A quinazoline compound and application thereof

Abstract

A quinazoline compound as shown in formula I, a pharmaceutically acceptable salt, solvate, prodrug, metabolite or isotopic compound thereof has good inhibitory effect on KRAS mutant protein.

Description

[0001] This application claims priority to Chinese patent applications 2020110658732 (filed on 2020 / 9 / 30), 2021101865969 (filed on 2021 / 2 / 10), 2021102831279 (filed on 2021 / 3 / 16), 2021104426662 (filed on 2021 / 4 / 23), 2021105740619 (filed on 2021 / 5 / 25), 2021106941282 (filed on 2021 / 6 / 22), 2021108016737 (filed on 2021 / 7 / 15), and CN202111032451X (filed on 2021 / 9 / 3). This application incorporates the full text of the aforementioned Chinese patent application. Technical Field

[0002] This invention relates to a quinazoline compound and its applications. Background Technology

[0003] RAS represents a group of closely related monomeric globular proteins (21 kDa molecular weight) of 189 amino acids that are associated with the plasma membrane and bind GDP or GTP. RAS acts as a molecular switch. When RAS contains bound GDP, it is in a quiescent or off position and is “inactive.” In response to cellular exposure to certain growth-promoting stimuli, RAS is induced to exchange its bound GDP for GTP. With GTP bound, RAS is “turned on” and can interact with and activate other proteins (its “downstream targets”). RAS proteins themselves have a very low inherent ability to hydrolyze GTP back to GDP, thereby turning themselves off. Turning off RAS requires an exogenous protein called a GTPase-activating protein (GAP), which interacts with RAS and greatly accelerates the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAP or convert GTP back to GDP will result in prolonged protein activation, and therefore prolonged signals transmitted to the cell telling it to continue growing and dividing. Since these signals lead to cell growth and division, overactivated RAS signaling can ultimately lead to cancer.

[0004] Structurally, the RAS protein contains a G domain responsible for the enzymatic activity of RAS—guanine nucleotide binding and hydrolysis (GTP enzyme reaction). It also contains a C-terminal extension region called the CAAX box, which can be post-translational modified and is responsible for targeting the protein to the membrane. The G domain is approximately 21-25 kDa in size and contains a phosphate-binding loop (P-loop). The P-loop represents the nucleotide-binding capsule in the protein and is the rigid portion of the domain containing conserved amino acid residues essential for nucleotide binding and hydrolysis (glycine 12, threonine 26, and lysine 16). The G domain also contains so-called switch I regions (residues 30-40) and switch II regions (residues 60-76), both dynamic parts of the protein, often described as a "spring-loaded" mechanism due to their ability to switch between resting and loaded states. The primary interaction is a hydrogen bond formed by threonine-35 and glycine-60 with the γ-phosphate of GTP, which maintains the active conformations of switch I and switch II regions, respectively. After hydrolysis of GTP and release of phosphate, both relax into the inactive GDP conformation.

[0005] The most notable members of the RAS subfamily are HRAS, KRAS, and NRAS, which are primarily involved in many types of cancer. However, many other members exist, including 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 of the three major isotypes of the RAS gene (HRAS, NRAS, or KRAS) are among the most common events in human tumorigenesis. Approximately 30% of all human tumors are found to carry some mutation in the RAS gene. Notably, KRAS mutations are detected in 25%–30% of tumors. In contrast, the rates of oncogenic mutations are much lower in members of the NRAS and HRAS families (8% and 3%, respectively). The most common KRAS mutations are found at residues G12 and G13 in the P-loop and at residue Q61. Among tumor-associated KRAS G12 mutations, KRAS G12D mutations occur most frequently, accounting for approximately 40%.

[0007] Given the importance of aberrant KRAS activation in cancer progression and the prevalence of KRAS gene mutations in human cancers, KRAS has long been a target of interest for drug developers. Despite progress in this area, there is still a need for improved KRAS G12D mutant protein inhibitors. Summary of the Invention

[0008] The technical problem to be solved by this invention is to overcome the lack of inhibitors for the KRAS G12D mutant protein in the prior art, and to provide a quinazoline compound and its application. The quinazoline compound provided by this invention has a good inhibitory effect on the KRAS G12D mutant protein.

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

[0010] This invention provides a quinazoline compound as shown in Formula I, and its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound.

[0011]

[0012] Wherein, ring 1 and ring 2 are independently C5-C6 aryl, 5-6 heteroaryl (with one or more heteroatoms selected from N, O, and S, and the number of heteroatoms being 1-3), C4-C8 cycloalkyl, or 4-8 heterocycloalkyl (with one or more heteroatoms selected from N, O, S, B, and P, and the number of heteroatoms being 1-4); (ring 1 and ring 2 are fused together).

[0013] p1 and p2 are independently 1, 2, 3, 4 or 5;

[0014] R A The radicals are H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl, and C4-C6 alkoxy.

[0015] R a C6-C substituted with one or more hydroxyl groups 10 aryl, amino-substituted C6-C 10 Aryl, Replacement C6-C 10 aryl groups, 6-10 heteroaryl groups substituted with one or more hydroxyl groups, and aryl groups substituted with one or more R groups a-3 Substituted 6-10 heteroaryl, C6-C 10 aryl, with one or more R a-1 The C6-C substituent is substituted and at least one of the substituents is halogen, C1-C6 alkyl, cyano or alkynyl. 10 aryl, with one or more R a-2Substituted C4-C8 cycloalkyl and C6-C 10 aryl or aryl group or one or more R a-4 Replacement C6-C 10 The aryl group; wherein the heteroatom in the 6-10 membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0016] R B It can be H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl, C4-C6 alkoxy, or Y. 1 ;

[0017] Y 1 For one or more The substituted heteroatom is a 3-10 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms, and is substituted by one or more R... 11 Substituted C1-C6 alkoxy groups, unsubstituted or R 12 The substituted heteroatom is a 4-10 membered heterocyclic alkyl group selected from N or O, with 1-3 heteroatoms, and is substituted by one or more R... 14 Substituted amino groups, -OR 13 C6-C substituted with one hydroxyl group 10 aryl, R 15 Substituted C1-C6 alkyl groups, R 16 Substituted C1-C6 thio groups or R 17 Replacement C3-C 10 cycloalkyl;

[0018] R Y1 and R Y2 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0019] for

[0020] M 1 It can be N, CH, or P (=O);

[0021] Ring B is an unsubstituted 4-10 membered heterocyclic alkyl group consisting of 1-3 heteroatoms or heterogroups selected from N and P (=O), containing only 1 N atom, and bounded by R. 10 The substituted heteroatoms or heterogroups are selected from N and P (=O), and the number of heteroatoms or heterogroups is 1-3, containing only 1 N atom. These are 4-10 member heterocyclic alkyl groups, unsubstituted or R-substituted heteroatoms. 7 The substituted heteroatoms are 5-6 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms; unsubstituted or R-substituted heterocyclic alkyl groups.7 The substituted heteroatoms are 7-12 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms. Or an unsubstituted 4-10 membered heterocyclic alkenyl group whose heteroatoms or heterogroups are selected from N and P (=O) and the number of heteroatoms or heterogroups is 1-3; one N atom of the 7-12 membered heterocyclic alkyl group is attached to ring 2;

[0022] R 7 -(CH2) m -CN, -C(=O)(CH2) n NH2, -C(=O)O-(C1-C4 alkyl), C1-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN; m is 0, 1, or 2; n is 1, 2, or 3;

[0023] R 10 Amino or

[0024] R 11 Independently halogen, Cyano, unsubstituted or R 11-6 Replacement C3-C 12 Cycloalkyl, unsubstituted or with one or more R 11-5 Substituted C1-C6 alkoxy groups, unsubstituted or substituted with one or more R groups 11-3 The substituted heteroatom is selected from N and O, and the number of heteroatoms is 1-3. It is a 4-10 membered heterocyclic alkyl group, unsubstituted or substituted with one or more R atoms. 11-4 The substituted heteroaryl group is a 5-6 member heteroaryl group whose heteroatoms are selected from N and O and the number of heteroatoms is 1-3, or a 4-10 member heterocyclic alkyl group whose heteroatoms are selected from N and S and the number of heteroatoms is 1-3.

[0025] R 11-5 Independently, it is a 4-10 membered heterocyclic alkyl group; wherein the heteroatom in the 4-10 membered heterocyclic alkyl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0026] R 11-1 and R 11-2 Independently H, unsubstituted or by one or more R 11-1-1 Substituted C1-C6 alkyl groups

[0027] R 11-3 For H, Cyano, C2-C6 acetylene, C3-C 12Cycloalkyl, C1-C6 alkoxy, halogen, unsubstituted or C1-C6 substituted 4-10 member heterocyclic alkyl, C1-C6 alkyl, R 11-3-1 Substituted C1-C6 alkyl groups, R 11-3-2 Substituted C1-C6 alkoxy or C2-C6 alkenyl groups;

[0028] R 11-4 It is a C1-C6 alkyl group;

[0029] R 11-6 For not replaced or by R 11-6-1 Substituted C1-C6 alkyl groups;

[0030] R 11-6-1 For not replaced or by R 11-6-1-1 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3. This refers to 4-10 membered heterocyclic alkyl groups or...

[0031] R 11-6-2 and R 11-6-3 Independently H or C1-C6 alkyl;

[0032] R 11-6-1-1 Independently H or C1-C6 alkyl;

[0033] R 11-1-1 For -OH, by R L The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0034] R 11-3-1 For C3-C 12 cycloalkyl, Or not replaced or by R 11-3-1-1 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0035] R 11-3-1-1 Independently H, or C1-C6 alkyl;

[0036] R 11-3-1-2 Independently

[0037] R 11-3-1-2-1 and R 11-3-1-2-2 Independently H or C1-C6 alkyl;

[0038] R 11-3-2 For C1-C 12 alkenyl;

[0039] R L For H or

[0040] R a-1 Independently hydroxyl, halogen, cyano, C1-C6 alkyl, C3-C 12 Cycloalkyl, unsubstituted or with one or more R a-1-1 Substituted C2-C6 ynyl group, with one or more R a-1-2 Substituted C1-C6 alkyl groups;

[0041] R a-2 Independently hydroxyl or C1-C6 alkyl;

[0042] R a-1-1 Halogens are independent of each other;

[0043] R a-1-2 Halogens are independent of each other;

[0044] R a-3 It is a C1-C6 alkyl group;

[0045] R a-4 for

[0046] R 12 It is a C1-C6 alkyl group;

[0047] R 13 H, C1-C6 alkyl, Or be R 13-1 Substituted C3-C6 cycloalkyl groups;

[0048] R 13-1 for Or be R 13-1-3 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0049] R 13-1-1 and R 13-1-2 Independently, it is H or a C1-C6 alkyl group;

[0050] R 13-1-3 Independently, it is H or a C1-C6 alkyl group;

[0051] R 14 For not replaced or by Substituted C1-C6 alkyl groups;

[0052] R 14-1-1 and R 14-1-2 Independently, it is H or a C1-C6 alkyl group;

[0053] R 15 for

[0054] R 15-1-1 and R 15-1-2Independently, it is H or a C1-C6 alkyl group;

[0055] R 16 for

[0056] R 16-1 and R 16-2 Independently H or C1-C6 alkyl;

[0057] R 17 for

[0058] R 17-1 and R 17-2 Independently H or C1-C6 alkyl;

[0059] Ring C is unsubstituted or replaced by R 9 The substituted heteroatom or heterogroup is selected from N and S (=O), and the number of heteroatoms or heterogroups is 1-3; and M 2 S (=O);

[0060] R 9 for

[0061] R 9-1 and R 9-2 It can be independently H, C1-C3 alkyl, C4-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN;

[0062] R 1 and R 4 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0063] R 2 R 3 and R 5 Independently -(CH2) n -R 2a Or 6-10 membered heterocyclic alkyl groups;

[0064] n is 1, 2, 3 or 4;

[0065] R 2a It can be H, -OH, -O-(C1-C3 alkyl), -O-(C4-C6 alkyl) or

[0066] R 2a-1 and R 2a-2 It can be independently H, -C(=O)CH3, C1-C3 alkyl, or C4-C6 alkyl;

[0067] When ring 1 is independently pyridine, R B for

[0068] In one embodiment, the quinazoline compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound,

[0069]

[0070] Wherein, ring 1 and ring 2 are independently C5-C6 aryl, 5-6-membered heteroaryl (heteroatoms selected from one or more of N, O, and S, with 1-3 heteroatoms), C4-C8 cycloalkyl, or 4-8-membered heterocycloalkyl (heteroatoms selected from one or more of N, O, S, B, and P, with 1-4 heteroatoms); (ring 1 and ring 2 are fused together).

[0071] p1 and p2 are independently 1, 2, 3, 4 or 5;

[0072] R A The radicals are H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl, and C4-C6 alkoxy.

[0073] R a C6-C substituted with one or more hydroxyl groups 10 aryl, amino-substituted C6-C 10 Aryl, Replacement C6-C 10 aryl groups, 6-10 heteroaryl groups substituted with one or more hydroxyl groups, and aryl groups substituted with one or more R groups a-3 Substituted 6-10 heteroaryl, C6-C 10 aryl, with one or more R a-1 The C6-C substituent is substituted and "at least one of the substituents is a halogen or a C1-C6 alkyl group". 10 aryl, with one or more R a-2 Substituted C4-C8 cycloalkyl and C6-C 10 aryl or aryl group or one or more R a-4 Replacement C6-C 10 The aryl group; wherein the heteroatom in the 6-10 membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0074] R B It can be H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl, C4-C6 alkoxy, or Y. 1 ;

[0075] Y 1 For one or more The substituted heteroatom is a 3-10 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms, and is substituted by one or more R... 11 Substituted C1-C6 alkoxy groups, unsubstituted or R 12 The substituted heteroatom is a 4-10 membered heterocyclic alkyl group selected from N or O, with 1-3 heteroatoms, and is substituted by one or more R... 14 Substituted amino groups, -OR 13 C6-C substituted with one hydroxyl group 10 aryl, R 15 Substituted C1-C6 alkyl groups, R 16 Substituted C1-C6 thio groups or R 17 Replacement C3-C 10 cycloalkyl;

[0076] R Y1 and R Y2 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0077] for

[0078] M 1 It can be N, CH, or P (=O);

[0079] Ring B is an unsubstituted 4-10 membered heterocyclic alkyl group consisting of 1-3 heteroatoms or heterogroups selected from N and P (=O), containing only 1 N atom, and bounded by R. 10 The substituted heteroatoms or heterogroups are selected from N and P (=O), and the number of heteroatoms or heterogroups is 1-3, containing only 1 N atom. These are 4-10 member heterocyclic alkyl groups, unsubstituted or R-substituted heteroatoms. 7 The substituted heteroatoms are 5-6 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms; unsubstituted or R-substituted heterocyclic alkyl groups. 7 The substituted heteroatoms are 7-12 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms. Or an unsubstituted 4-10 membered heterocyclic alkenyl group whose heteroatoms or heterogroups are selected from N and P (=O) and the number of heteroatoms or heterogroups is 1-3; one N atom of the 7-12 membered heterocyclic alkyl group is attached to ring 2;

[0080] R 7 -(CH2) m -CN, -C(=O)(CH2) n NH2, -C(=O)O-(C1-C4 alkyl), C1-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN; m is 0, 1, or 2; n is 1, 2, or 3;

[0081] R 10 Amino or

[0082] R 11 Independently halogen, Cyano, unsubstituted or R 11-6 Replacement C3-C 12 Cycloalkyl, unsubstituted or with one or more R 11-5 Substituted C1-C6 alkoxy groups, unsubstituted or substituted with one or more R groups 11-3 The substituted heteroatom is selected from N and O, and the number of heteroatoms is 1-3. It is a 4-10 membered heterocyclic alkyl group, unsubstituted or substituted with one or more R atoms. 11-4 The substituted heteroaryl group is a 5-6 member heteroaryl group whose heteroatoms are selected from N and O and the number of heteroatoms is 1-3, or a 4-10 member heterocyclic alkyl group whose heteroatoms are selected from N and S and the number of heteroatoms is 1-3.

[0083] R 11-5 Independently, it is a 4-10 membered heterocyclic alkyl group; wherein the heteroatom in the 4-10 membered heterocyclic alkyl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0084] R 11-1 and R 11-2 Independently H, unsubstituted or by one or more R 11-1-1 Substituted C1-C6 alkyl groups

[0085] R 11-3 For H, Cyano, C2-C6 acetylene, C3-C 12 Cycloalkyl, C1-C6 alkoxy, halogen, unsubstituted or C1-C6 substituted 4-10 member heterocyclic alkyl, C1-C6 alkyl, R 11-3-1 Substituted C1-C6 alkyl groups or R 11-3-2 Substituted C1-C6 alkoxy groups;

[0086] R 11-4 It is a C1-C6 alkyl group;

[0087] R 11-6 For not replaced or by R 11-6-1 Substituted C1-C6 alkyl groups;

[0088] R 11-6-1 For not replaced or by R 11-6-1-1The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3. This refers to 4-10 membered heterocyclic alkyl groups or...

[0089] R 11-6-2 and R 11-6-3 Independently H or C1-C6 alkyl;

[0090] R 11-6-1-1 Independently H or C1-C6 alkyl;

[0091] R 11-1-1 For -OH, by R L The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0092] R 11-3-1 For C3-C 12 cycloalkyl, Or not replaced or by R 11-3-1-1 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0093] R 11-3-1-1 Independently H, or C1-C6 alkyl;

[0094] R 11-3-1-2 Independently

[0095] R 11-3-1-2-1 and R 11-3-1-2-2 Independently H or C1-C6 alkyl;

[0096] R 11-3-2 For C1-C 12 alkenyl;

[0097] R L For H or

[0098] R a-1 Independently hydroxyl, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, unsubstituted or with one or more R a-1-1 Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R a-1-2 Substituted C1-C6 alkyl groups;

[0099] R a-2 Independently hydroxyl or C1-C6 alkyl;

[0100] R a-1-1 Halogens are independent of each other;

[0101] R a-1-2Halogens are independent of each other;

[0102] R a-3 It is a C1-C6 alkyl group;

[0103] R a-4 for

[0104] R 12 It is a C1-C6 alkyl group;

[0105] R 13 H, C1-C6 alkyl, Or be R 13-1 Substituted C3-C6 cycloalkyl groups;

[0106] R 13-1 for Or be R 13-1-3 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0107] R 13-1-1 and R 13-1-2 Independently H, C1-C6 alkyl;

[0108] R 13-1-3 Independently H, C1-C6 alkyl;

[0109] R 14 For not replaced or by Substituted C1-C6 alkyl groups;

[0110] R 14-1-1 and R 14-1-2 Independently H, C1-C6 alkyl;

[0111] R 15 for

[0112] R 15-1-1 and R 15-1-2 Independently H, C1-C6 alkyl;

[0113] R 16 for

[0114] R 16-1 and R 16-2 Independently H or C1-C6 alkyl;

[0115] R 17 for

[0116] R 17-1 and R 17-2 Independently H or C1-C6 alkyl;

[0117] Ring C is unsubstituted or replaced by R 9 The substituted heteroatoms or heterogroups are selected from N and S (=O), and the number of heteroatoms or heterogroups is 1-3; and M 2 S (=O);

[0118] R 9 for

[0119] R 9-1 and R 9-2 It can be independently H, C1-C3 alkyl, C4-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN;

[0120] R 1 and R 4 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0121] R 2 R 3 and R 5 Independently -(CH2) n -R 2a Or 6-10 membered heterocyclic alkyl groups;

[0122] n is 1, 2, 3 or 4;

[0123] R 2a It can be H, -OH, -O-(C1-C3 alkyl), -O-(C4-C6 alkyl) or

[0124] R 2a-1 and R 2a-2 It can be independently H, -C(=O)CH3, C1-C3 alkyl, or C4-C6 alkyl;

[0125] When ring 1 is independently pyridine, R B for

[0126] In one embodiment, the quinazoline compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound,

[0127]

[0128] Wherein, ring 1 and ring 2 are independently C5-C6 aryl, 5-6-membered heteroaryl (heteroatoms selected from one or more of N, O, and S, with 1-3 heteroatoms), C4-C8 cycloalkyl, or 4-8-membered heterocycloalkyl (heteroatoms selected from one or more of N, O, S, B, and P, with 1-4 heteroatoms); (ring 1 and ring 2 are fused together).

[0129] p1 and p2 are independently 1, 2, 3, 4 or 5;

[0130] R A The radicals are H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl, and C4-C6 alkoxy.

[0131] R a C6-C substituted with one or more hydroxyl groups 10 aryl, amino-substituted C6-C 10 Aryl, Replacement C6-C 10 aryl groups, 6-10 heteroaryl groups substituted with one or more hydroxyl groups, and aryl groups substituted with one or more R groups a-3 Substituted 6-10 heteroaryl, C6-C 10 aryl, with one or more R a-1 The C6-C substituent is substituted and "at least one of the substituents is a halogen or a C1-C6 alkyl group". 10 aryl or aryl group or one or more R a-2 Substituted C4-C8 cycloalkyl and C6-C 10 The aryl group; wherein the heteroatom in the 6-10 membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0132] R B It can be H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl, C4-C6 alkoxy, or Y. 1 ;

[0133] Y 1 For one or more The substituted heteroatom is a 3-10 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms, and is substituted by one or more R... 11 Substituted C1-C6 alkoxy groups, unsubstituted or R 12 The substituted heteroatom is a 4-10 membered heterocyclic alkyl group selected from N or O, with 1-3 heteroatoms, and is substituted by one or more R... 14 Substituted amino groups, -OR 13 C6-C substituted with one hydroxyl group 10 aryl, R15 Substituted C1-C6 alkyl groups, R 16 Substituted C1-C6 thio groups or R 17 Replacement C3-C 10 cycloalkyl;

[0134] R Y1 and R Y2 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0135] for

[0136] M 1 It can be N, CH, or P (=O);

[0137] Ring B is an unsubstituted 4-10 membered heterocyclic alkyl group consisting of 1-3 heteroatoms or heterogroups selected from N and P (=O), containing only 1 N atom, and bounded by R. 10 The substituted heteroatoms or heterogroups are selected from N and P (=O), and the number of heteroatoms or heterogroups is 1-3, containing only 1 N atom. These are 4-10 member heterocyclic alkyl groups, unsubstituted or R-substituted heteroatoms. 7 The substituted heteroatoms are 5-6 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms; unsubstituted or R-substituted heterocyclic alkyl groups. 7 The substituted heteroatoms are 7-12 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms. Or an unsubstituted 4-10 membered heterocyclic alkenyl group whose heteroatoms or heterogroups are selected from N and P (=O) and the number of heteroatoms or heterogroups is 1-3; one N atom of the 7-12 membered heterocyclic alkyl group is attached to ring 2;

[0138] R 7 -(CH2) m -CN, -C(=O)(CH2) n NH2, -C(=O)O-(C1-C4 alkyl), C1-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN; m is 0, 1, or 2; n is 1, 2, or 3;

[0139] R 10 Amino or

[0140] R 11 Independently halogen, Cyano, unsubstituted or R 11-6 Replacement C3-C 12Cycloalkyl, unsubstituted or with one or more R 11-5 Substituted C1-C6 alkoxy groups, unsubstituted or substituted with one or more R groups 11-3 The substituted heteroatom is selected from N and O, and the number of heteroatoms is 1-3. It is a 4-10 membered heterocyclic alkyl group, unsubstituted or substituted with one or more R atoms. 11-4 The substituted heteroaryl group is a 5-6 member heteroaryl group whose heteroatoms are selected from N and O and the number of heteroatoms is 1-3, or a 4-10 member heterocyclic alkyl group whose heteroatoms are selected from N and S and the number of heteroatoms is 1-3.

[0141] R 11-5 Independently, it is a 4-10 membered heterocyclic alkyl group; wherein the heteroatom in the 4-10 membered heterocyclic alkyl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0142] R 11-1 and R 11-2 Independently H, unsubstituted or by one or more R 11-1-1 Substituted C1-C6 alkyl groups

[0143] R 11-3 For H, Cyano, C2-C6 acetylene, C3-C 12 Cycloalkyl, C1-C6 alkoxy, halogen, unsubstituted or C1-C6 substituted 4-10 member heterocyclic alkyl, C1-C6 alkyl or R 11-3-1 Substituted C1-C6 alkyl groups;

[0144] R 11-4 It is a C1-C6 alkyl group;

[0145] R 11-6 For not replaced or by R 11-6-1 Substituted C1-C6 alkyl groups;

[0146] R 11-6-1 For not replaced or by R 11-6-1-1 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3. This refers to 4-10 membered heterocyclic alkyl groups or...

[0147] R 11-6-2 and R 11-6-3 Independently H or C1-C6 alkyl;

[0148] R 11-6-1-1 Independently H or C1-C6 alkyl;

[0149] R 11-1-1 For -OH, by R L The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0150] R 11-3-1 For C3-C 12 cycloalkyl, Or not replaced or by R 11-3-1-1 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0151] R 11-3-1-1 Independently H, or C1-C6 alkyl;

[0152] R 11-3-1-2 Independently

[0153] R 11-3-1-2-1 and R 11-3-1-2-2 Independently H or C1-C6 alkyl;

[0154] R L For H or

[0155] R a-1 Independently hydroxyl, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, unsubstituted or with one or more R a-1-1 Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R a-1-2 Substituted C1-C6 alkyl groups;

[0156] R a-2 Independently hydroxyl or C1-C6 alkyl;

[0157] R a-1-1 Halogens are independent of each other;

[0158] R a-1-2 Halogens are independent of each other;

[0159] R a-3 It is a C1-C6 alkyl group;

[0160] R 12 It is a C1-C6 alkyl group;

[0161] R 13 H, C1-C6 alkyl, Or be R 13-1 Substituted C3-C6 cycloalkyl groups;

[0162] R 13-1 for Or be R 13-1-3 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0163] R 13-1-1 and R 13-1-2 Independently H, C1-C6 alkyl;

[0164] R 13-1-3 Independently H, C1-C6 alkyl;

[0165] R 14 For not replaced or by Substituted C1-C6 alkyl groups;

[0166] R 14-1-1 and R 14-1-2 Independently H, C1-C6 alkyl;

[0167] R 15 for

[0168] R 15-1-1 and R 15-1-2 Independently H, C1-C6 alkyl;

[0169] R 16 for

[0170] R 16-1 and R 16-2 Independently H or C1-C6 alkyl;

[0171] R 17 for

[0172] R 17-1 and R 17-2 Independently H or C1-C6 alkyl;

[0173] Ring C is unsubstituted or replaced by R 9 The substituted heteroatoms or heterogroups are selected from N and S (=O), and the number of heteroatoms or heterogroups is 1-3; and M 2 S (=O);

[0174] R 9 for

[0175] R 9-1 and R 9-2 It can be independently H, C1-C3 alkyl, C4-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN;

[0176] R 1 and R 4 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0177] R 2R 3 and R 5 Independently -(CH2) n -R 2a Or 6-10 membered heterocyclic alkyl groups;

[0178] n is 1, 2, 3 or 4;

[0179] R 2a It can be H, -OH, -O-(C1-C3 alkyl), -O-(C4-C6 alkyl) or

[0180] R 2a-1 and R 2a-2 It can be independently H, -C(=O)CH3, C1-C3 alkyl, or C4-C6 alkyl;

[0181] When ring 1 is independently pyridine, R B for

[0182] In one particular scheme, R a for The asterisk (*) indicates that the location is a carbon atom with a chiral center. Indicates that it is Or a mixture thereof.

[0183] In one particular scheme, R a for

[0184]

[0185]

[0186] In one particular scheme, R A In this context, the halogen is preferably R. A For F and Cl.

[0187] In one particular scheme, R A In this context, the C1-C3 alkyl group is preferably methyl.

[0188] In one particular scheme, R is 11-3-2 In the substituted C1-C6 alkoxy group, the C1-C6 alkoxy group can be methoxy, ethoxy, or propoxy, with propoxy being preferred.

[0189] In one particular scheme, R 11-3-2 In this context, the material is C2-C6 alkenyl ethylene, propylene, n-butene, or isobutene, preferably ethylene.

[0190] In one particular scheme, R 11 In this context, the "heteroatoms are selected from N and O, and the number of heteroatoms or heterogroups is 1-3" refers to 4-10 membered heterocyclic alkyl groups; preferably, the "heteroatoms or heterogroups are selected from N and O, and the number of heteroatoms or heterogroups is 1-2" refers to 4-8 membered heteromonocyclic alkyl groups (e.g., "Heteroatoms or heterogroups are selected from N and O, and the number of heteroatoms or heterogroups is 1-2" 4-8 member heterobridged cycloalkyl groups (e.g. ) or "Heteroatoms or heterogroups are selected from N and O, and the number of heteroatoms or heterogroups is 1-2" 4-8 member heterospirocycloalkyl (e.g. ) or "Heteroatoms or heterogroups are selected from N and O, and the number of heteroatoms or heterogroups is 1-2" 9-10 membered heterocyclic alkyl groups (e.g. ); More preferably

[0191] In one particular scheme, R 11 In this context, the "heteroatoms are selected from N and O, and the number of heteroatoms or heterogroups is 1-3" refers to 4-10 membered heterocyclic alkyl groups; preferably, the "heteroatoms or heterogroups are selected from N and O, and the number of heteroatoms or heterogroups is 1-2" refers to 4-8 membered heteromonocyclic alkyl groups (e.g., "Heteroatoms or heterogroups are selected from N and O, and the number of heteroatoms or heterogroups is 1-2" 4-8 member heterobridged cycloalkyl groups (e.g. ) or "Heteroatoms or heterogroups are selected from N and O, and the number of heteroatoms or heterogroups is 1-2" 4-8 member heterospirocycloalkyl (e.g. ) or "Heteroatoms or heterogroups are selected from N and O, and the number of heteroatoms or heterogroups is 1-2" 9-10 membered heterocyclic alkyl groups (e.g. More

[0192] In one particular scheme, R is 11 The substituted C1-C6 alkoxy group can be

[0193]

[0194]

[0195]

[0196] In one of the schemes, Y 1 for

[0197]

[0198]

[0199]

[0200]

[0201] In one particular scheme, R is 11 The substituted C1-C6 alkoxy group can be

[0202]

[0203]

[0204]

[0205]

[0206]

[0207] In one of the schemes, Y 1 for

[0208]

[0209]

[0210]

[0211]

[0212]

[0213] In one embodiment, the quinazoline compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound,

[0214]

[0215] Wherein, ring 1 and ring 2 are independently C5-C6 aryl, 5-6-membered heteroaryl (heteroatoms selected from one or more of N, O, and S, with 1-3 heteroatoms), C4-C8 cycloalkyl, or 4-8-membered heterocycloalkyl (heteroatoms selected from one or more of N, O, S, B, and P, with 1-4 heteroatoms); (ring 1 and ring 2 are fused together).

[0216] p1 and p2 are independently 1, 2, 3, 4 or 5;

[0217] R A The radicals are H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl, and C4-C6 alkoxy.

