (m, 2H), 3.76 - 3.70 (m, 2H), 3.39 (s, 3H).

[0251] Step 4: [ka] A 50 mL three-neck flask was charged with 12-3 (850 mg, 2.872 mmol, 1.00 eq), dichloromethane (9 mL), N,N-diisopropylethylamine (390.75 mg, 2.872 mmol, 1.0 eq), and chloromethyl methyl ether (301.48 mg, 4.308 mmol, 1.5 eq) at 0 °C under stirring and nitrogen gas protection. The mixture was reacted at 25 °C for 1 h under stirring and nitrogen gas protection. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was quenched by adding water (50 mL) at 0 °C. The mixture was extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was evaporated under reduced pressure on a rotary evaporator to obtain the crude product. The obtained crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% ethyl acetate / petroleum ether. The solvent was removed from the obtained fraction using a rotary evaporator under reduced pressure to obtain compound 12-4 (pale yellow solid, 780 mg, yield: 79%). 1 H NMR (400 MHz, CDCl3) δ 7.67 - 7.61 (m, 2H), 7.40 - 7.28 (m, 3H), 5.26 (s, 2H), 3.84 - 3.77 (m, 2H), 3.76 - 3.70 (m, 2H), 3.51 (s, 3H), 3.38 (s, 3H).

[0252] Step 5: [ka] A 25 mL Schreck tube was charged with 12-4 (400 mg, 1.169 mmol, 1.00 eq) in 4 mL of anhydrous tetrahydrofuran, followed by a solution of n-butyllithium in n-hexane (2.5 mol / L, 0.61 mL, 1.52 mmol, 1.3 eq) at -78 °C under stirring and nitrogen gas protection. The mixture was reacted at -78 °C for 0.5 h. Next, a solution of pinacol isopropoxyboronate (411.94 mg, 2.104 mmol, 1.8 eq) in 1 mL of anhydrous tetrahydrofuran was slowly added dropwise to the reaction solution at -78 °C under stirring and nitrogen gas protection. The mixture was reacted at -78 °C under stirring and nitrogen gas protection for 1 h, and then at 25 °C under stirring and nitrogen gas protection for another 0.5 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction mixture was quenched by adding saturated ammonium chloride solution (50 mL) to the reaction mixture under stirring at 0 °C. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The filtrate was then rotary evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% methyl tert-butyl ether / petroleum ether. The solvent was then removed from the resulting fractions under reduced pressure on a rotary evaporator to give compound 12-5 (colorless oil, 440 mg, yield: 97%). 1 H NMR (400 MHz, CDCl3) δ 7.64 - 7.58 (m, 1H), 7.40 (d, J = 2.7 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.30 - 7.25 (m, 1H), 5.28 (s, 2H), 3.68 (t, J = 7.5 Hz, 2H), 3.50 (s, 3H), 3.43 (t, J = 7.5 Hz, 2H), 3.34 (s, 3H), 1.45 (s, 12H).

[0253] Step 6: [ka] Compound 5-1 (150 mg, 0.22 mmol, 1.0 eq), compound 12-5 (92.90 mg, 0.24 mmol, 1.1 eq), tris(dibenzylideneacetone)dipalladium(0) (21.45 mg, 0.022 mmol, 0.1 eq), 3-tert-butyl-4-(9-anthryl)-2,3-dihydro-1,3-benzoxaphosphole (15.47 mg, 0.044 mmol, 0.2 eq), potassium phosphate (149.13 mg, 0.66 mmol, 3.0 eq), toluene (2.0 mL), and water (0.4 mL) were sequentially added to a reaction flask at 25 °C under nitrogen gas protection. The mixture was stirred at 80 °C for 12 h, and the reaction progress was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was cooled to 25°C and concentrated under reduced pressure to remove excess solvent, yielding a crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a 0% to 10% methanol / dichloromethane mobile phase. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to yield compound 12-6 (white solid, 140 mg, yield: 74%). MS (ESI, m / z): 806.4 [M + H] + .

[0254] Step 7: [ka] Compound 12-6 (140 mg) obtained in Step 6 was chiral separated by supercritical fluid chromatography (chiral column: CHIRALPAK ID, 3 × 25 cm, 5 μm; mobile phase A: n-hexane / methyl tert-butyl ether (1 / 1) (0.5%, 2 mol / L ammonia / methanol), mobile phase B: ethanol; flow rate: 40 mL / min; elution with 10% mobile phase B; UV detection at 228 nm). The product with the shorter retention time (7.65 min): compound 12-6a (white solid, 55 mg, recovery: 40%). Compound 12-6a: MS (ESI, m / z): 806.4 [M + H]+ Product with a longer retention time (9.65 min): Compound 12-6b (white solid, 62 mg, yield: 44%). Compound 12-6b: MS (ESI, m / z): 806.4 [M + H] + .

[0255] Step 8: [ka] A solution of compound 12-6a (55 mg, 0.065 mmol, 1.00 eq) in methanol (2 mL) was added to a 1,4-dioxane solution of hydrochloric acid (4 mol / L, 2 mL) under stirring at 0 °C. The mixture was reacted at room temperature for 1.5 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase flash chromatography (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% hydrochloric acid) within 25 min. Detector: UV 254 nm. Compound 12a (yellow solid, 29 mg, yield: 59%) was obtained. MS (ESI, m / z): 662.3 [M + H] + ; 1 H NMR (400 MHz, CD3OD-d4) δ 7.68 (d, J = 8.4 Hz, 1H), 7.40 - 7.33 (m, 1H), 7.33 - 7.29 (m, 1H), 7.21 - 7.14 (m, 1H), 7.04 - 6.94 (m, 1H), 5.67 - 5.33 (m, 2H), 4.84 - 4.53 (m, 6H), 4.46 - 4.33 (m, 2H), 4.09 - 3.82 (m, 3H), 3.80 - 3.63 (m, 1H), 3.53 - 3.41 (m, 1H), 3.28 - 3.24 (m, 1H), 3.18 - 3.05 (m, 3H), 2.79 - 2.57 (m, 4H),2.53 - 2.44 (m, 1H), 2.43 - 2.30 (m, 3H), 2.29 - 2.08 (m, 4H); 19F NMR (377 MHz, CD3OD-d4) δ -134.56, -137.61, -174.26.

[0256] Step 9: [ka] A solution of compound 12-6b (55 mg, 0.065 mmol, 1.00 eq) in methanol (2 mL) was added to a 1,4-dioxane solution of hydrochloric acid (4 mol / L, 2 mL) under stirring at 0 °C. The mixture was reacted at room temperature for 1.5 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase flash chromatography (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% hydrochloric acid) within 25 min. Compound 12b (yellow solid, 25.9 mg, yield: 46%) was obtained using a detector: UV 254 nm. MS (ESI, m / z): 662.3 [M + H] + ; 1 H NMR (400 MHz, CD3OD-d4) δ 7.69 (d, J = 8.4 Hz, 1H), 7.43 - 7.27 (m, 2H), 7.20 - 7.16 (m, 1H), 7.03 - 6.94 (m, 1H), 5.64 - 5.51 (m, 1H), 5.45 - 5.31 (m, 1H), 4.84 - 4.73 (m, 4H), 4.70 -4.50 (m, 2H), 4.43 - 4.36 (m, 2H), 4.05 - 3.84 (m, 3H), 3.76 - 3.64 (m, 1H), 3.49 - 3.42 (m, 1H), 3.28 - 3.25 (m, 1H), 3.17 - 3.10 (m, 3H), 2.78 - 2.58 (m, 4H), 2.53 - 2.43 (m, 1H), 2.39 - 2.30 (m, 3H), 2.24 - 2.14 (m, 4H); 19 F NMR (376 MHz, CD3OD-d4) δ -134.36, -138.03, -174.28.

[0257] Example 13 4-((2S or 2R,6aS,7S,10R)-1,3-difluoro-14-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-7,10-epiminoazepino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol 13a', 4-((2R or 2S,6aS,7S,10R)-1,3-difluoro-14-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-7,10-epiminoazepino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol 13b [ka] The synthetic route is as follows: [ka]

[0258] Step 1: [ka] N-iodosuccinimide (29.87 g, 126.108 mmol, 1.5 eq) was added in batches to a solution of 3-bromo-2,4,5-trifluoroaniline (25 g, 105.09 mmol, 1 eq) and p-toluenesulfonic acid monohydrate (2.1 g, 10.506 mmol, 0.1 eq) in acetonitrile (300 mL) at 25 °C under stirring. The mixture was stirred at 60 °C under nitrogen gas protection for 3 hours. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove excess solvent. After removing the solvent, the remaining solid was redissolved in 500 mL of ethyl acetate. The resulting mixture was washed with saturated sodium thiosulfate solution (500 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The filtrate was then rotary evaporated under reduced pressure to obtain the crude product. The obtained crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% ethyl acetate / petroleum ether. The obtained fraction was subjected to rotary evaporation under reduced pressure to remove the solvent, yielding compound 13-1 (brown solid, 30 g, yield: 73%). 1 H-NMR (400 MHz, CDCl3) δ 4.20 (s, 2H); 19 F-NMR (377 MHz, CDCl3) δ -117.85, -128.47, -141.77.

[0259] Step 2: [ka] To a solution of compound 13-1 (17 g, 45.895 mmol, 1 eq) in ethanol (500 mL) was added bis(triphenylphosphine)palladium(II) dichloride (3.39 g, 4.59 mmol, 0.1 eq) and triethylamine (24.17 mL, 165.22 mmol, 3.6 eq) sequentially under stirring at 25 °C under nitrogen gas protection. The mixture was reacted at 80 °C under a carbon monoxide atmosphere at 5 atmospheres for 16 hours. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to remove excess solvent, yielding a crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to yield compound 13-2 (brown solid, 10.5 g, yield: 72%). 1 H-NMR (400 MHz, CDCl3) δ 5.67 (s, 2H), 4.50 - 4.35 (m, 2H), 1.44 - 1.36 (m, 3H); 19 F-NMR (377 MHz, CDCl3) δ -132.94, -135.73, -147.14.

[0260] Step 3: [ka] Trichloroacetyl isocyanate (4.74 g, 23.904 mmol, 1.5 eq) was slowly added dropwise to a solution of compound 13-2 (5 g, 15.936 mmol, 1 eq) in tetrahydrofuran (50 mL) at 0 °C under stirring under nitrogen gas protection, and the mixture was reacted at 25 °C for 0.5 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the mixture was concentrated under reduced pressure to remove excess solvent and obtain the crude product. The obtained crude product was purified by slurrying with methyl tert-butyl ether (50 mL) to obtain compound 13-3 (brown solid, 5.7 g, yield: 69%). MS (ESI, m / z): 484.8 / 486.8.

[0261] Step 4: [ka] Ammonia methanol solution (7 mol / L, 10 mL) was slowly added dropwise to a methanol solution (100 mL) of compound 13-3 (5.7 g, 11.13 mmol, 1 eq) at 0 °C under stirring, and the mixture was reacted at 25 °C for 1 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was concentrated under reduced pressure to remove excess solvent and obtain the crude product. The obtained crude product was purified by slurrying with methyl tert-butyl ether (50 mL) to obtain compound 13-4 (brown solid, 3.18 g, yield: 91%). 1 H-NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 11.58 (s, 1H); 19 F-NMR (377 MHz, DMSO) δ -125.47, -139.98, -143.15.

[0262] Step 5: [ka] Compound 13-4 (1 g, 3.22 mmol, 1 eq) in phosphorus oxychloride (15 mL) was slowly added dropwise to triethylamine (1 mL) at 0 °C under nitrogen gas protection, and the mixture was reacted at 100 °C for 16 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was concentrated under reduced pressure to remove excess solvent, yielding a crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to yield compound 13-4 (brown solid, 850 mg, yield: 75%). 19 F-NMR (377 MHz, DMSO) δ -115.15, -124.03, -137.27.

[0263] Step 6: [ka] Benzyl bromide (26.59 g, 147.67 mmol, 1.1 eq) was slowly added dropwise to a solution of 8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane (30 g, 134.2 mmol, 1 eq) and anhydrous potassium carbonate (39.09 g, 268.496 mmol, 2 eq) in acetonitrile (300 mL) at 0 °C under nitrogen gas protection and stirring. The mixture was reacted at 80 °C for 6 hours. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered to remove excess potassium carbonate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 30% methyl tert-butyl ether / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 13-6 (brown solid, 33 g, yield: 77%). MS (ESI, m / z): 303.4 [M+H] + ; 1 H-NMR (400 MHz, CDCl3) δ 7.30 (d, J = 4.5 Hz, 4H), 7.25 - 7.19 (m, 1H), 4.15 - 4.11 (m, 2H), 3.47 (s, 2H), 2.62 - 2.58 (m, 2H), 2.29 - 2.25 (m, 2H), 1.99 - 1.74 (m, 4H), 1.46 (s, 9H).

[0264] Step 7: [ka] To a mixture of compound 13-6 (33 g, 103.6 mmol, 1 eq) in water (330 mL) and dimethyl sulfoxide (825 mL) was added iodine (221.57 g, 829.312 mmol, 8 eq) and sodium bicarbonate (91.67 g, 1.04 mol, 10 eq) sequentially under stirring at 0 °C. The resulting mixture was reacted at 25 °C for 16 hours. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction mixture was cooled to 0 °C and quenched by slowly adding 1 L of saturated sodium thiosulfate solution. The mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with saturated brine (1 L x 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was evaporated under reduced pressure on a rotary evaporator to obtain the crude product. The crude product was purified by slurrying with methyl tert-butyl ether / n-hexane (1 / 5, 200 mL) to give compound 13-7 (white solid, 29 g, yield: 84%). MS (ESI, m / z): 261.1 [M- t Bu+H] + ; 1 H-NMR (400 MHz, CDCl3) δ 7.33 - 7.24 (m, 3H), 7.21 - 7.15 (m, 2H), 4.71 - 4.32 (m, 4H), 3.72 - 3.51 (m, 1H), 2.89 - 2.74 (m, 1H), 2.26 - 2.10 (m, 3H), 1.67 - 1.55 (m, 1H), 1.44 (s, 9H).

[0265] Step 8: [ka] Compound 13-7 (28 g) obtained in Step 7 was chiral separated by supercritical fluid chromatography (chiral column: CHIRALPAK IC, 5 × 25 cm, 5 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol (0.5%, 2 mol / L ammonia-methanol); flow rate: 200 mL / min; column temperature: 35 °C; elution with 40% mobile phase B; detector: UV 220 nm) to obtain two products. The product with the shorter retention time (5.26 min): compound 13-7a (white solid, 11 g, recovery: 39%), MS (ESI, m / z): 261.1 [M- t Bu+H] + Product with longer retention time (7.92 min): Compound 13-7b (white solid, 11 g, yield: 39%), MS (ESI, m / z): 261.1 [M- t Bu+H] + .

[0266] Step 9: [ka] At 0°C, under nitrogen gas protection, a solution of compound 13-7a (10 g, 30.025 mmol, 1 eq) and carbonylbis(triphenylphosphine)iridium(I) chloride (2.47 g, 3.00 mmol, 0.1 eq) in dichloromethane (100 mL) was slowly added with 1,1,3,3-tetramethyldisiloxane (12.74 g, 90.075 mmol, 3 eq). The mixture was reacted at 25°C for 1.5 hours. After the reaction solution became clear, the reaction system was cooled to -78°C and 1 mol / L allylmagnesium bromide (45 mL, 45.03 mmol, 1.5 eq) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and react for 1 hour. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction mixture was cooled to 0°C and quenched by slowly adding 500 mL of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with saturated brine (1 L x 1), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was subjected to rotary evaporation under reduced pressure to remove the solvent to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 20% methyl tert-butyl ether / petroleum ether to obtain two compounds. Compound 13-8a (colorless oily liquid, 7.26 g, yield: 67%). MS (ESI, m / z): 343.2 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.27 (m, 4H), 7.25 - 7.20 (m, 1H), 5.84 (s, 1H), 5.17 - 4.95 (m, 2H), 4.42 - 4.00 (m, 2H), 3.68 (d, J = 13.4 Hz, 1H), 3.50 (d, J = 13.5 Hz, 1H), 2.73 - 2.50 (m, 2H), 2.37 - 2.29 (m, 1H), 2.29 - 2.19 (m, 2H), 1.96 - 1.63 (m, 4H), 1.46 (s, 9H). Compound 13-8b (colorless oily liquid, 240 mg, 2%). MS (ESI, m / z): 343.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.27 (m, 4H), 7.25 - 7.17 (m, 1H), 5.81 (s, 1H), 5.15 - 5.00 (m, 2H), 4.22 - 3.91 (m, 3H), 3.06 (d, J = 13.8 Hz, 1H), 2.69 - 2.40 (m, 3H), 2.37 - 2.13 (m, 1H), 2.11 - 1.90 (m, 2H), 1.88 - 1.63 (m, 3H), 1.45 (s, 9H).

[0267] ステップ10:

change

[0268] Step 11: [ka] Sodium periodate (5.68 g, 25.235 mmol, 5 eq) was added to a solution of compound 13-9 (2 g, 5.047 mmol, 1 eq) in acetonitrile (32 mL) and water (8 mL) under stirring at 25 °C, and the mixture was reacted at 25 °C for 0.5 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the mixture was filtered to remove insoluble matter, and the filtrate was extracted with chloroform / isopropanol (3 / 1, 50 mL x 3). The solvent was removed by concentration under reduced pressure to obtain crude product 13-10 (pale yellow oily liquid, 1.7 g, yield: 93%), which was immediately used in the next step. MS (ESI, m / z): 345.1 [M+H] + .

[0269] Step 12: [ka] Sodium borohydride (280 mg, 7.034 mmol, 1.5 eq) was added to a solution of compound 13-10 (1.7 g, 4.689 mmol, 1 eq) in methanol (20 mL) under stirring at 0 °C, and the mixture was reacted at 25 °C for 1 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent, and the resulting mixture was purified by silica gel column chromatography using a gradient elution of 0% to 5% methanol / dichloromethane. The resulting fraction was subjected to rotary evaporation under reduced pressure to remove the solvent, yielding compound 13-11 (pale yellow oily liquid, 1.2 g, yield: 63%). MS (ESI, m / z): 347.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.35 - 7.28 (m, 4H), 7.25 - 7.20 (m, 1H), 4.44 - 4.30 (m, 1H), 4.18 - 4.00 (m, 2H), 3.59 (d, J = 13.7 Hz, 2H), 3.46 - 3.35 (m, 2H), 2.72 (d, J = 10.0 Hz, 1H), 2.45 (d, J = 10.8 Hz, 1H), 2.24 - 2.21 (m, 1H), 1.85 (s, 1H), 1.74 - 1.55 (m, 5H), 1.39 (s, 9H).

[0270] Step 13: [ka] Imidazole (196.49 mg, 2.742 mmol, 2 eq) and tert-butyldimethylsilyl chloride (326.26 mg, 2.056 mmol, 1.5 eq) were added sequentially to a dichloromethane (5 mL) solution of compound 13-11 (500 mg, 1.371 mmol, 1 eq) at 0 °C under nitrogen gas protection and stirred. The mixture was allowed to react at 25 °C for 16 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent. The resulting mixture was purified by silica gel column chromatography using a gradient elution of 0% to 20% ethyl acetate / petroleum ether. The resulting fraction was then evaporated under reduced pressure on a rotary evaporator to obtain compound 13-12 (colorless oil, 470 mg, yield: 70%). MS (ESI, m / z): 461.3 [M+H] + ;

[0271] Step 14: [ka] Palladium hydroxide / carbon (95 mg, palladium hydroxide content: 20%) was added to a solution of compound 13-12 (470 mg, 0.969 mmol, 1 eq) in ethanol (10 mL) under stirring at 25 °C. The mixture was reacted at 25 °C under a hydrogen gas atmosphere at 1 atmospheric pressure for 3 hours. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the palladium hydroxide / carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% methanol / dichloromethane as the mobile phase. The solvent was removed from the resulting fraction on a rotary evaporator under reduced pressure to obtain compound 13-13 (colorless oily liquid, 370 mg, yield: 97%). MS (ESI, m / z): 371.2 [M+H] + ; 1 H-NMR (400 MHz, CDCl3) δ 4.29 - 3.95 (m, 2H), 3.84 - 3.62 (m, 2H), 3.18 - 3.03 (m, 1H), 2.97 - 2.75 (m, 1H), 2.59 - 2.45 (m, 1H), 2.02 - 1.93 (m, 1H), 1.90 - 1.75 (m, 4H), 1.74 - 1.66 (m, 1H), 1.46 (s, 9H), 0.88 (s, 9H), 0.05 (s, 6H).

[0272] Step 15: [ka] Compound 13-13 (350 mg, 0.948 mmol, 1 eq) was added to a solution of compound 13-5 (331 mg, 0.948 mmol, 1 eq) and N,N-diisopropylethylamine (380.8 mg, 2.952 mmol, 3 eq) in dry dichloromethane (5 mL) at 0 °C under nitrogen gas protection and stirring. The mixture was reacted at 25 °C for 3 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was concentrated under reduced pressure to remove excess solvent, yielding a crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 20% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to yield compound 13-14 (yellow solid, 580 mg, yield: 87%). MS (ESI, m / z): 665.1 / 667.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 5.71 - 5.15 (m, 1H), 4.54 - 4.32 (m, 2H), 4.10 - 3.82 (m, 1H), 3.77 - 3.46 (m, 2H), 3.42 - 3.03 (m, 1H), 2.20 - 2.08 (m, 1H), 2.02 - 1.69 (m, 4H), 1.49 (s, 9H), 1.17 (s, 1H), 0.79 (s, 9H), -0.07 (s, 3H), -0.16 (s, 3H).

[0273] Step 16: [ka] Compound (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-methanol (151.45 mg, 0.904 mmol, 1.2 eq) was added to a solution of compound 13-14 (528 mg, 0.753 mmol, 1 eq), cesium carbonate (516.58 mg, 1.505 mmol, 2 eq), and triethylenediamine (17.79 mg, 0.151 mmol, 0.2 eq) in N,N-dimethylformamide (6 mL) at 25 °C under stirring under nitrogen gas protection. The mixture was reacted at 60 °C for 2.5 hours. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the mixture was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase chromatography (C18 column) with mobile phase A: water (0.1% aqueous ammonia); mobile phase B: methanol, eluting with 50% to 95% B phase within 30 min. Detector: UV 254 / 220 nm. Compound 13-15 (white solid, 325 mg, yield: 51%) was obtained. MS (ESI, m / z): 788.0 / 790.0 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 5.43 - 5.15 (m, 1H), 4.44 - 4.03 (m, 4H), 3.96 - 3.76 (m, 1H), 3.71 - 3.47 (m, 2H), 3.43 - 3.11 (m, 3H), 3.07 - 2.91 (m, 1H), 2.39 - 2.10 (m, 4H), 2.05 - 1.69 (m, 7H), 1.64 (s, 4H), 1.48 (s, 9H), 0.76 (s, 9H), -0.09 (s, 3H), -0.17 (s, 3H).

[0274] Step 17: [ka] Cesium fluoride (288.86 mg, 1.805 mmol, 5 eq) was added to a solution of compound 13-15 (300 mg, 0.361 mmol, 1 eq) in N,N-dimethylformamide (15 mL) at 25 °C under stirring under nitrogen gas protection, and the mixture was reacted at 80 °C for 24 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was concentrated under reduced pressure to remove excess solvent, yielding a crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% methanol / dichloromethane. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to yield compound 13-16 (white solid, 200 mg, yield: 80%). MS (ESI, m / z): 654.2 / 656.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 5.28 - 5.16 (m, 2H), 4.63 - 4.06 (m, 6H), 3.74 - 3.61 (m, 1H), 3.49 - 2.84 (m, 5H), 2.36 - 2.27 (m, 1H), 2.26 - 2.12 (m, 4H), 2.06 - 1.77 (m, 5H), 1.77 - 1.65 (m, 2H), 1.50 (s, 9H).

[0275] Step 18: [ka] Compound 13-16 (190 mg, 0.276 mmol, 1 eq), compound 5-2 (198.69 mg, 0.552 mmol, 2 eq), tris(dibenzylideneacetone)dipalladium(0) (26.58 mg, 0.028 mmol, 0.1 eq), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxaphosphole (19.18 mg, 0.055 mmol, 0.2 eq), potassium phosphate (184.85 mg, 0.828 mmol, 3 eq), toluene (4 mL), and water (0.8 mL) were sequentially added to a reaction flask at 25 °C under stirring and nitrogen gas protection, and the resulting mixture was reacted at 80 °C for 3 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the mixture was concentrated under reduced pressure to remove excess solvent, yielding a crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% methanol / dichloromethane. The solvent was removed from the resulting fractions under reduced pressure using a rotary evaporator to yield compound 13-17 (yellow solid, 180 mg, yield: 80%). MS (ESI, m / z): 790.8 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.44 - 7.37 (m, 1H), 7.24 - 7.20 (m, 1H), 7.14 - 7.08 (m, 1H), 5.28 - 5.21 (m, 1H), 4.63 - 3.98 (m, 6H), 3.90 - 3.74 (m, 1H), 3.40 - 3.16 (m, 3H), 3.04 (s, 1H), 2.58 - 2.42 (m, 2H), 2.38 - 2.12 (m, 5H), 2.11 - 1.84 (m, 7H), 1.72 - 1.55 (m, 4H), 1.50 (s, 9H), 0.99 - 0.95 (m, 3H), 0.88 (t, J = 6.6 Hz, 3H).

[0276] Step 19: [ka] Compound 13-17 (180 mg) obtained in Step 18 was separated by high-performance liquid chromatography (chiral column: CHIRAL ART Cellulose-SC, 2 × 25 cm, 5 μm; mobile phase A: n-hexane / [methyl tert-butyl ether (2 mol / L ammonia / methanol)] (50% / 50%), mobile phase B: ethanol; flow rate: 20 mL / min; column temperature: 35 °C; elution with 30% mobile phase B; detector: UV 224 / 294 nm). The product with the shorter retention time (3.9 min): compound 13-17a (white solid, 35 mg, recovery: 19%). MS (ESI, m / z): 790.8 [M+H]. + ;Product with longer retention time (4.9 min): Compound 13-17b (white solid, 125 mg, yield: 69%), MS (ESI, m / z): 790.8 [M+H] + .

[0277] Step 20: [ka] A 1 mL solution of 4 mol / L hydrochloric acid in 1,4-dioxane (4 mol / L) was added to a 1 mL solution of compound 13-17a (30 mg, 0.036 mmol, 1 eq) in methanol under stirring at 0 °C, and the mixture was reacted at 25 °C for 1 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was concentrated under reduced pressure to remove excess solvent, yielding a crude product. The crude product was purified by high-performance liquid chromatography (chromatography column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient elution with 25% to 55% mobile phase B; UV detection: 220 nm). The solvent was removed from the resulting fraction using a rotary evaporator under reduced pressure to obtain compound 13a' (white solid, 6 mg, yield: 24%). MS(ESI, m / z): 646.2 [M+H] + , 1 H-NMR (400 MHz, CD3OD) δ 7.64 - 7.58 (m, 1H), 7.38 - 7.31 (m, 1H), 7.29 - 7.24 (m, 1H), 7.17 - 7.11 (m, 1H), 6.97 - 6.89 (m, 1H), 5.20 - 5.12 (m, 1H), 4.63 - 4.43 (m, 2H), 4.33 - 4.23 (m, 2H), 4.20 - 4.12 (m, 1H), 3.73 - 3.67 (m, 1H), 3.66 - 3.61 (m, 1H), 3.51 - 3.45 (m, 1H), 3.27 - 3.18 (m, 3H), 3.07 - 2.98 (m, 1H), 2.62 - 2.53 (m, 1H), 2.52 - 2.42 (m, 2H), 2.41 - 2.11 (m, 3H), 2.10 - 1.94 (m, 3H), 1.93 - 1.81 (m, 2H), 1.81 - 1.71 (m, 2H), 1.41 - 1.33 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H); 19F-NMR (377 MHz, CD3OD) δ 136.03, -139.76, -173.60.

[0278] Step 21: [ka] A 4 mol / L solution of hydrochloric acid in 1,4-dioxane (2 mL) was added to a solution of compound 13-17b (125 mg, 0.150 mmol, 1 eq) in methanol (2 mL) under stirring at 0 °C, and the mixture was reacted at 25 °C for 1 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the mixture was concentrated under reduced pressure to remove excess solvent, yielding a crude product. The crude product was purified by reverse-phase chromatography (C18 column) (mobile phase A: water (0.1% hydrochloric acid); mobile phase B: acetonitrile, gradient elution from 5% to 95% B phase within 25 min; detector: UV 254 / 220 nm) to obtain compound 13b (yellow solid, 80 mg, yield: 72%). MS (ESI, m / z): 646.25 [M+H] + ; 1 H-NMR (400 MHz, CD3OD) δ 7.69 - 7.60 (m, 1H), 7.43 - 7.34 (m, 1H), 7.31 (d, J = 2.6 Hz, 1H), 7.22 - 7.14 (m, 1H), 6.96 (d, J = 2.6 Hz, 1H), 5.73 - 5.48 (m, 2H), 5.00 (d, J = 11.7 Hz, 1H), 4.84 - 4.71 (m, 3H), 4.58 - 4.47 (m, 1H), 4.46 - 4.39 (m, 1H), 4.35 (s, 1H), 4.27 - 4.16 (m, 1H), 4.07 - 3.89 (m, 2H), 3.88 - 3.75 (m, 2H), 3.53 - 3.42 (m, 1H), 2.85 - 2.20 (m, 10H), 2.20 - 2.08 (m, 3H), 2.07 - 1.93 (m, 1H), 1.03 - 0.84 (m, 3H); 19F-NMR (377 MHz, CD3OD) δ -132.98, -137.59, -174.33.

[0279] Example 14 9-((2R or 2S,5aS,6S,9R)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-2,3-dihydro-1H-cyclopenta[a]naphthalen-7-ol dihydrochloride 14a, 9-((2S or 2R,5aS,6S,9R)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-2,3-dihydro-1H-cyclopenta[a]naphthalen-7-ol dihydrochloride 14b [ka] The synthetic route is as follows: [ka]

[0280] Step 1: [ka] Under stirring conditions at −78° C. under nitrogen gas protection, n-butyllithium (2.5 mol / L n-hexane solution, 20.93 mL) was slowly added dropwise to a solution of 1,8-dibromonaphthalene (15 g, 49.831 mmol, 1.0 eq) in anhydrous tetrahydrofuran (150 mL), and the mixture was stirred at −78° C. for 1 hour. Next, N,N-dimethylformamide (4.26 mL, 52.323 mmol, 1.05 eq) was added dropwise to the reaction mixture and reacted at -78°C for 1 hour. Then, the mixture was allowed to warm to 25°C and reacted for 1 hour. The reaction process was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride solution (400 mL) at 0°C to quench the reaction. The mixture was extracted with ethyl acetate (400 mL x 3). The organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 5% ethyl acetate / petroleum ether. The solvent was removed from the obtained fraction on a rotary evaporator under reduced pressure to obtain compound 14-1 (white solid, 10.2 g, yield: 82%). 1 H NMR (400 MHz, CDCl3) δ 11.43 (s, 1H), 8.01 - 7.99 (m, 1H), 7.92 - 7.86 (m, 4H), 7.57 - 7.54 (m, 1H), 7.40 - 7.36 (m, 1H).

[0281] Step 2: [ka] Compound 14-1 (7.2 g, 29.096 mmol, 1.0 eq), ethyl (triphenylphosphoranylidene)acetate (11.74 g, 32.006 mmol, 1.1 eq), and toluene (100.0 mL) were sequentially added to a reaction flask at 25 °C under stirring and nitrogen gas protection. The resulting mixture was stirred at 100 °C under nitrogen gas protection for 2 h. The reaction process was monitored by thin-layer chromatography. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove excess reagents, yielding a crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a 0% to 20% ethyl acetate / petroleum ether mobile phase. The solvent was removed from the resulting fractions on a rotary evaporator under reduced pressure to yield compound 14-2 (yellow oil, 5.6 g, yield: 60%). 1 H NMR (400 MHz, CDCl3) δ 9.07 (d, J = 16.0 Hz, 1H), 7.90 - 7.84 (m, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.56 - 7.51 (m, 1H), 7.49 - 7.42 (m, 1H), 7.32 - 7.28 (m, 1H), 6.14 (d, J = 16.0 Hz, 1H), 4.34 - 4.26 (m, 2H), 1.41 - 1.33 (m, 3H).

[0282] Step 3: [ka] Compound 14-2 (5 g, 15.565 mmol, 1.0 eq), wet palladium on carbon (10% palladium content, 500 mg), ethanol (50 mL), and water (5 mL) were added to the reaction solution under stirring at room temperature. The mixture was reacted at 25 °C under a hydrogen gas atmosphere (10 atmospheres) for 2 h, and the reaction process was monitored by thin-layer chromatography. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 20% ethyl acetate / petroleum ether. The solvent was removed from the obtained fractions on a rotary evaporator under reduced pressure to obtain compound 14-3 (colorless oil, 2.3 g, yield: 46%). 1 H NMR (400 MHz, CDCl3) δ 7.88 - 7.79 (m, 2H), 7.78 - 7.73 (m, 1H), 7.47 - 7.36 (m, 2H), 7.26 - 7.22 (m, 1H), 4.19 - 4.10 (m, 2H), 3.91 - 3.83 (m, 2H), 2.79 - 2.75 (m, 2H), 1.25 - 1.22 (m, 3H).

[0283] Step 4: [ka] Compound 14-3 (2.1 g, 6.494 mmol, 1.0 eq), methanol (15 mL), and tetrahydrofuran (5 mL) were added to the reaction flask under stirring at 25 °C. Lithium hydroxide (327.46 mg, 12.988 mmol, 2.0 eq) dissolved in water (5 mL) was then added dropwise to the reaction mixture. The resulting mixture was stirred at 25 °C for 3 h, and the reaction process was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was concentrated to obtain the crude product. The pH of the crude product was adjusted to 4 with aqueous hydrochloric acid (1 mol / L). The mixture was filtered, and the cake was collected and dried to obtain compound 14-4 (white solid, 1.6 g, yield: 83%). 1H NMR (400 MHz, DMSO-d6) δ 8.02 - 7.96 (m, 1H), 7.94 - 7.86 (m, 2H), 7.55 - 7.46 (m, 2H), 7.39 - 7.33 (m, 1H), 3.75 - 3.68 (m, 2H), 2.65 - 2.60 (m, 2H).

[0284] Step 5: [ka] Compound 14-4 (1.3 g, 4.424 mmol, 1.0 eq) and polyphosphoric acid (40 g) were added sequentially to the reaction flask under stirring at 25 °C. The mixture was stirred at 80 °C for 3 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was poured into water (50 mL) to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 50% ethyl acetate / petroleum ether. The obtained fraction was concentrated under reduced pressure to remove the solvent, yielding compound 14-5 (colorless oil, 800 mg, yield: 66%). MS (ESI, m / z): 261.0 / 263.0 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.13 - 8.08 (m, 1H), 8.03 - 7.97 (m, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.59 - 7.53 (m, 1H), 3.95 - 3.87 (m, 2H), 2.76 - 2.69 (m, 2H).