[0218] R a C6-C substituted with one or more hydroxyl groups 10 aryl, amino-substituted C6-C 10 Aryl, Replacement C6-C 10 aryl groups, 6-10 heteroaryl groups substituted with one or more hydroxyl groups, and aryl groups substituted with one or more R groups a-3 Substituted 6-10 heteroaryl, C6-C 10 aryl, with one or more R a-1 The C6-C substituent is substituted and "at least one of the substituents is a halogen or a C1-C6 alkyl group". 10 aryl or aryl group or one or more R a-2 Substituted C4-C8 cycloalkyl and C6-C 10 The aryl group; wherein the heteroatom in the 6-10 membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0219] R B It can be H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl, C4-C6 alkoxy, or Y. 1 ;

[0220] Y 1 For one or more The substituted heteroatom is a 3-10 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms, and is substituted by one or more R... 11 Substituted C1-C6 alkoxy groups, unsubstituted or R 12 The substituted heteroatom is a 4-10 membered heterocyclic alkyl group selected from N or O, with 1-3 heteroatoms, and is substituted by one or more R... 14 Substituted amino groups, -OR 13 C6-C substituted with one hydroxyl group 10 aryl, R 15 Substituted C1-C6 alkyl groups, R 16 Substituted C1-C6 thio groups or R 17 Replacement C3-C 10 cycloalkyl;

[0221] R Y1and R Y2 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0222] for

[0223] M 1 It can be N, CH, or P (=O);

[0224] Ring B is an unsubstituted 4-10 membered heterocyclic alkyl group consisting of 1-3 heteroatoms or heterogroups selected from N and P (=O), containing only 1 N atom, and bounded by R. 10 The substituted heteroatoms or heterogroups are selected from N and P (=O), and the number of heteroatoms or heterogroups is 1-3, containing only 1 N atom. These are 4-10 member heterocyclic alkyl groups, unsubstituted or R-substituted heteroatoms. 7 The substituted heteroatoms are 5-6 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms; unsubstituted or R-substituted heterocyclic alkyl groups. 7 The substituted heteroatoms are 7-12 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms. Or an unsubstituted 4-10 membered heterocyclic alkenyl group whose heteroatoms or heterogroups are selected from N and P (=O) and the number of heteroatoms or heterogroups is 1-3; one N atom of the 7-12 membered heterocyclic alkyl group is attached to ring 2;

[0225] R 7 -(CH2) m -CN, -C(=O)(CH2) n NH2, -C(=O)O-(C1-C4 alkyl), C1-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN; m is 0, 1, or 2; n is 1, 2, or 3;

[0226] R 10 Amino or

[0227] R 11 Independently halogen, Cyano, unsubstituted or R 11-6 Replacement C3-C 12 Cycloalkyl, unsubstituted or with one or more R 11-5 Substituted C1-C6 alkoxy groups, unsubstituted or substituted with one or more R groups 11-3 The substituted heteroatom is selected from N and O, and the number of heteroatoms is 1-3. It is a 4-10 membered heterocyclic alkyl group, unsubstituted or substituted with one or more R atoms. 11-4The substituted heteroaryl group is a 5-6 member heteroaryl group whose heteroatoms are selected from N and O and the number of heteroatoms is 1-3, or a 4-10 member heterocyclic alkyl group whose heteroatoms are selected from N and S and the number of heteroatoms is 1-3.

[0228] R 11-5 Independently, it is a 4-10 membered heterocyclic alkyl group; wherein the heteroatom in the 4-10 membered heterocyclic alkyl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0229] R 11-1 and R 11-2 Independently H, unsubstituted or by one or more R 11-1-1 Substituted C1-C6 alkyl groups

[0230] R 11-3 For H, Cyano, C2-C6 acetylene, C3-C 12 Cycloalkyl, C1-C6 alkoxy, halogen, unsubstituted or C1-C6 substituted 4-10 member heterocyclic alkyl, C1-C6 alkyl or R 11-3-1 Substituted C1-C6 alkyl groups;

[0231] R 11-4 It is a C1-C6 alkyl group;

[0232] R 11-6 For not replaced or by R 11-6-1 Substituted C1-C6 alkyl groups;

[0233] R 11-6-1 For not replaced or by R 11-6-1-1 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3. This refers to 4-10 membered heterocyclic alkyl groups or...

[0234] R 11-6-2 and R 11-6-3 Independently H or C1-C6 alkyl;

[0235] R 11-6-1-1 Independently H or C1-C6 alkyl;

[0236] R 11-1-1 For -OH, by R L The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0237] R 11-3-1 For C3-C 12 Cycloalkyl, unsubstituted or R 11-3-1-1 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0238] R 11-3-1-1 Independently H or C1-C6 alkyl;

[0239] R L For H or

[0240] R a-1 Independently hydroxyl, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, unsubstituted or with one or more R a-1-1 Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R a-1-2 Substituted C1-C6 alkyl groups;

[0241] R a-2 Independently hydroxyl or C1-C6 alkyl;

[0242] R a-1-1 Halogens are independent of each other;

[0243] R a-1-2 Halogens are independent of each other;

[0244] R a-3 It is a C1-C6 alkyl group;

[0245] R 12 It is a C1-C6 alkyl group;

[0246] R 13 H, C1-C6 alkyl, Or be R 13-1 Substituted C3-C6 cycloalkyl groups;

[0247] R 13-1 for Or be R 13-1-3 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0248] R 13-1-1 and R 13-1-2 Independently H, C1-C6 alkyl;

[0249] R 13-1-3 Independently H, C1-C6 alkyl;

[0250] R 14 For not replaced or by Substituted C1-C6 alkyl groups;

[0251] R 14-1-1 and R 14-1-2 Independently H, C1-C6 alkyl;

[0252] R 15 for

[0253] R 15-1-1 and R 15-1-2 Independently H, C1-C6 alkyl;

[0254] R 16 for

[0255] R 16-1 and R 16-2 Independently H or C1-C6 alkyl;

[0256] R 17 for

[0257] R 17-1 and R 17-2 Independently H or C1-C6 alkyl;

[0258] Ring C is unsubstituted or replaced by R 9 The substituted heteroatoms or heterogroups are selected from N and S (=O), and the number of heteroatoms or heterogroups is 1-3; and M 2 S (=O);

[0259] R 9 for

[0260] R 9-1 and R 9-2 It can be independently H, C1-C3 alkyl, C4-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN;

[0261] R 1 and R 4 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0262] R 2 R 3 and R 5 Independently -(CH2) n -R 2a Or 6-10 membered heterocyclic alkyl groups;

[0263] n is 1, 2, 3 or 4;

[0264] R 2a It can be H, -OH, -O-(C1-C3 alkyl), -O-(C4-C6 alkyl) or

[0265] R 2a-1 and R2a-2 It can be independently H, -C(=O)CH3, C1-C3 alkyl, or C4-C6 alkyl;

[0266] When ring 1 is independently pyridine, R B for

[0267] In one embodiment, the quinazoline compound of formula I is a compound of formula I-CI.

[0268]

[0269] Among them, R b R c and R d Independently H or halogen;

[0270] W is C;

[0271] G is either C or N;

[0272] X and Z are N;

[0273] In It is a double bond;

[0274] In It is a double bond;

[0275] Y 1 For one or more R 11 Substituted C1-C6 alkoxy groups;

[0276] R 11 Independently for one or more R 11-3 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0277] R 11-3 For R 11-3-1 Substituted C1-C6 alkyl groups;

[0278] R 11-3-1 for

[0279] R 11-3-1-2 Independently

[0280] R 11-3-1-2-1 and R 11-3-1-2-2 It is independently H or C1-C6 alkyl.

[0281] In one particular scheme, R 11-3-1-2-1 and R 11-3-1-2-2It can be H, methyl, ethyl, propyl, n-butyl or tert-butyl independently.

[0282] In a certain scheme, when Y 1 For R 11 When the C1-C6 alkoxy group is substituted, the C1-C6 alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentoxy, isopentoxy, neopentoxy, n-hexyl, isohexyl, neohexyl, etc. (Preferred) )or For example, methoxy, n-propoxy, ethoxy, n-butoxy, isobutoxy, isopentoxy, neopentoxy, n-hexyloxy.

[0283] In one embodiment of the present invention, the quinoline compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound is used.

[0284]

[0285] Wherein, ring 1 and ring 2 are independently C5-C6 aryl, 5-6-membered heteroaryl (heteroatoms selected from one or more of N, O, and S, with 1-3 heteroatoms), C4-C8 cycloalkyl, or 4-8-membered heterocycloalkyl (heteroatoms selected from one or more of N, O, S, B, and P, with 1-4 heteroatoms); (ring 1 and ring 2 are fused together).

[0286] p1 and p2 are independently 1, 2, 3, 4 or 5;

[0287] R A The radicals are H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl, and C4-C6 alkoxy.

[0288] R a C6-C substituted with one or more hydroxyl groups 10 aryl, amino-substituted C6-C 10 aryl groups, 6-10 heteroaryl groups substituted with one or more hydroxyl groups, and aryl groups substituted with one or more R groups a-3 Substituted 6-10 heteroaryl, C6-C 10 aryl, with one or more R a-1 The C6-C substituent is substituted and "at least one of the substituents is a halogen or a C1-C6 alkyl group". 10 aryl or aryl group or one or more R a-2 Substituted C4-C8 cycloalkyl and C6-C 10The aryl group; wherein the heteroatom in the 6-10 membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0289] R B It can be H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl, C4-C6 alkoxy, or Y. 1 ;

[0290] Y 1 For one or more The substituted heteroatom is a 3-10 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms, and is substituted by one or more R... 11 Substituted C1-C6 alkoxy groups, unsubstituted or R 12 The substituted heteroatom is a 4-10 membered heterocyclic alkyl group selected from N or O, with 1-3 heteroatoms, and is substituted by one or more R... 14 Substituted amino groups, -OR 13 C6-C substituted with one hydroxyl group 10 aryl, R 15 Substituted C1-C6 alkyl groups, R 16 Substituted C1-C6 thio groups or R 17 Replacement C3-C 10 cycloalkyl;

[0291] R Y1 and R Y2 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0292] for

[0293] M 1 It can be N, CH, or P (=O);

[0294] Ring B is an unsubstituted 4-10 membered heterocyclic alkyl group consisting of 1-3 heteroatoms or heterogroups selected from N and P (=O), containing only 1 N atom, and bounded by R. 10 The substituted heteroatoms or heterogroups are selected from N and P (=O), and the number of heteroatoms or heterogroups is 1-3, containing only 1 N atom. These are 4-10 member heterocyclic alkyl groups, unsubstituted or R-substituted heteroatoms. 7 The substituted heteroatoms are 5-6 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms; unsubstituted or R-substituted heterocyclic alkyl groups. 7 The substituted heteroatoms are 7-12 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms. Or an unsubstituted 4-10 membered heterocyclic alkenyl group whose heteroatoms or heterogroups are selected from N and P (=O) and the number of heteroatoms or heterogroups is 1-3; one N atom of the 7-12 membered heterocyclic alkyl group is attached to ring 2;

[0295] R 7 -(CH2) m -CN, -C(=O)(CH2) n NH2, -C(=O)O-(C1-C4 alkyl), C1-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN; m is 0, 1, or 2; n is 1, 2, or 3;

[0296] R 10 Amino or

[0297] R 11 Independently halogen, Cyano, R 11-6 Replacement C3-C 12 Cycloalkyl, unsubstituted or with one or more R 11-5 Substituted C1-C6 alkoxy groups, unsubstituted or substituted with one or more R groups 11-3 The substituted heteroatom is selected from N and O, and the number of heteroatoms is 1-3. It is a 4-10 membered heterocyclic alkyl group, unsubstituted or substituted with one or more R atoms. 11-4 The substituted heteroaryl group is a 5-6 member heteroaryl group whose heteroatoms are selected from N and O and the number of heteroatoms is 1-3, or a 4-10 member heterocyclic alkyl group whose heteroatoms are selected from N and S and the number of heteroatoms is 1-3.

[0298] R 11-5 Independently, it is a 4-10 membered heterocyclic alkyl group; wherein the heteroatom in the 4-10 membered heterocyclic alkyl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0299] R 11-1 and R 11-2 Independently H, unsubstituted or by one or more R 11-1-1 Substituted C1-C6 alkyl groups

[0300] R 11-3 For H, Cyano, C2-C6 acetylene, C3-C 12 Cycloalkyl, C1-C6 alkoxy, halogen, unsubstituted or C1-C6 substituted 4-10 member heterocyclic alkyl, C1-C6 alkyl or R 11-3-1 Substituted C1-C6 alkyl groups;

[0301] R 11-4It is a C1-C6 alkyl group;

[0302] R 11-6 For not replaced or by R 11-6-1 Substituted C1-C6 alkyl groups;

[0303] R 11-6-1 The heteroatoms are selected from N and O, and the number of heteroatoms is 1-3. This refers to 4-10 membered heterocyclic alkyl groups or...

[0304] R 11-6-2 and R 11-6-3 Independently H or C1-C6 alkyl;

[0305] R 11-1-1 For -OH, by R L The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0306] R 11-3-1 For C3-C 12 cycloalkyl;

[0307] R L For H or

[0308] R a-1 Independently hydroxyl, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, unsubstituted or with one or more R a-1-1 Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R a-1-2 Substituted C1-C6 alkyl groups;

[0309] R a-2 Independently hydroxyl or C1-C6 alkyl;

[0310] R a-1-1 Halogens are independent of each other;

[0311] R a-1-2 Halogens are independent of each other;

[0312] R a-3 It is a C1-C6 alkyl group;

[0313] R 12 It is a C1-C6 alkyl group;

[0314] R 13 H, C1-C6 alkyl, Or be R 13-1 Substituted C3-C6 cycloalkyl groups;

[0315] R 13-1 for Or be R 13-1-3 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0316] R 13-1-1 and R 13-1-2 Independently, it is H or a C1-C6 alkyl group;

[0317] R 13-1-3 Independently, it is H or a C1-C6 alkyl group;

[0318] R 14 For not replaced or by Substituted C1-C6 alkyl groups;

[0319] R 14-1-1 and R 14-1-2 Independently, it is H or a C1-C6 alkyl group;

[0320] R 15 for

[0321] R 15-1-1 and R 15-1-2 Independently, it is H or a C1-C6 alkyl group;

[0322] R 16 for

[0323] R 16-1 and R 16-2 Independently H or C1-C6 alkyl;

[0324] R 17 for

[0325] R 17-1 and R 17-2 Independently H or C1-C6 alkyl;

[0326] Ring C is unsubstituted or replaced by R 9 The substituted heteroatom or heterogroup is selected from N and S (=O), and the number of heteroatoms or heterogroups is 1-3; and M 2 S (=O);

[0327] R 9 for

[0328] R 9-1 and R 9-2 It can be independently H, C1-C3 alkyl, C4-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN;

[0329] R1 and R 4 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0330] R 2 R 3 and R 5 Independently -(CH2) n -R 2a Or 6-10 membered heterocyclic alkyl groups;

[0331] n is 1, 2, 3 or 4;

[0332] R 2a It can be H, -OH, -O-(C1-C3 alkyl), -O-(C4-C6 alkyl) or

[0333] R 2a-1 and R 2a-2 It can be independently H, -C(=O)CH3, C1-C3 alkyl, or C4-C6 alkyl;

[0334] When ring 1 is independently pyridine, R B for

[0335]

[0336] In one embodiment of the present invention, the quinazoline compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound may be used.

[0337]

[0338] Wherein, ring 1 and ring 2 are independently C5-C6 aryl, 5-6 heteroaryl (with one or more heteroatoms selected from N, O, and S, and the number of heteroatoms being 1-3), C4-C8 cycloalkyl, or 4-8 heterocycloalkyl (with one or more heteroatoms selected from N, O, S, B, and P, and the number of heteroatoms being 1-4); (ring 1 and ring 2 are fused together).

[0339] p1 and p2 are independently 1, 2, 3, 4 or 5;

[0340] R A The radicals are H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl, and C4-C6 alkoxy.

[0341] R a C6-C substituted with one or more hydroxyl groups 10 aryl groups, 6-10 heteroaryl groups substituted with one or more hydroxyl groups, and aryl groups substituted with one or more R groupsa-3 Substituted 6-10 heteroaryl, C6-C 10 aryl or aryl group or one or more R a-1 The C6-C substituent is substituted and "at least one of the substituents is a halogen or a C1-C6 alkyl group". 10 aryl or aryl group or one or more R a-2 Substituted C4-C8 cycloalkyl and C6-C 10 The aryl group; wherein the heteroatom in the 6-10 membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0342] R B It can be H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl, C4-C6 alkoxy, or Y. 1 ;

[0343] Y 1 For one or more The substituted heteroatom is a 3-10 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms, and is substituted by one or more R... 11 Substituted C1-C6 alkoxy groups, unsubstituted or R 12 The substituted heteroatom is a 4-10 membered heterocyclic alkyl group selected from N or O, with 1-3 heteroatoms, and is substituted by one or more R... 14 Substituted amino groups, -OR 13 C6-C substituted with one hydroxyl group 10 aryl, R 15 Substituted C1-C6 alkyl groups, R 16 Substituted C1-C6 thio groups or R 17 Replacement C3-C 10 cycloalkyl;

[0344] R Y1 and R Y2 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0345] for

[0346] M 1 It can be N, CH, or P (=O);

[0347] Ring B is an unsubstituted 4-10 membered heterocyclic alkyl group consisting of 1-3 heteroatoms or heterogroups selected from N and P (=O), containing only 1 N atom, and bounded by R. 10The substituted heteroatoms or heterogroups are selected from N and P (=O), and the number of heteroatoms or heterogroups is 1-3, containing only 1 N atom. These are 4-10 member heterocyclic alkyl groups, unsubstituted or R-substituted heteroatoms. 7 The substituted heteroatoms are 5-6 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms; unsubstituted or R-substituted heterocyclic alkyl groups. 7 The substituted heteroatoms are 7-12 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms. Or an unsubstituted 4-10 membered heterocyclic alkenyl group whose heteroatoms or heterogroups are selected from N and P (=O) and the number of heteroatoms or heterogroups is 1-3; one N atom of the 7-12 membered heterocyclic alkyl group is attached to ring 2;

[0348] R 7 -(CH2) m -CN, -C(=O)(CH2) n NH2, -C(=O)O-(C1-C4 alkyl), C1-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN; m is 0, 1, or 2; n is 1, 2, or 3;

[0349] R 10 Amino or

[0350] R 11 Independently halogen, Cyano, unsubstituted or with one or more R 11-5 Substituted C1-C6 alkoxy groups, unsubstituted or substituted with one or more R groups 11-3 The substituted heteroatom is selected from N and O, and the number of heteroatoms is 1-3. It is a 4-10 membered heterocyclic alkyl group, unsubstituted or substituted with one or more R atoms. 11-4 The substituted heteroaryl group is a 5-6 member heteroaryl group whose heteroatoms are selected from N and O and the number of heteroatoms is 1-3, or a 4-10 member heterocyclic alkyl group whose heteroatoms are selected from N and S and the number of heteroatoms is 1-3.

[0351] R 11-5 Independently, it is a 4-10 membered heterocyclic alkyl group; wherein the heteroatom in the 4-10 membered heterocyclic alkyl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0352] R 11-1 and R 11-2 Independently H, unsubstituted or by one or more R 11-1-1 Substituted C1-C6 alkyl groups

[0353] R 11-3 For H, Cyanoyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, unsubstituted or C1-C6 substituted 4-10 member heterocyclic alkyl or C1-C6 alkyl;

[0354] R 11-4 It is a C1-C6 alkyl group;

[0355] R 11-1-1 For -OH, by R L The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0356] R L For H or

[0357] R a-1 Independently hydroxyl, halogen, C1-C6 alkyl, unsubstituted or modified by one or more R a-1-1 Substituted C2-C6 ynyl group, C3-C 12 cycloalkyl, with one or more R a-1-2 Substituted C1-C6 alkyl groups;

[0358] R a-2 Independently hydroxyl or C1-C6 alkyl;

[0359] R a-1-1 Halogens are independent of each other;

[0360] R a-1-2 Halogens are independent of each other;

[0361] R a-3 It is a C1-C6 alkyl group;

[0362] R 12 It is a C1-C6 alkyl group;

[0363] R 13 H, C1-C6 alkyl, Or be R 13-1 Substituted C3-C6 cycloalkyl groups;

[0364] R 13-1 for

[0365] R 13-1-1 and R 13-1-2 Independently, it is H or a C1-C6 alkyl group;

[0366] R 14 For not replaced or by Substituted C1-C6 alkyl groups;

[0367] R 14-1-1 and R 14-1-2Independently H, C1-C6 alkyl;

[0368] R 15 for

[0369] R 15-1-1 and R 15-1-2 Independently H, C1-C6 alkyl;

[0370] R 16 for

[0371] R 16-1 and R 16-2 Independently H or C1-C6 alkyl;

[0372] R 17 for

[0373] R 17-1 and R 17-2 Independently H or C1-C6 alkyl;

[0374] Ring C is unsubstituted or replaced by R 9 The substituted heteroatoms or heterogroups are selected from N and S (=O), and the number of heteroatoms or heterogroups is 1-3; and M 2 S (=O);

[0375] R 9 for

[0376] R 9-1 and R 9-2 It can be independently H, C1-C3 alkyl, C4-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN;

[0377] R 1 and R 4 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0378] R 2 R 3 and R 5 Independently -(CH2) n -R 2a Or 6-10 membered heterocyclic alkyl groups;

[0379] n is 1, 2, 3 or 4;

[0380] R 2a It can be H, -OH, -O-(C1-C3 alkyl), -O-(C4-C6 alkyl) or

[0381] R 2a-1 and R 2a-2 It can be independently H, -C(=O)CH3, C1-C3 alkyl, or C4-C6 alkyl;

[0382] When ring 1 is independently pyridine, R B for

[0383]

[0384] In one embodiment, the quinazoline compound as described in Formula I is,

[0385]

[0386] Wherein, ring 1 and ring 2 are independently C5-C6 aryl, 5-6-membered heteroaryl (heteroatoms selected from one or more of N, O, and S, with 1-3 heteroatoms), C4-C8 cycloalkyl, or 4-8-membered heterocycloalkyl (heteroatoms selected from one or more of N, O, S, B, and P, with 1-4 heteroatoms); (ring 1 and ring 2 are fused together).

[0387] p1 and p2 are independently 1, 2, 3, 4 or 5;

[0388] R A It can be H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl or C4-C6 alkoxy;

[0389] R a C6-C substituted with one or more hydroxyl groups 10 aryl, 6-10 heteroaryl groups substituted with one or more hydroxyl groups, C6-C 10 aryl, with one or more R a-1 The C6-C substituent is substituted and "at least one of the substituents is a halogen or a C1-C6 alkyl group". 10 The aryl group; wherein the heteroatom in the 6-10 membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0390] R B It can be H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C4-C6 alkyl, C4-C6 alkoxy, or Y. 1 ;

[0391] Y 1 For one or more The substituted heteroatom is a 3-10 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms, and is substituted by one or more R... 11Substituted C1-C6 alkoxy groups, unsubstituted or R 12 The substituted heteroatom is a 4-10 membered heterocyclic alkyl group selected from N or O, with 1-3 heteroatoms, and is substituted by one or more R... 14 Substituted amino groups, -OR 13 C6-C substituted with one hydroxyl group 10 aryl, R 15 Substituted C1-C6 alkyl groups, R 16 Substituted C1-C6 thio groups or R 17 Replacement C3-C 10 cycloalkyl;

[0392] R Y1 and R Y2 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0393] for

[0394] M 1 It can be N, CH, or P (=O);

[0395] Ring B is an unsubstituted 4-10 membered heterocyclic alkyl group consisting of 1-3 heteroatoms or heterogroups selected from N and P (=O), containing only 1 N atom, and bounded by R. 10 The substituted heteroatoms or heterogroups are selected from N and P (=O), and the number of heteroatoms or heterogroups is 1-3, containing only 1 N atom. These are 4-10 membered heterocyclic alkyl groups, unsubstituted or R-substituted. 7 The substituted heteroatoms are 5-6 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms; unsubstituted or R-substituted heterocyclic alkyl groups. 7 The substituted heteroatoms are 7-12 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms. One N atom in the 7-12 membered heterocyclic alkyl group is attached to ring 2;

[0396] R 7 -C(=O)O-(C1-C4 alkyl), C1-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN;

[0397] R 10 Amino or

[0398] R 11 Independently halogen, Not replaced or by one or more R 11-3The substituted heteroatom is selected from N and O, and the number of heteroatoms is 1-3. It is a 4-10 membered heterocyclic alkyl group, either unsubstituted or substituted with one or more R atoms. 11-4 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3. The heterocyclic aryl group is a 5-6 member.

[0399] R 11-1 and R 11-2 Independently H, unsubstituted or R 11-1-1 Substituted C1-C6 alkyl groups

[0400] R 11-3 For H, Halogens, unsubstituted or C1-C6 substituted 4-10 membered heterocyclic alkyl groups or C1-C6 alkyl groups;

[0401] R 11-4 It is a C1-C6 alkyl group;

[0402] R 11-1-1 For R L The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0403] R L For H or

[0404] R a-1 It can be independently a hydroxyl group, a halogen, or a C1-C6 alkyl group;

[0405] R 12 It is a C1-C6 alkyl group;

[0406] R 13 H, C1-C6 alkyl, Or be R 13-1 Substituted C3-C6 cycloalkyl groups;

[0407] R 13-1 for

[0408] R 13-1-1 and R 13-1-2 Independently H, C1-C6 alkyl;

[0409] R 14 For not replaced or by Substituted C1-C6 alkyl groups;

[0410] R 14-1-1 and R 14-1-2 Independently H, C1-C6 alkyl;

[0411] R 15 for

[0412] R 15-1-1 and R 15-1-2 Independently H, C1-C6 alkyl;

[0413] R 16 for

[0414] R 16-1 and R 16-2 Independently H or C1-C6 alkyl;

[0415] R 17 for

[0416] R 17-1 and R 17-2 Independently H or C1-C6 alkyl;

[0417] Ring C is unsubstituted or replaced by R 9 The substituted heteroatoms or heterogroups are selected from N and S (=O), and the number of heteroatoms or heterogroups is 1-3; and M 2 S (=O);

[0418] R 9 for

[0419] R 9-1 and R 9-2 It can be independently H, C1-C3 alkyl, C4-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN;

[0420] R 1 and R 4 It can be independently H, C1-C3 alkyl, or C4-C6 alkyl;

[0421] R 2 R 3 and R 5 Independently -(CH2) n -R 2a Or 6-10 membered heterocyclic alkyl groups;

[0422] n is 1, 2, 3 or 4;

[0423] R 2a It can be H, -OH, -O-(C1-C3 alkyl), -O-(C4-C6 alkyl) or

[0424] R 2a-1 and R 2a-2 It can be independently H, -C(=O)CH3, C1-C3 alkyl or C4-C6 alkyl.

[0425] In one embodiment, the quinazoline compound of formula I is a compound of formula I-AI.

[0426]

[0427] Among them, R b R c and R d Independently H or halogen;

[0428] W is C;

[0429] G is either C or N;

[0430] X and Z are N;

[0431] In It can be a single bond or a double bond;

[0432] In It can be a single bond or a double bond.

[0433] In one embodiment, the quinazoline compound of formula I is a compound of formula I-CI.

[0434]

[0435] Among them, R b R c and R d Independently H or halogen;

[0436] W is C;

[0437] G is either C or N;

[0438] X and Z are N;

[0439] In It is a double bond;

[0440] In It is a double bond;

[0441] When ring 1 is independently pyridine, R B for

[0442]

[0443] In one embodiment, the quinazoline compound of formula I is a compound of formula I-CI.

[0444]

[0445] Among them, R b R c and R d Independently H or halogen;

[0446] W is C;

[0447] G is either C or N;

[0448] X and Z are N;

[0449] In It is a double bond;

[0450] In It is a double bond;

[0451] R a For being Replacement C6-C 10 aryl;

[0452] Y 1 For one or more R 11 Substituted C1-C6 alkoxy groups;

[0453] R 11 For not replaced or by R 11-6 Replacement C3-C 12 Cycloalkyl or unsubstituted or with one or more R 11-3 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0454] R 11-6-1 For R 11-6-1-1 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0455] R 11-6-1-1 It is a C1-C6 alkyl group;

[0456] R 11-3-1 For C3-C 12 Cycloalkyl, unsubstituted or R 11-3-1-1 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0457] R 11-3-1-1 It is independently H or C1-C6 alkyl.

[0458] In one embodiment, the quinazoline compound of formula I is a compound of formula I-CI.

[0459]

[0460] Among them, R b R c and R d Independently H or halogen;

[0461] W is C;

[0462] G is either C or N;

[0463] X and Z are N;

[0464] In It is a double bond;

[0465] In It is a double bond;

[0466] R a C6-C substituted with amino group 10 aryl or aryl group or one or more R a-1 The C6-C substituent is substituted and "at least one of the substituents is a halogen or a C1-C6 alkyl group". 10 aryl;

[0467] Y 1 For one or more R 11 Substituted C1-C6 alkoxy or -OR 13 ;

[0468] R 11 Independently for R 11-6 Replacement C3-C 12 Cycloalkyl or unsubstituted or with one or more R 11-3 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0469] R 11-3 For C3-C 12 cycloalkyl, or R 11-3-1 Substituted C1-C6 alkyl groups;

[0470] R 11-6 For not replaced or by R 11-6-1 Substituted C1-C6 alkyl groups;

[0471] R 11-6-1 The heteroatoms are selected from N and O, and the number of heteroatoms is 1-3. This refers to 4-10 membered heterocyclic alkyl groups or...

[0472] R 11-6-2 and R 11-6-3 Independently H or C1-C6 alkyl;

[0473] R 11-3-1For C3-C 12 cycloalkyl;

[0474] R a-1 Independently hydroxyl, halogen, or C3-C 12 cycloalkyl;

[0475] R 13 For R 13-1 Substituted C3-C6 cycloalkyl groups;

[0476] R 13-1 For R 13-1-3 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0477] R 13-1-3 It is independently H or C1-C6 alkyl.

[0478] In one particular scheme, R a In, the C6-C substituted with amino groups 10 The aryl group can be

[0479] In one particular scheme, the Replacement C6-C 10 C6-C in aryl 10 The aryl group is either phenyl or naphthyl.

[0480] In one particular scheme, the unsubstituted C3-C 12 The cycloalkyl group can be cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0481] In one particular scheme, R 11-6-1-1 The C1-C6 alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0482] In one particular scheme, R 11-3-1-1 The C1-C6 alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0483] In one embodiment, in ring B, the 7-12 membered heterocyclic alkyl group that "has heteroatoms selected from one or more of N, O, and S, and has 2-3 heteroatoms" is a C7 monocyclic heterocyclic alkyl group that has "N heteroatoms and has 2 heteroatoms," a 7-12 membered bridged ring heterocyclic alkyl group that "has heteroatoms selected from N and O, has 2-3 heteroatoms, and contains at least 2 N atoms," a 7-12 membered spirocyclic heterocyclic alkyl group that "has N heteroatoms and has 2 heteroatoms," or a 7-12 membered fused ring heterocyclic alkyl group that "has N heteroatoms and has 2 heteroatoms," preferably a 7-12 membered bridged ring heterocyclic alkyl group that "has N heteroatoms and has 2 heteroatoms" or a 7-12 membered spirocyclic heterocyclic alkyl group that "has N heteroatoms and has 2 heteroatoms."

[0484] The preferred C7 monocyclic heterocyclic alkyl group is one with N heteroatoms and two heteroatoms.

[0485] The 7-12 membered bridged heterocyclic alkyl group, wherein the heteroatoms are selected from N and O, the number of heteroatoms is 2-3, and at least 2 N atoms are present, is preferably a 7-9 membered bridged heterocyclic alkyl group (e.g., More preferably, 7-8 membered bridged heterocyclic alkyl groups having "N heteroatom and 2 heteroatoms" (e.g. Further optimization Further optimization

[0486] The 7-17 membered spirocyclic heterocyclic alkyl group having "N as the heteroatom and two heteroatoms" is preferably a 7-10 membered spirocyclic heterocyclic alkyl group having "N as the heteroatom and two heteroatoms" (e.g. Preferred More preferably, 7-10 membered spirocyclic heterocyclic alkyl groups having "N as the heteroatom and two heteroatoms", wherein one ring is a four-membered heterocyclic alkyl group containing "one N atom", for example...

[0487] The 7-12 membered fused-ring heterocyclic alkyl group having "N as the heteroatom and two heteroatoms" is preferably a 7-10 membered fused-ring heterocyclic alkyl group having "N as the heteroatom and two heteroatoms," and more preferably a ternary or hexacyclic heterocyclic alkyl group having "N as the heteroatom and two heteroatoms" (e.g. ), tetra- and six-membered heterocyclic alkyl groups (e.g. ), five-membered and six-membered heterocyclic alkyl groups (e.g. ), hexa- and six-membered heterocyclic alkyl groups (e.g. ) or five-membered pentane-five-membered heterocyclic alkyl groups (e.g.

[0488] In one of the solutions, middle, for

[0489]

[0490] In one of the solutions, for

[0491]

[0492] In a certain scheme, when R 11 For R 11-6 Replacement C3-C 12 In the case of cycloalkyl groups, the C3-C 12 The cycloalkyl group can be cyclopropane, cyclobutane, cyclopentane, or cyclohexane, for example, cyclopropane.

[0493] In a certain scheme, when R 11-3 For C3-C 12 In the case of cycloalkyl groups, the C3-C 12 The cycloalkyl group can be cyclopropane, cyclobutane, cyclopentane, or cyclohexane, for example, cyclopropane.

[0494] In a certain scheme, when R 11-6 For R 11-6-1 When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group may be methyl, ethyl, propyl, n-butyl, or tert-butyl.

[0495] In a certain scheme, when R 11-6-1 When the heteroatom is a 4-10 member heterocyclic alkyl group selected from N and O, and the number of heteroatoms is 1-3, the 4-10 member heterocyclic alkyl group selected from N and O, and the number of heteroatoms is 1-3, can be a 6-9 member monocyclic, fused-ring, bridged-ring, or spirocyclic heterocyclic alkyl group selected from N and O, and the number of heteroatoms is 1-3.

[0496] In a certain scheme, when R 11-6-2 and R 11-6-3 When the alkyl group is C1-C6, the C1-C6 alkyl group can be methyl, ethyl, propyl, n-butyl, or tert-butyl.

[0497] In one particular scheme, R 11-3-1 It can be cyclopropane, cyclobutane, cyclopentane, or cyclohexane, for example, cyclopropane.

[0498] In one particular scheme, R 13-1 For R13-1-3 When the substituted heterocyclic alkyl group is a 4-10 member heterocyclic alkyl group whose heteroatoms are selected from N and O and whose number of heteroatoms is 1-3, the 4-10 member heterocyclic alkyl group whose heteroatoms are selected from N and O and whose number of heteroatoms is 1-3 can be a 6-9 member monocyclic, fused-ring, bridged-ring, or spirocyclic heterocyclic alkyl group whose heteroatoms are selected from N and O and whose number of heteroatoms is 1-3.

[0499] In a certain scheme, when R 11-1-3 When the alkyl group is C1-C6, the C1-C6 alkyl group can be methyl, ethyl, propyl, n-butyl, or tert-butyl.

[0500] In one particular scheme, R 13 for

[0501] In a certain scheme, when R a C6-C substituted with one or more hydroxyl groups 10 When the aryl group is present, the R... a for Indicates that it is Or a mixture thereof.

[0502] In a certain scheme, when R a When the 6-10-membered heteroaryl group is composed of one or more hydroxyl groups, the 6-10-membered heteroaryl group may be... For example, R a for Indicates that it is Or a mixture thereof.

[0503] In a certain scheme, when R a For C6-C 10 When the aryl group is present, the C6-C 10 The aryl group can be Indicates that it is Or a mixture thereof.

[0504] In a certain scheme, when R a For one or more R a-1 The C6-C substituent is a C1-C6 alkyl group that is at least one of the substituents being halogen or C1-C6 alkyl. 10 When the aryl group is present, the C6-C 10 The aryl group can be Indicates that it is Or a mixture thereof.

[0505] In a certain scheme, when R a For one or more R a-3When the 6-10 membered heteroaryl group is substituted, the R a-3 for For example

[0506] In one particular scheme, R a-3 The C1-C6 alkyl group can be methyl, ethyl, propyl, n-butyl, tert-butyl, for example, methyl.

[0507] In a certain scheme, when R a For one or more R a-2 Substituted C4-C8 cycloalkyl and C6-C 10 The aryl group, wherein the C4-C8 cycloalkyl group can be cyclobutane, cyclopentane or cyclohexane, preferably cyclobutane.

[0508] In a certain scheme, by one or more The substituted heterocyclic alkyl group is a 3-10 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms.

[0509] In a certain scheme, it is controlled by one or more The substituted heterocyclic alkyl group consisting of 3-10 members and having one or more heteroatoms selected from N, O, and S, with 1-4 heteroatoms, is considered a substituted heterocyclic alkyl group.

[0510] In one particular scheme, R Y1 and R Y2 In this context, the C1-C6 alkyl group can be methyl, ethyl, n-propyl, or isopropyl, with methyl being preferred.

[0511] In a certain scheme, it is not replaced or is replaced by R. 12 The substituted heterocyclic alkyl group consisting of 4-10 members, with 1-3 heteroatoms selected from N or O, can be unsubstituted or replaced by R. 12 The substituted heterocyclic alkyl group is a 6-9 member monocyclic, fused-ring, bridged-ring, or spirocyclic alkyl group having "N as the heteroatom and one or two heteroatoms"; the 4-10 member heterocyclic alkyl group is preferably...

[0512] In a certain scheme, when Y 1 C6-C substituted with one hydroxyl group 10 When the aryl group is present, the C6-C 10 The aryl group can be

[0513] In a certain scheme, when Y 1 C6-C substituted with one hydroxyl group10 When the aryl group is present, the Y 1 for

[0514] In one particular scheme, R is 15 In the substituted C1-C6 alkyl group, the C1-C6 alkyl group may be methyl, ethyl, n-propyl, or isopropyl.

[0515] In one particular scheme, R is 16 In the substituted C1-C6 thio group, the C1-C6 thio group may be methylthio, ethylthio, n-propylthio, or isopropylthio.

[0516] In one particular scheme, R is 17 Replacement C3-C 10 In cycloalkyl groups, the C3-C 10 The cycloalkyl group can be cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0517] In one embodiment, the 4-10 membered heterocyclic alkyl group in ring B, characterized by "heteroatoms or heterogroups selected from N and P (=O), with 1-3 heteroatoms or heterogroups, and containing only 1 N atom," can be... Azahexacyclic butanes (e.g.) ), tetrahydropyrrole or piperidinyl (e.g.) ).

[0518] In one scheme, within ring B, the object R is... 10 The substituted 4-10 membered heterocyclic alkyl groups, characterized by "heteroatoms or heteroatomic groups selected from N and P (=O), with 1-3 heteroatoms or heteroatomic groups and containing only 1 N," can be: 4-10 membered monocyclic heterocyclic alkyl groups; 4-10 membered bridged ring heterocyclic alkyl groups; or 4-10 membered monocyclic heterocyclic alkyl groups. The number of 4-10 spirocyclic heterocyclic alkyl groups is 1-3, and each contains only 1 N; or the number of 1-3 heteroatoms or heterogroups is 1-3, and each contains only 1 N; preferably, the number of 4-10 monocyclic heterocyclic alkyl groups is 1-3, and each contains only 1 N; or the number of 4-10 bridged heterocyclic alkyl groups is 1-3, and each contains only 1 N.

[0519] The 4-10 member monocyclic heterocyclic alkyl group described as having "heteroatoms or heteroatomic groups selected from N and P (=O), with 1-3 heteroatoms or heteroatomic groups, and containing only 1 N atom" can be a 4-10 member monocyclic heterocyclic alkyl group with "heteroatoms being N and the number of heteroatoms being 1," preferably.

[0520] The 4-10 membered bridged heterocyclic alkyl group, characterized by "heteroatoms or heteroatomic groups selected from N and P (=O), with 1-3 heteroatoms or heteroatomic groups and containing only 1 N atom," can preferably be a 7-10 membered bridged heterocyclic alkyl group, characterized by "the heteroatom being N and the number of heteroatoms being 1." More

[0521] The 4-10 membered spirocyclic heterocyclic alkyl group, wherein the heteroatom or heterogroup is selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and it contains only 1 N atom, is preferably a 7-10 membered spirocyclic heterocyclic alkyl group, wherein the heteroatom is N and the number of heteroatoms is 1.

[0522] The 4-10 member fused-ring heterocyclic alkyl group is selected from N and P (=O), and the number of heteroatoms or heterocyclic groups is 1-3, and it contains only 1 N. The alkyl group is preferably a 4-10 member fused-ring heterocyclic alkyl group with "the heteroatom is N and the number of heteroatoms is 1".

[0523] In one scheme, the R- 10 The substituted heterocyclic alkyl group consisting of 4-10 members, whose heteroatoms or heterogroups are selected from N and P (=O), number 1-3, and containing only 1 N atom, can be used as a substitute.

[0524] In one embodiment, in ring B, the heteroatom or heterogroup is selected from N and P (=O), and the number of heteroatoms or heterogroups is 1-3. A 4-10 membered heterocyclic alkenyl group can be...

[0525] In one embodiment, in ring B, the heteroatom is selected from one or more of N, O, and S, and the 5-6 membered heterocyclic alkyl group having 2-3 heteroatoms can be...

[0526] In one particular scheme, R 7 It can be one or more.

[0527] In one scheme, in ring B, R is... 7 The substituted heterocyclic alkyl group, consisting of 5-6 membered heteroatoms selected from one or more of N, O, and S, with 2-3 heteroatoms, can be...

[0528] In one particular scheme, R 7 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, with methyl being preferred.

[0529] In one particular scheme, R is 7 The substituted heterocyclic alkyl group consisting of 7-12 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms, can be...

[0530] In one of the solutions, middle, for

[0531] In one of the solutions, middle, for Preferred

[0532] In one embodiment, the "heteroatoms selected from N and S, with 1-3 heteroatoms" 4-10 membered heterocyclic alkyl groups can be...

[0533] In a certain scheme, when R 11 For not replaced or by one or more R 11-3 When the substituted heteroatom is selected from N and O, and the number of heteroatoms is 1-3, the substituted 4-10 membered heterocyclic alkyl group is described as R 11 The substituted C1-C6 alkoxy group can be cis, trans, or a mixture thereof.

[0534] In one particular scheme, R 11 In the context, the unsubstituted or unreplaced R... 11-4 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3. 5-6 membered heterocyclic aryl groups can be...

[0535] In one particular scheme, R 11 In this context, the alkoxy group of C1-C6 can be methoxy, ethoxy, isopropoxy, n-butyl, isobutyl, or tert-butyl, with methoxy being preferred.

[0536] In one particular scheme, R 11-5 In the 4-10 membered heterocyclic alkyl group, the heteroatom is selected from one or more of N and O, and the number of heteroatoms is 1-3; preferably pyrrolidinyl or tetrahydrofuranyl.

[0537] In one particular scheme, R is LIn substituted 4-10 membered heterocyclic alkyl groups, the heteroatoms are selected from N and O, and the number of heteroatoms is 1-3.

[0538]

[0539] In one particular scheme, R 11-1 and R 11-2 In, not replaced or by R 11-1-1 In the substituted C1-C6 alkyl group, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or n-butyl.

[0540] In one particular scheme, R 11-3 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, with methyl being preferred.

[0541] In one particular scheme, R 11-3 In the text, the alkynyl group of C2-C6 can be ethynyl, propynyl, 1-butynyl or 2-butynyl, preferably ethynyl, propynyl or 1-butynyl.

[0542] In one particular scheme, R 11-3 In this context, the alkoxy group of C1-C6 can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butyl, or tert-butyl, with methoxy being preferred.

[0543] In one particular scheme, R 11-4 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, preferably methyl or ethyl.

[0544] In one particular scheme, R 11-1-1 Can be

[0545] In one of the solutions, for

[0546] In one particular scheme, R a-1 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, preferably methyl or ethyl.

[0547] In one particular scheme, R a-1 In this context, the halogen is F, Cl, Br, or I, preferably F or Cl.

[0548] In one particular scheme, R a-1 In this context, the C2-C6 ynyl group can be ethynyl, propynyl, 1-butynyl, or 2-butynyl, preferably ethynyl or butynyl.

[0549] In one particular scheme, R a-1 In the context of C3-C 12 Cycloalkyl groups can be C3-C 12 Monocycloalkyl, C3-C 12 Bridged cycloalkyl or C3-C 12 Spirocycloalkyl, preferably C3-C 12 Monocycloalkyl or C3-C 12 Bridged cycloalkyl, preferably cyclopropane or bicyclo[1,1,1]pentane.

[0550] In one particular scheme, R is a-1-2 The C1-C6 alkyl group in the substituted C1-C6 alkyl group can be methyl, ethyl, n-propyl or isopropyl, with methyl being preferred.

[0551] In one particular scheme, R a-1-1 In this context, the halogen is F, Cl, Br, or I, with F being preferred.

[0552] In one particular scheme, R a-1-2 In this context, the halogen is F, Cl, Br, or I, with F being preferred.

[0553] In one particular scheme, R a-1 It can be hydroxyl, methyl, fluorine, chlorine, ethyl, ethynyl, butynyl, cyclopropane, bicyclo[1,1,1]pentyl, -CF3 or fluoroethynyl.

[0554] In one embodiment, ring 1 and / or ring 2 may be phenyl, pyridyl, piperidinyl, pyrroleyl, or thiophenyl; preferably, ring 1 and ring 2 may be...

[0555] In one particular scheme, R 12 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, with methyl being preferred.

[0556] In a certain scheme, it is not replaced or is replaced by R. 12 The substituted heteroatom or heterogroup is selected from N or O, and the number of heteroatoms or heterogroups is 1-3, which can be 4-10 membered heterocyclic alkyl groups.

[0557] In one particular scheme, R 13 In this context, the C3-C6 cycloalkyl group can be... Preferred

[0558] In one particular scheme, R 13-1-1 and R 13-1-2 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, for example, methyl.

[0559] In one particular scheme, R 13 for

[0560] In one particular scheme, R 14 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, preferably n-propyl.

[0561] In one particular scheme, R 14-1-1 and R 14-1-2 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, with methyl being preferred.

[0562] In one particular scheme, R 15-1-1 and R 15-1-2 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl.

[0563] In one particular scheme, R 16-1-1 and R 16-1-2 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl.

[0564] In one particular scheme, R 17-1-1 and R 17-1-2 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl.

[0565] In a certain scheme, it is controlled by one or more R 14 The substituted amino group is

[0566] In one embodiment, the quinazoline compound of formula I is a compound of formula I-CI.

[0567]

[0568] Among them, R b R c and R d Independently H or halogen;

[0569] W is C;

[0570] G is C;

[0571] X and Z are N;

[0572] In It is a double bond.

[0573] In a certain scheme, when R a C6-C substituted with one or more hydroxyl groups 10 When the aryl group is present, the R... afor Indicates that it is Or a mixture thereof.

[0574] In a certain scheme, when R a When the 6-10-membered heteroaryl group is composed of one or more hydroxyl groups, the 6-10-membered heteroaryl group may be... For example, R a for Indicates that it is Or a mixture thereof.

[0575] In a certain scheme, when R a For C6-C 10 When the aryl group is present, the C6-C 10 The aryl group can be Indicates that it is Or a mixture thereof.

[0576] In a certain scheme, when R a For one or more R a-1 The C6-C substituent is a C6-C substituent that is at least one of a halogen or a C1-C6 alkyl group. 10 When the aryl group is present, the C6-C 10 The aryl group can be Indicates that it is Or a mixture thereof.

[0577] In a certain scheme, it is controlled by one or more The substituted heterocyclic alkyl group is a 3-10 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms.

[0578] In a certain scheme, it is controlled by one or more The substituted heterocyclic alkyl group consisting of 3-10 members and having one or more heteroatoms selected from N, O, and S, with 1-4 heteroatoms, is considered a substituted heterocyclic alkyl group.

[0579] In one particular scheme, R Y1 and R Y2 In this context, the C1-C6 alkyl group can be methyl, ethyl, n-propyl, or isopropyl, with methyl being preferred.

[0580] In a certain scheme, it is not replaced or is replaced by R. 12 The substituted heterocyclic alkyl group consisting of 4-10 members, with 1-3 heteroatoms selected from N or O, can be unsubstituted or replaced by R. 12The substituted heterocyclic alkyl group is a 6-9 member monocyclic, fused-ring, bridged-ring, or spirocyclic alkyl group having "N as the heteroatom and one or two heteroatoms"; the 4-10 member heterocyclic alkyl group is preferably...

[0581] In a certain scheme, when Y 1 C6-C substituted with one hydroxyl group 10 When the aryl group is present, the C6-C 10 The aryl group can be

[0582] In a certain scheme, when Y 1 C6-C substituted with one hydroxyl group 10 When the aryl group is present, the Y 1 for

[0583] In one particular scheme, R is 15 In the substituted C1-C6 alkyl group, the C1-C6 alkyl group may be methyl, ethyl, n-propyl, or isopropyl.

[0584] In one particular scheme, R is 16 In the substituted C1-C6 thio group, the C1-C6 thio group may be methylthio, ethylthio, n-propylthio, or isopropylthio.

[0585] In one particular scheme, R is 17 Replacement C3-C 10 In cycloalkyl groups, the C3-C 10 The cycloalkyl group can be cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0586] In one embodiment, the 4-10 membered heterocyclic alkyl group in ring B, characterized by "heteroatoms or heterogroups selected from N and P (=O), with 1-3 heteroatoms or heterogroups, and containing only 1 N atom," can be... Azahexacyclic butanes (e.g.) ), tetrahydropyrrole or piperidinyl (e.g.) ).

[0587] In one particular scheme, R 7 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, with methyl being preferred.

[0588] In one particular scheme, R is 7 The substituted heterocyclic alkyl group consisting of 7-12 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms, can be...

[0589] In one of the solutions, middle, for

[0590] In one of the solutions, middle, for Preferred

[0591] In a certain scheme, when R 11 When the R is a 4-10 membered heterocyclic alkyl group, 11 The substituted C1-C6 alkoxy group can be cis, trans, or a mixture thereof.

[0592] In one particular scheme, R 11 In the context, the unsubstituted or unreplaced R... 11-4 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3. 5-6 membered heterocyclic aryl groups can be...

[0593] In one particular scheme, R is L In substituted 4-10 membered heterocyclic alkyl groups, the heteroatoms are selected from N and O, and the number of heteroatoms is 1-3.

[0594] In one particular scheme, R 11-1 and R 11-2 In, not replaced or by R 11-1-1 In the substituted C1-C6 alkyl group, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or n-butyl.

[0595] In one particular scheme, R 11-4 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, preferably methyl or ethyl.

[0596] In one particular scheme, R 11-1-1 Can be

[0597] In one of the solutions, for

[0598] In one particular scheme, R 12 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, with methyl being preferred.

[0599] In a certain scheme, it is not replaced or is replaced by R. 12The substituted heteroatom or heterogroup is selected from N or O, and the number of heteroatoms or heterogroups is 1-3, which can be 4-10 membered heterocyclic alkyl groups.

[0600] In one particular scheme, R 13 In this context, the C3-C6 cycloalkyl group can be... Preferred

[0601] In one particular scheme, R 13-1-1 and R 13-1-2 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, for example, methyl.

[0602] In one particular scheme, R 13 for

[0603] In one particular scheme, R 14 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, preferably n-propyl.

[0604] In one particular scheme, R 14-1-1 and R 14-1-2 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl, with methyl being preferred.

[0605] In one particular scheme, R 15-1-1 and R 15-1-2 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl.

[0606] In one particular scheme, R 16-1-1 and R 16-1-2 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl.

[0607] In one particular scheme, R 17-1-1 and R 17-1-2 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl.

[0608] In a certain scheme, it is controlled by one or more R 14 The substituted amino group is

[0609] In one embodiment, the quinazoline compound represented by Formula I is a compound represented by Formulas I-I.

[0610]

[0611] In one of the solutions, for

[0612] In one embodiment, ring B is an unsubstituted 4-10 membered heterocyclic alkyl group selected from N, with one heteroatom or heterogroup, and is replaced by R. 10 The substituted heteroatoms or heterogroups are selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and they contain only 1 N atom. The substituted heteroatoms or heterogroups are 4-10 membered monocyclic heterocyclic alkyl groups, and are replaced by R. 10 The substituted heteroatom or heterogroup is selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and it contains only 1 N, and it is a 4-10 membered bridged heterocyclic alkyl group or a substituted heterocyclic alkyl group. 7 The substituted heteroatom is a 7-12 membered bridged heterocyclic alkyl group selected from one or more of N, O and S, and the number of heteroatoms is 2-3.

[0613] Wherein, the 4-10 membered heterocyclic alkyl group, wherein "the heteroatom or heterogroup is selected from N and the number of heteroatoms or heterogroups is 1", can be...

[0614] The 4-10 member monocyclic heterocyclic alkyl group described as having "heteroatoms or heterogroups selected from N and P (=O), with 1-3 heteroatoms or heterogroups, and containing only 1 N atom" can be...

[0615] The so-called "being R" 10 The substituted heteroatom or heterogroup is selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and it contains only 1 N atom. A 4-10 membered bridged heterocyclic alkyl group can be used as follows:

[0616] The aforementioned R 7 The substituted heterocyclic alkyl group consisting of 7-12 membered bridged rings, whose heteroatoms are selected from one or more of N, O, and S, and which have 2-3 heteroatoms, can be...

[0617] In one particular scheme, R 2a-1 and R 2a-2 Independently H, -C(=O)CH3, C1-C3 alkyl or C4-C6 alkyl, and R 2a-1 and R 2a-2 They are not simultaneously C1-C3 alkyl or C4-C6 alkyl.

[0618] In one particular scheme, R 7 for Or C1-C6 alkyl.

[0619] In one embodiment, the quinazoline compound represented by Formula I is a compound represented by Formulas I-I.

[0620]

[0621] G is either C or N;

[0622] R a C6-C substituted with one or more hydroxyl groups 10 aryl, 6-10 heteroaryl groups substituted with one or more hydroxyl groups, C6-C 10 aryl or aryl group or one or more R a-1 The C6-C substituent is a C1-C6 alkyl group that is at least one of the substituents being halogen or C1-C6 alkyl. 10 aryl;

[0623] R b It is a halogen;

[0624] R c For H;

[0625] R d It is a halogen;

[0626] Y 1 For one or more The substituted heteroatom is a 3-10 membered heterocyclic alkyl group selected from one or more of N, O, and S, with 1-4 heteroatoms, and is substituted by one or more R... 11 Substituted C1-C6 alkoxy groups, unsubstituted or R 12 The substituted heteroatom is a 4-10 membered heterocyclic alkyl group selected from N or O, with 1-3 heteroatoms, and is substituted by one or more R... 14 Substituted amino groups, -OR 13 C6-C substituted with one hydroxyl group 10 aryl, R 15 Substituted C1-C6 alkyl groups, R 16 Substituted C1-C6 thio groups or R 17 Replacement C3-C 10 cycloalkyl;

[0627] In It is a single bond;

[0628] for

[0629] M 1 For N or CH;

[0630] Ring B is an unsubstituted 4-10 membered heterocyclic alkyl group with one N heteroatom, an unsubstituted 7-12 membered bridged heterocyclic alkyl group with two N heteroatoms, a 7-12 membered spirocyclic heterocyclic alkyl group, or a 7-12 membered fused-ring heterocyclic alkyl group, or R. 10The substituted heteroatoms or heterogroups are selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and they contain only 1 N atom. The substituted heteroatoms or heterogroups are 4-10 membered monocyclic heterocyclic alkyl groups, and are replaced by R. 10 The substituted heteroatom or heterogroup is selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and it contains only 1 N, and it is a 4-10 membered bridged heterocyclic alkyl group or a substituted heterocyclic alkyl group. 7 The substituted heteroatom is a 7-12 membered bridged heterocyclic alkyl group selected from one or more of N, O and S, and the number of heteroatoms is 2-3; one N atom of the 7-12 membered heterocyclic alkyl group is attached to ring 2;

[0631] Wherein, the 4-10 membered heterocyclic alkyl group, wherein "the heteroatom or heterogroup is selected from N and the number of heteroatoms or heterogroups is 1", can be...

[0632] The 4-10 member monocyclic heterocyclic alkyl group described as having "heteroatoms or heterogroups selected from N and P (=O), with 1-3 heteroatoms or heterogroups, and containing only 1 N atom" can be...

[0633] The so-called "being R" 10 The substituted heteroatom or heterogroup is selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and it contains only 1 N atom. A 4-10 membered bridged heterocyclic alkyl group can be used as follows:

[0634] The aforementioned R 7 The substituted heterocyclic alkyl group consisting of 7-12 membered bridged rings, whose heteroatoms are selected from one or more of N, O, and S, and which have 2-3 heteroatoms, can be... );

[0635] R 1 It is H, C1-C3 alkyl or C4-C6 alkyl;

[0636] R 2 -(CH2) n -R 2a ;

[0637] n is 1 or 2;

[0638] R 2a for

[0639] R 2a-1 and R 2a-2 It can be independently H, -C(=O)CH3, C1-C3 alkyl, or C4-C6 alkyl;

[0640] R 10 For amino,

[0641] R 7 -C(=O)O-(C1-C4 alkyl), C1-C6 alkyl, C1-C3 alkyl substituted with CN, or C4-C6 alkyl substituted with CN;

[0642] R 11 Optional, halogen, Not replaced or by one or more R 11-3 The substituted heteroatom is selected from N and O, and the number of heteroatoms is 1-3. It is a 4-10 membered heterocyclic alkyl group, either unsubstituted or substituted with one or more R atoms. 11-4 The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3. 5-6 membered heterocyclic aryl groups;

[0643] R 11-1 and R 11-2 Independently H, unsubstituted or R 11-1-1 Substituted C1-C6 alkyl groups

[0644] R 11-3 For H, Halogen, unsubstituted or C1-C6 substituted 4-10 membered heterocyclic alkyl or C1-C6 alkyl; the heteroatom is selected from N and O, and the number of heteroatoms is 1-3;

[0645] R 11-4 It is a C1-C6 alkyl group;

[0646] R 11-1-1 For R L The substituted heteroatoms are selected from N and O, and the number of heteroatoms is 1-3; 4-10 membered heterocyclic alkyl groups.

[0647] R L For H or

[0648] R a-1 Optionally hydroxyl, halogen, or C1-C6 alkyl;

[0649] R 12 It is a C1-C6 alkyl group;

[0650] R 13 H, C1-C6 alkyl, Or be R 13-1 Substituted C3-C6 cycloalkyl groups;

[0651] R 13-1 for

[0652] R 13-1-1 and R13-1-2 Independently H, C1-C6 alkyl;

[0653] R 14 For not replaced or by Substituted C1-C6 alkyl groups;

[0654] R 14-1-1 and R 14-1-2 Independently H, C1-C6 alkyl;

[0655] R 15 for

[0656] R 15-1-1 and R 15-1-2 Independently H, C1-C6 alkyl;

[0657] R 16 for

[0658] R 16-1 and R 16-2 Independently H or C1-C6 alkyl;

[0659] R 17 for

[0660] R 17-1 and R 17-2 It is independently H or C1-C6 alkyl.

[0661] In one embodiment, the quinazoline compound represented by Formula I is a compound represented by Formulas I-I.

[0662]

[0663] G is either C or N;

[0664] R a C6-C substituted with one or more hydroxyl groups 10 aryl, 6-10 heteroaryl with one or more hydroxyl groups, C6-C 10 aryl or aryl group or one or more R a-1 The C6-C substituent is a C1-C6 alkyl group that is at least one of the substituents being halogen or C1-C6 alkyl. 10 aryl;

[0665] R b It is a halogen;

[0666] R c For H;

[0667] R d It is a halogen;

[0668] Y1 3-10 membered heterocyclic alkyl groups with N atoms and 1 heteroatom, and R 11 Substituted C1-C6 alkoxy groups, unsubstituted or R 12 The substituted heteroatom or heterogroup is selected from N, O, and is a 4-10 membered heterocyclic alkyl group with two heteroatoms or heterogroups, and is substituted by one or more R 14 Substituted amino groups, -OR 13 Or C6-C substituted with a hydroxyl group 10 aryl;

[0669] In It is a single bond;

[0670] for

[0671] M 1 For N or CH;

[0672] Ring B is an unsubstituted 4-10 membered heterocyclic alkyl group with one N heteroatom, an unsubstituted 7-12 membered bridged heterocyclic alkyl group with two N heteroatoms, a 7-12 membered spirocyclic heterocyclic alkyl group, or a 7-12 membered fused-ring heterocyclic alkyl group, or R. 10 The substituted heteroatoms or heterogroups are selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and they contain only 1 N atom. These are 4-10 member monocyclic heterocyclic alkyl groups, replaced by R. 10 The substituted heteroatom or heterogroup is selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and it contains only 1 N, and it is a 4-10 membered bridged heterocyclic alkyl group or a substituted heterocyclic alkyl group. 7 The substituted heteroatom is a 7-12 membered bridged heterocyclic alkyl group selected from one or more of N, O and S, and the number of heteroatoms is 2-3.

[0673] Wherein, the 4-10 membered heterocyclic alkyl group, wherein "the heteroatom or heterogroup is selected from N and the number of heteroatoms or heterogroups is 1", can be...

[0674] The 4-10 member monocyclic heterocyclic alkyl group described as having "heteroatoms or heterogroups selected from N and P (=O), with 1-3 heteroatoms or heterogroups, and containing only 1 N atom" can be...

[0675] The so-called "being R" 10 The substituted heteroatom or heterogroup is selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and it contains only 1 N atom. A 4-10 membered bridged heterocyclic alkyl group can be used as follows:

[0676] The aforementioned R 7 The substituted heterocyclic alkyl group consisting of 7-12 membered bridged rings, whose heteroatoms are selected from one or more of N, O, and S, and which have 2-3 heteroatoms, can be... );

[0677] R 1 It is H or C1-C6 alkyl;

[0678] R 2 -(CH2) n -R 2a ;

[0679] n is 1 or 2;

[0680] R 2a for

[0681] R 2a-1 and R 2a-2 It can be independently H, -C(=O)CH3, or C1-C6 alkyl;

[0682] R 10 For amino,

[0683] R 10-1 and R 10-2 Independently H, C1-C6 alkyl;

[0684] R 7 for Or C1-C6 alkyl;

[0685] R 11 for Not replaced or by R 11-3 The substituted heteroatoms or heterogroups are selected from N and O, and the number of heteroatoms or heterogroups is 1-3, which are 4-10 membered heterocyclic alkyl groups;

[0686] R 11-1 and R 11-2 Independently H, C1-C6 alkyl;

[0687] R 11-3 It is a C1-C6 alkyl group;

[0688] R 12 It is a C1-C6 alkyl group;

[0689] R 13 For R 13-1 Substituted C3-C6 cycloalkyl groups;

[0690] R 13-1 for

[0691] R 13-1-1 and R 13-1-2 Independently H, C1-C6 alkyl;

[0692] R 14 For being Substituted C1-C6 alkyl groups;

[0693] R 14-1-1 and R 14-1-2 It is independently H or C1-C6 alkyl.