[0285] Step 6: [ka] To a solution of compound 14-5 (700 mg, 2.547 mmol, 1.0 eq) in anhydrous tetrahydrofuran (7.0 mL) was added diisobutylaluminum hydride (1 mol / L, 3 mL, 1.2 eq) dropwise at -78 °C under nitrogen gas protection. The mixture was stirred at -78 °C under nitrogen gas protection for 2 h, and the reaction process was monitored by thin-layer chromatography. After completion of the reaction, the reaction solution was quenched by pouring it into saturated aqueous ammonium chloride (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 50% ethyl acetate / petroleum ether. The obtained fractions were concentrated under reduced pressure to remove the solvent, yielding compound 14-6 (white solid, 650 mg, yield: 92%). 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 8.0 Hz, 1H), 7.90 - 7.80 (m, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.35 - 7.29 (m, 1H), 5.37 (d, J = 8.0 Hz, 1H), 5.20 - 5.10 (m, 1H), 3.96 - 3.84 (m, 1H), 3.57 - 3.46 (m, 1H), 2.48 - 2.37 (m, 1H), 1.93 - 1.81 (m, 1H).

[0286] Step 7: [ka] Compound 14-6 (640 mg, 2.311 mmol, 1.0 eq), triethylsilane (565.63 mg, 4.622 mmol, 2.0 eq), and trifluoroacetic acid (7.0 mL) were sequentially added to the reaction flask under stirring at 0 °C. The mixture was stirred at 0 °C for 2 h, and the reaction process was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove excess reagents and obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 1% ethyl acetate / petroleum ether. The obtained fraction was concentrated under reduced pressure to remove the solvent, yielding compound 14-7 (white solid, 600 mg, yield: 95%). 1 H NMR (400 MHz, DMSO-d6) δ 7.95 - 7.90 (m, 1H), 7.83 - 7.79 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.30 - 7.24 (m, 1H), 3.80 - 3.73 (m, 2H), 3.05 - 2.97 (m, 2H), 2.15 - 2.06 (m, 2H).

[0287] Step 8: [ka] Compound 14-7 (300 mg, 1.153 mmol, 1.0 eq), chloro-1,5-cyclooctadiene iridium(I) dimer (80.47 mg, 0.115 mmol, 0.1 eq), 4,4′-di-tert-butyl-2,2′-bipyridyl (32.58 mg, 0.115 mmol, 0.1 eq), bis(pinacolato)diboron (369.91 mg, 1.384 mmol, 1.2 eq), and n-hexane (3 mL) were sequentially added to a reaction flask at 25 °C under stirring and nitrogen gas protection. The resulting mixture was reacted at 60 °C for 2 h, and the reaction progress was monitored by thin-layer chromatography. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude intermediate product. A tetrahydrofuran / water mixture (2 / 1, 9 mL) was added to the crude intermediate product under stirring at 0°C, followed by the dropwise addition of hydrogen peroxide (30%, 9 mL) and acetic acid (4.5 mL). The mixture was reacted at 0°C for 0.5 hours, and the reaction process was monitored by thin-layer chromatography. After the reaction was completed, the pH was adjusted to 8 with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a 0% to 50% ethyl acetate / petroleum ether mobile phase. The obtained fraction was concentrated under reduced pressure to remove the solvent, yielding compound 14-8 (white solid, 250 mg, yield: 78%). 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 4.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 3.73 - 3.64 (m, 2H), 2.97 - 2.90 (m, 2H), 2.12 - 2.01 (m, 2H).

[0288] Step 9: [ka] At 0 °C under nitrogen gas protection, compound 14-8 (250 mg, 0.903 mmol, 1.0 eq), N,N-diisopropylethylamine (349.97 mg, 2.709 mmol, 3.0 eq), and dichloromethane (3.0 mL) were added to the reaction flask in sequence. Then, chloromethyl methyl ether (126.32 mg, 1.806 mmol, 2.0 eq) was slowly added dropwise to the reaction system, and the mixture was stirred at 25 °C for 1 h. The reaction process was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was poured into ice water (20 mL) to quench the reaction, and extracted with dichloromethane (20 mL × 3). The organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 20% ethyl acetate / petroleum ether. The obtained fraction was concentrated under reduced pressure to remove the solvent, yielding compound 14-9 (yellow solid, 220 mg, yield: 75%). 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 4.0 Hz, 1H), 7.50 (d, J = 4.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 5.30 (s, 2H), 3.76 - 3.68 (m, 2H), 3.42 (s, 3H), 3.00 - 2.93 (m, 2H), 2.15 - 2.03 (m, 2H).

[0289] Step 10: [ka] At 25 °C and under nitrogen gas protection, compound 14-9 (200 mg, 0.619 mmol, 1.0 eq), bis(pinacolato)diboron (214.93 mg, 0.805 mmol, 1.3 eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (53.04 mg, 0.062 mmol, 0.1 eq), potassium acetate (191.69 mg, 1.857 mmol, 3.0 eq), and 1,4-dioxane (2.0 mL) were sequentially added to a reaction flask. The mixture was stirred at 100 °C for 2 h, and the reaction progress was monitored by thin-layer chromatography. After completion of the reaction, the mixture was cooled to 25 °C and concentrated under reduced pressure to remove excess reagents, yielding the crude product. The crude product was purified by silica gel column chromatography with gradient elution using a 0% to 20% ethyl acetate / petroleum ether mobile phase. The obtained fraction was concentrated under reduced pressure to remove the solvent, yielding compound 14-10 (white solid, 160 mg, yield: 69%). 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.34 (d, J = 8.0 Hz, 1H), 5.28 (s, 2H), 3.50 (s, 3H), 3.33 - 3.27 (m, 2H), 3.08 - 3.02 (m, 2H), 2.22 - 2.12 (m, 2H), 1.43 (s, 12H).

[0290] Step 11: [ka] Compound 5-1 (25 mg, 0.037 mmol, 1.0 eq), compound 14-10 (13.83 mg, 0.037 mmol, 1.0 eq), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole (2.58 mg, 0.007 mmol, 0.2 eq), tris(dibenzylideneacetone)dipalladium(0) (3.57 mg, 0.004 mmol, 0.1 eq), potassium phosphate (16.57 mg, 0.074 mmol, 2.0 eq), water (0.1 mL), and toluene (0.5 mL) were sequentially added to a reaction flask at 25 °C under stirring and nitrogen gas protection. The resulting mixture was reacted at 80 °C for 16 h under stirring and nitrogen gas protection. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding a crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 10% methanol / dichloromethane. The obtained fraction was concentrated under reduced pressure to remove the solvent, yielding compound 14-11 (white solid, 30 mg, yield: 95%). MS (ESI, m / z): 788.3 [M + H] + .

[0291] Step 12: [ka] Compound 14-11 (30 mg) obtained in Step 11 of this example was chiral separated by high-performance liquid chromatography (chiral column: CHIRALPAK ID, 2 × 25 cm, 5 μm; mobile phase A: n-hexane / methyl tert-butyl ether (1 / 1) (0.5%, 2 mol / L ammonia / methanol); mobile phase B: methanol; flow rate: 20 mL / min; elution with 20% mobile phase B within 8 min; detector: UV 222 nm). The product with the shorter retention time (5.00 min): compound 14-11a (white solid, 13 mg, recovery: 43%). Compound 14-11a: MS (ESI, m / z): 788.3 [M + H]. +Product with a longer retention time (6.35 min): Compound 14-11b (white solid, 12 mg, yield: 40%). Compound 14-11b: MS (ESI, m / z): 788.3 [M + H] + .

[0292] Step 13: [ka] A 1,4-dioxane solution of hydrochloric acid (4 mol / L, 1 mL) was added dropwise to a methanol (1 mL) solution of compound 14-11a (13 mg, 0.016 mmol, 1.00 eq) at 0°C under stirring. The mixture was reacted at room temperature for 1 hour, and the reaction process was monitored by liquid mass spectrometry. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase flash chromatography (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% hydrochloric acid) within 25 minutes. Detector: UV 254 nm. Compound 14a (yellow solid, 4.8 mg, yield: 42%) was obtained. MS (ESI, m / z): 644.3 [M + H] + ; 1 H NMR (400 MHz, CD3OD) δ 7.61 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.01 - 6.94 (m, 1H), 5.64 - 5.37 (m, 2H), 4.83 - 4.71 (m, 2H), 4.69 - 4.57 (m, 2H), 4.46 - 4.27 (m, 2H), 4.07 - 3.83 (m, 3H), 3.75 - 3.62 (m, 1H), 3.49 - 3.41 (m, 1H), 2.99 - 2.87 (m, 2H), 2.80 - 2.58 (m, 3H), 2.56 - 2.28 (m, 6H), 2.26 - 2.08 (m, 4H), 1.96 - 1.79 (m, 2H); 19 F NMR (377 MHz, CD3OD) δ -135.06, -137.29, -174.17.

[0293] Step 14: [ka] A 1,4-dioxane solution of hydrochloric acid (4 mol / L, 1 mL) was added dropwise to a methanol (1 mL) solution of compound 14-11b (12 mg, 0.014 mmol, 1.00 eq) at 0°C under stirring. The mixture was reacted at room temperature for 1 hour, and the reaction process was monitored by liquid mass spectrometry. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase flash chromatography (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% hydrochloric acid) within 25 minutes. Detector: UV 254 nm. Compound 14b (yellow solid, 2.6 mg, yield: 24%) was obtained. MS (ESI, m / z): 644.3 [M + H] + ; 1 H NMR (400 MHz, CD3OD) δ 7.63 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 5.69 - 5.52 (m, 1H), 5.43 - 5.35 (m, 1H), 4.81 - 4.54 (m, 4H), 4.44 - 4.37 (m, 2H), 4.10 - 3.84 (m, 4H), 3.75 - 3.69 (m, 1H), 3.53 - 3.44 (m, 1H), 2.99 - 2.90 (m, 2H), 2.82 - 2.57 (m, 2H), 2.56 - 2.45 (m, 3H), 2.42 - 2.31 (m, 3H), 2.26 - 2.14 (m, 4H), 2.00 - 1.87 (m, 2H); 19 F NMR (377 MHz, CD3OD) δ -134.64, -137.87, -174.21.

[0294] Example 15 (2S,6R,7aS)-7a-((((2R or 2S,5aS,6S,9R)-2-(8-ethyl-3-hydroxynaphthalen-1-yl)-1,3-difluoro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-13-yl)oxy)methyl)-6-fluorohexahydro-1H-pyrrolidin-2-ol dihydrochloride 15a, (2S,6R,7aS)-7a-((((2S or 2R,5aS,6S,9R)-2-(8-ethyl-3-hydroxynaphthalen-1-yl)-1,3-difluoro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-13-yl)oxy)methyl)-6-fluorohexahydro-1H-pyrrolidin-2-ol dihydrochloride 15b [ka] The synthetic route is as follows: [ka]

[0295] Step 1: [ka] (2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-methanol (30 g, 179.0 mmol, 1.0 eq), imidazole (15.4 g, 214.8 mmol, 1.2 eq), and dichloromethane (300 mL) were sequentially added to a reaction flask at 0 °C under stirring and nitrogen gas protection. tert-Butyldiphenylchlorosilane (67.3 g, 232.6 mmol, 1.3 eq) was then slowly added. The resulting mixture was stirred at 25 °C under nitrogen gas protection for 2 hours. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was quenched by pouring it into saturated sodium bicarbonate solution and extracted with dichloromethane (300 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with 0% to 10% methanol / dichloromethane. The resulting fractions were concentrated under reduced pressure to remove the solvent, affording compound 15-1 (colorless oil, 63 g, yield: 84%). MS (ESI, m / z): 398.2 [M + H] + ; 1 H NMR (300 MHz, CDCl3) δ 7.77 - 7.64 (m, 4H), 7.50 - 7.35 (m, 6H), 5.35 - 5.09 (m, 1H), 3.49 (d, J = 9.6 Hz, 1H), 3.38 (d, J = 9.6 Hz, 1H), 3.27 - 2.99 (m, 3H), 2.98 - 2.83 (m, 1H), 2.26 - 2.14 (m, 1H), 2.13 - 1.94 (m, 2H), 1.95 - 1.63 (m, 3H), 1.09 (s, 9H).

[0296] Step 2: [ka] To a solution of compound 15-1 (39 g, 93.2 mmol, 1.0 eq) in carbon tetrachloride (400 mL) was added a solution of ruthenium(III) chloride trihydrate (4.42 g, 18.6 mmol, 0.2 eq) in water (400 mL) and sodium iodide (104.9 g, 465.9 mmol, 5.0 eq) under stirring at 0 °C. The mixture was stirred at 25 °C for 1 hour, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was poured into water (500 mL) to quench the reaction. The resulting mixture was extracted with dichloromethane (500 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to remove the solvent and obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 60% petroleum ether / methyl tert-butyl ether. The fractions were concentrated under reduced pressure to remove the solvent, yielding compound 15-2 (white solid, 19 g, yield: 47%). MS (ESI, m / z): 412.2 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.66 - 7.59 (m, 4H), 7.48 - 7.37 (m, 6H), 5.38 - 5.15 (m, 1H), 4.21 - 4.08 (m, 1H), 3.63 - 3.53 (m, 1H), 3.49 - 3.39 (m, 1H), 3.17 - 3.00 (m, 1H), 2.79 - 2.66 (m, 1H), 2.44 - 2.34 (m, 1H), 2.33 - 2.21 (m, 1H), 2.21 - 2.10 (m, 1H), 2.05 - 1.92 (m, 2H), 1.04 (s, 9H).

[0297] Step 3: [ka] Compound 15-2 (5 g, 11.541 mmol, 1.0 eq) and 18-crown ether-6 (6.42 g, 23.082 mmol, 2.0 eq) were dissolved in 50 mL of tetrahydrofuran at -78 °C under nitrogen gas protection and stirring. A solution of potassium tert-butoxide in tetrahydrofuran (1 mol / L, 15 mL) was then slowly added dropwise. The resulting mixture was reacted at -78 °C under nitrogen gas protection and stirring for 1 hour. 3-Phenyl-2-phenylsulfonyl-1,2-oxaziridine (4.76 g, 17.312 mmol, 1.5 eq) was then added dropwise. The mixture was reacted at -78 °C for 1 hour. The reaction process was monitored by thin-layer chromatography and liquid mass spectrometry. After the reaction was completed, the reaction solution was poured into 100 mL of water and extracted with ethyl acetate (100 mL x 3). The organic phase was concentrated to obtain the crude product. The crude product was purified by reverse-phase chromatography (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% aqueous ammonia solution) within 25 min. Detector: UV 254 / 220 nm. Compound 15-3 (yellow oil, 4.5 g, yield: 86%) was obtained. MS (ESI, m / z): 428.2 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.65 - 7.61 (m, 4H), 7.46 - 7.39 (m, 6H), 5.36 - 5.20 (m, 1H), 4.91 (s, 1H), 4.39 - 4.33 (m, 1H), 4.13 - 4.01 (m, 1H), 3.77 - 3.70 (m, 1H), 3.48 - 3.40 (m, 1H), 3.25 - 3.08 (m, 1H), 2.26 - 2.22 (m, 1H), 2.16 - 2.09 (m, 1H), 2.00 - 1.98 (m, 1H), 1.94 - 1.88 (m, 1H), 1.06 (s, 9H).

[0298] Step 4: [ka] Compound 15-3 (1.7 g, 3.777 mmol, 1.0 eq), 3-bromopropene (625.26 mg, 4.910 mmol, 1.3 eq), and 20 mL of N,N-dimethylformamide were added to a reaction flask at 0 °C under stirring and nitrogen gas protection. After complete dissolution, sodium hydride (60%, 226.6 mg, 5.665 mmol, 1.5 eq) was added in batches. The resulting mixture was reacted at 0 °C for 1 h, and the reaction solution was monitored by thin-layer chromatography and liquid mass spectrometry. After completion of the reaction, the reaction solution was poured into 100 mL of saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate (100 mL x 3). The resulting organic phase was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 50% methyl tert-butyl ether / petroleum ether to give two isomers, 15-4a and 15-4b, respectively. Compound 15-4a (pale yellow oil, 1.28 g, yield: 68%). MS (ESI, m / z): 468.2 [M + H] + ; 1 H NMR (400 MHz, CD3OD) δ 7.68 - 7.59 (m, 4H), 7.48 - 7.34 (m, 6H), 5.83 - 5.68 (m, 1H), 5.50 - 5.27 (m, 1H), 5.19 - 5.02 (m, 2H), 4.16 - 3.88 (m, 5H), 3.60 (d, J = 10.1 Hz, 1H), 3.43 - 3.23 (m, 2H), 2.71 - 2.50 (m, 1H), 2.19 - 1.93 (m, 3H), 1.05 (s, 9H); 19 F NMR (282 MHz, CD3OD) δ -173.50. Compound 15-4b (light yellow oil, 220 mg, yield: 12%). MS (ESI, m / z):468.2 [M + H] + ; 1H NMR (400 MHz, CDCl3) δ 7.64 - 7.59 (m, 4H), 7.49 - 7.36 (m, 6H), 6.00 - 5.88 (m, 1H), 5.33 - 5.11 (m, 3H), 4.62 - 4.56 (m, 1H), 4.42 - 4.35 (m, 1H), 4.27 - 4.13 (m, 2H), 3.48 (d, J = 10.4 Hz, 1H), 3.35 (d, J = 10.4 Hz, 1H), 3.08 - 2.93 (m, 1H), 2.69 - 2.60 (m, 1H), 2.18 - 1.95 (m, 3H), 1.04 (s, 9H); 19 F NMR (376 MHz, CDCl3) δ -173.11.