[0694] In one embodiment, the quinazoline compound represented by Formula I is a compound represented by Formulas I-I.

[0695]

[0696] Where G is C or N;

[0697] R a for

[0698] R b It is a halogen;

[0699] R c For H;

[0700] R d It is a halogen;

[0701] Y 1 for

[0702]

[0703]

[0704] In It is a single bond;

[0705] for

[0706]

[0707]

[0708] In one embodiment, the quinazoline compound represented by Formula I is a compound represented by Formulas I-I.

[0709]

[0710] Where G is C or N;

[0711] R a for

[0712]

[0713] R b It is a halogen;

[0714] R c For H;

[0715] R d It is a halogen;

[0716] Y 1 3-10 membered heterocyclic alkyl groups with N atoms and 1 heteroatom, and R 11 Substituted C1-C6 alkoxy groups, unsubstituted or R 12 The substituted heteroatom or heterogroup is selected from N, O, and is a 4-10 membered heterocyclic alkyl group with two heteroatoms or heterogroups, and is substituted by one or more R 14 Substituted amino groups, -OR 13 Or C6-C substituted with a hydroxyl group 10 aryl;

[0717] In It is a single bond;

[0718] for

[0719] M 1 For N or CH;

[0720] Ring B is an unsubstituted 4-10 membered heterocyclic alkyl group selected from N, with one heteroatom or heterogroup, and is surrounded by R. 10 The substituted heteroatoms or heterogroups are selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and they contain only 1 N atom. The substituted heteroatoms or heterogroups are 4-10 membered monocyclic heterocyclic alkyl groups, and are replaced by R. 10 The substituted heteroatom or heterogroup is selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and it contains only 1 N, and it is a 4-10 membered bridged heterocyclic alkyl group or a substituted heterocyclic alkyl group. 7 The substituted heteroatom is a 7-12 membered bridged heterocyclic alkyl group selected from one or more of N, O and S, with 2-3 heteroatoms;

[0721] Wherein, the 4-10 membered heterocyclic alkyl group, wherein "the heteroatom or heterogroup is selected from N and the number of heteroatoms or heterogroups is 1", can be...

[0722] The 4-10 member monocyclic heterocyclic alkyl group described as having "heteroatoms or heterogroups selected from N and P (=O), with 1-3 heteroatoms or heterogroups, and containing only 1 N atom" can be...

[0723] The so-called "being R" 10 The substituted heteroatom or heterogroup is selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and it contains only 1 N atom. A 4-10 membered bridged heterocyclic alkyl group can be used as follows:

[0724] The aforementioned R 7 The substituted heterocyclic alkyl group consisting of 7-12 membered bridged rings, whose heteroatoms are selected from one or more of N, O, and S, and which have 2-3 heteroatoms, can be...

[0725] R 1 It is H, C1-C3 alkyl or C4-C6 alkyl;

[0726] R 2 -(CH2) n -R 2a ;

[0727] n is 1 or 2;

[0728] R 2a for

[0729] R 2a-1 and R 2a-2 It can be independently H, -NH-C(=O)CH3 or C1-C6 alkyl;

[0730] R 10 For amino,

[0731] R 7 for Or C1-C6 alkyl;

[0732] R 11 for Not replaced or by R 11-3 The substituted heteroatoms or heterogroups are selected from N and O, and the number of heteroatoms or heterogroups is 1-3, which are 4-10 membered heterocyclic alkyl groups;

[0733] R 11-1 and R 11-2 Independently H, C1-C6 alkyl;

[0734] R 11-3 It is a C1-C6 alkyl group;

[0735] R 12It is a C1-C6 alkyl group;

[0736] R 13 For R 13-1 Substituted C3-C6 cycloalkyl groups;

[0737] R 13-1 for

[0738] R 13-1-1 and R 13-1-2 Independently H, C1-C6 alkyl;

[0739] R 14 For being Substituted C1-C6 alkyl groups;

[0740] R 14-1-1 and R 14-1-2 It is independently H or C1-C6 alkyl.

[0741] In one embodiment, the quinazoline compound represented by Formula I is a compound represented by Formulas I-I.

[0742]

[0743] G is either C or N;

[0744] R a for

[0745] R b It is a halogen;

[0746] R c For H;

[0747] R d It is a halogen;

[0748] Y 1 for

[0749]

[0750] In It is a single bond;

[0751] for

[0752]

[0753] In one embodiment, the quinazoline compound represented by Formula I is a compound represented by Formulas I-I.

[0754]

[0755] G is either C or N;

[0756] R a for

[0757]

[0758] R b It is a halogen;

[0759] R c For H;

[0760] R d It is a halogen;

[0761] Y 1 3-10 membered heterocyclic alkyl groups with N atoms and 1 heteroatom, and R 11 Substituted C1-C6 alkoxy groups, unsubstituted or R 12 The substituted heteroatom or heterogroup is selected from N, O, and is a 4-10 membered heterocyclic alkyl group with two heteroatoms or heterogroups, and is substituted by one or more R 14 Substituted amino groups, -OR 13 Or C6-C substituted with a hydroxyl group 10 aryl;

[0762] In It is a single bond;

[0763] for

[0764] M 1 For N or CH;

[0765] Ring B is an unsubstituted 4-10 membered heterocyclic alkyl group selected from N, with one heteroatom or heterogroup, and is surrounded by R. 10 The substituted heteroatoms or heterogroups are selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and they contain only 1 N atom. The substituted heteroatoms or heterogroups are 4-10 membered monocyclic heterocyclic alkyl groups, and are replaced by R. 10 The substituted heteroatom or heterogroup is selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and it contains only 1 N, and it is a 4-10 membered bridged heterocyclic alkyl group or a substituted heterocyclic alkyl group. 7 The substituted heteroatom is a 7-12 membered bridged heterocyclic alkyl group selected from one or more of N, O and S, with 2-3 heteroatoms;

[0766] Wherein, the 4-10 membered heterocyclic alkyl group, wherein "the heteroatom or heterogroup is selected from N and the number of heteroatoms or heterogroups is 1", can be...

[0767] The 4-10 member monocyclic heterocyclic alkyl group described as having "heteroatoms or heterogroups selected from N and P (=O), with 1-3 heteroatoms or heterogroups, and containing only 1 N atom" can be...

[0768] The so-called "being R" 10 The substituted heteroatom or heterogroup is selected from N and P (=O), the number of heteroatoms or heterogroups is 1-3, and it contains only 1 N atom. A 4-10 membered bridged heterocyclic alkyl group can be used as follows:

[0769] The aforementioned R 7 The substituted heterocyclic alkyl group consisting of 7-12 membered bridged rings, whose heteroatoms are selected from one or more of N, O, and S, and which have 2-3 heteroatoms, can be...

[0770] R 1 It is H or C1-C6 alkyl;

[0771] R 2 -(CH2) n -R 2a ;

[0772] n is 1 or 2;

[0773] R 2a for

[0774] R 2a-1 and R 2a-2 It can be independently H, -NH-C(=O)CH3 or C1-C6 alkyl;

[0775] R 10 For amino,

[0776] R 7 for Or C1-C6 alkyl;

[0777] R 11 for Not replaced or by R 11-3 The substituted heteroatoms or heterogroups are selected from N and O, and the number of heteroatoms or heterogroups is 1-3, which are 4-10 membered heterocyclic alkyl groups;

[0778] R 11-1 and R 11-2 Independently H, C1-C6 alkyl;

[0779] R 11-3 It is a C1-C6 alkyl group;

[0780] R 12 It is a C1-C6 alkyl group;

[0781] R 13 For R 13-1 Substituted C3-C6 cycloalkyl groups;

[0782] R 13-1 for

[0783] R 13-1-1 and R 13-1-2 Independently H, C1-C6 alkyl;

[0784] R 14 For being Substituted C1-C6 alkyl groups;

[0785] R 14-1-1 and R 14-1-2 It is independently H or C1-C6 alkyl.

[0786] In one embodiment, the quinazoline compound represented by Formula I is a compound represented by Formulas I-I.

[0787]

[0788] G is either C or N;

[0789] R a for

[0790]

[0791] R b It is a halogen;

[0792] R c For H;

[0793] R d It is a halogen;

[0794] Y 1 for

[0795]

[0796] In It is a single bond;

[0797] for

[0798] In one embodiment, the quinazoline compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound has any of the following structures.

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827] The asterisk (*) indicates that the location is a carbon atom with a chiral center. Indicates that it is Or a mixture thereof.

[0828] In one embodiment, the quinazoline compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound has any of the following structures.

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849] In one embodiment, the quinazoline compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound,

[0850]

[0851] Wherein, ring 1 and ring 2 are independently C5-C6 aryl, 5-6-membered heteroaryl (heteroatoms selected from one or more of N, O, and S, with 1-3 heteroatoms), C4-C8 cycloalkyl, or 4-8-membered heterocycloalkyl (heteroatoms selected from one or more of N, O, S, B, and P, with 1-4 heteroatoms); (ring 1 and ring 2 are fused together).

[0852] p1 and p2 are independently 1, 2, 3, 4 or 5;

[0853] R A It can be H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl or C1-C3 alkoxy;

[0854] R a C6-C substituted with one or more hydroxyl groups 10 aryl;

[0855] R B It can be H, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, or Y. 1 ;

[0856] Y 1 For one or more The substituted heterocyclic alkyl group is a 3-10 membered heterocyclic alkyl group selected from one or more of N, O and S, and the number of heteroatoms is 1-4.

[0857] R Y1 and R Y2 Independently, it is H or C1-C3 alkyl;

[0858] for

[0859] M 1 It can be N, CH, or P (=O);

[0860] Ring B is an unsubstituted heterocyclic alkyl group of 4-10 members, selected from N and P (=O), with 1-3 heteroatoms or heterogroups, and containing only 1 N atom. 7 The substituted heteroatoms are 7-12 membered heterocyclic alkyl groups selected from one or more of N, O, and S, with 2-3 heteroatoms. One N atom of the 7-12 membered heterocyclic alkyl group is attached to a quinazoline ring;

[0861] R 7 It is -C(=O)O-(C1-C4 alkyl) or C1-C3 alkyl substituted with CN;

[0862] Ring C is unsubstituted or replaced by R 9 The substituted heteroatoms or heterogroups are selected from N and S (=O), and the number of heteroatoms or heterogroups is 1-3; and M 2 S (=O);

[0863] R 9 for

[0864] R 9-1 and R 9-2 It is independently H, C1-C3 alkyl, or C1-C3 alkyl substituted with CN;

[0865] R 1 and R 4 Independently, it is H or C1-C3 alkyl;

[0866] R 2 R 3 and R 5 Independently -(CH2) n -R 2a ;

[0867] n is 1, 2, 3 or 4;

[0868] R 2a It is H, -OH, -O- (C1-C3 alkyl) or

[0869] R 2a-1 and R 2a-2 It is independently H or C1-C3 alkyl.

[0870] In one embodiment, the quinazoline compound of formula I is a compound of formula IA.

[0871]

[0872] Among them, R a for

[0873] Indicates that it is Or a mixture of them;

[0874] R b R c and R d Independently, it is H, halogen, C1-C3 alkyl, or C1-C3 alkoxy;

[0875] W is C;

[0876] X and Z are N;

[0877] Y 1 for

[0878] In It can be a single bond or a double bond;

[0879] In It can be a single bond or a double bond.

[0880] In one particular scheme, R b R c and R d In this context, the halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0881] In one particular scheme, R b R c and R d In this context, the C1-C3 alkyl group is methyl, ethyl, propyl, or isopropyl.

[0882] In one particular scheme, R b R c and R d In this context, the C1-C3 alkyl group is methoxy, ethoxy, propoxy, or isopropoxy.

[0883] In one particular scheme, R 7 In the -C(=O)O-(C1-C4 alkyl), the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, preferably tert-butyl.

[0884] In one particular scheme, R 7 In the CN-substituted C1-C3 alkyl group, the C1-C3 alkyl group is methyl, ethyl, n-propyl or isopropyl, preferably methyl.

[0885] In one embodiment, the 4-10 membered heterocyclic alkyl group in ring C, characterized by "heteroatoms or heterogroups selected from N and S (=O), with 1-3 heteroatoms or heterogroups," is preferably a 6-7 membered heterocyclic alkyl group, characterized by "heteroatoms or heterogroups selected from N and S (=O), with 1 or 2 heteroatoms or heterogroups."

[0886] In one particular scheme, R 9-1 and R 9-2 In this context, the C1-C3 alkyl group is methyl, ethyl, n-propyl, or isopropyl.

[0887] In one particular scheme, R 9-1 and R 9-2 In the text, the C1-C3 alkyl group substituted with CN is methyl, ethyl, n-propyl or isopropyl.

[0888] In one particular scheme, R 1 and R 4 In this context, the C1-C3 alkyl group is methyl, ethyl, n-propyl, or isopropyl, preferably methyl.

[0889] In one particular scheme, R 2a In the -O-(C1-C3 alkyl), the C1-C3 alkyl group is methyl, ethyl, n-propyl or isopropyl.

[0890] In one particular scheme, R 2a-1 and R 2a-2 In this context, the C1-C3 alkyl group is methyl, ethyl, n-propyl, or isopropyl, preferably methyl.

[0891] In one of the solutions, middle, for

[0892] In one of the solutions, middle, for

[0893] In one embodiment, the quinazoline compound represented by Formula I is a compound represented by Formula IB.

[0894]

[0895] In one particular scheme, R b It is a halogen.

[0896] In one particular scheme, R c For H.

[0897] In one particular scheme, R d It is a halogen.

[0898] In one of the solutions, In It is a single key.

[0899] In one of the solutions, for

[0900] In one of the solutions, for

[0901] In one of the schemes, M 1 It can be N or CH.

[0902] In one embodiment, ring B is an unsubstituted 4-10 membered heterocyclic alkyl group with N as the heteroatom and one heteroatom, or an unsubstituted 7-12 membered bridged heterocyclic alkyl group, 7-12 membered spirocyclic heterocyclic alkyl group, or 7-12 membered fused heterocyclic alkyl group with N as the heteroatom and two heteroatoms; one of the N atoms in the 7-12 membered bridged heterocyclic alkyl group, 7-12 membered spirocyclic heterocyclic alkyl group, or 7-12 membered fused heterocyclic alkyl group is attached to a quinazoline ring.

[0903] In one embodiment, ring B is an unsubstituted 7-12 membered bridged heterocyclic alkyl, 7-12 membered spirocyclic heterocyclic alkyl, or 7-12 membered fused heterocyclic alkyl with N as the heteroatom and two heteroatoms; one of the N atoms in the 7-12 membered bridged heterocyclic alkyl, 7-12 membered spirocyclic heterocyclic alkyl, or 7-12 membered fused heterocyclic alkyl is attached to a quinazoline ring.

[0904] In one embodiment, ring B is an unsubstituted 7-12 membered bridged heterocyclic alkyl or 7-12 membered spirocyclic heterocyclic alkyl with N as the heteroatom and two heteroatoms; one N atom of the 7-12 membered bridged heterocyclic alkyl or 7-12 membered spirocyclic heterocyclic alkyl is attached to a quinazoline ring.

[0905] In one embodiment, ring B is an unsubstituted 7-12-membered bridged heterocyclic alkyl or 7-12-membered spirocyclic heterocyclic alkyl with N as the heteroatom and two heteroatoms; one N atom of the 7-12-membered bridged heterocyclic alkyl or 7-12-membered spirocyclic heterocyclic alkyl is attached to a quinazoline ring.

[0906] The 7-12 membered bridged heterocyclic alkyl group described as having "N heteroatom and two heteroatoms" is...

[0907] The 7-12 membered spirocyclic heterocyclic alkyl group described above, which has "N as the heteroatom and two heteroatoms", includes a four-membered heterocyclic alkyl group containing "one N atom" in one of its rings, wherein the N atom in the four-membered heterocyclic alkyl group is connected to a quinazoline ring.

[0908] In one particular scheme, R 1 It is H or C1-C3 alkyl.

[0909] In one particular scheme, R 2 -(CH2) n -R 2a .

[0910] In a certain scheme, n is either 1 or 2.

[0911] In one particular scheme, R 2a for

[0912] In one particular scheme, R 2a-1 and R 2a-2 Independently H or C1-C3 alkyl, and R 2a-1 and R 2a-2 They are not all C1-C3 alkyl groups.

[0913] In one particular scheme, R 2a-1 and R 2a-2 For H.

[0914] In one of the solutions,

[0915] for

[0916] Ring B is a 7-12 membered heterocyclic alkyl group, in which "heteroatoms are selected from N, S and O, and the number of heteroatoms is 2-3".

[0917] In one of the solutions,

[0918] for

[0919] Ring B is a 7-12 membered bridged heterocyclic alkyl group with N heteroatoms and 2 heteroatoms.

[0920] In one of the solutions,

[0921] Ring B is a 7-12 membered spirocyclic heterocyclic alkyl group with N heteroatoms and 2 heteroatoms.

[0922] In one of the solutions,

[0923] for

[0924] In one of the solutions,

[0925] for

[0926] Ring B is an unsubstituted 4-7 membered heterocyclic alkyl group consisting of 1-3 heteroatoms or heterogroups selected from N and P (=O) and containing only 1 N.

[0927] Ring C is unsubstituted or replaced by R 9 The substituted heteroatom or heterogroup is selected from N and S (=O), and the number of heteroatoms or heterogroups is 1-3, and it contains only 1 N.

[0928] In one of the solutions,

[0929] for

[0930] In one embodiment, the quinazoline compound represented by Formula I is a compound represented by Formula IB.

[0931]

[0932] R a for

[0933] Indicates that it is Or a mixture of them;

[0934] R b It is a halogen;

[0935] R c For H;

[0936] R d It is a halogen;

[0937] Y 1 for

[0938] In It is a single bond;

[0939] for

[0940] M 1 For N or CH;

[0941] Ring B is an unsubstituted 4-10 membered heterocyclic alkyl group with one N heteroatom or an unsubstituted 7-12 membered bridged heterocyclic alkyl group, 7-12 membered spirocyclic heterocyclic alkyl group, or 7-12 membered fused heterocyclic alkyl group with two N atoms; one N atom of the 7-12 membered bridged heterocyclic alkyl group, 7-12 membered spirocyclic heterocyclic alkyl group, or 7-12 membered fused heterocyclic alkyl group is attached to a quinazoline ring;

[0942] R 1 It is H or C1-C3 alkyl;

[0943] R 2 -(CH2) n -R 2a ;

[0944] n is 1, 2, 3 or 4;

[0945] R 2a For H, -OH or

[0946] R 2a-1 and R 2a-2 It is independently H or C1-C3 alkyl.

[0947] In one embodiment, the quinazoline compound represented by Formula I is a compound represented by Formula IB.

[0948]

[0949] R a for

[0950] Indicates that it is Or a mixture of them;

[0951] R b It is a halogen;

[0952] R c For H;

[0953] R d It is a halogen;

[0954] Y 1 for

[0955] In It is a single bond;

[0956] for

[0957] M 1 For N or CH;

[0958] Ring B is an unsubstituted 7-12 membered bridged heterocyclic alkyl, 7-12 membered spirocyclic heterocyclic alkyl, or 7-12 membered fused heterocyclic alkyl with N as the heteroatom and two heteroatoms; one of the N atoms in the 7-12 membered bridged heterocyclic alkyl, 7-12 membered spirocyclic heterocyclic alkyl, or 7-12 membered fused heterocyclic alkyl is attached to a quinazoline ring;

[0959] R 1 It is H or C1-C3 alkyl;

[0960] R 2 -(CH2) n -R 2a ;

[0961] n is 1, 2, or 3;

[0962] R 2a For H, -OH or

[0963] R 2a-1 and R 2a-2 Independently H or C1-C3 alkyl, and R 2a-1 and R 2a-2 They are not all C1-C3 alkyl groups.

[0964] In one embodiment, the quinazoline compound represented by Formula I is a compound represented by Formula IB.

[0965]

[0966] R a for

[0967] Indicates that it is Or a mixture of them;

[0968] R b It is a halogen;

[0969] R c For H;

[0970] R d It is a halogen;

[0971] Y 1 for

[0972] In It is a single bond;

[0973] for

[0974] M 1 Let N be the number of people in the group.

[0975] Ring B is an unsubstituted 7-12 membered bridged heterocyclic alkyl or 7-12 membered spirocyclic heterocyclic alkyl with N as the heteroatom and 2 heteroatoms; one N atom of the 7-12 membered bridged heterocyclic alkyl or 7-12 membered spirocyclic heterocyclic alkyl is attached to a quinazoline ring;

[0976] R 1 It is H or C1-C3 alkyl;

[0977] R 2 -(CH2) n -R 2a ;

[0978] n is 1, 2, or 3;

[0979] R 2a for

[0980] R 2a-1 and R 2a-2 For H.

[0981] In one embodiment, the quinazoline compound represented by Formula I is a compound represented by Formula IB.

[0982]

[0983] R a for

[0984] Indicates that it is Or a mixture of them;

[0985] R b It is a halogen;

[0986] R c For H;

[0987] R d It is a halogen;

[0988] Y 1 for

[0989] In It is a single bond;

[0990] for

[0991] M 1 Let N be the number of people in the group.

[0992] Ring B is an unsubstituted 7-12 membered bridged heterocyclic alkyl or 7-12 membered spirocyclic heterocyclic alkyl with N as the heteroatom and 2 heteroatoms; one N atom of the 7-12 membered bridged heterocyclic alkyl or 7-12 membered spirocyclic heterocyclic alkyl is attached to a quinazoline ring;

[0993] The 7-12 membered bridged heterocyclic alkyl group described as having "N heteroatom and two heteroatoms" is...

[0994] The 7-12 membered spirocyclic heterocyclic alkyl group described above, which has "N as the heteroatom and two heteroatoms", includes a four-membered heterocyclic alkyl group containing "one N atom" in one of its rings, wherein the N atom in the four-membered heterocyclic alkyl group is connected to a quinazoline ring.

[0995] In one embodiment, the quinazoline compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound has one of the following configurations, wherein the carbon atom marked with "*" represents an S-configuration or an R-configuration carbon atom.

[0996] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 1.946 min.

[0997] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 5.115 min.

[0998] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 2.104 min.

[0999] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 3.656 min.

[1000] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 10 min; detector: UV 220 / 254 nm; retention time: 2.705 min.

[1001] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 10 min; detector: UV 220 / 254 nm; retention time: 6.915 min.

[1002] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 15 min; detector: UV 220 / 254 nm; retention time: 5.828 min.

[1003] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% B phase over 15 min; detector: UV 220 / 254 nm; retention time: 9.588 min.

[1004] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 2.549 min.

[1005] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 3.363 min.

[1006] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 20% phase B over 9 min; detector: UV 220 / 254 nm; retention time: 6.871 min.

[1007] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 20% phase B over 9 min; detector: UV 220 / 254 nm; retention time: 4.373 min.

[1008] The HPLC conditions were as follows: chiral column: Lux 3um Cellulose-2, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 12 min; detector: UV 220 / 254 nm; retention time: 4.914 min.

[1009] The HPLC conditions were as follows: chiral column: Lux 3um Cellulose-2, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 12 min; detector: UV 220 / 254 nm; retention time: 7.935 min.

[1010] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 2.844 min.

[1011] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 4.215 min.

[1012] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 4.5 min; detector: UV 220 / 254 nm; retention time: 2.562 min.

[1013] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 4.5 min; detector: UV 220 / 254 nm; retention time: 3.662 min.

[1014] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 2.856 min.

[1015] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 4.120 min.

[1016] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 4.5 min; detector: UV 220 / 254 nm; retention time: 2.317 min.

[1017] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 4.5 min; detector: UV 220 / 254 nm; retention time: 3.182 min.

[1018] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 10 min; detector: UV 220 / 254 nm; retention time: 4.576 min.

[1019] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 10 min; detector: UV 220 / 254 nm; retention time: 8.266 min.

[1020] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 3.616 min.

[1021] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 5.340 min.

[1022] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 10 min; detector: UV 220 / 254 nm; retention time: 5.189 min.

[1023] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 10 min; detector: UV 220 / 254 nm; retention time: 7.314 min.

[1024] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 3.5 min; detector: UV 220 / 254 nm; retention time: 1.347 min.

[1025] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 3.5 min; detector: UV 220 / 254 nm; retention time: 2.180 min.

[1026] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 1.690 min.

[1027] The HPLC conditions were as follows: chiral column: CHIRALPAK IG-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 2.820 min.

[1028] The HPLC conditions were as follows: chiral column: CHIRALPAK IG-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 50% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 4.257 min.

[1029] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 50% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 2.734 min.

[1030] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 20% phase B over 5.5 min; detector: UV 220 / 254 nm; retention time: 3.619 min.

[1031] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 20% phase B over 5.5 min; detector: UV 220 / 254 nm; retention time: 2.324 min.

[1032] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 1.433 min.

[1033] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 1.905 min.

[1034] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 30% phase B over 10 min using an isogradient; detector: UV 220 / 254 nm; retention time: 3.80 min.

[1035] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 220 / 254 nm; retention time: 5.950 min.

[1036] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 8 min; detector: UV 220 / 254 nm; retention time: 3.40 min.

[1037] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 8 min; detector: UV 220 / 254 nm; retention time: 5.31 min.

[1038] CHIRALPAK IG-3, 4.6 x 50 mm, 3 μm; Mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), Mobile phase B: ethanol; Flow rate: 1 mL / min; Isogradient elution with 50% phase B over 6 min; Detector: UV 220 / 254 nm; Retention time: 1.203 min;

[1039] The HPLC conditions were as follows: chiral column: CHIRALPAK IG-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 50% phase B over 6 min using an isogradient; detector: UV 220 / 254 nm; retention time: 2.391 min.

[1040] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 2.960 min.

[1041] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 4.715 min.

[1042] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 10% phase B over 8 min using an isogradient; detector: UV 220 / 254 nm; retention time: 3.759 min.

[1043] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 10% phase B over 8 min using an isogradient; detector: UV 220 / 254 nm; retention time: 5.749 min.

[1044] The HPLC conditions were as follows: chiral column: CHIRALPAK IE-3, 3.0 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 3.306 min.

[1045] The HPLC conditions were as follows: chiral column: CHIRALPAK IE-3, 3.0 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 4.803 min.

[1046] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 2.737 min.

[1047] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 4.713 min.

[1048] The HPLC conditions were as follows: chiral column: CHIRALPAK IE-3, 4.6 x 50 mm, 3 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: methanol; flow rate: 1 mL / min; elution with 50% phase B over 6 min using an isogradient; detector: UV 220 / 254 nm; retention time: 1,200 min.

[1049] The HPLC conditions were as follows: chiral column: CHIRALPAK IE-3, 4.6 x 50 mm, 3 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: methanol; flow rate: 1 mL / min; isogradient elution with 50% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 3.550 min.

[1050] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane: methyl tert-butyl ether 1:1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 5% phase B over 10 min using an isogradient; detector: UV 220 / 254 nm; retention time: 5.305 min.

[1051] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane: methyl tert-butyl ether 1:1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 5% phase B over 10 min at an isogradient; detector: UV 220 / 254 nm; retention time: 7.357 min.

[1052] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 3.197 min.

[1053] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 10% phase B over 6 min at an isogradient; detector: UV 220 / 254 nm; retention time: 4.394 min.

[1054] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 10% phase B over 7 min at an isogradient; detector: UV 220 / 254 nm; retention time: 4.100 min.

[1055] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 7 min; detector: UV 220 / 254 nm; retention time: 5.751 min.

[1056] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 30% phase B over 4 min using an isogradient; detector: UV 220 / 254 nm; retention time: 1.910 min.

[1057] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 30% phase B over 4 min at an isogradient; detector: UV 220 / 254 nm; retention time: 2.941 min.

[1058] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 10% phase B over 8 min using an isogradient; detector: UV 220 / 254 nm; retention time: 3.684 min.

[1059] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 8 min; detector: UV 220 / 254 nm; retention time: 6.409 min.

[1060] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 8 min; detector: UV 220 / 254 nm; retention time: 3.667 min.

[1061] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 8 min; detector: UV 220 / 254 nm; retention time: 6.387 min.

[1062] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 5 min; detector: UV 220 / 254 nm; retention time: 1.686 min.

[1063] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 10% phase B over 5 min at an isogradient; detector: UV 220 / 254 nm; retention time: 2.959 min.

[1064] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 20% phase B over 6 min at an isogradient; detector: UV 220 / 254 nm; retention time: 2.759 min.

[1065] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 20% phase B over 6 min at an isogradient; detector: UV 220 / 254 nm; retention time: 4.652 min.

[1066] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 30% phase B over 5 min at an isogradient; detector: UV 220 / 254 nm; retention time: 1.963 min.

[1067] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 30% phase B over 5 min at an isogradient; detector: UV 220 / 254 nm; retention time: 3.148 min.

[1068] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 8 min; detector: UV 220 nm; retention time: 4.211 min.

[1069] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 10% phase B over 8 min using an isogradient; detector: UV 220 nm; retention time: 6.385 min.

[1070] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 6 min; detector: UV 254 nm; retention time: 3.762 min.

[1071] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 8 min; detector: UV 254 nm; retention time: 5.467 min.

[1072] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 5.5 min at an isogradient; detector: UV 254 nm; retention time: 2.173 min.

[1073] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 5.5 min at an isogradient; detector: UV 254 nm; retention time: 3.537 min.

[1074] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 2.045 min.

[1075] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 3.463 min.

[1076] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 6 min; detector: UV 254 nm; retention time: 5.080 min.

[1077] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 6 min; detector: UV 254 nm; retention time: 3.566 min.

[1078] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 15 min; detector: UV 254 nm; retention time: 5.980 min.

[1079] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 15 min; detector: UV 254 nm; retention time: 10.313 min.

[1080] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / methyl tert-butyl ether = 1 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 20% phase B over 6 min at an isogradient; detector: UV 254 nm; retention time: 2.202 min.

[1081] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / methyl tert-butyl ether = 1 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 20% phase B over 6 min using an isogradient; detector: UV 254 nm; retention time: 1.694 min.

[1082] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 254 nm; retention time: 3.894 min.

[1083] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 254 nm; retention time: 1.814 min.

[1084] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 2.813 min.

[1085] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 1.965 min.

[1086] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 10% phase B over 8 min using an isogradient; detector: UV 254 nm; retention time: 3.932 min.

[1087] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 10% phase B over 10 min at an isogradient; detector: UV 254 nm; retention time: 7.304 min.

[1088] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 10% phase B over 10 min at an isogradient; detector: UV 254 nm; retention time: 4.668 min.

[1089] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 10% phase B over 10 min at an isogradient; detector: UV 254 nm; retention time: 6.605 min.

[1090] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 30% phase B over 4 min using an isogradient; detector: UV 254 nm; retention time: 1.465 min.

[1091] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 30% phase B over 4 min using an isogradient; detector: UV 254 nm; retention time: 2.173 min.

[1092] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = (5 / 1) (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min at an isogradient; detector: UV 220 / 254 nm; retention time: 2.097 min.

[1093] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = (5 / 1) (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min at an isogradient; detector: UV 220 / 254 nm; retention time: 3.541 min.

[1094] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 50% phase B over 6 min using an isogradient; detector: UV 220 / 254 nm; retention time: 1.741 min.

[1095] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 50% phase B over 6 min using an isogradient; detector: UV 220 / 254 nm; retention time: 3.291 min.

[1096] The HPLC conditions were as follows: chiral column: XA-CHIRALPAK AD-3, 4.6 x 250 mm, 3 μm; mobile phase A: n-hexane (0.5% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 50% phase B over 19 min; detector: UV 254 nm; retention time: 8.374 min.

[1097] The HPLC conditions were as follows: chiral column: XA-CHIRALPAK AD-3, 4.6 x 250 mm, 3 μm; mobile phase A: n-hexane (0.5% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 50% phase B over 19 min; detector: UV 254 nm; retention time: 13.763 min.

[1098] Its origin Made, The HPLC conditions were as follows: chiral column NB-Lux 5μm i-Cellulose-5, 2.12 x 25 cm, 5 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.5% 2 mol / L ammonia-methanol solution), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: elution with 8% phase B over 40 min; detector: 220 nm; retention time: 16.81 min.

[1099] Its origin Made, The HPLC conditions were as follows: chiral column NB-Lux 5μm i-Cellulose-5, 2.12 x 25 cm, 5 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.5% 2 mol / L ammonia-methanol solution), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: elution with 8% phase B over 40 min; detector: 220 nm; retention time: 25.09 min.

[1100] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 8.5 min; detector: UV 254 nm; retention time: 4.033 min.

[1101] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 8.5 min; detector: UV 254 nm; retention time: 6.5-15 min.

[1102] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 20% phase B over 6 min at an isogradient; detector: UV 220 nm; retention time: 3.401 min.

[1103] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 20% phase B over 6 min at an isogradient; detector: UV 220 nm; retention time: 4.503 min.

[1104] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 3.0 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 50% phase B over 4 min; detector: UV 220 nm; retention time: 1.442 min.

[1105] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 3.0 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 50% phase B over 4 min using an isogradient; detector: UV 220 nm; retention time: 2.226 min.

[1106] The HPLC conditions were as follows: chiral column: CHIRAL ART Amylose-C Neo, 50 x 4.6 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol / acetonitrile = 2 / 1; flow rate: 1 mL / min; elution with 50% phase B over 6.5 min using an isogradient; detector: UV 230 nm; retention time: 2.045 min.

[1107] The HPLC conditions were as follows: chiral column: CHIRAL ART Amylose-C Neo, 50 x 4.6 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol / acetonitrile = 2 / 1; flow rate: 1 mL / min; elution with 50% phase B over 6.5 min using an isogradient; detector: UV 230 nm; retention time: 4.319 min.

[1108] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 12.5 min; detector: UV 220 nm; retention time: 7.498 min.

[1109] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 12.5 min; detector: UV 220 nm; retention time: 9.454 min.

[1110] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 40% phase B over 6 min at an isogradient; detector: UV 220 nm; retention time: 2.457 min.

[1111] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 40% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 3.982 min.

[1112] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 20% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 4.024 min.

[1113] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 20% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 5.203 min.

[1114] The HPLC conditions were as follows: chiral column: XA-CHIRALPAK AS-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: acetonitrile; flow rate: 1.67 mL / min; isogradient elution with 20% phase B over 2 min; detector: UV 220 nm; retention time: 0.821 min.

[1115] The HPLC conditions were as follows: chiral column: XA-CHIRALPAK AS-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: acetonitrile; flow rate: 1.67 mL / min; isogradient elution with 20% phase B over 2 min; detector: UV 220 nm; retention time: 1.215 min.

[1116] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane (0.2% n-butane), mobile phase B: isopropanol:acetonitrile (2:1); flow rate: 1 mL / min; elution with 20% phase B over 8 min using an isogradient; detector: UV 254 nm; retention time: 4.688 min.

[1117] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane (0.2% n-butane), mobile phase B: isopropanol:acetonitrile (2:1); flow rate: 1 mL / min; elution with 20% phase B over 8 min using an isogradient; detector: UV 254 nm; retention time: 6.033 min.

[1118] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / dichloromethane (5:1) (0.1% diethylamine); mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 12.5 min; detector: UV 220 nm; retention time: 8.927 min.

[1119] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / dichloromethane (5 / 1) (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 12.5 min; detector: UV 220 nm; retention time: 9.894 min.

[1120] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol (10 mmol ammonia); flow rate: 2 mL / min; gradient elution with 40%–50% phase B over 8 min; detector: UV 220 nm; retention time: 5.095 min.

[1121] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol (10 mmol ammonia); flow rate: 2 mL / min; gradient elution with 40%–50% phase B over 8 min; detector: UV 220 nm; retention time: 6.135 min.

[1122] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol (10 mmol ammonia); flow rate: 2 mL / min; isogradient elution with 50% phase B over 4 min; detector: UV 220 nm; retention time: 1.742 min.

[1123] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol (10 mmol ammonia); flow rate: 2 mL / min; isogradient elution with 50% phase B over 4 min; detector: UV 220 nm; retention time: 2.904 min.

[1124] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 254 nm; retention time: 4.874 min.

[1125] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 254 nm; retention time: 2.414 min.

[1126] The HPLC conditions were as follows: chiral column: CHIRALPAK IF-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; gradient: elution with 20% phase B over 12 min; detector: UV 220 / 254 nm; retention time: 6.743 min.

[1127] The HPLC conditions were as follows: chiral column: CHIRALPAK IF-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; gradient: elution with 20% phase B over 12 min; detector: UV 220 / 254 nm; retention time: 9.968 min.

[1128] Its origin Prepared; The HPLC conditions were as follows: chiral column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.5% 2 mol / L ammonia-methanol solution), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: elution with 30% mobile phase B over 10 min; detector: UV 250 / 220 nm; retention time: 3.2 min.

[1129] Its origin Made, The HPLC conditions were as follows: chiral column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.5% 2 mol / L ammonia-methanol solution), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: elution with 30% mobile phase B over 10 min; detector: UV 250 / 220 nm; retention time: 5.7 min.

[1130] Its origin Made, The HPLC conditions were as follows: chiral column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol solution), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: elution with 30% mobile phase B over 23 min; detector: UV 250 / 220 nm; retention time: 5.8 min.

[1131] Its origin Made, HPLC conditions were as follows: chiral column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol solution), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: elution with 30% mobile phase B over 23 min; detector: UV 250 / 220 nm; shortest retention time: 15.8 min.

[1132] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 20% phase B over 6 min using an isogradient; detector: UV 220 / 254 nm; retention time: 3.994 min.

[1133] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 20% phase B over 6 min at an isogradient; detector: UV 220 / 254 nm; retention time: 4.737 min.

[1134] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 20% phase B over 17 min at an isogradient; detector: UV 254 nm; retention time: 11.543 min.

[1135] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 20% phase B over 17 min using an isogradient; detector: UV 254 nm; retention time: 6.706 min.

[1136] Its origin Made, The HPLC conditions were as follows: chiral column: CHIRALPAK IA, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol solution), mobile phase B: isopropanol; flow rate: 20 mL / min; gradient: elution with 30% mobile solution for 11.5 min; detector: UV 220 / 210 nm; retention time: 4.342 min.

[1137] Its origin Made, The HPLC conditions were as follows: chiral column: CHIRALPAK IA, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol solution), mobile phase B: isopropanol; flow rate: 20 mL / min; gradient: elution with 30% mobile solution for 11.5 min; detector: UV 220 / 210 nm; retention time: 7.54 min.

[1138] The HPLC conditions were as follows: chiral column: CHIRAL ART Cellulose-SC, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2 mol / L ammonia-methanol solution), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: elution with 20% phase B over 12 min; detector: UV 220 / 254 nm; retention time: 5.875 min.

[1139] The HPLC conditions were as follows: chiral column: CHIRAL ART Cellulose-SC, 2 x 25 cm, 5 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.5% 2 mol / L ammonia-methanol solution), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: elution with 20% phase B over 12 min; detector: UV 220 / 254 nm; retention time: 8.193 min.

[1140] Its origin Made, The HPLC conditions were as follows: chiral column: CHIRALCEL AY-H, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2 mol / L ammonia-methanol solution), mobile phase B: isopropanol / acetonitrile = 2 / 1; flow rate: 20 mL / min; gradient: elution with 30% mobile phase B over 13 min; detector: UV 226 / 254 nm; retention time: 3.7 min.

[1141] Its origin Made, The HPLC conditions were as follows: chiral column: CHIRALCEL AY-H, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2 mol / L ammonia-methanol solution), mobile phase B: isopropanol / acetonitrile = 2 / 1; flow rate: 20 mL / min; gradient: elution with 30% mobile phase B over 13 min; detector: UV 226 / 254 nm; retention time: 6.8 min.

[1142] Its origin Made, The HPLC conditions were as follows: chiral column: CHIRALPAK IE, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol solution), mobile phase B: isopropanol / acetonitrile = 2 / 1; flow rate: 20 mL / min; elution with a 10% gradient of mobile phase B over 18 min; detector: UV 226 / 254 nm; retention time: 6 min.

[1143] Its origin Made, The HPLC conditions were as follows: chiral column: CHIRALPAK IE, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol solution), mobile phase B: isopropanol / acetonitrile = 2 / 1; flow rate: 20 mL / min; elution with a 10% gradient of mobile phase B over 18 min; detector: UV 226 / 254 nm; retention time: 8.5 min.

[1144] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 6 min; detector: UV 220 nm; retention time: 3.123 min.

[1145] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 10% phase B over 6 min at an isogradient; detector: UV 220 nm; retention time: 5.171 min.

[1146] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 50% phase B over 6 min; detector: UV 254 nm; retention time: 1.508 min.

[1147] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 50% phase B over 6 min at an isogradient; detector: UV 254 nm; retention time: 2.593 min.

[1148] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 2.156 min.

[1149] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min at an isogradient; detector: UV 220 nm; retention time: 4.420 min.

[1150] Its origin and Made, The HPLC conditions were as follows: chiral column: CHIRALPAKIC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 254 nm; retention time: 2.198 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min at an isogradient; detector: UV 254 nm; retention time: 3.411 min.

[1151] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 2.239 min.

[1152] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min at an isogradient; detector: UV 220 nm; retention time: 3.881 min.

[1153] The HPLC conditions were as follows: chiral column: CHIRAL Cellulose-SB, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / methyl tert-butyl ether = 1 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 8.5 min; detector: UV 220 / 254 nm; retention time: 5.962 min.

[1154] The HPLC conditions were as follows: chiral column: CHIRAL Cellulose-SB, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / methyl tert-butyl ether = 1 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 30% phase B over 8.5 min at an isogradient; detector: UV 220 / 254 nm; retention time: 7.373 min.

[1155] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 20% phase B over 8 min using an isogradient; detector: UV 220 / 254 nm; retention time: 1.999 min.

[1156] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 20% phase B over 8 min at an isogradient; detector: UV 220 / 254 nm; retention time: 3.292 min.

[1157] The HPLC conditions were as follows: chiral column: N-Lux 3μm Cellulose-4 (H18-063498), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid, mobile phase B: methanol (0.1% diethylamine); flow rate: 3 mL / min; isogradient elution with 40% phase B over 10 min; detector: UV 220 nm; retention time: 3.734 min.

[1158] The HPLC conditions were as follows: chiral column: N-Lux 3μm Cellulose-4 (H18-063498), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid, mobile phase B: methanol (0.1% diethylamine); flow rate: 3 mL / min; elution with 40% phase B over 10 min at an isogradient; detector: UV 220 nm; retention time: 2.913 min.

[1159] The HPLC conditions were as follows: chiral column: CHIRAL ART Cellulose-SB, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 4.5 min; detector: UV 220 nm; retention time: 1.346 min.

[1160] The HPLC conditions were as follows: chiral column: CHIRAL ART Cellulose-SB, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 10% phase B over 4.5 min at an isogradient; detector: UV 220 nm; retention time: 2.438 min.

[1161] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 20% phase B over 3.5 min; detector: UV 220 / 254 nm; retention time: 1.198 min.

[1162] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 20% phase B over 4 min at an isogradient; detector: UV 220 / 254 nm; retention time: 1.880 min.

[1163] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 3.0 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min at an isogradient; detector: UV 210 nm; retention time: 4.125 min.

[1164] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 3.0 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min at an isogradient; detector: UV 210 nm; retention time: 2.126 min.

[1165] The HPLC conditions were as follows: chiral column: XA-CHIRALPAK IG-3, 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid, mobile phase B: isopropanol (10 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 4.214 min.

[1166] The HPLC conditions were as follows: chiral column: XA-CHIRALPAK IG-3, 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid, mobile phase B: isopropanol (10 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% phase B over 6 min at an isogradient; detector: UV 220 nm; retention time: 2.706 min.

[1167] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 3.0 x 100 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 2 mL / min; isogradient elution with 30% phase B over 4 min; detector: UV 254 nm; retention time: 1.083 min.

[1168] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 3.0 x 100 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 2 mL / min; isogradient elution with 30% phase B over 4 min; detector: UV 254 nm; retention time: 2.010 min.

[1169] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol (10 mmol / L ammonia); flow rate: 1 mL / min; elution with 50% phase B over 4 min using an isogradient; detector: UV 220 nm; retention time: 2.761 min.

[1170] The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol (10 mmol / L ammonia); flow rate: 1 mL / min; elution with 50% B phase over 4 min using an isogradient; detector: UV 220 nm; retention time: 1.705 min.

[1171] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 40% phase B over 3.5 min; detector: UV 254 nm; retention time: 2.301 min.

[1172] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 40% phase B over 4.5 min at an isogradient; detector: UV 254 nm; retention time: 1.465 min.

[1173] The HPLC conditions were as follows: chiral column: N-Lux 3um Cellulose-4 (H17-388767), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (0.1% diethylamine); flow rate: 3.5 mL / min; isogradient elution with 48% phase B over 6 min; detector: UV 220 nm; retention time: 2.41 min.

[1174] The HPLC conditions were as follows: chiral column: N-Lux 3um Cellulose-4 (H17-388767), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (0.1% diethylamine); flow rate: 3.5 mL / min; elution with 48% phase B over 6 min at an isogradient; detector: UV 220 nm; retention time: 3.66 min.

[1175] The HPLC conditions were as follows: chiral column: N--CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 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; elution with 10% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 4.514 min.

[1176] The HPLC conditions were as follows: chiral column: N--CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 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; elution with 10% phase B over 6 min at an isogradient; detector: UV 220 nm; retention time: 4.948 min.

[1177] The HPLC conditions were as follows: chiral column: N-CHIRALPAK IG-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: isopropanol (10 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 0.845 min.

[1178] The HPLC conditions were as follows: chiral column: N-CHIRALPAK IG-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: isopropanol (10 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% phase B over 6 min at an isogradient; detector: UV 220 nm; retention time: 1.905 min.

[1179] The HPLC conditions were as follows: chiral column: N-CHIRALPAK IE-3 (Lot No. IF3SCK-SD016), 3 x 100 mm; 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; gradient: isogradient elution with 50% phase B over 8 min; detector: UV 220 nm; retention time: 4.857 min.

[1180] The HPLC conditions were as follows: chiral column: N-CHIRALPAK IE-3 (Lot No. IF3SCK-SD016), 3 x 100 mm; 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; gradient: isogradient elution with 50% phase B over 8 min; detector: UV 220 nm; retention time: 5.877 min.

[1181] The HPLC conditions were as follows: chiral column: N-Lux 3u i-Cellulose-5, 0.46 x 10 cm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol: dichloromethane = 1:1 (20 mmol / L ammonia); flow rate: 2 mL / min; gradient: isogradient elution with 50% B phase; detector: UV 230 nm; retention time: 4.976 min.

[1182] The HPLC conditions were as follows: chiral column: N-Lux 3u i-Cellulose-5, 0.46 x 10 cm, μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol: dichloromethane = 1:1 (20 mmol / L ammonia); flow rate: 2 mL / min; gradient: isogradient elution with 50% B phase; detector: UV 230 nm; retention time: 5.657 min.

[1183] The HPLC conditions were as follows: chiral column: N-Lux 3μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3.0 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (0.1% diethylamine); flow rate: 4 mL / min; gradient: isogradient elution with 35% phase B; detector: UV 220 nm; retention time: 9.221 min.

[1184] The HPLC conditions were as follows: chiral column: N-Lux 3μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3.0 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (0.1% diethylamine); flow rate: 4 mL / min; gradient: isogradient elution with 35% phase B; detector: UV 220 nm; retention time: 7.830 min.

[1185] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3 (Lot No. ID3SCK-TB004), 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% phase B over 4 min; detector: UV 220 nm; retention time: 1.822 min.

[1186] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3 (Lot No. ID3SCK-TB004), 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% phase B over 4 min; detector: UV 220 nm; retention time: 1.296 min.

[1187] The HPLC conditions were as follows: chiral column: CHIRALART Cellulose-SB (Ser. No. 105CA80166), 4.6 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 over 4 min; detector: UV 230 nm; retention time: 2.055 min.

[1188] The HPLC conditions were as follows: chiral column: CHIRALART Cellulose-SB (Ser. No. 105CA80166), 4.6 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 over 4 min; detector: UV 230 nm; retention time: 1.632 min.

[1189] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3 (Lot No. ID3SCK-TB004), 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% phase B over 4 min; detector: UV 230 nm; retention time: 1.878 min.

[1190] The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3 (Lot No. ID3SCK-TB004), 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% phase B over 4 min; detector: UV 230 nm; retention time: 1.217 min.

[1191] The HPLC conditions were as follows: chiral column: N-CHIRALPAK IG-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% phase B over 4 min at an isogradient; detector: UV 230 nm; retention time: 2.601 min.

[1192] The HPLC conditions were as follows: chiral column: N-CHIRALPAK IG-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% phase B over 4 min at an isogradient; detector: UV 230 nm; retention time: 0.815 min.

[1193] The HPLC conditions were as follows: chiral column: N-CHIRALPAK IG-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 10% phase B over 6.5 min at an isogradient; detector: UV 230 nm; retention time: 4.553 min.

[1194] The HPLC conditions were as follows: chiral column: N-CHIRALPAK IG-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 10% phase B over 6.5 min at an isogradient; detector: UV 230 nm; retention time: 4.074 min.

[1195] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 3 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% phase B over 4 min; detector: UV 230 nm; retention time: 2.80 min.

[1196] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 3 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% phase B over 4 min; detector: UV 230 nm; retention time: 2.318 min.

[1197] The HPLC conditions were as follows: chiral column: Cellulose-SB, 3 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 10% B phase over 3 min; detector: UV 220 nm; retention time: 1.911 min.

[1198] The HPLC conditions were as follows: chiral column: Cellulose-SB, 3 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 10% phase B over 3 min; detector: UV 220 nm; retention time: 2.171 min.

[1199] The HPLC conditions were as follows: chiral column: CHIRAL ARTCellulose-SB, 3 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 10% B phase over 3 min; detector: UV 220 nm; retention time: 2.148 min.

[1200] The HPLC conditions were as follows: chiral column: CHIRAL ART Cellulose-SB, 3 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 10% B phase over 3 min; detector: UV 220 nm; retention time: 2.443 min.

[1201] The HPLC conditions were as follows: chiral column: N-Lux 3um Cellulose-4 (H17-388767), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: ethanol (20 mmol / L ammonia); flow rate: 3.5 mL / min; isogradient elution with 35% phase B over 6.5 min; detector: UV 220 nm; retention time: 3.455 min.

[1202] The HPLC conditions were as follows: chiral column: N-Lux 3um Cellulose-4 (H17-388767), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: ethanol (20 mmol / L ammonia); flow rate: 3.5 mL / min; isogradient elution with 35% phase B over 6.5 min; detector: UV 220 nm; retention time: 4.723 min.

[1203] The HPLC conditions were as follows: chiral column: N-Lux 3μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (0.1% diethylamine); flow rate: 4 mL / min; gradient: elution with 50% phase B over 6 min; detector: UV 254 nm; retention time: 1.349 min.

[1204] The HPLC conditions were as follows: chiral column: N-Lux 3μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (0.1% diethylamine); flow rate: 4 mL / min; gradient: elution with 50% phase B over 6 min; detector: UV 254 nm; retention time: 1.903 min.

[1205] The HPLC conditions were as follows: chiral column: N-Lux 3μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3 μm; supercritical mobile phase A: carbon dioxide, mobile phase B: methanol (0.1% diethylamine); flow rate: 4 mL / min; gradient: elution with 50% phase B over 6 min; detector: UV 254 nm; retention time: 2.715 min.

[1206] The HPLC conditions were as follows: chiral column: N-Lux 3μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (0.1% diethylamine); flow rate: 4 mL / min; gradient: elution with 50% phase B over 6 min; detector: UV 254 nm; retention time: 3.767 min.

[1207] The HPLC conditions were as follows: chiral column: N-Lux 3μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (0.1% diethylamine); flow rate: 4 mL / min; gradient: elution with 40% phase B over 7 min; detector: UV 220 nm; retention time: 3.698 min.

[1208] The HPLC conditions were as follows: chiral column: N-Lux 3μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (0.1% diethylamine); flow rate: 4 mL / min; gradient: elution with 40% phase B over 7 min; detector: UV 220 nm; retention time: 5.109 min.

[1209] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; gradient: elution with 50% phase B over 4 min; detector: UV 254 nm; retention time: 0.617 min.

[1210] The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; gradient: elution with 50% phase B over 4 min; detector: UV 254 nm; retention time: 1.334 min.

[1211] In this invention, the quinazoline compounds represented by Formula I, their pharmaceutically acceptable salts, solvates, prodrugs, metabolites, or isotopic compounds may have one or more chiral carbon atoms, thus allowing the separation of optically pure isomers, such as pure enantiomers, racemates, or mixed isomers. Pure single isomers can be obtained using separation methods in the art, such as chiral crystallization into salts or separation using chiral preparative columns.

[1212] In this invention, the quinazoline compounds represented by Formula I, their pharmaceutically acceptable salts, solvates, prodrugs, metabolites, or isotopic compounds, if stereoisomers exist, may exist as a single stereoisomer or a mixture thereof (e.g., a racemic mixture). The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified, and enriched by asymmetric synthetic methods or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-performance liquid chromatography, etc.), and can also be obtained through chiral resolution by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of this invention is not less than 95% relative to all stereoisomers of the compound.

[1213] In this invention, the quinazoline compounds represented by Formula I, their pharmaceutically acceptable salts, solvates, prodrugs, metabolites, or isotopic compounds, if stereoisomers exist, may exist as a single tautomer or a mixture thereof, preferably in the form of a more stable tautomer predominantly. For example, when containing the following structural fragments:

[1214] and

[1215] The compounds disclosed herein also include crystalline and amorphous forms of those compounds having the same type of activity, pharmaceutically acceptable salts and active metabolites, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrous forms), conformational polymorphs and amorphous forms of the compounds, and mixtures thereof.

[1216] The compounds described herein may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched to have the same atomic number but a different atomic mass or mass number than those found in nature. All isotopic variants of the compounds disclosed herein, whether or not radioactive, are covered within the scope of this disclosure. For example, hydrogen has three naturally occurring isotopes called 1H (protium), 2H (deuterium), and 3H (tritium). Protium is the most abundant hydrogen isotope in nature. Enrichment of deuterium may provide certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide compounds that can be used to study drug elimination and metabolic pathways in vivo. Isotope-enriched compounds may be prepared using conventional techniques well known to those skilled in the art.

[1217] The quinazoline compounds of Formula I described in this invention, their pharmaceutically acceptable salts, solvates, prodrugs, metabolites, or isotopic compounds, can be synthesized by methods similar to those known in the chemical field, with steps and conditions referencing those of similar reactions in the art, particularly those described herein. Starting materials are typically derived from commercial sources, such as Aldrich, or can be readily prepared using methods known to those skilled in the art (obtainable through online databases such as SciFinder and Reaxys).

[1218] This invention provides a pharmaceutical composition comprising the quinazoline compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate, a prodrug, a metabolite or isotopic compound thereof, and one or more pharmaceutical excipients. In the pharmaceutical composition, the amount of the quinazoline compound of Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite or isotopic compound thereof may be a therapeutically effective amount.

[1219] This invention also provides the use of the above-described quinazoline compounds as shown in Formula I, their pharmaceutically acceptable salts, solvates, prodrugs, metabolites, or isotopic compounds, or the above-described pharmaceutical compositions, in the preparation of KRAS mutant protein inhibitors. In the described application, the KRAS mutant protein may be the KRAS G12D mutant protein; the KRAS mutant protein inhibitor is used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the efficacy of the KRAS G12D mutant protein inhibitor.

[1220] The present invention also provides the use of the above-described quinazoline compounds as shown in Formula I, their pharmaceutically acceptable salts, solvates, prodrugs, metabolites or isotopic compounds, or the above-described pharmaceutical compositions in the preparation of a medicament, wherein the medicament is preferably used for the prevention and / or treatment of cancers mediated by KRAS mutations; the KRAS mutant protein may be a KRAS G12D mutant protein; the cancer may be hematologic malignancies, pancreatic cancer, MYH-related polyposis, colorectal cancer, or lung cancer, etc.

[1221] This invention also provides the use of the above-described quinazoline compounds as shown in Formula I, their pharmaceutically acceptable salts, solvates, prodrugs, metabolites, or isotopic compounds, or the above-described pharmaceutical compositions, in the preparation of a medicament, preferably a medicament for the prevention and / or treatment of cancer. Examples of cancers include hematologic malignancies, pancreatic cancer, MYH-related polyposis, colorectal cancer, or lung cancer.

[1222] This invention also provides the use of the above-described quinazoline compounds as shown in Formula I, their pharmaceutically acceptable salts, solvates, prodrugs, metabolites, or isotopic compounds, or the above-described pharmaceutical compositions, in the preparation of a medicament. The medicament may be used for the prevention and / or treatment of cancers mediated by KRAS mutations, wherein the KRAS mutant protein may be a KRAS G12D mutant protein; and the cancer may be hematological malignancies, pancreatic cancer, MYH-related polyposis, colorectal cancer, or lung cancer, etc.

[1223] This invention also provides the use of the above-described quinazoline compounds as shown in Formula I, their pharmaceutically acceptable salts, solvates, prodrugs, metabolites, or isotopic compounds, or the above-described pharmaceutical compositions, in the preparation of a medicament. The medicament may be a drug for the prevention and / or treatment of cancer. Examples of cancers include hematologic malignancies, pancreatic cancer, MYH-related polyposis, colorectal cancer, or lung cancer.

[1224] This invention also provides a method for treating, preventing, and / or treating cancers mediated by KRAS mutations, comprising administering to a patient a therapeutically effective amount of the aforementioned quinazoline compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate, a prodrug, a metabolite, or an isotopic compound, or a pharmaceutical composition thereof. The cancers include, for example, hematologic malignancies, pancreatic cancer, MYH-related polyposis, colorectal cancer, or lung cancer. The KRAS mutant protein may be a KRAS G12D mutant protein.

[1225] The present invention also provides a method for treating, preventing, and / or treating cancer, comprising administering to a patient a therapeutically effective amount of the above-described quinazoline compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate, a prodrug, a metabolite or isotopic compound thereof, or a pharmaceutical composition thereof. The cancers described include, for example, hematologic malignancies, pancreatic cancer, MYH-related polyposis, colorectal cancer, or lung cancer.

[1226] This disclosure also relates to a method for treating a mammalian hyperproliferative disease, the method comprising administering to said mammal a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[1227] Ras mutations, including but not limited to Ras mutations of K-Ras, H-Ras, or N-Ras that have been identified in hematologic cancers or malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Therefore, some embodiments involve administering the disclosed compound (e.g., in the form of a pharmaceutical composition) to a patient requiring treatment for a hematologic cancer or malignancy.

[1228] In certain specific embodiments, this disclosure relates to a method for treating lung cancer, the method comprising administering an effective amount of any of the above-described compounds (or a pharmaceutical composition comprising the compounds) to a subject in need of it.

[1229] In this invention, the cancers or malignant tumors mentioned include, but are not limited to, leukemia and lymphoma. In some embodiments, the blood diseases mentioned are, for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In some embodiments, the lymphomas mentioned include, for example, all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[1230] In some embodiments of this invention, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, 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, adenomas, carcinoids, and undifferentiated carcinomas.

[1231] In some embodiments of this invention, the cancers mentioned include, for example, acute myeloid leukemia, juvenile cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical malformations, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical malformations, embryonal tumors, germ cell tumors, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). ML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, central nervous system cancers, endometrial cancer, ependymoma, esophageal cancer, granulomatous neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, gonadal germ cell tumors, ocular cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, heart disease, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroblastoma. Endocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma, occult primary, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell carcinoma, fungal infections, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinuses, neuroblastoma of the nasal cavity and sinuses, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer. Oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleural pulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric (stomach) cancer, small cell lung cancer, small bowel 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 tumors, cancers uncommon in childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral cancer. In some embodiments, the non-cancerous hyperplastic diseases mentioned include benign skin hyperplasia (e.g., psoriasis), restenosis, or prostate cancer (e.g., benign prostatic hyperplasia (BPH)).

[1232] Terminology Definition

[1233] The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for patient use. The term "patient" preferably refers to a mammal, and more preferably a human.

[1234] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt as defined herein and possesses all the functions of the parent compound. Pharmaceutically acceptable salts can be prepared by adding a suitable acid to a suitable organic solvent containing an organic base, following conventional methods.

[1235] Examples of salt formation include: For alkali addition salts, it is possible to prepare salts of alkali metals (such as sodium, potassium, or lithium) or alkaline earth metals (such as aluminum, magnesium, calcium, zinc, or bismuth) by treating the compounds of the present invention having suitable acidic protons with alkali metal or alkaline earth metal hydroxides or alkoxides (e.g., ethanol or methanol) or suitable basic organic amines (e.g., diethanolamine, choline, or meglumine) in an aqueous medium.

[1236] Alternatively, for acid addition salts, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; and salts formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheponic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, oxalic acid, pyruvic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, citric acid, cinnamic acid, p-toluenesulfonic acid, or trimethylacetic acid.

[1237] In this invention, the quinazoline compounds, pharmaceutically acceptable salts, solvates, prodrugs, metabolites, or isotopic compounds represented by Formula I can also be obtained by peripheral modification of the prepared quinazoline compounds, pharmaceutically acceptable salts, solvates, prodrugs, metabolites, or isotopic compounds represented by Formula I, using conventional methods in the art.

[1238] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, and ethanol.

[1239] The term "prodrug" refers to a compound obtained by chemically modifying a drug, which has no or low activity in vitro, but releases an active drug in vivo through enzymatic or non-enzymatic conversion to exert its pharmacological effect.

[1240] The term "metabolites" refers to intermediate and final metabolites in metabolism.

[1241] The term "isotopic compound" refers to a compound in which one or more atoms exist in their non-natural abundance form. For example, the non-natural abundance of hydrogen atoms means that approximately 95% of them are deuterium.

[1242] The term "pharmaceutical excipients" can refer to those excipients widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for dissolving the 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 excipients may be inert fillers or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[1243] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[1244] The pharmaceutical compositions of this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, 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, lotions, drops, or serum preparations. Examples of parenteral formulations include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[1245] “Treatment” means any treatment of disease in a mammal, including: (1) preventing disease, i.e. causing the symptoms of clinical disease to not develop; (2) suppressing disease, i.e. preventing the development of clinical symptoms; and (3) alleviating disease, i.e. causing the clinical symptoms to subside.