[0299] ステップ5:

change

[0300] Step 6: [ka] A solution of compound 15-5 (480 mg, 1.005 mmol, 1.0 eq) in tetrahydrofuran (5 mL) was added dropwise with 1 mol / L tetra-n-butylammonium fluoride (2 mL) in tetrahydrofuran under stirring at 25 °C. The mixture was stirred at 60 °C for 2 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% ammonia-methanol / dichloromethane. The fraction was concentrated under reduced pressure to remove the solvent and obtain compound 15-6 (colorless oil, 240 mg, yield: 95%). MS (ESI, m / z): 216.1 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 5.96 - 5.85 (m, 1H), 5.34 - 5.15 (m, 3H), 4.20 - 4.13 (m, 1H), 4.03 - 3.92 (m, 2H), 3.63 (d, J = 10.8 Hz, 1H), 3.46 - 3.38 (m, 1H), 3.28 (d, J = 10.8 Hz, 1H), 3.24 - 3.19 (m, 1H), 3.18 - 3.06 (m, 2H), 2.17 - 2.04 (m, 4H).

[0301] Step 7: [ka] Compound 4-1 (2 g, 3.790 mmol, 1.00 eq), compound 5-2 (1.64 g, 4.548 mmol, 1.2 eq), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole (263.6 mg, 0.758 mmol, 0.2 eq), tris(dibenzylideneacetone)dipalladium(0) (365.34 mg, 0.379 mmol, 0.1 eq), potassium phosphate (1.69 g, 7.580 mmol, 2.0 eq), water (4 mL), and toluene (20 mL) were sequentially added to a reaction flask at 25 °C under stirring and nitrogen gas protection. The resulting mixture was reacted at 80 °C for 2 h under stirring and nitrogen gas protection. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding a crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 50% ethyl acetate / petroleum ether. The obtained fraction was concentrated under reduced pressure to remove the solvent, yielding compound 15-7 (white solid, 2 g, yield: 78%). MS (ESI, m / z): 637.3 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.73 - 7.69 (m, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.25 - 7.20 (m, 1H), 7.11 - 7.05 (m, 1H), 5.33 - 5.28 (m, 3H), 4.61 - 4.54 (m, 1H), 4.37 - 4.16 (m, 4H), 3.53 - 3.51 (m, 3H), 3.33 - 3.24 (m, 1H), 2.55 - 2.39 (m, 2H), 2.04 - 1.87 (m, 4H), 1.52 (s, 9H), 1.02 - 0.93 (m, 3H).

[0302] Step 8: [ka] Triethylenediamine (6.17 mg, 0.05 mmol, 0.2 eq), compound 15-7 (175 mg, 0.261 mmol, 1.0 eq), cesium carbonate (179.11 mg, 0.522 mmol, 2.0 eq), compound 15-6 (65.09 mg, 0.287 mmol, 1.1 eq), and N,N-dimethylformamide (3 mL) were sequentially added to a reaction flask under stirring at 25 °C under nitrogen gas protection. The resulting mixture was reacted at 80 °C under nitrogen gas protection and stirring for 2 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the crude product was purified by reverse-phase chromatography (C18 column) and eluted with a 5% to 95% methanol / water mobile phase (0.1% aqueous ammonium bicarbonate) within 25 min. Detector: UV 254 / 220 nm. Compound 15-8 (off-white solid, 150 mg, yield: 65%) was obtained. MS (ESI, m / z): 832.4 [M + H] + .

[0303] Step 9: [ka] Compound 15-8 (150 mg, 0.18 mmol, 1.00 eq), 1,3-dimethylbarbituric acid (56.16 mg, 0.36 mmol, 2.00 eq), tetrakis(triphenylphosphine)palladium(0) (20.79 mg, 0.018 mmol, 0.1 eq), and dichloromethane (2 mL) were sequentially added to a reaction flask at 25 °C under stirring and nitrogen gas protection. The mixture was reacted at room temperature for 16 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase flash chromatography (C18 column) and eluted with a 5% to 95% methanol / water mobile phase (0.1% ammonium bicarbonate) within 25 min. Detector: UV 254 nm to obtain compound 15-9 (white solid, 108 mg, yield: 75%). MS (ESI, m / z): 792.4 [M + H] + .

[0304] Step 10: [ka] Compound 15-9 (108 mg) obtained in Step 9 of this example was chiral separated by high-performance liquid chromatography (chiral column: CHIRALPAK IE, 2 × 25 cm, 5 μm; mobile phase A: n-hexane (0.1%, 2 mol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 20 mL / min; elution with 40% mobile phase B within 21 min; detector: UV 226 / 206 nm). Among them, the compound with the shorter retention time (11.53 min): compound 15-9a (white solid, 50 mg, recovery: 46%), MS (ESI, m / z): 792.4 [M + H]. + Among them, the compound with the longer retention time (16.70 min): Compound 15-9b (white solid, 53 mg, recovery: 49%), MS (ESI, m / z): 792.4 [M + H] + .

[0305] Step 11: [ka] A 1,4-dioxane solution of hydrochloric acid (4 mol / L, 2 mL) was added dropwise to a methanol (2 mL) solution of compound 15-9a (50 mg, 0.060 mmol, 1.00 eq) at 0 °C under stirring. The mixture was reacted at room temperature for 2 h, and the reaction process was monitored by liquid mass spectrometry. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase flash chromatography (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% hydrochloric acid) within 25 min. Detector: UV 254 nm. Compound 15a (yellow solid, 18 mg, yield: 40%) was obtained. MS (ESI, m / z): 648.3 [M + H] + ; 1H NMR (300 MHz, DMSO-d6+D2O) δ 7.70 (d, J = 8.1 Hz, 1H), 7.44 - 7.37 (m, 1H), 7.34 (d, J = 2.7 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 2.7 Hz, 1H), 5.78 - 5.54 (m, 1H), 5.04 (d, J = 14.1 Hz, 1H), 4.84 - 4.53 (m, 6H), 4.36 - 4.21 (m, 2H), 3.99 - 3.82 (m, 1H), 3.77 - 3.72 (m, 2H), 3.62 - 3.56 (m, 1H), 3.46 - 3.33 (m, 1H), 2.79 - 2.58 (m, 2H), 2.43 - 2.30 (m, 4H), 2.16 - 1.90 (m, 4H), 0.92 - 0.78 (m, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -132.31, -139.59, -174.60.

[0306] Step 12: [ka] A 1,4-dioxane solution of hydrochloric acid (4 mol / L, 2 mL) was added dropwise to a methanol (2 mL) solution of compound 15-9b (53 mg, 0.063 mmol, 1.00 eq) at 0 °C under stirring. The mixture was reacted at room temperature for 2 hours, and the reaction process was monitored by liquid mass spectrometry. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase flash chromatography (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% hydrochloric acid) within 25 minutes. Detector: UV 254 nm. Compound 15b (yellow solid, 24 mg, yield: 40%) was obtained. MS (ESI, m / z): 648.3 [M + H] + ; 1H NMR (300 MHz, DMSO-d6+D2O) δ 7.69 (d, J = 8.1 Hz, 1H), 7.44 - 7.37 (m, 1H), 7.34 (d, J = 2.7 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.97 (d, J = 2.7 Hz, 1H), 5.73 - 5.56 (m, 1H), 5.05 - 4.95 (m, 1H), 4.82 - 4.50 (m, 6H), 4.29 (d, J = 5.1 Hz, 2H), 3.98 - 3.84 (m, 1H), 3.77 - 3.63 (m, 3H), 3.46 - 3.34 (m, 1H), 2.79 - 2.59 (m, 1H), 2.48 - 2.28 (m, 5H), 2.20 - 1.88 (m, 4H), 0.92 - 0.84 (m, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -132.39, -139.31, -174.51.

[0307] Example 16 4-((2R or 2S,5aS,6S,9R)-1,3-difluoro-13-(((2R,6S,7aS)-2-fluoro-6-methoxytetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol dihydrochloride 16a, 4-((2S or 2R,5aS,6S,9R)-1,3-difluoro-13-(((2R,6S,7aS)-2-fluoro-6-methoxytetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol dihydrochloride 16b [ka] The synthetic route is as follows: [ka]

[0308] Step 1: [ka] Compound 15-3 (1.26 g, 2.80 mmol, 1 eq) and methyl iodide (0.24 mL, 3.64 mmol, 1.3 eq) were dissolved in N,N-dimethylformamide (15 mL) at 0 °C under nitrogen gas protection. Sodium hydride (60% dispersion in mineral oil, 167.95 mg, 4.20 mmol, 1.5 eq) was added batchwise to the mixture at 0 °C under stirring under nitrogen gas protection. The resulting mixture was reacted at 0 °C under stirring under nitrogen gas protection for 1 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was added dropwise to saturated ammonium chloride solution (60 mL) at 0 °C. The mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 20% methyl tert-butyl ether / petroleum ether. The fractions were concentrated under reduced pressure to remove the solvent, yielding compound 16-1 (colorless oil, 870 mg, yield: 67%). MS (ESI, m / z): 442.2 [M + H] + ; 1H NMR (400 MHz, CDCl3) δ 7.69 - 7.55 (m, 4H), 7.46 - 7.37 (m, 6H), 5.49 - 5.30 (m, 1H), 4.17 - 4.03 (m, 1H), 3.98 - 3.90 (m, 1H), 3.91 - 3.81 (m, 1H), 3.55 - 3.47 (m, 1H), 3.43 - 3.40 (m, 3H), 3.40 - 3.27 (m, 1H), 2.68 - 2.47 (m, 1H), 2.15 - 2.05 (m, 1H), 2.02 - 1.86 (m, 2H), 1.04 (s, 9H); 19 F NMR (377 MHz, CDCl3) δ -171.77.

[0309] Step 2: [ka] Borane-dimethyl sulfide (1 mol / L, 0.97 mL, 9.7 mmol, 5 eq) was added dropwise to a solution of compound 16-1 (900 mg, 1.94 mmol, 1 eq) in tetrahydrofuran (10 mL) at 0 °C under stirring under nitrogen gas protection. The resulting mixture was reacted at 25 °C under stirring for 2 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, methanol (15 mL) was slowly added dropwise to the reaction solution under stirring at 0 °C. The mixture was refluxed at 60 °C under stirring for 30 min. The mixture was then concentrated under reduced pressure to remove the solvent and obtain the crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution with 0% to 35% methyl tert-butyl ether / petroleum ether. The fractions were concentrated under reduced pressure to remove the solvent and obtain compound 16-2 (colorless oil, 840 mg, yield: 96%). MS (ESI, m / z): 428.1 [M + H] + ; 1H NMR (400 MHz, CDCl3) δ 7.74 - 7.63 (m, 4H), 7.47 - 7.31 (m, 6H), 5.28 - 5.09 (m, 1H), 4.03 - 3.91 (m, 1H), 3.70 - 3.62 (m, 1H), 3.53 - 3.43 (m, 1H), 3.33 - 3.22 (m, 1H), 3.18 (s, 3H), 3.17 - 2.98 (m, 3H), 2.26 - 2.06 (m, 3H), 2.04 - 1.95 (m, 1H), 1.06 (s, 9H); 19 F NMR (377 MHz, CDCl3) δ -172.93.

[0310] Step 3: [ka] A solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 mol / L, 3.73 mL, 3.73 mmol, 2 eq) was added dropwise to a solution of compound 16-2 (840 mg, 1.87 mmol, 1 eq) in tetrahydrofuran (10 mL) under stirring at 0 °C. The resulting mixture was reacted for 1 h under stirring at 60 °C. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, yielding a crude product. The resulting crude product was purified by silica gel column chromatography using a gradient elution of 0% to 7% methanol / dichloromethane. The resulting fraction was concentrated under reduced pressure to remove the solvent, yielding compound 16-3 (colorless oil, 210 mg, yield: 56%). MS (ESI, m / z): 190.3 [M + H] + .

[0311] Step 4: [ka] Triethylenediamine (4.02 mg, 0.036 mmol, 0.20 eq), compound 15-7 (120 mg, 0.18 mmol, 1 eq), and cesium carbonate (122.82 mg, 0.36 mmol, 2 eq) were dispersed in N,N-dimethylformamide (1 mL) at 25 °C under stirring and nitrogen gas protection. Next, a solution of 16-3 (42.80 mg, 0.22 mmol, 1.2 eq) in N,N-dimethylformamide (1 mL) was added dropwise to the above mixture at 25 °C under stirring and nitrogen gas protection. The resulting mixture was reacted at 80 °C under stirring and nitrogen gas protection for 2 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was cooled to room temperature and filtered. The cake was washed with dichloromethane (2 mL × 3). The filtrate was subjected to rotary evaporation under reduced pressure to remove the solvent, yielding the crude product. The crude product was purified by reverse-phase chromatography (C18 column) and eluted with a 40% to 95% methanol / water mobile phase (0.1% aqueous ammonia) within 30 min. Detector: UV 254 / 220 nm. The obtained fraction was subjected to rotary evaporation under reduced pressure to remove the solvent. The crude product was then purified a second time by preparative thin-layer chromatography (TLC) with dichloromethane / methanol (15 / 1). Compound 16-4 (white solid, 108 mg, yield: 71%) was obtained. MS (ESI, m / z): 806.4 [M + H] + .

[0312] Step 5: [ka] Compound 16-4 (105 mg) obtained in Step 4 of this example was chiral separated by preparative supercritical fluid chromatography (chiral column: CHIRALPAK ID, 2 × 25 cm, 5 μm; mobile phase A: n-hexane / methyl tert-butyl ether (2 / 1) (0.5%, 2 mol / L ammonia / methanol); mobile phase B: methanol; flow rate: 20 mL / min; elution with 10% B phase within 16 min; detector: UV 224 / 292 nm). Among them, the product with the shorter retention time (8.61 min): compound 16-4a (white solid, 38 mg, recovery: 36%), MS (ESI, m / z): 806.4 [M + H]. + Among them, the product with a longer retention time (12.68 min): Compound 16-4b (white solid, 34 mg, recovery: 32%), MS (ESI, m / z): 806.4 [M + H] + .

[0313] Step 6: [ka] A 1,4-dioxane solution of hydrochloric acid (4 mol / L, 1 mL) was added dropwise to a methanol (1 mL) solution of compound 16-4a (38 mg, 0.047 mmol, 1 eq) at 0 °C under stirring. The resulting mixture was reacted at 25 °C under stirring for 1.5 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent and obtain the crude product. The crude product was purified by reverse-phase chromatography (C18 column) and eluted with a 40% to 95% methanol / water mobile phase (0.1% hydrochloric acid) within 30 min. Detector: UV 254 / 220 nm. Product 16a (yellow solid, 20.5 mg, yield: 59%) was obtained. MS (ESI, m / z): 662.3 [M + H] + ; 1H NMR (400 MHz, DMSO-d6+D2O) δ 7.76 - 7.65 (m, 1H), 7.44 - 7.36 (m, 1H), 7.36 - 7.29 (m, 1H), 7.19 - 7.10 (m, 1H), 7.03 - 6.94 (m, 1H), 5.78 - 5.53 (m, 1H), 5.07 - 4.92 (m, 1H), 4.81 - 4.69 (m, 1H), 4.69 - 4.54 (m, 4H), 4.34 - 4.21 (m, 3H), 4.01 - 3.86 (m, 2H), 3.76 - 3.59 (m, 2H), 3.40 - 3.33 (m, 1H), 3.25 (s, 3H), 2.72 - 2.53 (m, 3H), 2.42 - 2.29 (m, 3H), 2.16 - 1.85 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H); 19 F NMR (377 MHz, DMSO-d6+D2O) δ -132.33, -139.56, -174.51.

[0314] ステップ7:

change

[0315] Example 17 (5aS,6S,9R)-1,3-Difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-2-(5-methoxy-2-(1H-pyrazol-3-yl)phenyl)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline dihydrochloride 17 [ka] The synthetic route is as follows: [ka]

[0316] Step 1 [ka] 1-(2-Bromo-4-methoxyphenyl)ethanone (5 g, 21.83 mmol, 1 eq) was dissolved in toluene (20.0 mL) under stirring at 25 °C. 1,1-Dimethoxy-N,N-dimethyl-methylamine (3.64 g, 30.5 mmol, 1.4 eq) was added to the mixture under stirring at 25 °C. The resulting mixture was reacted at 110 °C under stirring for 16 hours. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was quenched with water (50 mL). The mixture was extracted with ethyl acetate (2 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 100% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 17-1 (pale yellow solid, 2.5 g, yield: 40%). MS (ESI, m / z): 284.0 / 286.0 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.40 (d, J = 12.8 Hz, 1H), 3.83 (s, 3H), 3.03 - 3.01 (m, 6H).

[0317] Step 2 [ka] Compound 17-1 (2.3 g, 8.1 mmol, 1 eq) was dissolved in ethanol (20 mL) under stirring at 25 °C. Hydrazine hydrate (98%, 1.1 mL, 20 mmol, 2.4 eq) was added to the mixture under stirring at 25 °C. The resulting mixture was reacted at 100 °C under stirring for 2 hours. The reaction process was monitored by thin-layer chromatography and liquid mass spectrometry. After the reaction was completed, the solvent was removed from the reaction solution using a rotary evaporator under reduced pressure to obtain the crude product. The crude product was diluted with water (20 mL), and the aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the filtrate was evaporated under reduced pressure to obtain compound 17-2 (pale yellow oil, 2 g, yield: 98%). MS (ESI, m / z): 252.9 / 254.9 [M + H] + ; 1 H NMR (CDCl3) δ 7.61 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 2.6 Hz, 1H), 6.89 (dd, J = 8.6, 2.6 Hz, 1H), 6.65 (d, J = 2.1 Hz, 1H), 3.86 (s, 3H).