[1246] "Effective amount" means that when administered to a patient requiring treatment, the amount of the compound is sufficient to (i) treat the relevant disease, (ii) reduce, improve, or eliminate one or more symptoms of a particular disease or condition, or (iii) delay the onset of one or more symptoms of a particular disease or condition described herein. The amount corresponding to this amount of the carbonyl heterocyclic compound as shown in Formula II or its pharmaceutically acceptable salt, or the pharmaceutical composition as described above, will vary depending on factors such as the specific compound, the disease condition and its severity, and the characteristics of the patient requiring treatment (e.g., weight), but nonetheless it can still be routinely determined by those skilled in the art.

[1247] The "prevention" mentioned in this invention refers to the reduction of the risk of acquiring or developing a disease or disorder.

[1248] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and similar alkyl groups. Unless otherwise specified, alkyl groups are unsubstituted.

[1249] The term "cycloalkyl" refers to a stable 3- to 16-membered saturated cyclic group consisting of 2 to 11 carbon atoms. Unless otherwise specified in this specification, a cycloalkyl group can be monocyclic ("monocyclic heterocyclic") or a bicyclic, tricyclic, or more cyclic system, which may include fused (fused ring), bridged (bridged ring), or spirocyclic (spiro ring) ring systems (e.g., bicyclic systems ("bicyclic heterocyclic")). A bicyclic cycloalkyl system may include one or more heteroatoms in one or both rings and is saturated. Unless a substituent is specifically specified, cycloalkyl is unsubstituted.

[1250] The term "heterocyclic alkyl" refers to a stable 3- to 16-membered saturated cyclic group consisting of 2-11 carbon atoms and 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in this specification, a heterocyclic alkyl group can be monocyclic ("monocyclic heterocyclic alkyl") or a bicyclic, tricyclic, or more cyclic system, which may include fused (fused ring), bridged (bridged ring), or spirocyclic (spiro ring) ring systems (e.g., bicyclic systems ("bicyclic heterocyclic alkyl"). A bicyclic alkyl system may include one or more heteroatoms in one or both rings; and is saturated. Unless a substituent is specifically specified, a heterocyclic alkyl group is unsubstituted.

[1251] The term "aryl" refers to either phenyl or naphthyl.

[1252] The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably containing one, two, or three independent aromatic 5-6 membered monocyclic or 9-10 membered bicyclic rings selected from nitrogen, oxygen, and sulfur, such as furanyl, pyridinyl, pyridinyl, pyrazinyl, thiophene, isozolyl, oxazolyl, diazolyl, imidazole, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazole, indolyl, inzolyl, benzothiazolyl, benziisothiazolyl, benzozolyl, benziisozolyl, quinolinyl, isoquinolinyl, etc.

[1253] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[1254] The reagents and raw materials used in this invention are all commercially available.

[1255] The positive and progressive effects of this invention are as follows: the quinazoline compounds provided by this invention have a good inhibitory effect on KRAS G12D mutant protein. Detailed Implementation

[1256] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[1257] Example 1

[1258] 1.1 (Synthesis Method I)

[1259] (R or S)-4-(4-((1R,4R)-2,5-diazabicyclo[2.2.2]octane-2-yl)-6-chloro-2-(3-(dimethylamino)azabicyclobutane-1-yl)-8-fluoroquinazoline-7-yl)naphthol 1a; (S or R)-4-(4-((1R,4R)-2,5-diazabicyclo[2.2.2]octane-2-yl)-6-chloro-2-(3-(dimethylamino)azabicyclobutane-1-yl)-8-fluoroquinazoline-7-yl)naphthol 1b

[1260]

[1261] The synthesis route is shown below:

[1262]

[1263] Step 1

[1264]

[1265] 2-Amino-4-bromo-5-chloro-3-fluorobenzoic acid (15.0 g, 55.9 mmol, 1.0 equivalent) and urea (33.6 g, 558.7 mmol, 10.0 equivalent) were added to a 500 mL round-bottom flask under stirring at 25 °C. The mixture was heated to 150 °C and stirred at this temperature for 6 hours. After the reaction was complete, the temperature was lowered to 25 °C, 750 mL of water was added for dilution, and the mixture was stirred for 30 minutes. The mixture was then filtered, and the filter cake was washed with water (50 mL x 3). The solid was collected and dried under reduced pressure to give the crude product of compound 1-1 (yellow solid, 15.5 g, purity 56%). This compound did not require further purification and was used directly for the next synthesis. MS (ESI, m / z): 290.9 / 292.9 / 294.8 [MH] - ; 1 H NMR (400MHz, DMSO-d6) δ7.79 (d, J = 1.8Hz, 1H), 6.86 (s, 1H), 5.41 (s, 1H).

[1266] Step 2

[1267]

[1268] Compound 1-1 (5.0 g, 56% purity, 9.5 mmol, 1.0 equivalence), N,N-diisopropylethylamine (7.5 mL, 40.9 mmol, 4.3 equivalence), and phosphorus oxychloride (75.0 mL) were added sequentially to a reaction flask under nitrogen protection and stirring at 25°C. The resulting mixture was stirred at 90°C for 5 hours. The reaction process was monitored by liquid chromatography-mass spectrometry and thin-layer chromatography. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove excess reagents. Then, 200 mL of water was added to the crude product, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with 300 mL of saturated brine, 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, eluting with a gradient of 0%–12% ethyl acetate / petroleum ether. The resulting fraction was purified by rotary evaporation under reduced pressure to remove the solvent, yielding compounds 1–2 (yellow solid, 2.2 g, 70% yield). MS (ESI, m / z): 328.8 / 330.8 / 332.8 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.21 (d, J=2.0Hz, 1H).

[1269] Step 3

[1270]

[1271] Under nitrogen-protected stirring at 0°C, an ultra-dry solution of (1R,4R)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (257.0 mg, 1.2 mmol, 1.0 equivalent) in 1.0 mL of 1,4-dioxane (4.0 mL) was added dropwise to a mixture of compounds 1-2 (400.0 mg, 1.2 mmol, 1.0 equivalent), ultra-dry 1,4-dioxane (4.0 mL), and triethylamine (367.6 mg, 3.6 mmol, 3 equivalent). The mixture was reacted at 25°C for 16 h, and the reaction was monitored by liquid chromatography-mass spectrometry and thin-layer chromatography. After the reaction was complete, the crude product was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with a gradient of 10%–36% ethyl acetate / petroleum ether. The solvent was removed from the resulting fraction by rotary evaporation under reduced pressure to give compounds 1–3 (white solid, 550 mg, 90% yield). MS (ESI, m / z): 505.2 / 507.2 / 509.2 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ7.94(s,1H),5.22–5.15(m,1H),4.54–4.50(m,1H),4.33–4.26(m,1H),4.06–3 .97(m,1H),3.83–3.78(m,1H),3.68–3.57(m,1H),2.36–2.10(m,2H),2.02–1.82(m,2H),1.50(s,9H).

[1272] Step 4

[1273]

[1274] Under stirring at room temperature, N,N-diisopropylethylamine (1.9 mL, 10.9 mmol, 10 Equivalent) and 3-(dimethylamino)azacyclobutane dihydrochloride (282.1 mg, 1.6 mmol, 1.5 Equivalent) were added to a solution of N-methylpyrrolidone (5.0 mL) containing compounds 1-3 (550 mg, 1.1 mmol, 1 Equivalent). The resulting mixture was stirred at 60 °C for 2 h, and the reaction was monitored by liquid chromatography-mass spectrometry and thin-layer chromatography. After the reaction was complete, the reaction solution was cooled to 25 °C. The reaction solution was purified directly by reversed-phase rapid chromatography (C18 column) with elution over 20 min using a 50%–95% acetonitrile / water mobile phase (0.1% ammonium bicarbonate); detector: UV 254 nm; to give compounds 1-4 (pale yellow solid, 480 mg, 78% yield). MS(ESI,m / z):569.2 / 571.2 / 573.2[M+H] + ; 1H NMR(300MHz,DMSO-d6)δ7.92(s,1H),4.84(s,1H),4.21–4.16(m,2H),4.10–4.05(m,2H),3.98–3.95(m,1H), 3.86–3.82(m,2H),3.70–3.46(m,2H),3.15–3.07(m,1H),2.19–2.12(m,7H),1.88–1.75(m,3H),1.42(s,9H).

[1275] Step 5

[1276]

[1277] Under nitrogen-protected stirring at 25°C, 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)naphthyl-2-ol (213.3 mg, 0.8 mmol, 1.5 equivalent), potassium phosphate (223.4 mg, 1.0 mmol, 2 equivalent), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (41.4 mg, 0.05 mmol, 0.1 equivalent) were added to a tetrahydrofuran / water (10 / 1, 4 mL) solution of compounds 1-4 (300.0 mg, 0.5 mmol, 1 equivalent). The reaction mixture was stirred at 60°C for 1.5 h, and the reaction process was monitored by liquid chromatography-mass spectrometry and thin-layer chromatography. After the reaction was complete, the reaction solution was cooled to 25°C. The concentrated reaction solution was purified by reversed-phase rapid chromatography (C18 column) using a mobile phase of 50%–95% acetonitrile / water (0.1% ammonium bicarbonate) over 20 minutes; detector: UV 254 nm; yielding compounds 1–5 (a mixture of two stereoisomers, white solid, 240 mg, 72% yield). MS (ESI, m / z): 633.4 / 635.4 [M+H] + .

[1278] Step 6

[1279]

[1280] Compounds 1-5 (240 mg) obtained in step 5 were chirally separated by preparative chiral high-performance liquid chromatography (HPLC): chiral column CHIRALPAK IC, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia), mobile phase B: isopropanol; flow rate: 20 mL / min; elution with 50% of phase B over 23.25 min; detector UV 220 / 210 nm. Two products were obtained, with the shorter retention time (8.87 min) being compound 1-5a, tert-butyl(1R,4R)-5-((R or S)-6-chloro-2-(3-(dimethylamino)azelanoic-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid ester (off-white solid, 90 mg, recovery 38%). The product with a longer retention time (13.91 minutes) was compound 1-5b, tert-butyl(1R,4R)-5-((S or R)-6-chloro-2-(3-(dimethylamino)azelanoic-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid ester (off-white solid, 80 mg, recovery 33%).

[1281] Compounds 1-5a: MS (ESI, m / z): 633.4 / 635.4 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ9.99(s,1H),7.96(s,1H),7.80(d,J=8.3Hz,1H),7.46–7.41 (m,1H),7.27(d,J=2.4Hz,1H),7.22–7.20(m,2H),7.11(d,J=2.4Hz,1H),4.91(s,1H ),4.28–4.19(m,2H),4.15–4.12(m,3H),3.90–3.83(m,2H),3.72–3.63(m,1H),3.56 –3.49(m,1H),3.32–3.30(m,1H),2.24–2.10(s,7H),1.91–1.80(m,3H),1.43(s,9H).

[1282] Compounds 1-5b: MS (ESI, m / z): 633.4 / 635.4 [M+H] + ; 1H NMR(300MHz,DMSO-d6)δ10.06(s,1H),8.04(s,1H),7.87(d,J=8.3Hz,1H),7.5 4–7.48(m,1H),7.34–7.28(m,3H),7.11(d,J=2.4Hz,1H),4.99(s,1H),4.36–4. 27(m,2H),4.21–4.13(m,3H),4.03–3.93(m,2H),3.81–3.72(m,1H),3.64–3.58 (m,1H),3.39–3.37(m,1H),2.35–2.23(s,7H),1.98–1.84(m,3H),1.50(s,9H).

[1283] The chiral resolution methods for some chiral compounds in this application, along with their retention times and ee values, are shown in Table 1 below.

[1284] Table 1

[1285]

[1286]

[1287]

[1288]

[1289]

[1290]

[1291]

[1292]

[1293]

[1294]

[1295]

[1296]

[1297]

[1298]

[1299]

[1300]

[1301]

[1302] Step 7

[1303]

[1304] At 25°C, trifluoroacetic acid (1 mL) was added dropwise to a solution of compounds 1-5a (90 mg, 0.1 mmol, 1.0 equivalence) in dichloromethane (5 mL). After the addition was complete, the reaction mixture was stirred at this temperature for 1 hour, and the reaction was monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase rapid chromatography (C18 column) using a 50%–95% acetonitrile / water mobile phase (0.1% ammonium bicarbonate) over 15 minutes; detector: UV 254 nm; yielding 1a (white solid, 50 mg, 65% yield). Compound 1b (white solid, 45 mg, 67% yield) could be obtained by the same method.

[1305] Compound 1a: MS (ESI, m / z): 533.2 / 535.2 [M+H] + ; 1 H NMR(300MHz, DMSO-d6)δ9.99(s,1H),7.94(d,J=1.7Hz,1H),7.80(d,J=8.3Hz,1H),7.46–7.41(m,1H),7.27(d,J=2.4Hz,1H),7.24–7.18(m,2H),7.0 3(d,J=2.4Hz,1H),4.64(s,1H),4.16–4.00(m,4H),3.86–3.81(m,2H),3. 37–3.35(m,1H),3.12–3.02(m,3H),2.19–2.11(s,7H),1.89–1.70(m,3H); 19 F NMR (282 MHz, DMSO-d6) δ -123.51. Chiral analysis conditions for compound 1a were: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 1.946 min; ee > 99%.

[1306] Compound 1b: MS (ESI, m / z): 533.2 / 535.2 [M+H] + ; 1H NMR(300MHz, DMSO-d6)δ9.98(s,1H),7.94(d,J=1.7Hz,1H),7.80(d,J=8.3Hz,1H),7.46–7.41(m,1H),7.27(d,J=2.4Hz,1H),7.24–7.22(m,2H),7.0 3(d,J=2.4Hz,1H),4.64(s,1H),4.16–4.00(m,4H),3.86–3.81(m,2H),3. 37–3.35(m,1H),3.12–3.02(m,3H),2.19–2.11(s,7H),1.89–1.70(m,3H); 19 F NMR (282 MHz, DMSO-d6) δ -123.50. Chiral analysis conditions for compound 1b were: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 5.115 min; ee > 99%.

[1307] Other similar compounds of this application can be prepared by the synthetic method shown in Example 1 above. Table 2 below shows some of the compounds prepared according to the above synthetic method and their characterization data.

[1308] Table 2

[1309]

[1310]

[1311]

[1312]

[1313]

[1314]

[1315]

[1316]

[1317]

[1318]

[1319]

[1320]

[1321]

[1322]

[1323]

[1324]

[1325]

[1326]

[1327]

[1328]

[1329]

[1330]

[1331]

[1332]

[1333]

[1334]

[1335]

[1336]

[1337] 1.2 Confirmation of the configuration of compound 4a

[1338] Single crystal cultivation and data collection

[1339] 1) Single crystal cultivation

[1340] First, 5 mg of compound 4a (batch number #EB2106527-197C1) was dissolved in 0.5 mL of MeOH and filtered into a clean sample vial. A small amount of polymer HPMCP was added to the filtrate as a template. The vial was then sealed with a perforated sealing film and placed in a fume hood for slow evaporation at room temperature. After one day, long, sheet-like single crystals were obtained. This single crystal sample was then used for single-crystal X-ray diffraction analysis.

[1341] 2) Instruments and parameters

[1342] Single-crystal X-ray data for compound 4a were collected using a Bruker D8 Venture diffractometer with a Ga target Kα radiation source (λ = 1 / 2). During data collection, the crystal was maintained at 296K. Single-crystal structure analysis was performed in Olex2 software. The initial structure was calculated using the Intrinsic Phasing method of the SHELXT program, and the structure was refined using the least squares method of the SHELXL program.

[1343] Single-crystal X-ray diffraction analysis

[1344] Compound 4a has a single-crystal structure belonging to the orthorhombic crystal system, space group P212121, and its molecular formula is C. 29 H 30 ClFN6O·CH4O. Each asymmetric unit contains one molecule of compound 4a and one molecule of MeOH, and each unit cell contains four asymmetric units. The refined crystal structure parameters are shown in Table 17.

[1345] Table 17. Crystallographic data and structural refinement parameters of compound 4a

[1346]

[1347]

[1348] As can be seen from the above, the configuration of compound 4a is as follows:

[1349]

[1350] Example 2 (Synthesis Method II)

[1351] (R or S)-4-(6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-4-(piperidin-4-yl)quinazolin-7-yl)naphth-2-phenol 20a; (S or R)-4-(6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-4-(piperidin-4-yl)quinazolin-7-yl)naphth-2-phenol 20b

[1352]

[1353] The synthesis route is shown below:

[1354]

[1355] Step 1:

[1356]

[1357] At room temperature, compounds 1-2 (1.5 g, 4.5 mmol, 1.0 equivalence) and 1-(tert-butyl)-4-methylpiperidine-1,4-dicarboxylate (1.1 g, 4.5 mmol, 1.0 equivalence) were added sequentially to a 50 mL Shrek tube. Nitrogen gas was purged three times. Under a nitrogen atmosphere, anhydrous tetrahydrofuran (15 mL) was added. The mixture was cooled to -78°C, and bis(trimethylsilylaminolithium) (6.8 mL, 6.8 mmol, 1.5 equivalence) was added dropwise. After the addition was complete, the mixture was brought back to room temperature and stirred for 2 hours. The reaction was monitored by liquid chromatography-mass spectrometry and thin-layer chromatography. After the reaction was complete, the reaction was quenched with 0.5 M sodium dihydrogen phosphate (20 mL), and then extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with 200 mL of saturated brine, 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, eluting with a gradient of 0%–20% ethyl acetate / petroleum ether. The solvent was removed from the resulting fraction by rotary evaporation under reduced pressure to give compound 20-1 (yellow solid, 0.79 g, 33% yield). MS (ESI, m / z): 480.0 / 482.0 / 484.0 [M- t Bu+H] + ; 1 H NMR (300MHz, CDCl3) δ7.98(d,J=2.0Hz,1H),3.75–3.69(m,2H),3.65(s,3H),3.61–3.47(m,2H),2.48-2.32(s,4H),1.45(s,9H).

[1358] Step 2:

[1359]

[1360] Under stirring at room temperature, N,N-diisopropylethylamine (2.5 mL, 14.7 mmol, 10 Equivalent) and 3-(dimethylamino)azacyclobutane dihydrochloride (381.8 mg, 2.2 mmol, 1.5 Equivalent) were added to an N-methylpyrrolidone (8.0 mL) solution of compound 20-1 (790 mg, 1.5 mmol, 1 Equivalent) and stirred at 60 °C for 2 h. The reaction was monitored by liquid chromatography-mass spectrometry and thin-layer chromatography. After the reaction was complete, the reaction solution was cooled to 25 °C. The reaction solution was purified directly by reversed-phase rapid chromatography (C18 column) with elution over 20 min using a 50%–95% acetonitrile / water mobile phase (0.1% ammonium bicarbonate); detector: UV 254 nm; yielding compound 20-2 (pale yellow oily liquid, 450 mg, yield 51%). MS(ESI,m / z):600.2 / 602.2 / 604.2[M+H] +.

[1361] Step 3:

[1362]

[1363] Compound 20-2 (450 mg, 0.75 mmol, 1 equivalent) was added to a reaction flask at room temperature, followed by dimethyl sulfoxide (5.0 mL) and water (0.5 mL), and finally lithium chloride (159 mg, 3.7 mmol, 5 equivalent). The resulting mixture was stirred at 150°C for 3 hours, and the reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was cooled to 25°C. The reaction solution was purified directly by reversed-phase rapid chromatography (C18 column) with elution over 20 minutes using a 50%–95% acetonitrile / water mobile phase (0.1% ammonium bicarbonate); detector: UV 254 nm; yield: compound 20-3 (pale yellow solid, 200 mg, 49% yield). MS (ESI, m / z): 542.2 / 544.2 / 546.2 [M+H] + ; 1 H NMR (300MHz, CDCl3) δ7.76(d,J=2.0Hz,1H),4.28(m,4H),4.09(m,2H),3.42–3.30(m,1H),3.28–3.17(m,1H),2.94(m,2H),2.24(s,6H),1.87(m, 4H),1.49(s,9H).

[1364] Step 4:

[1365]

[1366] Under nitrogen-protected stirring at 25°C, 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)naphthyl-2-ol (149 mg, 0.6 mmol, 1.5 equivalent), potassium phosphate (170 mg, 0.8 mmol, 2 equivalent), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (31 mg, 0.04 mmol, 0.1 equivalent) were added to a tetrahydrofuran / water (10 / 1, 4 mL) solution of compound 20-3 (200 mg, 0.4 mmol, 1 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)naphthyl-2-ol (149 mg, 0.6 mmol, 1.5 equivalent), potassium phosphate (170 mg, 0.8 mmol, 2 equivalent), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (31 mg, 0.04 mmol, 0.1 equivalent)). The resulting mixture was stirred at 60°C for 1.5 h, and the reaction was monitored by liquid chromatography-mass spectrometry and thin-layer chromatography. After the reaction was complete, the reaction solution was cooled to 25°C. The concentrated reaction solution was purified by reversed-phase rapid chromatography (C18 column) using a mobile phase of 50%–95% acetonitrile / water (0.1% ammonium bicarbonate) over 20 minutes; detector: UV 254 nm; yield: compound 20-4 (a mixture of two stereoisomers, pale yellow solid, 200 mg, 89% yield). MS (ESI, m / z): 606.3 / 608.3 [M+H] + ; 1 H NMR(300MHz, CDCl3)δ7.83(d,J=1.6Hz,1H),7.71(d,J=8.3Hz,1H),7.44–7.36(m,1H),7.28–7.25(m,2H),7.23–7.16(m,1H),7.05 (d,J=2.4Hz,1H),4.34(m,4H),4.16(m,2H),3.45(s,1H),3.32–3.19(m,1H),2.98(s,2H),2.27(s,6H),1.91(m,4H),1.49(s,9H).

[1367] Step 5:

[1368]

[1369] Compound 20-4 (240 mg) obtained in step 4 was chirally resolved by preparative chiral high-performance liquid chromatography: chiral column Lux 5 μm Cellulose-4, 2.12 x 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 30% of phase B over 15 min; detector UV 220 / 210 nm. Two products were obtained. The product with the shorter retention time (7.5 min) was compound 20-4a, tert-butyl(R or S)-4-(6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)piperidine-1-carboxylic acid ester (pale yellow solid, 85 mg, recovery 42%), MS (ESI, m / z): 606.3 / 608.3 [M+H] + The product with a longer retention time (11.8 minutes) was compound 20-4b, tert-butyl(S or R)-4-(6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)piperidine-1-carboxylic acid ester (pale yellow solid, 75 mg, recovery 37%), MS (ESI, m / z): 606.3 / 608.3 [M+H] + .

[1370] Step 6:

[1371]

[1372] At 25°C, under stirring, trifluoroacetic acid (1 mL) was added dropwise to a dichloromethane (3 mL) solution of compound 20-4a (85 mg, 0.1 mmol, 1.0 equivalence). After the addition was complete, the reaction mixture was stirred at this temperature for 1 hour, and the reaction process was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase rapid chromatography (C18 column) using a 50%–95% acetonitrile / water mobile phase (0.1% ammonium bicarbonate) over 15 minutes; detector: UV 254 nm; yielding 20a (pale yellow solid, 22 mg, yield 31%). Compound 20b (pale yellow solid, 33 mg, yield 52%) could be obtained by the same method.

[1373] Compound 20a: MS (ESI, m / z): 506.2 / 508.2 [M+H] + ; 1H NMR(300MHz, DMSO-d6)δ8.25(s,1H),7.81(d,J=8.3Hz,1H),7.44(m,1H),7.31–7.14(m,3H),7.06(d,J=2.4Hz, 1H),4.18(m,2H),3.95(m,2H),3.70(s,1H),3.17(m,1H),3.07(m,2H),2.79(m,2H),2.14(s,6H),1.79(s,4H). The chiral analysis conditions for compound 20a were as follows: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 1.433 min; ee > 99%.

[1374] Compound 20b: MS (ESI, m / z): 506.2 / 508.2 [M+H] + ; 1 H NMR(300MHz, DMSO-d6)δ8.25(s,1H),7.81(d,J=8.3Hz,1H),7.44(m,1H),7.31–7.14(m,3H),7.06(d,J=2.4Hz, 1H),4.18(m,2H),3.95(m,2H),3.70(s,1H),3.17(m,1H),3.07(m,2H),2.79(m,2H),2.14(s,6H),1.79(s,4H). The chiral analysis conditions for compound 20b were as follows: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 1.905 min; ee > 98%.

[1375] Example 3

[1376] (S or R)-4-(4-(azacyclobutane-3-yl)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoroquinazoline-7-yl)naphth-2-phenol bis(trifluoroacetate) 21a; (R or S)-4-(4-(azacyclobutane-3-yl)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoroquinazoline-7-yl)naphth-2-phenol bis(trifluoroacetate) 21b

[1377]

[1378] Step 1:

[1379]

[1380] Compound 21-4 was synthesized according to Example 2 (Synthetic Method II). Compound 21-4 (pale yellow solid): MS (ESI, m / z): 578.3 / 580.3 [M+H] + .

[1381] Step 2:

[1382]

[1383] Compound 21-4 (210 mg) obtained in step 1 was chirally separated by preparative chiral high-performance liquid chromatography: chiral column NB_Lux 5 μm i-Cellulose-5, 2.12 x 25 cm, 5 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.5% 2 mol / L ammonia-methanol), mobile phase B: isopropanol; flow rate: 18 mL / min; elution with 30% of phase B over 30 min; detector UV 220 nm. Two products were obtained. The product with the shorter retention time (5.8 minutes) was compound 21-4a, (S or R)-3-(6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphthyl-1-yl)quinazoline-4-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (pale yellow solid, 97 mg, recovery 46%). The product with the longer retention time (13.1 minutes) was compound 21-4b, (R or S)-3-(6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphthyl-1-yl)quinazoline-4-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (pale yellow solid, 100 mg, recovery 47%).

[1384] Step 3:

[1385]

[1386] At 25°C, under stirring, trifluoroacetic acid (1.5 mL) was added dropwise to a solution of compound 21-4a (97 mg, 0.16 mmol, 1.0 equivalence) in dichloromethane (4.5 mL). After the addition was complete, the reaction mixture was allowed to continue reacting at this temperature for 1 hour, and the reaction process was monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) under the following conditions: XSelect CSH Prep C18 OBD Column, 19 x 150 mm, 5 μm; mobile phase A: water (0.05% trifluoroacetic acid); mobile phase B: acetonitrile; flow rate: 25 mL / min; elution gradient: 2% B phase for 2 min, followed by a 2% → 9% B phase gradient for 2.5 min, and finally a 9% → 30% B phase gradient for 9.5 min; detector: UV 254 / 220 nm; yield 21a (yellow solid, 72 mg, 63% yield). Compound 21b (pale yellow solid, 76 mg, 65% yield) was obtained using the same method.

[1387] Compound 21a: MS (ESI, m / z): 478.2 / 480.2 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ7.96(d,J=1.6Hz,1H),7.78(d,J=8.3Hz,1H),7.46–7.41(m,1H),7.29(d,J=2.4Hz,1H),7 .23–7.16(m,2H),7.03(d,J=2.4Hz,1H),5.09–4.98(m,1H),4.72–4.51(m,8H),4.40–4.26(m,1H),3.00(s,6H); 19 F NMR (282 MHz, CD3OD) δ -77.76, -125.02. The chiral analysis conditions for compound 21a were: CHIRALPAK IC-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 10 min; detector: UV 220 / 254 nm; retention time: 3.80 min; ee > 99%.

[1388] Compound 21b: MS (ESI, m / z): 478.2 / 480.2 [M+H] + ; 1H NMR(300MHz,CD3OD)δ7.96(d,J=1.6Hz,1H),7.78(d,J=8.3Hz,1H),7.46–7.41(m,1H),7.29(d,J=2.4Hz,1H),7 .23–7.16(m,2H),7.03(d,J=2.4Hz,1H),5.09–4.98(m,1H),4.72–4.51(m,8H),4.40–4.26(m,1H),3.00(s,6H); 19 F NMR (282 MHz, CD3OD) δ -77.93, -125.02. The chiral analysis conditions for compound 21b were: CHIRALPAK IC-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 5.950 min; ee > 99%.

[1389] Example 4 (Synthesis Method III)

[1390] (S or R)-3-(6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)azacyclobutane-3-carboxamide bis(trifluoroacetate) 22a; (R or S)-3-(6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)azacyclobutane-3-carboxamide bis(trifluoroacetate) 22b

[1391]

[1392] The synthesis route is shown below:

[1393]

[1394] Step 1:

[1395]

[1396] Compounds 1-2 (2.0 g, 5.75 mmol, 1.0 equivalent) and methyl 1-(tert-butoxycarbonyl)azacyclobutane-3-carboxylate (1.3 g, 5.75 mmol, 1.0 equivalent) were added sequentially to a 50 mL Shrek tube under stirring at 25°C. The mixture was purged three times with nitrogen. Anhydrous tetrahydrofuran (20 mL) was then added under a nitrogen atmosphere, and the mixture was cooled to -78°C. Bistrimethylsilylaminolithium (1.2 mol / L tetrahydrofuran solution, 5.6 mL, 6.90 mmol, 1.2 equivalent) was added dropwise to the mixture. After the addition was complete, the mixture was slowly brought to room temperature and the reaction continued for 2 hours. The reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was quenched with 0.5 mol / L sodium dihydrogen phosphate solution (20 mL) and extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting with a gradient of 0%–20% ethyl acetate / petroleum ether. The resulting fraction was purified by rotary evaporation under reduced pressure to remove the solvent, yielding compound 22-1 (yellow solid, 1.9 g, 64% yield). MS (ESI, m / z): 508.1 / 510.1 / 512.1 [M+H] + ; 1 H NMR (300MHz, CDCl3) δ7.53 (d, J = 2.0Hz, 1H), 4.73–4.67 (m, 4H), 3.76 (s, 3H), 1.47 (s, 9H).

[1397] Step 2:

[1398]

[1399] Under stirring at 25°C, N,N-diisopropylethylamine (4.7 g, 36.36 mmol, 10.0 equivalence) and 3-(dimethylamino)azacyclobutane dihydrochloride (940 mg, 5.43 mmol, 1.5 equivalence) were added to a solution of compound 22-1 (1.85 g, 3.63 mmol, 1.0 equivalence) in 18.0 mL of N-methylpyrrolidone. The mixture was reacted at 60°C for 2 h, and the reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was cooled to 25°C. The reaction solution was purified directly by reversed-phase rapid chromatography (C18 column) with elution of 50%–95% acetonitrile / water (0.1% ammonium bicarbonate) over 20 min; detector: UV 254 nm; to give compound 22-2 (yellow solid, 450 mg, yield 51%). MS(ESI, m / z): 572.1 / 574.1 [M+H] + ; 1H NMR (300MHz, CDCl3) δ7.23 (d, J = 1.9 Hz, 1H), 4.63–4.59 (m, 4H), 4.42–4.18 (m, 4H), 3.73 (s, 3H), 3.39–3.32 (s, 1H), 2.34 (s, 6H), 1.47 (s, 9H).

[1400] Step 3:

[1401]

[1402] Compound 22-2 (380 mg, 0.65 mmol, 1.0 equivalence) and 7 mol / L ammonia-methanol solution (20 mL) were added to a 100 mL sealed container at 25°C. The mixture was reacted at 50°C for 16 hours under sealed conditions. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated to give crude product 22-3 (yellow solid, 370 mg). This crude product was used directly for the next step without further purification. MS (ESI, m / z): 557.2 / 559.2 [M+H] + .