[0318] Step 3 [ka] Compound 17-2 (1 g, 3.95 mmol, 1 eq) and 3,4-dihydro-2H-pyran (0.4 g, 5 mmol, 1.26 eq) were dissolved in tetrahydrofuran (20 mL) under stirring at 25 °C. Next, 4-methylbenzenesulfonic acid (68 mg, 0.395 mmol, 0.1 eq) was added to the mixture under stirring at 25 °C. The resulting mixture was reacted for 16 h under stirring at 70 °C. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was quenched by pouring it into saturated sodium bicarbonate solution (100 mL) under stirring at 0 °C. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 24% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 17-3 (colorless oil, 1.2 g, yield: 90%). MS (ESI, m / z): 337.1 / 339.1 [M + H] + ; 1 H NMR (CDCl3) δ 7.68 - 7.63 (m, 2H), 7.18 (d, J = 2.6 Hz, 1H), 6.90 (dd, J = 8.6, 2.6 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 5.44 (dd, J = 9.1, 3.2 Hz, 1H), 3.82 (s, 3H), 1.75 - 1.49 (m, 8H).

[0319] Step 4 [ka] Compound 17-3 (1 g, 2.97 mmol, 1 eq), bis(pinacolato)diboron (900 mg, 3.55 mmol, 1.2 eq), potassium acetate (580 mg, 5.91 mmol, 2 eq), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (220 mg, 0.3 mmol, 0.1 eq) were dissolved in 1,4-dioxane (20 mL) at 25 °C under stirring and argon gas protection. The mixture was reacted at 100 °C for 2 h under argon gas protection and stirring. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was cooled to 25 °C. The reaction solution was filtered through diatomaceous earth, and the cake was washed with ethyl acetate (100 mL). The filtrate was rotary evaporated under reduced pressure to remove the solvent, yielding approximately 2.2 g of a brown oily crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 45% ethyl acetate / petroleum ether. The solvent was removed from the resulting fractions using a rotary evaporator under reduced pressure to give compound 17-4 (colorless oil, 420 mg, yield: 47%). MS (ESI, m / z): 385.1 [M + H] + .

[0320] Step 5 [ka] Compound 5-1 (50 mg, 0.078 mmol, 1.0 eq), compound 17-4 (39 mg, 0.101 mmol, 1.3 eq), tris(dibenzylideneacetone)dipalladium(0) (7.15 mg, 0.008 mmol, 0.1 eq), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxaphosphole (5.15 mg, 0.016 mmol, 0.2 eq), and potassium phosphate (33.14 mg, 0.156 mmol, 2.0 eq) were dissolved in 0.5 mL of toluene and 0.1 mL of water at 25 °C under nitrogen gas protection. The mixture was reacted at 80 °C for 16 h, and the reaction progress was monitored by thin-layer chromatography and liquid mass spectrometry. After completion of the reaction, the reaction solution was quenched by adding water (5 mL). The mixture was extracted with dichloromethane (3 × mL), and the combined organic phases were further dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase chromatography (C18 column) using a 5% to 95% methanol / water mobile phase (0.1% ammonium bicarbonate solution) within 25 min. Detector: UV 254 / 220 nm. Compound 17-5 (yellow oil, 15 mg, yield: 23%) was obtained. MS (ESI, m / z): 818.4 [M + H] + .

[0321] Step 6 [ka] Compound 17-5 (15 mg, 0.015 mmol, 1.0 eq) and trimethylsilane (10.55 mg, 0.090 mmol, 5 eq) were dissolved in 0.6 mL of dichloromethane at 0 °C under nitrogen gas protection and stirred. Trifluoroacetic acid (0.2 mL) was slowly added dropwise to the solution. The mixture was stirred at 25 °C for 1 h, and the reaction process was monitored by thin-layer chromatography and liquid mass spectrometry. After the reaction was completed, the crude product was purified by reverse-phase chromatography (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% hydrochloric acid) within 25 min. Compound 17 (yellow solid, 9.6 mg, yield: 74%) was obtained. MS (ESI, m / z): 634.3 [M + H] + . 1 H NMR (300 MHz, DMSO-d6+D2O) δ 7.81 - 7.71 (m, 1H), 7.53 - 7.48 (m, 1H), 7.22 - 7.13 (m, 1H), 6.97 - 6.89 (m, 1H), 5.88 - 5.78 (m, 1H), 5.71 - 5.40 (m, 1H), 5.09 - 4.87 (m, 1H), 4.70 - 4.42 (m, 6H), 4.33 - 4.20 (m, 2H), 3.87 - 3.72 (m, 5H), 3.64 - 3.60 (m, 1H), 3.35 - 3.21 (m, 1H), 2.66 - 2.56 (m, 1H), 2.45 (s, 1H), 2.37 - 2.25 (m, 1H), 2.24 - 2.11 (m, 2H), 2.11 - 1.82 (m, 5H). 19 F NMR (282 MHz, DMSOd6) δ -132.55, -139.52, -172.73.

[0322] Example 18 4-((2R or 2S,5aS,6S,9R)-1,3-difluoro-13-(((2R,6S and 7aS)-2-fluoro-6-(methoxymethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol dihydrochloride 18a, 4-((2S or 2R,5aS,6S,9R)-1,3-difluoro-13-(((2R,6S and 7aS)-2-fluoro-6-(methoxymethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol dihydrochloride 18b [ka] Synthetic Route [ka]

[0323] Step 1: [ka] Compound 15-2 (16 g, 36.930 mmol, 1.0 eq), tetrahydrofuran (150 mL), and hexamethylphosphoric triamide (25 mL) were sequentially added to a reaction flask at -78 °C under stirring and nitrogen gas protection. After stirring to dissolve, a tetrahydrofuran solution of lithium diisopropylamide (1 mol / L, 46.5 mL, 1.5 eq) was added dropwise, and the resulting mixture was reacted at -78 °C under stirring and nitrogen gas protection for 30 minutes. Paraformaldehyde (3.5 g, 73.860 mmol, 2.0 eq) was added to the reaction system at -78 °C under stirring and nitrogen gas protection, and the mixture was then slowly warmed to 25 °C. The mixture was reacted at 25 °C under stirring and nitrogen gas protection for 2.5 hours, and the reaction process was monitored by liquid mass spectrometry and thin layer chromatography. After the reaction was completed, the reaction mixture was quenched by slowly adding saturated aqueous ammonium chloride (500 mL) at 0 °C. The mixture was extracted with ethyl acetate (500 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding a crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 100% petroleum ether / methyl tert-butyl ether. The fractions were concentrated under reduced pressure to remove the solvent, yielding two compounds. The less polar product: Compound 18-1a (yellow oil, 5.5 g, yield: 32%), MS (ESI, m / z): 442.2 [M + H]. + . 1H NMR (400 MHz, CDCl3) δ 7.68 - 7.55 (m, 4H), 7.50 - 7.35 (m, 6H), 5.34 - 5.17 (m, 1H), 4.23 - 4.06 (m, 1H), 3.88 - 3.74 (m, 1H), 3.70 - 3.62 (m, 1H), 3.59 (d, J = 10.4 Hz, 1H), 3.44 (d, J = 10.4 Hz, 1H), 3.19 - 3.07 (m, 1H), 3.06 - 2.94 (m, 1H), 2.33 - 2.16 (m, 2H), 2.07 - 1.93 (m, 1H), 1.88 - 1.79 (m, 1H), 1.05 (s, 9H); 19 F NMR (377 MHz, CDCl3) δ -173.94. The more polar crude product was further purified by reverse-phase chromatography (C18 column) using a 30% to 75% acetonitrile / water mobile phase (0.05% trifluoroacetic acid) within 30 min to give compound 18-1b (yellow oil, 1.5 g, yield: 9.3%). MS (ESI, m / z): 442.2 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.65 - 7.57 (m, 4H), 7.49 - 7.37 (m, 6H), 5.47 - 5.28 (m, 1H), 4.15 - 4.03 (m, 1H), 3.82 - 3.76 (m, 1H), 3.71 - 3.62 (m, 2H), 3.45 - 3.40 (m, 1H), 3.40 - 3.26 (m, 1H), 2.91 - 2.81 (m, 1H), 2.63 - 2.45 (m, 1H), 2.21 - 2.16 (m, 1H), 1.97 - 1.85 (m, 1H), 1.85 - 1.78 (m, 1H), 1.05 (s, 9H); 19 F NMR (377 MHz, CDCl3) δ -169.64.

[0324] Step 2: [ka] Sodium hydride (60%, 99.81 mg, 2.496 mmol, 2.0 eq) was added in batches to a solution of compound 18-1a (580 mg, 1.248 mmol, 1.0 eq) and methyl iodide (372.83 mg, 2.496 mmol, 2.0 eq) in N,N-dimethylformamide (6 mL) at 0 °C under nitrogen gas protection and stirring. The resulting mixture was reacted at 25 °C for 1 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was quenched by pouring it into saturated ammonium chloride solution and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with 0% to 30% ethyl acetate / petroleum ether mobile phase. The resulting fractions were concentrated under reduced pressure to remove the solvent, affording compound 18-2 (colorless oil, 540 mg, yield: 90%). MS (ESI, m / z): 442.2 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.66 - 7.56 (m, 4H), 7.48 - 7.36 (m, 6H), 5.35 - 5.17 (m, 1H), 4.21 - 4.07 (m, 1H), 3.73 - 3.68 (m, 1H), 3.57 (d, J = 10.4 Hz, 1H), 3.50 - 3.45 (m, 1H), 3.42 (d, J = 10.4 Hz, 1H), 3.33 (s, 3H), 3.19 - 2.99 (m, 2H), 2.37 - 2.18 (m, 2H), 2.07 - 1.88 (m, 2H), 1.04 (s, 9H); 19 F NMR (377 MHz, CDCl3) δ -173.49.

[0325] Step 3: [ka] A solution of compound 18-2 (540 mg, 1.126 mmol, 1.0 eq) in anhydrous tetrahydrofuran (5 mL) was slowly added dropwise with lithium aluminum hydride (1 mol / L, 1.7 mL, 1.689 mmol, 1.5 eq) in tetrahydrofuran at 0 °C under stirring and nitrogen gas protection. The resulting mixture was reacted at 60 °C for 2 h under stirring and nitrogen gas protection. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction mixture was quenched by slowly adding water (0.5 mL), 20% aqueous sodium hydroxide solution (0.5 mL), and water (1.5 mL) sequentially under stirring at 0 °C. The mixture was filtered to remove insoluble materials. The cake was washed with methanol / tetrahydrofuran (10 / 1, 10 mL x 3), combined, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with 0% to 10% ammonia in methanol / dichloromethane (7 mol / L). The resulting fractions were concentrated under reduced pressure to remove the solvent, affording compound 18-3 (off-white solid, 280 mg, yield: 69%). MS (ESI, m / z): 204.1 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 5.24 - 5.03 (m, 1H), 3.32 - 3.26 (m, 3H), 3.25 (s, 3H), 3.22 (s, 1H), 3.18 - 3.13 (m, 1H), 3.13 - 3.06 (m, 1H), 3.02 - 2.83 (m, 1H), 2.70 - 2.61 (m, 1H), 2.52 - 2.37 (m, 1H), 2.07 - 1.80 (m, 3H), 1.66 - 1.56 (m, 1H); 19 F NMR (377 MHz, CDCl3) δ -171.74.

[0326] Step 4: [ka] Triethylenediamine (5.29 mg, 0.045 mmol, 0.2 eq) and cesium carbonate (153.53 mg, 0.448 mmol, 2.0 eq) were sequentially added to a solution of compound 15-7 (150 mg, 0.224 mmol, 1.0 eq) and compound 18-3 (47.89 mg, 0.224 mmol, 1.0 eq) in N,N-dimethylformamide (1.5 mL) at 25 °C under nitrogen gas protection. The resulting mixture was reacted at 80 °C for 2 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was quenched by pouring it into saturated ammonium chloride solution, extracted with ethyl acetate (20 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with 0% to 10% methanol / dichloromethane mobile phase. The resulting fractions were concentrated under reduced pressure to remove the solvent, affording compound 18-4 (pale yellow solid, 140 mg, yield: 73%). MS (ESI, m / z): 820.3 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.74 - 7.66 (m, 1H), 7.52 (d, J = 2.8 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.23 - 7.19 (m, 1H), 7.13 - 7.03 (m, 1H), 5.45 - 5.18 (m, 3H), 5.15 - 4.85 (m, 1H), 4.60 - 3.97 (m, 7H), 3.56 - 3.49 (m, 3H), 3.43 (s, 1H), 3.39 (d, J = 6.4 Hz, 2H), 3.32 (s, 3H), 3.30 - 3.05 (m, 3H), 2.87 - 2.57 (m, 2H), 2.56 - 2.41 (m, 2H), 2.42 - 2.10 (m, 3H), 2.08 - 1.80 (m, 5H), 1.78 - 1.70 (m, 3H), 1.52 (s, 9H).

[0327] Step 5: [ka] Compound 18-4 (140 mg) obtained in Step 4 of this example was chiral separated by high-performance liquid chromatography (chiral column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: n-hexane:methyl tert-butyl ether (1:1) (0.5%, 2 mol / L ammonia-methanol); mobile phase B: methanol; flow rate: 20 mL / min; elution with 10% B phase within 8.5 min; detector: UV 216 / 226 nm). Two compounds were obtained: compound 18-4a (white solid, 42 mg, recovery: 30%), with a shorter retention time (5.11 min); MS (ESI, m / z): 820.3 [M + H]. + Among them, the compound with the longer retention time (6.505 min): Compound 18-4b (white solid, 42 mg, recovery rate: 30%), MS (ESI, m / z): 820.3 [M + H] + .

[0328] Step 6: [ka] A solution of compound 18-4a (42 mg, 0.049 mmol, 1.0 eq) in methanol (1 mL) was added dropwise with HCl (4 mol / L, 1 mL) at 0 °C under stirring. The mixture was stirred at 25 °C for 1 h, and the reaction process was monitored by liquid mass spectrometry. After completion of the reaction, the solvent was removed using a rotary evaporator under reduced pressure. The crude product was purified by reverse-phase chromatography (C18 column) and eluted with a 5% to 95% methanol / water mobile phase (0.1% HCl) within 30 min. Compound 18a (white solid, 30.2 mg, 82% yield) was obtained. MS (ESI, m / z): 676.3 [M + H] + ; 11H NMR (400 MHz, DMSO-d6 + D2O) δ 7.73 - 7.64 (m, 1H), 7.43 - 7.35 (m, 1H), 7.33 (d, J = 2.6 Hz, 1H), 7.18 - 7.11 (m, 1H), 6.97 (d, J = 2.6 Hz, 1H), 5.70 - 5.50 (m, 1H), 5.11 - 4.98 (m, 1H), 4.82 - 4.68 (m, 1H), 4.67 - 4.53 (m, 4H), 4.33 - 4.21 (m, 2H), 3.97 - 3.82 (m, 2H), 3.80 - 3.56 (m, 2H), 3.44 - 3.41 (m, 1H), 3.40 - 3.33 (m, 1H), 3.26 (s, 3H), 3.11 - 3.01 (m, 1H), 2.82 - 2.69 (m, 1H), 2.60 - 2.55 (m, 1H), 2.47 - 2.29 (m, 4H), 2.17 - 1.87 (m, 5H), 0.85 (t, J = 7.6 Hz, 3H); 19 19F NMR (377 MHz, DMSO-d6 + D2O) δ -132.25, -139.52, -173.12。

[0329] Step 7:

Chem.

[0330] Example 19 4-((5aS,6S,9R)-1,3-Difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-7-fluorobenzo[d]thiazol-2-amine dihydrochloride 19 [ka] Synthetic Route: [ka]

[0331] Step 1: [ka] To a solution of compound 5-1 (20.0 mg, 0.03 mmol, 1.0 eq) in 1,4-dioxane / water (5 / 1, 1.2 mL) was added (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (14.62 mg, 0.045 mmol, 1.5 eq), cesium carbonate (20.3 mg, 0.06 mmol, 2.0 eq), and tetrakis(triphenylphosphine)palladium(0) (3.61 mg, 0.003 mmol, 0.1 eq) at 25 °C under stirring under nitrogen gas protection. The reaction mixture was stirred at 100 °C for 16 hours, and the reaction progress was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction mixture was cooled to 25 °C. The reaction solution was concentrated and then purified by silica gel column chromatography using a gradient elution with a mobile phase of 0% to 10% methanol / dichloromethane. The obtained fraction was evaporated under reduced pressure using a rotary evaporator to remove the solvent, giving compound 19-1 (white solid, 8 mg, yield: 31%). MS (ESI, m / z): 828.0 [M + H] +and compound 19-2 (white solid, 10 mg, yield: 44%). MS (ESI, m / z): 728.0 [M + H] + .

[0332] Step 2: [ka] A solution of compound 19-1 (8.0 mg, 0.01 mmol, 1.0 eq) and compound 19-2 (10.0 mg, 0.01 mmol, 1.0 eq) in methanol (1.0 mL) was slowly added dropwise to the solution. The mixture was stirred at 25 °C for 1 hour, and the reaction process was monitored by liquid mass spectrometry. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) using a reverse-phase column (XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 μm); mobile phase A: water (0.1% hydrochloric acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; elution with 5% to 95% mobile phase B for 30 min; UV detection at 254 / 220 nm) to give compound 19 (yellow solid, 4.10 mg, 27% yield). MS (ESI, m / z): 628.05 [M + H] + ; 1 H NMR (400 MHz, CD3OD) δ 7.65 - 7.52 (m, 1H), 7.37 - 7.21 (m, 1H), 5.68 - 5.54 (m, 2H), 4.71 - 4.68 (m, 1H), 4.48 - 4.29 (m, 3H), 4.13 - 3.85 (m, 4H), 3.83 - 3.72 (m, 1H), 3.51 - 3.42 (m, 1H), 2.90 - 2.46 (m, 4H), 2.43 - 2.31 (m, 3H), 2.31 - 2.06 (m, 5H); 19 F NMR (377 MHz, CD3OD) δ -113.73, -134.44, -136.41, -174.19.

[0333] Example 20 4-((2R or 2S,5aS,6S,9R)-1,3-difluoro-13-(((6'R,7a'S)-6'-fluorotetrahydrospiro[cyclopropane-1,3'-pyrrolidine]-7a'(5'H)-methoxy)-5a,6,7,8,9,10-hexahydro-5H-[6,9]epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol dihydrochloride 20a, 4-((2S or 2R,5aS,6S,9R)-1,3-difluoro-13-(((6'R,7a'S)-6'-fluorotetrahydrospiro[cyclopropane-1,3'-pyrrolidine]-7a'(5'H)-methoxy)-5a,6,7,8,9,10-hexahydro-5H-[6,9]epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol dihydrochloride 20b [ka] Synthetic Route: [ka]

[0334] Step 1: [ka] A solution of compound SPH (670 mg, 1.502 mmol, 1.0 eq) in tetrahydrofuran (5 mL) was added with tetra-n-butylammonium fluoride (1 mol / L, 3 mL, 2.0 eq) in tetrahydrofuran at 25 °C under stirring under nitrogen gas protection. The mixture was reacted at 25 °C for 16 h under stirring, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution of 0% to 10% ammonia in methanol / dichloromethane. The fraction was concentrated under reduced pressure to remove the solvent and obtain compound 20-1 (pale yellow solid, 290 mg, yield: 99%). MS (ESI, m / z): 186.2 [M + H] + ; 1 H NMR (300 MHz, CDCl3) δ 5.26 - 5.00 (m, 1H), 3.52 - 3.12 (m, 4H), 2.50 - 2.30 (m, 2H), 2.18 - 1.96 (m, 2H), 1.87 - 1.74 (m, 1H), 1.39 - 1.26 (m, 1H), 0.94 - 0.83 (m, 1H), 0.71 - 0.60 (m, 2H), 0.51 - 0.41 (m, 1H).

[0335] Step 2: [ka] Compound 15-7 (150 mg, 0.224 mmol, 1.0 eq), triethylenediamine (5.29 mg, 0.045 mmol, 0.2 eq), cesium carbonate (153.23 mg, 0.448 mmol, 2.0 eq), compound 20-1 (48.01 mg, 0.246 mmol, 1.1 eq), and N,N-dimethylformamide (2 mL) were sequentially added to a reaction flask at 25 °C under stirring and nitrogen gas protection. The resulting mixture was stirred at 80 °C under nitrogen gas protection for 5 h, and the reaction process was monitored by liquid mass spectrometry. After completion of the reaction, the reaction solution was cooled to room temperature and filtered. The cake was washed with dichloromethane (2 mL x 3). The combined filtrate was rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase chromatography (C18 column) using a 5% to 95% methanol / water mobile phase (0.1% aqueous ammonia) in 25 min. Detector: UV 254 / 220 nm. Compound 20-2 (white solid, 95 mg, yield: 50%) was obtained. MS (ESI, m / z): 802.5 [M + H] + .

[0336] Step 3: [ka] Compound 20-2 (95 mg) obtained in Step 2 of this example was chiral separated by high-performance liquid chromatography (separation conditions: chiral column: CHIRALPAK ID, 2 × 25 cm, 5 μm; mobile phase A: n-hexane / methyl tert-butyl ether (1 / 1) (0.5%, 2 mol / L ammonia / methanol); mobile phase B: methanol; flow rate: 20 mL / min; elution with 15% B within 9.5 min; detector: UV 226 / 292 nm). Two compounds were obtained, of which the product with the shorter retention time (4.17 min): compound 20-2a (pale yellow solid, 37 mg, recovery: 39%), MS (ESI, m / z): 802.4 [M + H]. +Among them, the product with the longer retention time (6.78 min): Compound 20-2b (pale yellow solid, 35 mg, recovery: 37%), MS (ESI, m / z): 802.4 [M + H] + .

[0337] Step 4: [ka] A 1,4-dioxane solution of hydrochloric acid (4 mol / L, 1 mL) was added dropwise to a methanol (1 mL) solution of compound 20-2a (37 mg, 0.044 mmol, 1.0 eq) at 0 °C under stirring. The mixture was reacted at room temperature for 1 h, and the reaction process was monitored by liquid mass spectrometry. After the reaction was completed, the reaction solution was concentrated to obtain the crude product. The resulting crude product was purified by high-performance liquid chromatography (chromatography column: Xselect CSH C18 OBD, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% hydrochloric acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution with 9% to 24% B phase within 10 min; detector: UV 220 / 254 nm) to obtain compound 20a (yellow solid, 15.5 mg, yield: 48%). MS (ESI, m / z): 658.4 [M + H] + ; 11H NMR (400 MHz, DMSO-d6+D2O) δ 7.72 - 7.67 (m, 1H), 7.44 - 7.37 (m, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.18 - 7.13 (m, 1H), 6.97 (d, J = 2.6 Hz, 1H), 5.62 - 5.43 (m, 1H), 5.11 - 5.02 (m, 1H), 4.78 - 4.51 (m, 5H), 4.35 - 4.23 (m, 2H), 4.02 - 3.83 (m, 1H), 3.80 - 3.67 (m, 1H), 3.60 (d, J = 14.2 Hz, 1H), 2.74 - 2.54 (m, 3H), 2.49 - 2.40 (m, 1H), 2.40 - 2.32 (m, 2H), 2.30 - 2.19 (m, 1H), 2.18 - 2.06 (m, 1H), 2.06 - 1.90 (m, 3H), 1.87 - 1.78 (m, 1H), 1.53 - 1.44 (m, 1H), 1.25 - 1.16 (m, 1H), 1.06 - 0.91 (m, 2H), 0.88 - 0.81 (m, 3H); 19 19F NMR (377 MHz, DMSO-d6) δ -132.30, -139.61, -172.83。

[0338] Step 5:

Chemical formula

[0339] Example 21 4-((2R or 2S,5aS,6S,9R)-1,3-difluoro-13-(((2R,6R,7aS)-2-fluoro-6-(hydroxymethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol dihydrochloride 21a, 4-((2S or 2R,5aS,6S,9R)-1,3-difluoro-13-(((2R,6R,7aS)-2-fluoro-6-(hydroxymethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol dihydrochloride 21b [ka] The synthetic route is as follows: [ka]

[0340] Step 1: [ka] Compound 18-1b (700 mg, 1.506 mmol, 1.0 eq), allyl bromide (325.99 mg, 2.560 mmol, 2.0 eq), and anhydrous N,N-dimethylformamide (10 mL) were sequentially added to a reaction flask at 0 °C under stirring under nitrogen gas protection. Sodium hydride (60% dispersion in mineral oil, 102.39 mg, 2.560 mmol, 2.0 eq) was then added in batches. The resulting mixture was stirred at 0 °C under nitrogen gas protection for 1 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was quenched by pouring it into saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with 0% to 50% ethyl acetate / petroleum ether. The resulting fractions were concentrated under reduced pressure to remove the solvent, yielding compound 21-1 (colorless oil, 600 mg, yield: 78%). MS (ESI, m / z): 482.2 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.66 - 7.57 (m, 4H), 7.48 - 7.35 (m, 6H), 5.76 - 5.64 (m, 1H), 5.48 - 5.31 (m, 1H), 5.17 - 5.01 (m, 2H), 4.17 - 4.04 (m, 1H), 3.87 - 3.81 (m, 2H), 3.74 (d, J = 10.4, 1H), 3.62 - 3.50 (m, 2H), 3.46 - 3.30 (m, 2H), 2.90 - 2.82 (m, 1H), 2.66 - 2.52 (m, 1H), 2.20 - 2.10 (m, 1H), 1.98 - 1.81 (m, 2H), 1.04 (s, 9H).

[0341] Step 2: [ka] A solution of compound 21-2 (400 mg, 0.789 mmol, 1.0 eq) in anhydrous tetrahydrofuran (6 mL) was added dropwise to a solution of lithium aluminum hydride (1 mol / L, 2 mL, 1.5 eq) in tetrahydrofuran at 0 °C under nitrogen gas protection. The mixture was stirred at 60 °C for 16 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was cooled to 0 °C, and water (0.5 mL), 20% sodium hydroxide (0.5 mL), and water (1.5 mL) were added dropwise. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with 0% to 10% ammonia in methanol / dichloromethane. The fractions were concentrated under reduced pressure to give compound 21-2 (colorless oil, 80 mg, yield: 42%). MS (ESI, m / z): 230.1 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 5.95 - 5.84 (m, 1H), 5.29 - 5.07 (m, 3H), 3.99 - 3.94 (m, 2H), 3.47 - 3.41 (m, 1H), 3.38 - 3.31 (m, 2H), 3.28 - 3.22 (m, 1H), 3.17 - 3.06 (m, 2H), 2.97 - 2.90 (m, 1H), 2.86 - 2.72 (m, 1H), 2.29 - 2.14 (m, 2H), 2.09 - 1.98 (m, 2H), 1.66 - 1.56 (m, 1H).

[0342] Step 3: [ka] Triethylenediamine (5.29 mg, 0.045 mmol, 0.2 eq), compound 15-7 (150 mg, 0.224 mmol, 1.0 eq), cesium carbonate (153.53 mg, 0.448 mmol, 2.0 eq), compound 21-2 (59.42 mg, 0.224 mmol, 1.0 eq), and N,N-dimethylformamide (1.5 mL) were sequentially added to a reaction flask under stirring at 25 °C under nitrogen gas protection. The resulting mixture was reacted at 80 °C under nitrogen gas protection and stirring for 5 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction was completed, the crude product was purified by reverse-phase chromatography (C18 column) and eluted with a 5% to 95% methanol / water mobile phase (0.1% aqueous ammonium bicarbonate solution) within 25 min. Detector: UV 254 / 220 nm. Compound 21-3 (white solid, 80 mg, yield: 40%) was obtained. MS (ESI, m / z): 846.4 [M + H] + .

[0343] Step 4: [ka] Compound 21-3 (80 mg, 0.084 mmol, 1.0 eq), 1,3-dimethylbarbituric acid (41.53 mg, 0.252 mmol, 3.0 eq), tetrakis(triphenylphosphine)palladium(0) (20.49 mg, 0.017 mmol, 0.2 eq), and dichloromethane (1 mL) were sequentially added to a reaction flask under stirring at 25 °C under nitrogen gas protection. The mixture was reacted at room temperature for 16 h, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase flash chromatography (C18 column) and eluted with a 5% to 95% methanol / water mobile phase (0.1% ammonium bicarbonate) within 25 min. Detector: UV 254 nm to obtain compound 21-4 (white solid, 45 mg, yield: 63%). MS (ESI, m / z): 806.4 [M + H] + .

[0344] Step 5: [ka] Compound 21-4 (45 mg) obtained in Step 4 of this example was chiral separated by high-performance liquid chromatography (chiral column: CHIRALPAK ID, 2 × 25 cm, 5 μm; mobile phase A: n-hexane / methyl tert-butyl ether (1 / 1) (0.5%, 2 mol / L ammonia / methanol); mobile phase B: methanol; flow rate: 20 mL / min; elution with 10% mobile phase B within 9 min; detector: UV 226 / 292 nm). Among them, the compound with the shorter retention time (5.05 min) was compound 21-4a (white solid, 15 mg, recovery: 39%). MS (ESI, m / z): 806.4 [M + H] + Among them, the compound with the longer retention time (6.47 min): Compound 21-4b (white solid, 12 mg, recovery: 31%). MS (ESI, m / z): 806.4 [M + H] + .

[0345] Step 6: [ka] A 1,4-dioxane solution of hydrochloric acid (4 mol / L, 0.5 mL) was added dropwise to a solution of compound 21-4a (15 mg, 0.013 mmol, 1.00 eq) in methanol (0.5 mL) under stirring at 0 °C. The mixture was reacted at room temperature for 1 hour, and the reaction process was monitored by liquid mass spectrometry. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase flash chromatography (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% hydrochloric acid) within 25 minutes. Detector: UV 254 nm. Compound 21a (yellow solid, 9 mg, yield: 80%) was obtained. MS (ESI, m / z): 662.3 [M + H] + ; 1H NMR (400 MHz, CD3OD) δ 7.67 - 7.61 (m, 1H), 7.39 - 7.34 (m, 1H), 7.33 - 7.29 (m, 1H), 7.20 - 7.15 (m, 1H), 7.02 - 6.90 (m, 1H), 5.66 - 5.40 (m, 2H), 4.81 - 4.57 (m, 4H), 4.47 - 4.33 (m, 2H), 4.24 - 4.03 (m, 1H), 3.92 - 3.80 (m, 1H), 3.79 - 3.59 (m, 5H), 3.15 - 3.02 (m, 1H), 2.97 - 2.75 (m, 2H), 2.70 - 2.53 (m, 1H), 2.48 - 2.37 (m, 3H), 2.37 - 2.10 (m, 5H), 1.01 - 0.88 (m, 3H); 19 F NMR (377 MHz, CD3OD) δ -134.82, -136.70, -172.47.

[0346] Step 7: [ka] A 1,4-dioxane solution of hydrochloric acid (4 mol / L, 0.5 mL) was added dropwise to a solution of compound 21-4b (12 mg, 0.014 mmol, 1.00 eq) in methanol (0.5 mL) under stirring at 0 °C. The mixture was reacted at room temperature for 1 hour, and the reaction process was monitored by liquid mass spectrometry. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase flash chromatography (C18 column) and eluted with a 5% to 95% acetonitrile / water mobile phase (0.1% hydrochloric acid) within 30 minutes. Detector: UV 254 nm. Compound 21b (yellow solid, 8 mg, yield: 73%) was obtained. MS (ESI, m / z): 662.3 [M + H] + ; 1H NMR (400 MHz, CD3OD) δ 7.67 - 7.62 (m, 1H), 7.40 - 7.35 (m, 1H), 7.31 (d, J = 2.6 Hz, 1H), 7.20 - 7.15 (m, 1H), 6.95 - 6.91 (m, 1H), 5.66 - 5.32 (m, 2H), 4.84 - 4.64 (m, 4H), 4.62 - 4.52 (m, 1H), 4.43 - 4.34 (m, 2H), 4.22 - 4.04 (m, 1H), 3.93 - 3.79 (m, 1H), 3.78 - 3.57 (m, 5H), 3.18 - 3.01 (m, 1H), 2.94 - 2.74 (m, 1H), 2.69 - 2.52 (m, 1H), 2.51 - 2.34 (m, 4H), 2.32 - 2.12 (m, 4H), 1.02 - 0.94 (m, 3H); 19 F NMR (376 MHz, CD3OD) δ -134.58, -137.14, -172.48.

[0347] Example 22 1-((5aS,6S,9R)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)isoquinolin-3-amine 22 [ka] The synthetic route is as follows: [ka]

[0348] Step 1 [ka] At 25 °C, under nitrogen gas protection and stirring, 1-bromoisoquinolin-3-amine (901 mg, 4.04 mmol, 1 eq), hexabutyldistannane (5.6 g, 9.70 mmol, 2.4 eq), tris(dibenzylideneacetone)dipalladium(0) (370 mg, 0.404 mmol, 0.1 eq), tricyclohexylphosphine (339 mg, 1.21 mmol, 0.3 eq), lithium chloride (1.02 g, 24.2 mmol, 6 eq), and 1,4-dioxane (20 mL) were sequentially added to the reaction flask. The resulting mixture was reacted at 100 °C under nitrogen gas protection and stirring for 20 h. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After completion of the reaction, the reaction solution was cooled to 25 °C. The reaction mixture was quenched...