[1403] Step 4:

[1404]

[1405] Under nitrogen protection and stirring at 25°C, 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)naphthol (349 mg, 1.50 mmol, 1.5 equivalence), sodium carbonate (182 mg, 3.00 mmol, 2.0 equivalence), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (70 mg, 0.15 mmol, 0.1 equivalence) were added to a 1,4-dioxane / water (5 / 1, 5.0 mL) solution of compound 22-3 (370 mg), along with stirring. The mixture was reacted at 80°C under a nitrogen atmosphere for 1.5 h, with the reaction process monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was cooled to 25°C and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted using a 0% → 10% methanol / dichloromethane gradient. The resulting fraction was subjected to rotary evaporation under reduced pressure to remove the solvent, yielding compound 22-4 (a mixture of two stereoisomers, brown solid, 385 mg, 93% yield). MS (ESI, m / z): 621.2 / 623.2 [M+H] + .

[1406] Step 5:

[1407]

[1408] Compound 22-4 (385 mg) obtained in step 4 was subjected to chiral resolution under the following conditions: chiral column: CHIRALPAK ID, 2 x 25 cm, 5 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.5%, 2 mol / L ammonia-methanol solution); mobile phase B: isopropanol; flow rate: 20 mL / min; gradient: elution with 30% phase B over 13 min; detector: UV 220 nm; two products were obtained. The compound with the shorter retention time (4.02 min) was 22-4a, (S or R)-3-carbamoyl-3-(6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-( 3-Hydroxynaphth-1-yl)quinazolin-4-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (yellow solid, 166 mg, recovery 43%); the compound with a longer retention time (7.55 min) is 22-4b, (R or S)-3-carbamoyl-3-(6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (yellow solid, 157 mg, recovery 40%).

[1409] Step 6:

[1410]

[1411] Trifluoroacetic acid (1.5 mL) was added dropwise to a solution of compound 22-4a (160 mg, 0.26 mmol, 1.0 equivalence) in dichloromethane (4.5 mL) under stirring at 25°C. The mixture was reacted at this temperature for 1 hour, and the reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reversed-phase chromatography (C18 column) with elution over 15 minutes using a mobile phase of 2%–32% acetonitrile / water (0.05% TFA); detector: UV 254 / 220 nm; to obtain compound 22a (yellow solid, 139.2 mg, yield 72%). Compound 22b (yellow solid, 128.8 mg, yield 71%) could be obtained by the same method.

[1412] Compound 22a: MS (ESI, m / z): 521.3 / 523.2 [M+H] + ; 1H NMR(300MHz,DMSO-d6)δ10.91(s,1H),10.11(s,1H),9.37(s,1H),9.19(s, 1H),7.84–7.81(m,2H),7.52(d,J=1.5Hz,1H),7.48–7.40(m,2H),7.31(d, J=2.4Hz,1H),7.26–7.21(m,1H),7.13(d,J=8.4Hz,1H),7.06(d,J=2.4Hz, 1H),4.76–4.70(m,4H),4.53–4.42(m,4H),4.33–4.26(m,1H),2.86(s,6H); 19 FNMR (282 MHz, DMSO-d6) δ -73.69, -122.74. The chiral analysis conditions for compound 22a were: CHIRALPAK ID-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 8 min; detector: UV 220 / 254 nm; retention time: 3.40 min; ee > 99%.

[1413] Compound 22b: MS (ESI, m / z): 521.15 / 523.15 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ10.91(s,1H),10.11(s,1H),9.37(s,1H),9.19(s, 1H),7.84–7.81(m,2H),7.52(d,J=1.5Hz,1H),7.48–7.40(m,2H),7.31(d, J=2.4Hz,1H),7.26–7.21(m,1H),7.13(d,J=8.4Hz,1H),7.06(d,J=2.4Hz, 1H),4.76–4.70(m,4H),4.53–4.42(m,4H),4.33–4.26(m,1H),2.86(s,6H). 19 FNMR (282 MHz, DMSO-d6) δ -73.80, -122.74. Chiral analysis conditions for compound 22b were: CHIRALPAK ID-3, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 8 min; detector: UV 220 / 254 nm; retention time: 5.31 min; ee > 99%.

[1414] Example 5 (Synthesis Method IV)

[1415] (S or R)-4-(6-chloro-4-(1,4-diaza-1-yl)-2-(3-(dimethylamino)azacyclobutan-1-yl)-8-fluoroquinazolin-7-yl)naphth-2-phenol 23

[1416]

[1417] The synthesis route is shown below:

[1418]

[1419] Step 1:

[1420]

[1421] Sodium methoxide (0.98 g, 17.23 mmol, 1.2 equivalence) was added to a 1-2 (5 g, 14.38 mmol, 1.00 equivalence) methanol (5 mL) solution under nitrogen atmosphere with stirring. The mixture was reacted at 25°C for 4 hours under nitrogen atmosphere, and the reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted by a gradient of 0% → 10% ethyl acetate / petroleum ether. The obtained fraction was subjected to rotary evaporation under reduced pressure to remove the solvent, giving compound 23-1 (pale yellow solid, 4.3 g, 87% yield). MS (ESI, m / z): 324.9 / 326.9 / 328.9 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.06 (d, J=2.0Hz, 1H), 4.25 (s, 3H).

[1422] Step 2:

[1423]

[1424] Under nitrogen protection and stirring at 25°C, 3-(dimethylamino)azacyclobutane dihydrochloride (3.42 g, 19.76 mmol, 1.5 equivalence) and N,N-diisopropylethylamine (8.53 g, 66.00 mmol, 5.0 equivalence) were added to a solution of 23-1 (4.3 g, 13.19 mmol, 1.00 equivalence) in 43.0 mL of N-methylpyrrolidone. The mixture was reacted at 60°C for 2 h under nitrogen atmosphere. The reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was cooled to 25°C. The reaction solution was purified directly by reversed-phase chromatography (C18 column) with elution over 25 min using a 5%–95% acetonitrile / water mobile phase (0.1% ammonia); detector: UV 254 / 220 nm, to give compound 23-2 (white solid, 4.9 g, 95% yield). MS(ESI,m / z):389.0 / 391.0 / 393.0[M+H] + ; 1 H NMR (300MHz, CDCl3) δ7.83 (d, J = 1.9Hz, 1H), 4.31–4.25 (m, 2H), 4.12–4.07 (m, 5H), 3.28–3.20 (m, 1H), 2.26 (s, 6H).

[1425] Step 3:

[1426]

[1427] Under nitrogen-protected stirring at 25°C, water (5.0 mL), potassium phosphate (4.36 g, 19.50 mmol, 1.00 equivalence) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)naphthol (3.61 g, 12.68 mmol, 1.3 equivalence) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (810 mg, 0.98 mmol, 0.10 equivalence) were added sequentially to a tetrahydrofuran (50.0 mL) solution of compound 23-2 (4 g, 9.75 mmol, 1.00 equivalence) at 50.0 mL. The mixture was reacted at 65°C for 2 h under nitrogen atmosphere. The reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was cooled to 25°C and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted by a 0% → 10% methanol / dichloromethane gradient. The solvent in the resulting fraction was removed by rotary evaporation under reduced pressure to give compound 23-3 (off-white solid, 4 g, 90% yield). MS (ESI, m / z): 453.2 / 455.2 [M+H] + ; 1H NMR(300MHz, CDCl3)δ7.83(d,J=1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.38–7.34(m,1H),7.25–7.23(m,2H),7 .17–7.13(m,1H),7.06–7.04(m,1H),4.35–4.26(m,2H),4.17–4.07(s,5H),3.23–3.17(m,1H),2.23(s,6H).

[1428] Step 4:

[1429]

[1430] Hydrochloric acid aqueous solution (4 mol / L, 10.0 mL) was added to a tetrahydrofuran (50.0 mL) solution of compound 23-3 (4 g, 8.39 mmol, 1.00 equivalent) under stirring at 25°C. The mixture was reacted at 80°C for 2 h under a nitrogen atmosphere. The reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was completed, the reaction solution was cooled to 25°C and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted by a 0% → 20% dichloromethane / methanol gradient. The obtained fraction was subjected to rotary evaporation under reduced pressure to remove the solvent, giving compound 23-4 (a mixture of two stereoisomers, pale yellow solid, 2.6 g, 70% yield). MS (ESI, m / z): 439.1 / 441.1 [M+H] + ; 1 H NMR (300MHz, DMSO-d6) δ11.85(s,1H),9.99(s,1H),7.89(d,J=1.5Hz,1H),7.80(d,J=8.3Hz,1H),7.46–7.41(m,1H ),7.27–7.17(m,3H),7.03(d,J=2.4Hz,1H),4.18–4.08(m,2H),3.94–3.89(m,2H),3.17–3.11(m,1H),2.11(s,6H).

[1431] Step 5:

[1432]

[1433] Compound 23-4 (2.6 g) obtained in step 4 was subjected to chiral resolution under the following conditions: chiral column NB_CHIRALPAK AD-H, 3 x 25 cm, 5 μm; mobile phase A: supercritical carbon dioxide fluid, mobile phase B: methanol; flow rate: 60 mL / min; column temperature: 35 °C; elution with 55% mobile phase B for 15 min; UV detector 215 nm; two products were obtained. The compound with the shortest retention time (5.46 min) was 23-4a, (S or R)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazoline-4-phenol (pale yellow solid, 1.23 g, 47% recovery); the compound with the longer retention time (9.15 min) was 23-4b, (R or S)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazoline-4-phenol (pale yellow solid, 1.25 g, 48% recovery).

[1434] Step 6:

[1435]

[1436] Under nitrogen atmosphere and stirring, a solution of compound 23-4b (100 mg, 0.23 mmol, 1.00 equivalence) in N-methylpyrrolidone (2.0 mL) was treated with tripyrrolylphosphonium hexafluorophosphate (318 mg, 0.68 mmol, 3.0 equivalence) and triethylamine (138 mg, 1.37 mmol, 6.00 equivalence). The mixture was reacted at 25°C for 0.5 h under nitrogen atmosphere. Then, tert-butyl 1,4-diazacycloheptan-1-carboxylate (68 mg, 0.34 mmol, 1.5 equivalence) was added to the reaction mixture, and the reaction was continued at 25°C for another 1.5 h. The reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction, the reaction solution was directly purified by reversed-phase chromatography (C18 column) using a mobile phase of 5%–95% acetonitrile / methanol 1 / 1 / water (0.1% ammonium bicarbonate) over 25 minutes; detector: UV 254 / 220 nm; yielding compound 23-5 (pale yellow solid, 75 mg, yield 52%). MS (ESI, m / z): 621.2 / 623.2 [M+H] + ; 1HNMR (300MHz, CDCl3) δ7.72–7.68(m,2H),7.39–7.31(m,2H),7.26(d,J=2.4Hz,1H),7.21–7.15(m,2H),4.35–4.25(m,2H),4.15–3.9 0(m,4H),3.78–3.56(m,4H),3.53–3.40(m,1H),3.22–3.16(m,2H),2.24–2.09(m,7H),1.85–1.81(m,1H),1.47(s,5H),1.40(s,4H).

[1437] Step 7:

[1438]

[1439] Trifluoroacetic acid (1 mL) was added dropwise to a solution of compound 23-5 (75 mg, 0.12 mmol, 1.00 equivalence) in dichloromethane (3 mL) under stirring at room temperature. The mixture was reacted at 25°C for 1 h, and the reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reversed-phase chromatography (C18 column) with elution over 25 min using a 5%–95% (acetonitrile / methanol 1 / 1) / water mobile phase (0.1% ammonium bicarbonate); detector: UV 254 / 220 nm; to obtain compound 23 (white solid, 21.0 mg, 35% yield). MS (ESI, m / z): 521.2 / 523.2 [M+H] + ; 1 H NMR (300MHz, DMSO-d6) δ9.99 (s, 1H), 7.90 (d, J = 1.7Hz, 1H), 7.80 (d, J = 8.3Hz, 1H),7.46–7.41(m,1H),7.26(d,J=2.4Hz,1H),7.23–7.21(m,2H),7.04(d,J=2. 4Hz,1H),4.10–4.05(m,2H),3.98–3.90(m,4H),3.87–3.82(m,2H),3.15–3.08 (m,1H),3.07–3.01(m,2H),2.83–2.78(m,2H),2.11(s,6H),1.97–1.90(m,2H); 19 F NMR(282MHz,DMSO-d6)δ-123.51.

[1440] The chiral separation conditions for some chiral compounds prepared by the synthetic method shown in Example 5 (Synthetic Method IV) are as follows:

[1441]

[1442] Chiral column: CHIRALPAK ID, 2 x 25 cm, 5 μm; mobile phase A: n-hexane / methyl tert-butyl ether = 1 / 1 (0.5% 2 mol / L ammonia-methanol solution), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: elution with 30% of phase B over 12 min, detector UV 220 nm. Two products were obtained, with the shorter retention time (9.14 min) for compound 27-5a, tert-butyl(1R,6S or 1S,6R)-5-((S or R)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylic acid ester (white solid). Compound 27-5b, a white solid, was found to have a longer retention time (11.442 minutes). Compound 27-5a was a white solid. Compound 27-5a was obtained by removing the protecting group from compound 27; compound 27-5b was obtained by removing the protecting group from compound 28.

[1443]

[1444] Chiral column: CHIRAL ART Amylose-SA, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol solution), mobile phase B: isopropanol; flow rate: 20 mL / min; gradient: elution with 40% phase B over 16 min, detector UV 220 nm. Two products were obtained. The compound with the shorter retention time (6.5 min) was 35-5a, tert-butyl(3aR, 6aR or 3aS, 6aS)-4-((S or R)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)hexahydropyrrole[3,2-b]pyrrole-1(2H)-carboxylic acid ester (white solid). The compound with the longest retention time (13.5 minutes) was 35-5b, tert-butyl(3aS, 6aS or 3aR, 6aR)-4-((S or R)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)hexahydropyrrole[3,2-b]pyrrole-1(2H)-carboxylic acid ester (white solid). Compound 35-5a was deprotected to give compound 35; compound 35-5b was deprotected to give compound 36.

[1445]

[1446] Chiral column: CHIRALPAK ID, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol solution), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: elution with 30% of phase B over 25 min, detector UV 220 / 254 nm. Two products were obtained. The compound with the shorter retention time (11.46 min) was 37-5a, tert-butyl(1S,5S or 1R,5R)-8-((S or R)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)-6,8-diazabicyclo[3.2.2]nonane-6-carboxylic acid ester (white solid). The compound with the longest retention time (18.52 minutes) was 37-5b, tert-butyl(1R,5R or 1S,5S)-8-((S or R)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)-6,8-diazabicyclo[3.2.2]nonane-6-carboxylic acid ester (white solid). Compound 37-5a was deprotected to give compound 37; compound 37-5b was deprotected to give compound 38.

[1447] Other similar compounds of this application can be prepared by the synthetic method shown in Example 5 (Synthetic Method IV) above. Table 3 below shows some of the compounds prepared according to the above synthetic method and their characterization data.

[1448] Table 3

[1449]

[1450]

[1451]

[1452]

[1453]

[1454]

[1455]

[1456]

[1457]

[1458] Example 6 (Synthesis Method V)

[1459] (S or R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-8-fluoro-2-((S)-1-methylpyrrolidone-2-yl)methoxy)quinazolin-7-yl)naphthol 39a; (R or S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-8-fluoro-2-((S)-1-methylpyrrolidone-2-yl)methoxy)quinazolin-7-yl)naphthol 39b

[1460]

[1461] The synthesis route is shown below:

[1462]

[1463] Step 1:

[1464]

[1465] Compound 1-2 (8 g, 23.00 mmol, 1.00 equivalent) was dissolved in 80 mL of dichloromethane under nitrogen protection and stirring at 25°C. Triethylamine (7.35 g, 69.00 mmol, 3.0 equivalent) and (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (5.14 g, 23.00 mmol, 1.00 equivalent) were added sequentially to this solution, and the reaction was carried out at 25°C for 1 h, monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted using a gradient of 0% → 10% ethyl acetate / dichloromethane. The resulting fraction was subjected to rotary evaporation under reduced pressure to remove the solvent, yielding compound 39-1 (white solid, 10.00 g, yield 81%). MS(ESI,m / z):505.0 / 507.0 / 509.0[M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.75 (d, J = 2.0Hz, 1H), 4.45–4.33 (m, 4H), 3.72–3.56 (m, 2H), 1.98–1.94 (m, 2H), 1.75–1.68 (m, 2H), 1.52 (s, 9H).

[1466] Step 2:

[1467]

[1468] Under nitrogen protection at 25°C, N-methyl-L-proline (238 mg, 1.96 mmol, 1.5 Equivalent) and potassium carbonate (497 mg, 3.42 mmol, 2.6 Equivalent) were added to a 5.0 mL solution of compound 39-1 (700 mg, 1.31 mmol, 1.00 Equivalent) in acetonitrile. The mixture was reacted at 80°C for 16 h under nitrogen atmosphere, and the reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was completed, the reaction solution was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted by a 0% → 10% methanol / dichloromethane gradient. The solvent was removed from the resulting fraction by rotary evaporation under reduced pressure to give compound 39-2 (white solid, 400 mg, 49% yield). MS (ESI, m / z): 584.3 / 586.3 / 588.3 [M+H] + ; 1 H NMR(400MHz, CDCl3) δ7.69(d,J=2.0Hz,1H),4.55–4.51(m,1H),4.37–4.27(m,5H),3.61–3.52(m,2H),3.15–3.1 0(m,1H),2.78–2.72(m,1H),2.52(s,3H),2.35–2.27(m,1H),2.11–2.02(m,1H),1.96–1.75(m,7H),1.52(s,9H).

[1469] Step 3:

[1470]

[1471] Under nitrogen-protected stirring at 25°C, 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)naphthol (277 mg, 1.03 mmol, 1.5 equivalent), potassium phosphate (276 mg, 1.30 mmol, 2.0 equivalent), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) chloride (47 mg, 0.06 mmol, 0.10 equivalent) were added to a tetrahydrofuran / water (10 / 1, 4 mL) solution of compound 39-2 (400 mg, 0.65 mmol, 1.0 equivalent), potassium phosphate (276 mg, 1.30 mmol, 2.0 equivalent), and palladium(II) chloride (47 mg, 0.06 mmol, 0.10 equivalent) were added. The mixture was stirred at 60°C for 2 h, and the reaction was monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction solution was cooled to 25°C and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted using a 0% → 10% methanol / dichloromethane gradient. The solvent was removed from the resulting fraction by rotary evaporation under reduced pressure to give compound 39-3 (a mixture of two stereoisomers, a yellow solid, 180 mg, yield 41%). MS (ESI, m / z): 648.3 / 650.2 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ10.10(s,1H),8.00(s,1H),7.80(d,J=8.3Hz,1H),7.46–7.42(m,1H), 7.29(d,J=2.4Hz,1H),7.27–7.18(m,2H),7.07(d,J=2.4Hz,1H),4.48–4.33(m,3H),4.29–4.25 (m,2H),4.20–4.14(m,1H),3.63–3.54(m,2H),2.96–2.92(m,1H),2.61–2.54(m,1H),2.35(s, 3H),2.20–2.13(m,1H),1.97–1.90(m,1H),1.85–1.70(m,4H),1.70–1.60(m,3H),1.47(s,9H).

[1472] Step 4:

[1473]

[1474] Compound 39-3 (180 mg) obtained in step 3 was subjected to chiral resolution under the following conditions: chiral column NB-Lux 5 μm i-Cellulose-5, 2.12 x 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 20% mobile phase B for 25 min; detector: UV 220 / 254 nm; two products were obtained. The compound with the shortest retention time (11.7 min) was 39-3a, tert-butyl(1R,5S)-3-(6-chloro-8-fluoro-7-((S or R)-3-hydroxynaphthyl-1-yl)-2-((S)-1-methylpyrrolidone-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (white solid, 80 mg, recovery 42%). The compound with the longest retention time (21.18 min) was 39-3b, tert-butyl(1R,5S)-3-(6-chloro-8-fluoro-7-((R or S)-3-hydroxynaphth-1-yl)-2-((S)-1-methylpyrrolidone-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (white solid, 70 mg, 37% recovery).

[1475] The chiral resolution methods for some similar chiral compounds in this application, and their respective retention times and ee values ​​are shown in Table 4 below.

[1476] Table 4

[1477]

[1478]

[1479]

[1480]

[1481]

[1482]

[1483]

[1484]

[1485]

[1486]

[1487]

[1488]

[1489]

[1490]

[1491]

[1492]

[1493]

[1494]

[1495]

[1496]

[1497]

[1498]

[1499]

[1500]

[1501]

[1502] Step 5:

[1503]

[1504] Under stirring at 25°C, trifluoroacetic acid (1 mL) was added dropwise to a dichloromethane (3 mL) solution of compound 39-3a (80 mg, 0.14 mmol, 1.0 equivalence). After the addition was complete, the reaction mixture was stirred at this temperature for 1 hour, and the reaction process was monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase chromatography (C18 column) using a 5%–95% (acetonitrile / methanol (1:1)) / water mobile phase (0.1% ammonium bicarbonate) over 40 minutes; detector: UV 254 nm; to obtain compound 39a (white solid, 31 mg, yield 45%). Compound 39b (white solid, 30.3 mg, yield 54%) could be obtained by the same method.

[1505] Compound 39a: MS (ESI, m / z): 548.3 / 550.3 [M+H] + ; 1H NMR (300MHz, CD3OD): δ7.97–7.96(m,1H),7.76(d,J=8.3Hz,1H),7.45–7.39 (m,1H),7.27(d,J=2.4Hz,1H),7.25–7.18(m,2H),7.04(d,J=2.4Hz,1H),4.5 5–4.40(m,4H),3.68–3.64(m,4H),3.15–3.08(m,1H),2.85–2.80(m,1H),2.5 5(d,J=1.3Hz,3H),2.43–2.34(m,1H),2.19–2.07(m,1H),1.97–1.67(m,7H); 19 F NMR (282 MHz, CD3OD) δ -123.19. The chiral analysis conditions for compound 39a were: CHIRALPAK IG-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 50% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 1.203 min; ee > 99%.

[1506] Compound 39b: MS (ESI, m / z): 548.3 / 550.3 [M+H] + ; 1 H NMR (300MHz, CD3OD): δ7.95–7.94(m,1H),7.74(d,J=8.3Hz,1H),7.43–7.37 (m,1H),7.25(d,J=2.4Hz,1H),7.23–7.16(m,2H),7.02(d,J=2.4Hz,1H),4.5 3–4.40(m,4H),3.67–3.61(m,4H),3.15–3.07(m,1H),2.89–2.82(m,1H),2.5 5(d,J=2.1Hz,3H),2.45–2.36(m,1H),2.16–2.07(m,1H),1.89–1.70(m,7H); 19 F NMR (282 MHz, CD3OD) δ -123.23. Chiral analysis conditions for compound 39b were: CHIRALPAK IG-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 50% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 2.391 min; ee > 99%.

[1507] Other similar compounds of this application can be prepared by the synthetic method shown in Example 6 above. Table 5 below shows some of the compounds prepared according to the above synthetic method and their characterization data.

[1508] Table 5

[1509]

[1510]

[1511]

[1512]

[1513]

[1514]

[1515]

[1516]

[1517]

[1518]

[1519]

[1520]

[1521]

[1522]

[1523]

[1524]

[1525]

[1526]

[1527]

[1528]

[1529]

[1530]

[1531]

[1532]

[1533]

[1534]

[1535]

[1536]

[1537]

[1538]

[1539]

[1540]

[1541]

[1542]

[1543]

[1544]

[1545]

[1546]

[1547]

[1548]

[1549]

[1550]

[1551] Example 7 (Synthesis Method VI)

[1552] (S or R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-2-((6-(dimethylamino)hexyl)oxy)-8-fluoroquinazolin-7-yl)naphth-2-phenol 67

[1553]

[1554] The synthesis route is shown below:

[1555]

[1556] Step 1:

[1557]

[1558] Under nitrogen-protected stirring at 25°C, N,N-diisopropylethylamine (8.69 g, 66.57 mmol, 1.5 equivalence) and chloromethyl methyl ether (4.69 g, 57.69 mmol, 1.3 equivalence) were added to a solution of 1-bromo-3-hydroxynaphthalene (10 g, 44.38 mmol, 1.0 equivalence) in dichloromethane (100 mL). The mixture was reacted at 25°C for 3 h, and the reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted by a gradient of 0% to 10% ethyl acetate / petroleum ether. The solvent was removed from the resulting fraction by rotary evaporation under reduced pressure to give compound 67-1 (white solid, 10.5 g, 87% yield). MS (ESI, m / z): 267.1 / 269.1 [M+H] + ; 1 H NMR (300MHz, CDCl3) δ8.16–8.11(m,1H),7.75–7.71(m,1H),7.57(d,J=2.4H z,1H),7.50–7.43(m,2H),7.39(d,J=2.4Hz,1H),5.28(s,2H),3.52(s,3H).

[1559] Step 2:

[1560]

[1561] Under nitrogen atmosphere and stirring at 25°C, potassium acetate (14.70 g, 142.26 mmol, 4.0 equivalence), pinacol diborate (12.36 g, 46.23 mmol, 1.3 equivalence), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.05 g, 3.55 mmol, 0.1 equivalence) were added sequentially to a 100 mL solution of 67-1 (10 g, 35.56 mmol, 1.0 equivalence). The mixture was reacted at 100°C for 1 hour under nitrogen atmosphere, and the reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was completed, the mixture was cooled to 25°C and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted using a gradient of 0%–20% ethyl acetate / petroleum ether. The solvent was removed from the resulting fraction by rotary evaporation under reduced pressure to give compound 67-2 (white solid, 10 g, 85% yield). MS (ESI, m / z): 315.2 [M+H] + ; 1H NMR(300MHz, CDCl3)δ8.72–8.66(m,1H),7.82(d,J=2.7Hz,1H),7.79–7.73(m,1H), 7.51(d,J=2.7Hz,1H),7.49–7.40(m,2H),5.33(s,2H),3.54(s,3H),1.44(s,12H).

[1562] Step 3:

[1563]

[1564] Under nitrogen protection at 25°C, compounds 39-1 (9 g, 16.89 mmol, 1.0 equivalent), 67-2 (5.59 g, 16.89 mmol, 1.0 equivalent), 1,4-dioxane (80 mL), water (20 mL), sodium carbonate (3.77 g, 33.78 mmol, 2.0 equivalent), and tris(2,4-dibenzylacetone)palladium(0) (775 mg, 0.85 mmol, 0.05 equivalent), 4-(2,6-dimethoxyphenyl)-3-tert-butyl-2,3-dihydro-1,3-benzoxophosphorus heterocyclic) (558 mg, 1.69 mmol, 0.1 equivalent) were added sequentially to a 250 mL three-necked flask. The mixture was reacted at 60°C for 2 hours under nitrogen atmosphere. The reaction process was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was completed, the reaction solution was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted using a gradient of 0%–20% ethyl acetate / petroleum ether. The resulting fraction was purified by rotary evaporation under reduced pressure to obtain a mixture of 67-3 and 67-4. This mixture was purified by reversed-phase chromatography (C18 column), eluting over 20 minutes with a mobile phase of 40%–90% acetonitrile / water (0.1% ammonium bicarbonate); detector: UV 254 / 220 nm; yielding compounds 67-3 (a racemic mixture of two stereoisomers, yellow solid, 6 g, 55% yield) and 67-4 (a racemic mixture of two stereoisomers, yellow solid, 5 g, 37% yield).

[1565] Compound 67-3: MS (ESI, m / z): 613.2 / 615.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ7.88–7.85(m,2H),7.58(d,J=2.5Hz,1H),7.53–7.47(m,1H),7.32–7.30(m,2H),7.21(d,J=2.4Hz,1H),5.36(s,2H), 4.56–4.41(m,4H),3.77–3.65(m,2H),3.58(s,3H),2.06–2.00(m,2H),1.87–1.79(m,2H),1.56(s,9H).

[1566] Compound 67-4: MS (ESI, m / z): 765.2 / 767.2 [M+H] + ; 1 H NMR (300MHz, CDCl3) δ8.86(d,J=8.4Hz,1H),8.03(d,J=2.5Hz,1H),7.96(s,1H),7.89–7.81(m,2H),7.59(d,J=2.1Hz,1H),7.56(d,J=2.1Hz,1H),7.53 –7.32(m,5H),7.29-7.27(m,1H),5.40-5.35(m,4H),4.64-4.42(m,4H),3. 80-3.68(m,2H),3.59(s,3H),3.57(s,3H),2.07-1.93(m,4H),1.56(s,9H).

[1567] Step 4:

[1568]

[1569] Compound 67-3 (6 g) obtained in step 3 was subjected to chiral resolution under the following conditions: chiral column NB_CHIRALPAK IC, 5 x 25 cm, 5 μm; mobile phase A: supercritical carbon dioxide fluid, mobile phase B: ethanol; flow rate: 160 mL / min; column temperature: 35 °C; elution with 45% mobile phase B for 15 min; detector UV 225 nm. Two products were obtained. The compound with the shorter retention time (9.03 min) was 67-3a, tert-butyl(1R,5S)-3-(2,6-dichloro-8-fluoro-7-((S or R)-3-(methoxymethoxy)naphth-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (yellow solid, 2.5 g, recovery 41%). The specific rotation of compound 67-3a was [α]. D 25=15.4 (c = 0.100 g / 100 mL, methanol, ee > 99%); the compound with the longer retention time (10.78 min) is 67-3b, tert-butyl(1R,5S)-3-(2,6-dichloro-8-fluoro-7-((R or S)-3-(methoxymethoxy)naphth-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester (yellow solid, 2.9 g, recovery 48%).

[1570] Step 5:

[1571]

[1572] Under stirring at 20°C, potassium tert-butoxide (0.65 mL, 0.65 mmol, 4.0 equivalence) was added dropwise to a tetrahydrofuran (1 mL) solution of 67-3a (100 mg, 0.16 mmol, 1.0 equivalence) and 2-methyl-2,6-diazospiro[3.3]heptane ditrifluoroacetate (80 mg, 0.23 mmol, 1.5 equivalence). After the addition was complete, the reaction mixture was incubated at 20°C for 1 hour, and the reaction was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, 5 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, 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, with the mobile phase eluted by a 0% → 10% methanol / dichloromethane gradient. The resulting fraction was purified by rotary evaporation under reduced pressure to obtain compound 67-5 (pale yellow solid, 45 mg, 42% yield). MS (ESI, m / z): 689.3 / 691.4 [M+H] + ; 1 H NMR (300MHz, DMSO-d6) δ7.93(d,J=8.3Hz,1H),7.82(d,J=1.7Hz,1H),7.61(d,J=2.5Hz,1H),7.55–7.50(m,1H),7.37–7.26(m,2H),7.2 3(d,J=2.5Hz,1H),5.38(s,2H),4.34–4.24(m,4H),4.18-4.16(m,4H),3.59-3.46(m,9H),2.37(s,3H),1.86–1.74(m,4H),1.47(s,9H).