Claims

1. A compound represented by formula I, formula II, formula III or formula IV, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof. 【Chemistry 1】 provided that formula I, II, or III satisfies the following condition 1 or condition 2: Situation 1: X is N, O or S; each n1 and n4 is independently 1, 2, 3, or 4; Each L is independently -O-(CR Ｌ－１ R Ｌ－２ ) ｎ２ - ＊ , -(CR Ｌ－３ R Ｌ－４ ) ｎ３ - ＊ or 【Chemistry 2】 and ＊ is R １ represents one end connected to n2 and n3 each independently represent 0, 1, 2, 3, or 4; Each R Ｌ－１ , R Ｌ－２ , R Ｌ－３ and R Ｌ－４ are each independently H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, one or more R Ｌ－１－１ C substituted by １ ~C ６ is alkyl or halogen; Each R Ｌ－１－１ are each independently halogen or C １ ~C ６ is an alkoxy; Each R １ is one or more R １－１ and wherein one or more of R １－１ The heteroatoms in the 4-10 membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R １－１ are each independently a halogen; R ２ and R １３ are each independently H or halogen; R ３ and R １４ are each independently C ６ ~C １０ Aryl, "one or more R ３－１ C substituted by ６ ~C １０ aryl," 5- to 10-membered heteroaryl or "one or more R ３－２ "5- to 10-membered heteroaryl substituted with one or more R ３－２ The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R ３－１ and R ３－２ are each independently OH, halogen, or C １ ~C ６ alkyl, one or more R ３－１－１ C substituted by １ ~C ６ Alkyl, C ２ ~C ６ Alkynyl, 3- to 8-membered cycloalkyl, -S-C(R ３－１－２ ) ３ , -S(R ３－１－３ ) ５ , Amino, C １ ~C ６ alkyl or 5-10 membered heteroaryl; Alternatively, any two adjacent R ３－１ R ３－１－４ "5- to 10-membered heteroaryl substituted with one or more R ３－１－４ The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R ３－１－１ are each independently oxo (=O), OH, C １ ~C ６ alkoxy or halogen; Each R ３－１－２ And each R ３－１－３ are each independently a halogen; Each R ３－１－４ are each independently C １ ~C ６ is alkyl, R ４ is H, OH, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, "one or more R ４－１ C substituted by １ ~C ６ alkyl", cyano or halogen; Each R ４－１ are each independently a halogen; X １ is C(R １ａ R １ｂ ) or O, X ２ is C(R ２ａ R ２ｂ ) or O, X ３ is C(R ３ａ R ３ｂ ) or O, R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ３ａ and R ３ｂ are each independently H, C １ ~C ６ is alkyl or halogen; R ５ is H or OH, R ６ is H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, 3-8 membered cycloalkyl, halogen, or one or more R ６－１ C substituted by １ ~C ６ is alkyl, Each R ６－１ are independently halogens, R ７ and R ８ are linked to form Ring A, Ring A being a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R ７－１ a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocycle substituted by one or more R ７－２ "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl having one, two or three heteroatoms selected from N, O and S" substituted by Each R ７－１ and R ７－２ are each independently C １ ~C ６ alkyl, oxy or halogen; R ９ , R １０ , R １１ , R １２ , R １５ and R １６ are each independently H, C １ ~C ６ is alkyl or halogen; Situation 2: X is N, O or S; n1 and n4 are independently 1, 2, 3, or 4; Each L is independently -O-(CR Ｌ－１ R Ｌ－２ ) ｎ２ - ＊ , -(CR Ｌ－３ R Ｌ－４ ) ｎ３ - ＊ or 【Chemistry 3】 and ＊ is R １ represents one end connected to n2 and n3 each independently represent 0, 1, 2, 3, or 4; R Ｌ－１ , R Ｌ－２ , R Ｌ－３ and R Ｌ－４ are each independently H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, one or more R Ｌ－１－１ C substituted by １ ~C ６ is alkyl or halogen; Each R Ｌ－１－１ are each independently halogen or C １ ~C ６ is an alkoxy; Each R １ is one or more R １－１ and wherein one or more of R １－１ The heteroatoms in the 4-10 membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R １－１ are each independently a halogen, a hydroxyl, or —O—C １ ~C ６ Alkyl, C １ ~C ６ alkyl, or one or more R １－１－１ C substituted by １ ~C ６ is alkyl, Each R １－１－１ are each independently hydroxy, —O—C １ ~C ６ alkyl, 4- to 10-membered heterocycloalkyl, or one or more R １－１－１－１ wherein said 4- to 10-membered heterocycloalkyl and said one or more R １－１－１－１ The heteroatoms in the 4- to 10-membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R １－１－１－１ are each independently C １ ~C ６ is alkyl, R ２ and R １３ are each independently H or halogen; R ３ teeth 【Chemistry 4】 and R ３ but 【Chemistry 5】 If R ４ is F, R １４ are each independently C ６ ~C １０ Aryl, "one or more R ３－１ C substituted by ６ ~C １０ aryl," 5- to 10-membered heteroaryl or "one or more R ３－２ "5- to 10-membered heteroaryl substituted with one or more R ３－２ The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R ３－１ and R ３－２ are each independently OH, halogen, or C １ ~C ６ alkyl, one or more R ３－１－１ C substituted by １ ~C ６ Alkyl, C ２ ~C ６ Alkynyl, 3- to 8-membered cycloalkyl, -S-C(R ３－１－２ ) ３ , -S(R ３－１－３ ) ５ , Amino, C １ ~C ６ alkyl, 5- to 10-membered heteroaryl, one or more R ３－１－４ or -O-C １ ~C ６ alkyl, and the 5- to 10-membered heteroaryl and the "one or more R ３－１－４ The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Alternatively, any two adjacent R ３－１ R ３－１－４ a 5- to 6-membered carbocycle, a 5- to 6-membered heterocyclyl, or one or more R ３－１－４ and forming a 5- to 6-membered heterocyclyl substituted with said 5- to 6-membered heterocyclyl and said "one or more R ３－１－４ The heteroatoms of the 5- to 6-membered heterocyclyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R ３－１－１ are each independently oxo (=O), OH, C １ ~C ６ alkoxy or halogen; Each R ３－１－２ and R ３－１－３ are each independently a halogen; Each R ３－１－４ are each independently C １ ~C ６ is alkyl, R ４ is H, OH, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, "one or more R ４－１ C substituted by １ ~C ６ alkyl", cyano or F; Each R ４－１ are each independently a halogen; X １ is C(R １ａ R １ｂ ) or O, X ２ is C(R ２ａ R ２ｂ ) or O, X ３ is C(R ３ａ R ３ｂ ) or O, R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ３ａ and R ３ｂ are each independently H, C １ ~C ６ is alkyl or halogen; R ５ is H or OH, R ６ is H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, 3- to 8-membered cycloalkyl, halogen, or one or more R ６－１ C substituted by １ ~C ６ is alkyl, Each R ６－１ are independently halogens, R ７ and R ８ are linked to form Ring A, Ring A being a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R ７－１ a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocycle substituted by one or more R ７－２ "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocyclyl in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three" substituted by Each R ７－１ and R ７－２ are each independently C １ ~C ６ alkyl, oxo or halogen; R ９ , R １０ , R １１ , R １２ , R １５ and R １６ are each independently H, C １ ~C ６ is alkyl or halogen; In formula IV, X is N, O or S; each n1 is independently 1, 2, 3, or 4; Each L is independently -O-(CR Ｌ－１ R Ｌ－２ ) ｎ２ - ＊ , -(CR Ｌ－３ R Ｌ－４ ) ｎ３ - ＊ or 【Chemistry 6】 and ＊ is R １ represents one end connected to n2 and n3 each independently represent 0, 1, 2, 3, or 4; Each R Ｌ－１ , R Ｌ－２ , R Ｌ－３ and R Ｌ－４ are each independently H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, one or more R Ｌ－１－１ C substituted by １ ~C ６ is alkyl or halogen; Each R Ｌ－１－１ are each independently halogen or C １ ~C ６ is an alkoxy; Each R １ is one or more R １－１ and wherein one or more of R １－１ The heteroatoms in the 4-10 membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R １－１ are each independently a halogen, a hydroxyl, or —O—C １ ~C ６ Alkyl, C １ ~C ６ alkyl, or one or more R １－１－１ C substituted by １ ~C ６ is alkyl, Each R １－１－１ are each independently hydroxy, —O—C １ ~C ６ alkyl, 4- to 10-membered heterocycloalkyl, or one or more R １－１－１－１ wherein said 4- to 10-membered heterocycloalkyl and said one or more R １－１－１－１ The heteroatoms in the 4- to 10-membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R １－１－１－１ are each independently C １ ~C ６ is alkyl, Each R ２ and R １３ are each independently H or halogen; R ３Ｘ is a 5- to 10-membered heteroaryl or "one or more R ３Ｘ－１ "5- to 10-membered heteroaryl substituted with one or more R ３Ｘ－１ The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R ３Ｘ－１ are each independently C １ ~C ６ C substituted with alkyl, amino, or one or more halogens １ ~C ６ is alkyl, Each R ９ , each R １０ are each independently H, C １ ~C ６ alkyl or halogen.

2. In the above situation 1, the compound represented by formula I, formula II or formula III, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, or an isotope thereof is (1) Each R １ may further comprise one or more R １－１ and wherein one or more of the R １－１ the heteroatoms in the 11-membered heterocycloalkyl are independently one, two or three of N, O, or S, and the number of heteroatoms is one, two or three; (2) Each R １－１ Each of the groups independently represents hydroxy, —O—C １ ~C ６ Alkyl, C １ ~C ６ alkyl, or one or more R １－１－１ C substituted by １ ~C ６ is alkyl, Each R １－１－１ are each independently hydroxy, —O—C １ ~C ６ alkyl, 4- to 10-membered heterocycloalkyl, or one or more R １－１－１－１ wherein said 4- to 10-membered heterocycloalkyl and said one or more R １－１－１－１ The heteroatoms in the 4- to 10-membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R １－１－１－１ are each independently C １ ~C ６ The condition that it is alkyl, (3) Each R ３－１ and R ３－２ each independently represents one or more R ３－１－４ or -O-C １ ~C ６ alkyl, and the "one or more R ３－１－４ The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Alternatively, any two adjacent R ３－１ R ３－１－４ a 5- to 6-membered carbocycle, a 5- to 6-membered heterocyclyl, or one or more R ３－１－４ and the "5- to 6-membered heterocyclyl" and the "one or more R ３－１－４ the heteroatoms of "5- to 6-membered heterocyclyl substituted by" are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; A compound represented by formula I, formula II, formula III or formula IV according to claim 1, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof, characterized in that it satisfies one or more of the following:

3. The compound represented by formula I, formula II or formula III, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof, (1) The condition that X is O, (2) n1 is 1 or 2, preferably 1; (3) n2 and n3 each independently represent 1 or 2; (4) R Ｌ－１ , R Ｌ－２ , R Ｌ－３ and R Ｌ－４ each independently represents H, one or more R Ｌ－１－１ C substituted by １ ~C ６ the condition that it is alkyl or halogen; (5) Each R Ｌ－１－１ are each independently C １ ~C ６ The condition that it is alkoxy, (6) R ２ is a halogen, (7) R ３ "One or more R ３－１ C substituted by ６ ~C １０ aryl" or "one or more R ３－２ "5-10 membered heteroaryl substituted with one or more R ３－１ C substituted by ６ ~C １０ The condition that the compound is "aryl"; (8) Each R ３－１ each independently represents a 5- to 10-membered heteroaryl; １ ~C ６ alkyl, one or more R ３－１－１ C substituted by １ ~C ６ Alkyl, 3-8 membered cycloalkyl, OH, halogen, C １ ~C ６ Alkyl or C ２ ~C ６ Alkynyl, preferably OH, halogen, C １ ~C ６ Alkyl or C ２ ~C ６ The condition that it is alkynyl, (9) R ４ is H, halogen, cyano, OH, C １ ~C ６ Alkoxy or one or more R ４－１ C substituted by １ ~C ６ The condition that it is alkyl, (10) X １ is C(R １ａ R １ｂ ) (11) X ２ is C(R ２ａ R ２ｂ ) (12) X ３ is C(R ３ａ R ３ｂ ) (13) R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ３ａ and R ３ｂ are each independently H or halogen; (14) R ５ is OH, (15) R ６ H, halogen, C １ ~C ６ alkyl, one or more R ６－１ C substituted by １ ~C ６ the condition that it is alkyl, or 3- to 8-membered cycloalkyl; (16) Ring A is a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused carbocyclic ring, one or more R ７－１ or "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocycle, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3," (17) R ９ , R １０ , R １１ and R １２ are each independently H or C １ ~C ６ The condition that it is alkyl, (18) Each R ３－２ are each independently C １ ~C ６ alkyl, amino, halogen or one or more R ３－１－１ C substituted by １ ~C ６ The condition that it is alkyl, (19) Each R ３－１－１ are each independently C １ ~C ６ the condition that it is alkoxy or halogen; A compound represented by formula I, formula II, formula III or formula IV according to claim 1 or 2, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, or an isotope thereof, characterized in that it satisfies one or more of the following:

4. The compound represented by formula I, formula II or formula III, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof, (1) R Ｌ－１ , R Ｌ－２ , R Ｌ－３ and R Ｌ－４ are each independently H, (2) R ４ is H or a halogen; (3) R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ３ａ and R ３ｂ are each independently H, (4) R ６ is a halogen, (5) Ring A is a 5- to 6-membered saturated or unsaturated monocyclic carbocyclic ring; A compound represented by formula I, formula II, formula III or formula IV according to claim 1 or 2, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof, characterized in that it satisfies one or more of the following:

5. In formula I, X is O; n1 is 1, R １ is one or more R １－１ is a 4- to 10-membered heterocycloalkyl substituted by Each R １－１ are each independently a halogen; R ２ is a halogen, R ４ is H or a halogen; R ３ "One or more R ３－１ C substituted by ６ ~C １０ aryl" Each R ３－１ are each independently OH, halogen, or C １ ~C ６ Alkyl or C ２ ~C ６ is alkynyl, L is -O-(CR Ｌ－１ R Ｌ－２ ) ｎ２ - ＊ and R Ｌ－１ Or R Ｌ－２ are each independently H; n2 is 1, R ９ and R １０ are each independently H; In formula II, X １ is C(R １ａ R １ｂ ) or O, X ２ is C(R ２ａ R ２ｂ ) or O, X ３ is C(R ３ａ R ３ｂ ) or O, R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ３ａ and R ３ｂ are each independently H or halogen; L is -O-(CR Ｌ－１ R Ｌ－２ ) ｎ２ - ＊ , -(CR Ｌ－３ R Ｌ－４ ) ｎ３ - ＊ or 【Chemistry 7】 and ＊ is R １ represents one end connected to n2 and n3 each independently represent 1 or 2; R Ｌ－１ , R Ｌ－２ , R Ｌ－３ and R Ｌ－４ each independently represents H, one or more R Ｌ－１－１ C substituted by １ ~C ６ is alkyl or halogen; Each R Ｌ－１－１ are each independently C １ ~C ６ is an alkoxy; R １ is one or more R １－１ 4-10 membered heterocycloalkyl substituted by Each R １－１ are each independently a halogen; R ５ is H or OH, R ６ is H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, 3- to 8-membered cycloalkyl, halogen, or one or more R ６－１ C substituted by １ ~C ６ is alkyl, Each R ６－１ are each independently a halogen; R ７ and R ８ are linked to form Ring A, Ring A being a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R ７－１ or "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocycle, wherein the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3," Each R ７－１ are each independently C １ ~C ６ alkyl, oxo or halogen; R １１ and R １２ are each independently H, C １ ~C ６ A compound of formula I, II, III or IV according to claim 1, characterized in that it is alkyl or halogen, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof.

6. X １ is C(R １ａ R １ｂ ) and X ２ is C(R ２ａ R ２ｂ ) and X ３ is C(R ３ａ R ３ｂ ) and R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ３ａ and R ３ｂ are each independently H or halogen; R １ is one or more R １－１ is a 4- to 10-membered heterocycloalkyl substituted by Each R １－１ are each independently a halogen; L is -O-(CR Ｌ－１ R Ｌ－２ ) ｎ２ - ＊ and R Ｌ－１ Or R Ｌ－２ are each independently H; n2 is 1, R ５ is OH, R ６ is a halogen, Ring A is a 5-membered saturated monocyclic carbocyclic ring; R １１ and R １２ A compound represented by formula I, formula II, formula III or formula IV according to claim 5, characterized in that each of them is independently H, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof.

7. The compound represented by formula I, formula II, formula III or formula IV, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof, (1) R １ In the above, "one or more R １－１ The "4- to 10-membered heterocycloalkyl" in the "4- to 10-membered heterocycloalkyl substituted by" is an 8- to 10-membered heterocycloalkyl containing an N atom, and may further be a bicyclo[3.3.0]octaheterocycloalkyl containing an N atom, for example, 【Chemistry 8】 The condition that (2) R ４ , R ６ , R ３－１ , R Ｌ－１ , R Ｌ－２ , R Ｌ－３ , R Ｌ－４ , R ７－１ , R ７－２ , R ９ , R １０ , R １１ , R １２ , R １－１ , R １－１－１ , R １－１－１－１ , R ３－１－４ , R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R １５ , R １６ , R ３Ｘ－１ and R ３－２ In the above, １ ~C ６ alkyl," "one or more R ４－１ C substituted by １ ~C ６ alkyl," "one or more R ３－１－１ C substituted by １ ~C ６ alkyl," "one or more R Ｌ－１－１ C substituted by １ ~C ６ Alkyl," "-O-C １ ~C ６ alkyl," "one or more R １－１－１ C substituted by １ ~C ６ Alkyl," "C １ ~C ６ "5-10 membered heteroaryl substituted with alkyl," "one or more R ６－１ C substituted by １ ~C ６ "Alkyl" and "C substituted with one or more halogens １ ~C ６ "C" in "Alkyl" １ ~C ６ each "alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, and is preferably methyl or ethyl; (3) R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R １－１ , R ２ , R ４ , R ６ , R ３－１ , R ３－１－１ , R ３－１－２ , R ３－１－３ , R ４－１ , R ６－１ , R Ｌ－１ , R Ｌ－２ , R Ｌ－３ , R Ｌ－４ , R Ｌ－１－１ , R ７－１ , R ７－２ , R ９ , R １０ , R １１ , R １３ , R ３－２ , R １５ , R １６ , R ３Ｘ－１ and R １２ wherein each halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine; (4) R ４ , R ６ , R ３－１－１ , R Ｌ－１ , R Ｌ－２ , R Ｌ－３ , R Ｌ－４ and R Ｌ－１－１ In the above, １ ~C ６ the proviso that each "alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, preferably methoxy or ethoxy; (5) R ６ , R ３－２ and R ３－１ wherein each of the 3- to 8-membered cycloalkyl groups is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and preferably cyclopropyl or cyclobutyl; (6) R ３－１ and R ３－２ In the above, ２ ~C ６ Alkynyl" is C ２ ~C ４ alkynyl, preferably ethynyl; (7) R ３ and R １４ In the above, ６ ~C １０ aryl" and "one or more R ３－１ C substituted by ６ ~C １０ Aryl "C" ６ ~C １０ each "aryl" is independently phenyl or naphthyl, preferably naphthyl; (8) R ３ , R ３－１ , R ３－２ and R １ In the above "5- to 10-membered heteroaryl", C １ ~C ６ 5-10 membered heteroaryl substituted with alkyl, and "one or more R ３－２ each "5- to 10-membered heteroaryl" in "5- to 10-membered heteroaryl substituted by" is independently a 9- to 10-membered heteroaryl; (9) R １－１－１ In the above, the 4- to 10-membered heterocycloalkyl and the "one or more R １－１－１－１ The 4-10 membered heterocycloalkyl substituted by is independently a 5-6 membered monocyclic heterocycloalkyl, the heteroatoms being N and / or O, which may be 1 or 2 in number, and may further be piperidinyl, piperazine or morpholinyl, and further 【Chemistry 9】 Conditions that may be, (10) R １－１－１ In the formula (I), two R １－１－１ and the carbon atoms connected thereto together form a 3- to 8-membered cycloalkyl, which is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (11) R ３Ｘ In the above, the "5- to 10-membered heteroaryl" and the "one or more R ３Ｘ－１ each "5- to 10-membered heteroaryl" in "5- to 10-membered heteroaryl substituted by" is independently pyridine; (12) R ３ and R １４ Each independently represents "one or more R ３－１ C substituted by ６ ~C １０ aryl" and any two adjacent R ３－１ together with the carbon atom to which they are attached form a 5- to 10-membered heteroaryl, or "one or more R ３－１－４ When forming "5- to 10-membered heteroaryl substituted by R ３ and R １４ are each independently 【Chemistry 10】 The condition that A compound represented by formula I, formula II, formula III or formula IV according to any one of claims 1 to 6, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof, characterized in that it satisfies one or more of the following:

8. The compound represented by formula I, formula II, formula III or formula IV, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof, (1)-L-R １ teeth 【Chemistry 11】 and preferably 【Chemistry 12】 and more preferably 【Chemistry 13】 The condition that (2) R ２ is fluorine, (3) R ３ teeth 【Chemistry 14】 and preferably 【Chemistry 15】 The condition that (4) R ４ is H, fluorine, chlorine, cyano, trifluoromethyl, hydroxy, methoxy or ethoxy, preferably hydrogen or fluorine; (5) R ９ , R １０ , R １１ and R １２ are each independently H or methyl, preferably H; (6) X １ , X ２ , X ３ are each independently CH ２ , O, CHF or CF ２ and preferably CH ２ The condition that (7) R ５ is OH or H, preferably OH; (8) R ６ is H, chlorine, fluorine, methyl, trifluoromethyl or cyclopropyl, preferably chlorine; (9) Ring A is 【Chemistry 16】 and preferably 【Chemistry 17】 For example, 【Chemistry 18】 The condition that (10) R １３ is fluorine, (11) R １４ teeth 【Chemistry 19】 The condition that (12) R ３Ｘ teeth 【Chemistry 20】 The condition that A compound represented by formula I, formula II, formula III or formula IV according to claim 1 or 2, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof, characterized in that it satisfies one or more of the following:

9. The compound represented by formula I, formula II or formula III, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof, Scheme 1: In the compounds of formula I, II or III, X is N, O or S; n1 and n4 are independently 1, 2, 3, or 4; Each L is independently -O-(CR Ｌ－１ R Ｌ－２ ) ｎ２ - ＊ , -(CR Ｌ－３ R Ｌ－４ ) ｎ３ - ＊ or 【Chemistry 21】 and ＊ is R １ represents one end connected to n2 and n3 each independently represent 0, 1, 2, 3, or 4; R Ｌ－１ , R Ｌ－２ , R Ｌ－３ and R Ｌ－４ are each independently H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, one or more R Ｌ－１－１ C substituted by １ ~C ６ is alkyl or halogen; Each R Ｌ－１－１ are each independently halogen or C １ ~C ６ is an alkoxy; Each R １ is one or more R １－１ and wherein one or more of R １－１ The heteroatoms in the 4-10 membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R １－１ are each independently a halogen; R ２ and R １３ are each independently H or halogen; R ３ and R １４ are each independently C ６ ~C １０ Aryl, "one or more R ３－１ C substituted by ６ ~C １０ aryl," 5- to 10-membered heteroaryl, or "one or more R ３－２ "5- to 10-membered heteroaryl substituted with one or more R ３－２ The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R ３－１ and R ３－２ are each independently OH, halogen, or C １ ~C ６ alkyl, one or more R ３－１－１ C substituted by １ ~C ６ Alkyl, C ２ ~C ６ Alkynyl, 3- to 8-membered cycloalkyl, -S-C(R ３－１－２ ) ３ , -S(R ３－１－３ ) ５ , Amino, C １ ~C ６ alkyl or 5-10 membered heteroaryl; Alternatively, any two adjacent R ３－１ together with the carbon atom to which they are attached, form a 5- to 10-membered heteroaryl, or "one or more R ３－１－４ "5- to 10-membered heteroaryl substituted with one or more R ３－１－４ The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R ３－１－１ are each independently oxo (=O), OH, C １ ~C ６ alkoxy or halogen; Each R ３－１－２ and R ３－１－３ are each independently a halogen; Each R ３－１－４ are each independently C １ ~C ６ is alkyl, R ４ is H, OH, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, "one or more R ４－１ C substituted by １ ~C ６ alkyl", cyano or halogen; Each R ４－１ are each independently a halogen; X １ is C(R １ａ R １ｂ ) or O, X ２ is C(R ２ａ R ２ｂ ) or O, X ３ is C(R ３ａ R ３ｂ ) or O, R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ３ａ and R ３ｂ are each independently H, C １ ~C ６ is alkyl or halogen; R ５ is H or OH, R ６ is H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, 3- to 8-membered cycloalkyl, halogen or one or more R ６－１ C substituted by １ ~C ６ is alkyl, Each R ６－１ are independently halogens, R ７ and R ８ are linked to form Ring A, Ring A being a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R ７－１ a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocycle, "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring heterocycloyl, in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one or more R ７－２ "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl having one, two or three heteroatoms selected from N, O and S" substituted by Each R ７－１ and R ７－２ are each independently C １ ~C ６ alkyl, oxo or halogen; R ９ , R １０ , R １１ , R １２ , R １５ and R １６ are each independently H, C １ ~C ６ is alkyl or halogen; Scheme 2: In the compounds of formula I, II or III, X is N, O or S; n1 and n4 are independently 1, 2, 3, or 4; Each L is independently -O-(CR Ｌ－１ R Ｌ－２ ) ｎ２ - ＊ , -(CR Ｌ－３ R Ｌ－４ ) ｎ３ - ＊ or 【Chemical 22】 and ＊ is R １ is connected to represent one end, n2 and n3 each independently represent 0, 1, 2, 3, or 4; R Ｌ－１ , R Ｌ－２ , R Ｌ－３ and R Ｌ－４ are each independently H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, one or more R Ｌ－１－１ C substituted by １ ~C ６ is alkyl or halogen; Each R Ｌ－１－１ are each independently halogen or C １ ~C ６ is an alkoxy; Each R １ is one or more R １－１ and wherein one or more of R １－１ The heteroatoms in the 4-10 membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R １－１ are each independently a halogen; R ２ and R １３ are each independently H or halogen; R ３ and R １４ are each independently C ６ ~C １０ Aryl, "one or more R ３－１ C substituted by ６ ~C １０ aryl," 5- to 10-membered heteroaryl, or "one or more R ３－２ "5- to 10-membered heteroaryl substituted with one or more R ３－２ The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R ３－１ and R ３－２ are each independently OH, halogen, or C １ ~C ６ alkyl, one or more R ３－１－１ C substituted by １ ~C ６ Alkyl, C ２ ~C ６ Alkynyl, 3- to 8-membered cycloalkyl, -S-C(R ３－１－２ ) ３ , -S(R ３－１－３ ) ５ or amino, Alternatively, any two adjacent R ３－１ together with the carbon atom to which they are attached, form a 5- to 10-membered heteroaryl, or "one or more R ３－１－４ "5- to 10-membered heteroaryl substituted with one or more R ３－１－４ The heteroatoms of the 5- to 10-membered heteroaryl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R ３－１－１ are each independently oxo (=O), OH, C １ ~C ６ alkoxy or halogen; Each R ３－１－２ and R ３－１－３ are each independently a halogen; Each R ３－１－４ are each independently C １ ~C ６ is alkyl, R ４ is H, OH, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, "one or more R ４－１ C substituted by １ ~C ６ alkyl", cyano or halogen; Each R ４－１ are each independently a halogen; X １ is C(R １ａ R １ｂ ) or O, X ２ is C(R ２ａ R ２ｂ ) or O, X ３ is C(R ３ａ R ３ｂ ) or O, R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ３ａ and R ３ｂ are each independently H, C １ ~C ６ is alkyl or halogen; R ５ is H or OH, R ６ is H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, 3- to 8-membered cycloalkyl, halogen or one or more R ６－１ C substituted by １ ~C ６ is alkyl, Each R ６－１ are independently halogens, R ７ and R ８ are linked to form Ring A, Ring A being a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R ７－１ a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocycle, "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring heterocycloyl, in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one or more R ７－２ "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic, or fused-ring heterocycloyl having one, two, or three heteroatoms selected from N, O, and S" substituted by Each R ７－１ and R ７－２ are each independently C １ ~C ６ alkyl, oxo or halogen; R ９ , R １０ , R １１ , R １２ , R １５ and R １６ are each independently H, C １ ~C ６ is alkyl or halogen; Scheme 3: In Formula I or Formula II: where X is N, O or S; n1 is 1, 2, 3 or 4; L is -O-(CR Ｌ－１ R Ｌ－２ ) ｎ２ - ＊ , -(CR Ｌ－３ R Ｌ－４ ) ｎ３ - ＊ or 【Chemistry 23】 and ＊ is R １ represents one end connected to n2 and n3 each independently represent 0, 1, 2, 3, or 4; R Ｌ－１ , R Ｌ－２ , R Ｌ－３ and R Ｌ－４ are each independently H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, one or more R Ｌ－１－１ C substituted by １ ~C ６ alkyl or halogen; Each R Ｌ－１－１ Each independently represents a halogen or C １ ~C ６ is an alkoxy; R １ is one or more R １－１ and wherein one or more of R １－１ The heteroatoms in the 4-10 membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R １－１ are each independently a halogen; R ２ is H or a halogen; R ３ is C ６ ~C １０ Aryl, "one or more R ３－１ C substituted by ６ ~C １０ aryl" or 5- to 10-membered heteroaryl, the heteroatoms of said 5- to 10-membered heteroaryl are independently one, two or three of N, O or S, and the number of heteroatoms is one, two or three; Each R ３－１ are each independently OH, halogen, or C １ ~C ６ alkyl, one or more R ３－１－１ C substituted by １ ~C ６ Alkyl, C ２ ~C ６ Alkynyl, 3- to 8-membered cycloalkyl, -S-C(R ３－１－２ ) ３ Or -S(R ３－１－３ ) ５ and Each R ３－１－１ are each independently oxo (=O), OH, C １ ~C ６ alkoxy or halogen; Each R ３－１－２ and R ３－１－３ are each independently a halogen; R ４ is H, OH, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, "one or more R ４－１ C substituted by １ ~C ６ alkyl", cyano or halogen; Each R ４－１ are each independently a halogen; X １ is C(R １ａ R １ｂ ) or O, X ２ is C(R ２ａ R ２ｂ ) or O, X ３ is C(R ３ａ R ３ｂ ) or O, R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ３ａ and R ３ｂ are each independently H, C １ ~C ６ is alkyl or halogen; R ５ is H or OH, R ６ is H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, 3- to 8-membered cycloalkyl, halogen or one or more R ６－１ C substituted by １ ~C ６ is alkyl, Each R ６－１ are independently halogens, R ７ and R ８ are linked to form Ring A, Ring A being a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R ７－１ a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocycle, "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring heterocycloyl, in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one or more R ７－２ "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl having one, two or three heteroatoms selected from N, O and S" substituted by Each R ７－１ and R ７－２ are each independently C １ ~C ６ alkyl, oxo (=O) or halogen; R ９ , R １０ , R １１ and R １２ are each independently H, C １ ~C ６ is alkyl or halogen; Scheme 4: In Formula I or Formula II: X is N, O or S; n1 is 1, 2, 3 or 4; L is independently -O-(CR Ｌ－１ R Ｌ－２ ) ｎ２ - ＊ , -(CR Ｌ－３ R Ｌ－４ ) ｎ３ - ＊ or 【Chemistry 24】 and ＊ is R １ represents one end connected to n2 and n3 each independently represent 0, 1, 2, 3, or 4; R Ｌ－１ , R Ｌ－２ , R Ｌ－３ and R Ｌ－４ are each independently H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, one or more R Ｌ－１－１ C substituted by １ ~C ６ is alkyl or halogen; Each R Ｌ－１－１ are each independently halogen or C １ ~C ６ is an alkoxy; R １ is one or more R １－１ and wherein one or more of R １－１ The heteroatoms in the 4-10 membered heterocycloalkyl substituted by are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3; Each R １－１ are each independently a halogen; R ２ is H or a halogen; R ３ is C ６ ~C １０ Aryl, "one or more R ３－１ C substituted by ６ ~C １０ aryl" or 5- to 10-membered heteroaryl, the heteroatoms of said 5- to 10-membered heteroaryl are independently one, two or three of N, O or S, and the number of heteroatoms is one, two or three; Each R ３－１ are each independently OH, halogen, or C １ ~C ６ alkyl, one or more R ３－１－１ C substituted by １ ~C ６ Alkyl, C ２ ~C ６ Alkynyl, 3- to 8-membered cycloalkyl, -S-C(R ３－１－２ ) ３ Or -S(R ３－１－３ ) ５ and Each R ３－１－１ are each independently oxo (=O), OH, C １ ~C ６ alkoxy or halogen; Each R ３－１－２ and R ３－１－３ are each independently a halogen; R ４ is H, OH, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, "one or more R ４－１ C substituted by １ ~C ６ alkyl", cyano or halogen; Each R ４－１ are each independently a halogen; X １ is C(R １ａ R １ｂ ) or O, X ２ is C(R ２ａ R ２ｂ ) or O, X ３ is C(R ３ａ R ３ｂ ) or O, R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ３ａ and R ３ｂ are each independently H, C １ ~C ６ is alkyl or halogen; R ５ is H or OH, R ６ is H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, 3- to 8-membered cycloalkyl, halogen, or one or more R ６－１ C substituted by １ ~C ６ is alkyl, Each R ６－１ are independently halogens, R ７ and R ８ are linked to form Ring A, Ring A being a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocyclic ring, one or more R ７－１ a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring carbocycle, "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused ring heterocycloyl, in which the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three," or one or more R ７－２ "a 5- to 6-membered saturated or unsaturated monocyclic, spirocyclic or fused-ring heterocycloyl having one, two or three heteroatoms selected from N, O and S" substituted by Each R ７－１ and R ７－２ are each independently C １ ~C ６ is alkyl or halogen; R ９ , R １０ , R １１ and R １２ are each independently H, C １ ~C ６ is alkyl or halogen; A compound of formula I, II, III or IV according to claim 1 or 2, characterized in that it is any one of the schemes, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof.

10. The compound represented by formula I, II, III or IV according to claim 1 or 2, characterized in that the compound represented by formula I, II, III or IV is any one of the following compounds: a compound represented by formula I, II, III or IV, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, or an isotope thereof. 【Chemistry 25】 【change】 【change】 【change】

11. The stereoisomer of the compound represented by formula I, II, III or IV according to claim 1 or 2, characterized in that it is any one of the following compounds: a compound represented by formula I, II, III or IV, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, or an isotope thereof. 【Chemistry 26】 【change】 【Table 1】 【Chemical 27】 【change】 【change】 【change】 【change】 【change】 (wherein the "*" mark represents a carbon atom in the S configuration or a carbon atom in the R configuration, 【Chemistry 28】 teeth 【Chemical Formula 29】 or 【Chemistry 30】 Represents.)

12. The pharma- ceutically acceptable salt of the compound of formula I, II, III or IV is a hydrochloride salt of the compound of formula I, II, III or IV, and / or the number of pharma- ceutically acceptable salts of the compound of formula I, formula II, formula III or formula IV may be 1, 2, 3, 4 or 5; The pharma- ceutically acceptable salt of the compound represented by formula I, formula II, formula III or formula IV according to claim 1 or 2 is preferably any one of the following compounds: a compound represented by formula I, formula II, formula III or formula IV, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof. 【Chemistry 31】 【change】

13. The pharma- ceutically acceptable salt of the compound represented by formula I, formula II, formula III or formula IV according to claim 1 or 2, characterized in that it is any one of the following compounds: a compound represented by formula I, formula II or formula III, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof. 【Chemistry 32】 【change】 (wherein the "*" mark represents a carbon atom in the S configuration or a carbon atom in the R configuration, 【Chemical 33】 teeth 【Chemical 34】 or 【Chemistry 35】 Represents.)

14. A compound represented by the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemical 36】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 (wherein the "*" mark represents a carbon atom in the S configuration or a carbon atom in the R configuration, 【Chemical 37】 teeth 【Chemical 38】 or 【Chemical Formula 39】 Represents.)

15. A pharmaceutical composition comprising a compound represented by formula I, II, III or IV according to any one of claims 1 to 13, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof, and a pharmaceutical excipient.

16. Use of a compound of formula I, II, III or IV according to any one of claims 1 to 13, a pharma- ceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof or an isotope thereof, or a pharmaceutical composition according to claim 15, in the preparation of a KRAS mutant protein inhibitor or a medicament, comprising The medicament is used for preventing or treating cancer mediated by KRAS mutations, The KRAS mutant protein is preferably a KRAS G12D mutant protein, The cancers mediated by the KRAS mutant protein include blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, lung cancer, brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, and endometrial cancer. , cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma, preferably blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, lung cancer, colorectal cancer and non-small cell lung cancer, more preferably blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer or lung cancer.

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