[1573] Step 6:

[1574]

[1575] Under stirring at 0°C, trifluoroacetic acid (0.3 mL) and triethylsilane (30 mg, 0.26 mmol, 4.0 equivalence) were added to a 0.8 mL solution of dichloromethane (45 mg, 0.06 mmol, 1.0 equivalence) at 67-5°C. The mixture was reacted at 25°C for 1 hour, and the reaction was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction solution was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) under the following conditions: column: XBridge Prep C18 OBD, 19 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium bicarbonate solution); mobile phase B: acetonitrile; flow rate: 25 mL / min; elution gradient: 10% B for 2 min, then 10% B to 21% B over 2.5 min, and finally 21% B to 45% B over 10.5 min; detector: UV 220 nm; retention time: 9.62 min. The resulting fraction was concentrated under reduced pressure to give 67 (white solid, 11.3 mg, yield 31%). MS (ESI, m / z): 545.3 / 547.4 [M+H] + ; 1 H NMR(300MHz, DMSO-d6)δ9.98(s,1H),7.79(d,J=8.3Hz,1H),7.75(d,J=1.6Hz,1H),7.46-7.41(m,1H),7.26(d,J=2.4Hz,1H),7.25–7 .19(m,2H),7.03(d,J=2.4Hz,1H),4.25-4.19(m,2H),4.11(s,4H),3.51-3.40(m,4H),3.26(s,4H),2.18(s,3H),1.72–1.61(m,4H); 19 F NMR(282MHz,DMSO-d6)δ-123.43.

[1576] Other similar compounds of this application can be prepared by the synthetic method shown in Example 7 above. Table 6 below shows some of the compounds prepared according to the above synthetic method and their characterization data.

[1577] Table 6

[1578]

[1579]

[1580]

[1581]

[1582]

[1583]

[1584]

[1585]

[1586]

[1587]

[1588]

[1589]

[1590]

[1591]

[1592]

[1593]

[1594]

[1595]

[1596]

[1597]

[1598]

[1599]

[1600]

[1601]

[1602]

[1603]

[1604]

[1605]

[1606]

[1607]

[1608]

[1609]

[1610]

[1611]

[1612]

[1613]

[1614]

[1615]

[1616]

[1617]

[1618]

[1619]

[1620]

[1621]

[1622]

[1623]

[1624]

[1625]

[1626]

[1627]

[1628]

[1629]

[1630]

[1631]

[1632]

[1633]

[1634]

[1635]

[1636]

[1637]

[1638]

[1639]

[1640]

[1641]

[1642]

[1643]

[1644]

[1645]

[1646]

[1647]

[1648]

[1649]

[1650]

[1651]

[1652]

[1653]

[1654]

[1655]

[1656]

[1657]

[1658]

[1659]

[1660]

[1661]

[1662]

[1663]

[1664]

[1665]

[1666]

[1667]

[1668]

[1669]

[1670]

[1671]

[1672]

[1673]

[1674]

[1675]

[1676]

[1677]

[1678]

[1679]

[1680]

[1681]

[1682]

[1683]

[1684]

[1685]

[1686]

[1687]

[1688]

[1689]

[1690]

[1691]

[1692]

[1693]

[1694]

[1695]

[1696]

[1697]

[1698]

[1699]

[1700]

[1701] Example 8 (Synthesis Method VII)

[1702] (S or R)-1-((6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)imino)-1-thiomorpholine-1-oxide 71a; (R or S)-1-((6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)imino)-1-thiomorpholine-1-oxide 71b

[1703]

[1704] The synthesis route is shown below:

[1705]

[1706] Step 1:

[1707]

[1708] Under nitrogen-protected stirring at 25°C, compounds 1-2 (700 mg, 2.01 mmol, 1.00 equivalence), 1,4-dioxane (8.0 mL), tert-butyl-1-imino-1-oxothiomorpholine-4-carboxylic acid tert-butyl ester (496 mg, 2.01 mmol, 1.0 equivalence), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (245 mg, 0.40 mmol, 0.2 equivalence), potassium tert-butoxide (262 mg, 2.21 mmol, 1.1 equivalence), and tris(dibenzylacetone)palladium(0) (194 mg, 0.20 mmol, 0.1 equivalence) were added sequentially to a 25 mL Shrek tube. The mixture was reacted at 80°C for 1 hour under a nitrogen atmosphere. The reaction process was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was completed, the reaction solution was cooled to 25°C and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted by a gradient of 0%–30% ethyl acetate / petroleum ether. The resulting fraction was purified by rotary evaporation under reduced pressure to obtain compound 71-1 (yellow solid, 460 mg, yield 41%). MS (ESI, m / z): 527.1 / 529.1 / 531.1 [M+H] + ; 1 H NMR (300MHz, DMSO-d6) δ8.24 (d, J = 1.9 Hz, 1H), 4.13–3.97 (m, 4H), 3.77–3.59 (m, 4H), 1.43 (s, 9H).

[1709] Step 2:

[1710]

[1711] Under nitrogen atmosphere and stirring at 25°C, compound 71-1 (460 mg, 0.83 mmol, 1.0 equivalence), N-methylpyrrolidone (12.0 mL), 3-(dimethylamino)azacyclobutane dihydrochloride (131 mg, 1.24 mmol, 1.5 equivalence), and N,N-diisopropylethylamine (1.12 g, 8.27 mmol, 10.0 equivalence) were added sequentially to a 25 mL Shrek tube. The mixture was reacted at 60°C for 2 hours under nitrogen atmosphere. The reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was cooled to 25°C. The reaction solution was purified directly by reversed-phase chromatography (C18 column) with elution over 35 minutes using a mobile phase of 10%–95% acetonitrile / water (0.1% ammonium bicarbonate); detector: UV 254 / 220 nm. Compound 71-2 was obtained (yellow solid, 350 mg, yield 67%). MS (ESI, m / z): 591.2 / 593.2 / 595.2 [M+H] + ; 1H NMR(400MHz, CDCl3)δ7.98(d,J=1.9Hz,1H),4.25–4.17(m,4H),4.10–4.04(m,2H),3.95–3.8 7(m,2H),3.81–3.75(m,2H),3.40–3.34(m,2H),3.27–3.21(m,1H),2.26(s,6H),1.49(s,9H).

[1712] Step 3:

[1713]

[1714] Under nitrogen-protected stirring at 25°C, water (0.8 mL), potassium phosphate (237 mg, 1.0 mmol, 1.0 equivalence) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)naphthol (150.6 mg, 0.53 mmol, 1.00 equivalence) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) chloride (43.8 mg, 0.05 mmol, 0.1 equivalence) were added sequentially to an 8 mL solution of tetrahydrofuran (330 mg, 0.53 mmol, 1.0 equivalence) of compound 71-2 (330 mg, 0.53 mmol, 1.0 equivalence) and palladium(II) chloride (43.8 mg, 0.05 mmol, 0.1 equivalence) under [nitrogen atmosphere] for 1 h were reacted. The reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was cooled to 25°C and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted using a 0% → 15% methanol / dichloromethane gradient. The resulting fraction was subjected to rotary evaporation under reduced pressure to remove the solvent, yielding compound 71-3 (a mixture of two stereoisomers, a yellow solid, 320 mg, yield 87%). MS (ESI, m / z): 655.4 / 657.4 [M+H] + ; 1 HNMR (300MHz, CDCl3) δ8.05 (d, J = 1.5Hz, 1H),7.70(d,J=8.2Hz,1H),7.41–7.35(m,1H),7.32–7.29(m,1H),7.26(d,J=2.4Hz,1H),7.21–7.15(m,1H),7.05(d,J=2.4Hz,1H),4.33 –4.20(m,4H),4.14–4.06(m,2H),4.01–3.92(m,2H),3.83–3.74(m,2H),3.42–3.32(m,2H),3.25–3.16(m,1H),2.24(s,6H),1.52(s,9H).

[1715] Step 4:

[1716]

[1717] Compound 71-3 (320 mg) obtained in step 3 was subjected to chiral resolution under the following conditions: chiral column: CHIRALPAK ID, 2 x 25 cm, 5 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.5% 2 mol / L ammonia-methanol solution); mobile phase B: isopropanol; flow rate: 20 mL / min; gradient: elution with 10% phase B over 60 min; detector: UV 220 / 210 nm; two products were obtained. The compound with the shortest retention time (28.92 min) was 71-3a, (S or R) tert-butyl 1-((6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazoline-4-yl)imino)-1-thiomorpholine-4-carboxylic acid ester 1-oxide (yellow solid, 111 mg, 35% recovery); the compound with the longer retention time (43.175 min) was 71-3b, (R or S) tert-butyl 1-((6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazoline-4-yl)imino)-1-thiomorpholine-4-carboxylic acid ester 1-oxide (yellow solid, 116 mg, 37% recovery).

[1718] Step 5:

[1719]

[1720] Under stirring at 25°C, trifluoroacetic acid (1.00 mL) was added dropwise to a solution of compound 71-3a (100 mg, 0.145 mmol, 1.00 equivalent) in dichloromethane (4.00 mL). After the addition was complete, the reaction mixture was reacted at room temperature for 1 hour, and the reaction process was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction mixture was concentrated to obtain the crude product. The crude product was purified by reversed-phase chromatography (C18 column) with elution over 20 minutes using a 5%–40% acetonitrile / water mobile phase (0.5% ammonium bicarbonate); detector: UV254 / 220 nm; to obtain compound 71a (white solid, 40 mg, yield 49%). Compound 71b (white solid, 48 mg, yield 53%) could be obtained by the same method.

[1721] Compound 71a: MS (ESI, m / z): 555.2 / 557.2 [M+H] + ; 1H NMR(300MHz, DMSO-d6)δ9.98(s,1H),8.05(d,J=1.5Hz,1H),7.80(d,J=8.3Hz,1H),7.46–7.41(m,1H),7.27(d,J=2.4Hz,1H),7.25–7.18(m ,2H),7.04(d,J=2.4Hz,1H),4.13–4.07(m,2H),3.99–3.83(m,4H),3.48–3.40(m,2H),3.30–3.27(m,2H),3.17–3.04(m,3H),2.13(s,6H); 19 F NMR (282 MHz, DMSO-d6) δ -124.87. The chiral analysis conditions for compound 71a were: CHIRALPAK IF-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; gradient: elution with 20% phase B over 12 min; detector: UV 220 / 254 nm; retention time: 6.743 min; ee > 99%.

[1722] Compound 71b: MS (ESI, m / z): 555.2 / 557.2 [M+H] + ; 1 H NMR(300MHz, DMSO-d6)δ9.98(s,1H),8.05(d,J=1.5Hz,1H),7.80(d,J=8.3Hz,1H),7.46–7.41(m,1H),7.27(d,J=2.4Hz,1H),7.25–7.18(m ,2H),7.04(d,J=2.4Hz,1H),4.13–4.07(m,2H),3.99–3.83(m,4H),3.48–3.40(m,2H),3.30–3.27(m,2H),3.17–3.04(m,3H),2.13(s,6H); 19 F NMR (282 MHz, DMSO-d6) δ -124.87. The chiral analysis conditions for compound 71b were: CHIRALPAK IF-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; gradient: elution with 20% phase B over 12 min; detector: UV 220 / 254 nm; retention time: 9.968 min; ee > 99%.

[1723] Example 9

[1724] (4R or S)-4-amino-1-(((R or S)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)imino)hexahydro-1-thiopyran-1-oxide 72a; (4R or S)-4-amino-1-(((S or R)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)imino)hexahydro-1-thiopyran-1-oxide 72b ; (4S or R)-4-amino-1-(((R or S)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphthyl-1-yl)quinazolin-4-yl)imino)hexahydro-1-thiopyran 1-oxide 72c; (4S or R)-4-amino-1-(((S or R)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphthyl-1-yl)quinazolin-4-yl)imino)hexahydro-1-thiopyran 1-oxide 72d

[1725]

[1726] Step 1:

[1727]

[1728] Compound 72-3 was synthesized according to Example 8 (Synthetic Method VII). Compound 72-3 (mixture of four stereoisomers, yellow solid, 320 mg): MS (ESI, m / z): 669.2 / 671.2 [M+H] + .

[1729] Step 2:

[1730]

[1731] Compound 72-3 (310 mg) obtained in step 1 was chirally resolved by preparative chiral high-performance liquid chromatography (HPLC) under the following conditions: chiral column CHIRAL ART Amylose-SA, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol solution), mobile phase B: isopropanol; flow rate: 40 mL / min; gradient elution: 20% of mobile phase B over 30 min; detector: UV 250 / 220 nm. Two products were obtained. The compound with the shorter retention time (15 min) was 72-3a (a mixture of two stereoisomers, yellow solid, 133 mg, recovery 43%); the compound with the longer retention time (20 min) was 72-3b (a mixture of two stereoisomers, yellow solid, 140 mg, recovery 45%).

[1732] Step 3:

[1733]

[1734] Compound 72-3a (133 mg) obtained in step 2 was chirally separated by preparative chiral high-performance liquid chromatography (HPLC) under the following conditions: chiral column CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; mobile phase A: n-hexane / dichloromethane = 5 / 1 (0.5% 2 mol / L ammonia-methanol solution); mobile phase B: ethanol; flow rate: 20 mL / min; gradient elution with 30% mobile phase B over 10 min; detector: UV 250 / 220 nm; two products were obtained. The compound with the shortest retention time (3.2 min) was 72-3aa, tert-butyl((1s,4R or 1r,4S)-1-(((S or R)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)imino)-1-hexahydro-1-thiopyran-4-yl)carbamate (yellow solid, 117 mg, 87% recovery). The compound with the longest retention time (5.7 min) was 72-3ab, tert-butyl((1r,4S or 1s,4R)-1-(((S or R)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)imino)-1-hexahydro-1-thiopyran-4-yl)carbamate (yellow solid, 11 mg, 8% recovery).

[1735] Step 4:

[1736]

[1737] Compound 72-3b (140 mg) obtained in step 2 was chirally separated by preparative chiral high-performance liquid chromatography (HPLC) under the following conditions: chiral column CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol solution), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: elution with 30% mobile phase B over 23 min; detector: UV 250 / 220 nm; two products were obtained. The compound with the shortest retention time (5.8 min) was 72-3ba, tert-butyl((1s,4R or 1r,4S)-1-(((R or S)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphthyl-1-yl)quinazolin-4-yl)imino)-1-hexahydro-1-thiopyran-4-yl)carbamate (yellow solid, 110 mg, 78% recovery); The compound with the longest retention time (15.8 min) was 72-3bb, tert-butyl((1r,4S or 1s,4R)-1-(((R or S)-6-chloro-2-(3-(dimethylamino)azacyclobutane-1-yl)-8-fluoro-7-(3-hydroxynaphth-1-yl)quinazolin-4-yl)imino)-1-hexahydro-1-thiopyran-4-yl)carbamate (yellow solid, 15 mg, 10% recovery).

[1738] Step 5:

[1739]

[1740] Trifluoroacetic acid (1.0 mL) was added dropwise to a solution of compound 72-3aa (100 mg, 0.14 mmol, 1.0 equivalence) in dichloromethane (4.0 mL) under stirring at 25°C. After the addition was complete, the reaction mixture was allowed to react at this temperature for 0.5 h, and the reaction process was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated to obtain the crude product. The crude product was purified by reversed-phase chromatography (C18 column) with elution over 20 min using a mobile phase of 35%–65% acetonitrile / water (0.5% ammonium bicarbonate); detector: UV 254 / 220 nm; to obtain compound 72a (white solid, 56 mg, yield 67%). Compounds 72b (white solid, 5 mg, yield 49%), 72c (white solid, 50 mg, yield 60%), and 72d (white solid, 5.8 mg, yield 46%) were also obtained by the same method.

[1741] Compound 72a: MS (ESI, m / z): 569.3 / 571.3 [M+H] + ; 1H NMR (300MHz, CD3OD) δ8.10(d,J=1.4Hz,1H),7.75(d,J=8.3Hz,1H),7.44–7.39(m,1H),7.26–7.17(m,3H),7.04–7.02(m,1H),4.31 –4.26(m,2H),4.07–4.02(m,2H),3.95–3.78(m,4H),3.31–3.25(m,1H),3.22–3.15(m,1H),2.37–2.25(m,8H),2.20–2.09(m,2H); 19 F NMR (282MHz, CD3OD) δ-126.72.

[1742] Compound 72b: MS (ESI, m / z): 569.3 / 571.3 [M+H] + ; 1 H NMR (300MHz, CD3OD) δ8.18 (d, J=1.7 Hz,1H),7.76(d,J=8.2Hz,1H),7.45–7.39(m,1H),7.27–7.17(m,3H),7.03(d,J=2.4Hz,1H),4.31–4.13 (m,4H),4.07–4.02(m,2H),3.66–3.52(m,2H),3.31–3.14(m,2H),2.34–2.24(m,8H),2.11–1.98(m,2H); 19 F NMR (282MHz, CD3OD) δ-126.71.

[1743] Compound 72c: MS (ESI, m / z): 569.2 / 571.2 [M+H] + ; 1 H NMR (300MHz, CD3OD) δ8.11(d,J=1.7Hz,1H),7.75(d,J=8.3Hz,1H),7.44–7.39(m,1H),7.26–7.17(m,3H),7.03(d,J=2.4H z,1H),4.31–4.25(m,2H),4.07–4.02(m,2H),3.95–3.76(m,4H),3.30–3.15(m,2H),2.36–2.25(m,8H),2.20–2.08(m,2H); 19 F NMR (282MHz, CD3OD) δ-126.67.

[1744] Compound 72d: MS (ESI, m / z): 569.2 / 571.2 [M+H] +; 1 H NMR (300MHz, CD3OD) δ8.18(d,J=1.6Hz,1H),7.76(d,J=8.4Hz,1H),7.45–7.39(m,1H),7.27–7.18(m,3H),7.03(d,J=2.4H z,1H),4.31–4.14(m,4H),4.07–4.02(m,2H),3.66–3.52(m,2H),3.30–3.14(m,2H),2.33–2.25(m,8H),2.11–1.98(m,2H); 19 F NMR (282MHz, CD3OD) δ-126.70.

[1745] Example 10 (Synthesis Method IX)

[1746] 4-(2-(3-(dimethylamino)propoxy)-4-(piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphth-2-phenol 73

[1747]

[1748] The synthesis route is shown below:

[1749]

[1750] Step 1:

[1751]

[1752] Under nitrogen atmosphere and stirring at 25°C, potassium carbonate (620 mg, 4.48 mmol, 2.0 equivalent) and benzyl bromide (460 mg, 2.69 mmol, 1.2 equivalent) were added to a solution of 1-bromo-3-hydroxynaphthalene (500 mg, 2.24 mmol, 1.0 equivalent) in N,N-dimethylformamide (5.0 mL). The mixture was reacted at 25°C under nitrogen atmosphere for 2 hours, and the reaction was monitored by thin-layer chromatography. After the reaction was complete, the reaction solution was extracted with ethyl acetate (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted by a gradient of 0% → 10% ethyl acetate / petroleum ether. The solvent was removed from the resulting fraction by rotary evaporation under reduced pressure to give compound 73-1 (colorless oil, 500 mg, 70% yield). 1H NMR (400MHz, CDCl3) δ8.22–8.08(m,1H),7.74–7.67(m,1H),7.59(d,J=2.4, 1H),7.52–7.39(m,6H),7.39–7.31(m,1H),7.20(d,J=2.4,1H),5.17(s,2H).

[1753] Step 2:

[1754]

[1755] Under stirring at 25°C, N,N-dimethylacetamide (8.5 g, 64.43 mmol, 4.0 equivalence) and benzyl-1-piperazine carbonate (3.6 g, 16.11 mmol, 1.0 equivalence) were added sequentially to a solution of 2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-carboxylate (5.0 g, 16.10 mmol, 1.0 equivalence) in N,N-dimethylacetamide (30 mL). The mixture was reacted at 50°C for 3 h, and the reaction was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction solution was extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with 100 mL of saturated brine, 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, with the mobile phase eluted by a 0% → 10% methanol / dichloromethane gradient. The solvent was removed from the resulting fraction by rotary evaporation under reduced pressure to give compound 73-2 (white solid, 6.3 g, 76% yield). MS (ESI, m / z): 488.2 / 490.2 [M+H] + ; 1 H NMR(300MHz, CDCl3)δ7.42–7.29(m,5H),5.17(s,2H),4.53(s,2H),3.65–3.57 (m,4H),3.59–3.56(m,2H),3.50–3.48(m,4H),2.64–2.60(m,2H),1.48(s,9H).

[1756] Step 3:

[1757]

[1758] Under nitrogen atmosphere and stirring at 25°C, 3-dimethylamino-1-propanol (603 mg, 5.84 mmol, 1.2 Equivalent), cesium carbonate (4.8 g, 14.60 mmol, 3.0 Equivalent), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (407 mg, 0.49 mmol, 0.1 Equivalent) were added sequentially to a 73-2 (2.5 g, 4.87 mmol, 1.0 Equivalent) solution of 1,4-dioxane (10.0 mL). The mixture was reacted at 90°C under nitrogen atmosphere for 2 hours, and the reaction process was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was completed, the reaction solution was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted using a 0% → 10% methanol / dichloromethane gradient. The solvent was removed from the resulting fraction by rotary evaporation under reduced pressure to give compound 73-3 (brownish-yellow oil, 1.4 g, yield 51%). MS (ESI, m / z): 555.5 [M+H] + ; 1 H NMR (300MHz, CDCl3) δ7.41–7.35(m,5H),5.19(s,2H),4.48(s,2H),4.34(t,J=6.5Hz,2H),3.65–3.56(m,6H) ,3.46–3.41(m,4H),2.62–2.58(m,2H),2.50(t,J=7.5Hz,2H),2.28(s,6H),2.03–1.94(m,2H),1.51(s,9H).

[1759] Step 4:

[1760]

[1761] Trifluoroacetic acid (5 mL) was added dropwise to a solution of 73-3 (1.4 g, 2.50 mmol, 1.0 equivalence) in 12.0 mL of dichloromethane under stirring at 25°C. The mixture was reacted at 25°C for 1 hour, and the reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was concentrated to obtain crude product 73-4 (brownish-yellow oil, 1.1 g, 95% yield). This crude product was used directly for the next step without further purification. MS (ESI, m / z): 455.3 [M+H] + .

[1762] Step 5:

[1763]

[1764] Under nitrogen atmosphere and stirring at 25°C, 73-1 (530 mg, 1.68 mmol, 1.1 Equivalent), cesium carbonate (1.5 g, 4.57 mmol, 3.0 Equivalent), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (108 mg, 0.23 mmol, 0.15 Equivalent), and tris(dibenzylacetone)palladium(O) (141 mg, 0.15 mmol, 0.1 Equivalent) were added sequentially to a solution of 73-4 (700 mg, 1.52 mmol, 1.0 Equivalent) in 8.0 mL of 1,4-dioxane (73-4) (700 mg, 1.52 mmol, 1.0 Equivalent), and tris(dibenzylacetone)palladium(O) (141 mg, 0.15 mmol, 0.1 Equivalent) (73-4, 700 mg, 1.52 mmol, 1.0 Equivalent). The mixture was reacted at 85°C under nitrogen atmosphere for 5 hours, and the reaction process was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was completed, the reaction solution was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, with the mobile phase eluted using a 0% → 10% methanol / dichloromethane gradient. The solvent was removed from the resulting fraction by rotary evaporation under reduced pressure to give compound 73-5 (white solid, 500 mg, yield 46%). MS (ESI, m / z): 687.4 [M+H] + .

[1765] Step 6:

[1766]

[1767] Palladium hydroxide on carbon (20 mg) was added to a solution of 73-5 (120 mg, 0.18 mmol, 1.0 equivalence) in ethyl acetate (20.0 mL) under nitrogen protection and stirring at 25°C. The mixture was reacted at 70°C under a hydrogen atmosphere (10 atm) for 5 hours, and the reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was filtered with diatomaceous earth, and the filter cake was washed with ethyl acetate (50 mL x 3). The filtrate was concentrated to obtain the crude product. The crude product was purified by reversed-phase chromatography (C18 column) using a mobile phase of 5%–95% acetonitrile / water (0.1% formic acid) over 20 minutes; detector: UV 254 / 220 nm; to give compound 73 (white solid, 3.1 mg, yield 3.5%). MS (ESI, m / z): 463.2 [M+H] + ; 1H NMR(300MHz, DMSO-d6)δ9.68(s,1H),8.01(d,J=8.4Hz,1H),7.67(d,J=7.8Hz,1H),7.42–7.36(m,1H),7.30–7.24(m,1H),6.85(d,J=2.2Hz,1H),6.7 6(d,J=2.2Hz,1H),4.23(t,J=6.6Hz,2H),4.06(s,2H),3.42–3.22(m,6H), 2.86–2.78(m,6H),2.33(t,J=7.1Hz,2H),2.14(s,6H),1.87–1.77(m,2H).

[1768] Example 11 (Synthesis Method X)

[1769] 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-1-(3-(dimethylamino)propyl)-8-fluoro-7-((S or R)-3-hydroxynaphth-1-yl)quinazolin-2(1H)-one 74a; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-1-(3-(dimethylamino)propyl)-8-fluoro-7-((R or S)-3-hydroxynaphth-1-yl)quinazolin-2(1H)-one 74b

[1770]

[1771] The synthesis route is shown below:

[1772]

[1773] Step 1:

[1774]

[1775] At 25°C, 1.7 g (3.19 mmol, 1.0 equivalent) of 39-1 and 20.0 mL of glacial acetic acid were added to a 50 mL round-bottom flask. The mixture was reacted at 80°C for 3 hours, with the reaction process monitored by LC-MS. After the reaction was complete, the reaction solution was cooled to 25°C and concentrated to obtain an intermediate. The intermediate was dissolved in 50 mL of dichloromethane, and at 25°C, 870 mg (3.82 mmol, 1.2 equivalent) of di-tert-butyl dicarbonate and 1.4 mL of triethylamine were added to the solution. The mixture was reacted at the same temperature for 1 hour, with the reaction process monitored by LC-MS. After the reaction was complete, the reaction solution was concentrated to obtain the crude product. The crude product was purified by reversed-phase chromatography (C18 column) with elution over 15 minutes using a 50%–95% methanol / water mobile phase (0.1% formic acid); detector: UV 254 / 220 nm; yielding compound 74-1 (white solid, 1.2 g, 72% yield). MS (ESI, m / z): 487.1 / 489.1 / 491.1 [M+H] + ; 1 H NMR (300MHz, DMSO-d6) δ11.24(s,1H),7.81(d,J=2.0Hz,1H),4.32–4.18(m,4H),3.51–3.45(m,2H),1.79–1.64(m,4H),1.46(s,9H).

[1776] Step 2:

[1777]

[1778] At 25°C, (3-bromopropyl)dimethylamine hydrobromide (0.56 g, 2.14 mmol, 1.0 equivalence) and potassium carbonate (1.25 g, 8.57 mmol, 4.0 equivalence) were added to a 15 mL solution of acetonitrile containing 74-1 (1.1 g, 2.14 mmol, 1.0 equivalence). The mixture was reacted at 80°C for 2 h, and the reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was cooled to 25°C and concentrated to obtain the crude product. The crude product was purified by silica gel col...

Claims

1. A quinazoline compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, in, Ring 1 is a C5-C6 aryl group; Ring 2 is a 5-6 membered heteroaryl group whose heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3; ring 1 and ring 2 are fused together; p1 and p2 are independently 1, 2, 3, 4 or 5; R A It is H or halogen; R a C6-C substituted with one or more hydroxyl groups 10 aryl, amino-substituted C6-C 10 aryl, C6-C 10 aryl, with one or more R a-1 The C6-C substituent is substituted and at least one of the substituents is halogen, C1-C6 alkyl, cyano or C2-C6 ynyl. 10 aryl or aryl group or one or more R a-4 Replacement C6-C 10 aryl; R B For Y 1 ; Y 1 For one or more R 11 Substituted C1-C6 alkoxy groups; for ; M 1 Let N be the number of people in the group. Ring B is a 7-9 membered bridged heterocyclic alkyl group with N atoms and two heteroatoms; one N atom in the 7-9 membered bridged heterocyclic alkyl group is attached to ring 2. R 11 For not replaced or by one or more R 11-3 Replacement , , or ; R 11-3 It is a C1-C6 alkoxy, halogen, C1-C6 alkyl or R 11-3-1 Substituted C1-C6 alkyl groups; R 11-3-1 For C3-C 12 cycloalkyl or ; R 11-3-1-2 for ; R 11-3-1-2-1 and R 11-3-1-2-2 Independently H or C1-C6 alkyl; R a-1 Independently hydroxyl, halogen, cyano, C1-C6 alkyl, C3-C 12 Cycloalkyl or unsubstituted C2-C6 ynyl group; R a-4 for .

2. The quinazoline compound of formula I as described in claim 1, characterized in that, The quinazoline compounds of formula I are compounds of formula I-AI. Among them, R b R c and R d Independently H or halogen; W is C; X and Z are N; G is C; " in " is a double bond.

3. The quinazoline compound of formula I as described in claim 1, characterized in that, The quinazoline compound or its pharmaceutically acceptable salt as shown in Formula I is any of the following schemes. Option 13: The quinazoline compounds shown in Formula I are compounds shown in Formulas I-I. ； Where G is C; R a C6-C substituted with one or more hydroxyl groups 10 aryl, C6-C 10 aryl or aryl group or one or more R a-1 The C6-C substituent is a C1-C6 alkyl group that is at least one of a halogen or a C1-C6 alkyl group. 10 aryl; R b It is a halogen; R c For H; R d It is a halogen; Ring B is an unsubstituted 7-9 membered bridged heterocyclic alkyl group with N atoms and two heteroatoms; one N atom of the 7-9 membered bridged heterocyclic alkyl group is attached to ring 2. R 11-3 It is a halogen or a C1-C6 alkyl group; R a-1 Optionally hydroxyl, halogen, or C1-C6 alkyl; Option 14: The quinazoline compounds shown in Formula I are compounds shown in Formulas I-I. ； Where G is C; R a C6-C substituted with one or more hydroxyl groups 10 aryl, C6-C 10 aryl or aryl group or one or more R a-1 The C6-C substituent is a C1-C6 alkyl group that is at least one of a halogen or a C1-C6 alkyl group. 10 aryl; R b It is a halogen; R c For H; R d It is a halogen; Ring B is an unsubstituted 7-9 membered bridged heterocyclic alkyl group with N heteroatoms and two heteroatoms. R 11-3 It is a C1-C6 alkyl group; Option 15: The quinazoline compounds shown in Formula I are compounds shown in Formulas I-I. ； Where G is C; R a for , , , , , , , , or ; R b It is a halogen; R c For H; R d It is a halogen; Y 1 for or ; for , , , , , , , , or ; Option 17: The quinazoline compounds shown in Formula I are compounds shown in Formulas I-I. ； Where G is C; R a for , , , , , , , , or ; R b It is a halogen; R c For H; R d It is a halogen; Y 1 for ; for ; Option 18: Among the quinazoline compounds represented by Formula I R a C6-C substituted with one or more hydroxyl groups 10 aryl, amino-substituted C6-C 10 aryl, C6-C 10 aryl, with one or more R a-1 The C6-C substituent is substituted and "at least one of the substituents is a halogen or a C1-C6 alkyl group". 10 aryl or aryl group or one or more R a-4 Replacement C6-C 10 aryl; R a-1 Independently hydroxyl, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl or unsubstituted C2-C6 ynyl group; Option 19: Among the quinazoline compounds represented by Formula I R a C6-C substituted with one or more hydroxyl groups 10 aryl, amino-substituted C6-C 10 aryl, C6-C 10 aryl, with one or more R a-1 The C6-C substituent is substituted and "at least one of the substituents is a halogen or a C1-C6 alkyl group". 10 aryl; Option 22: In the quinazoline compounds shown in Formula I, R a C6-C substituted with one or more hydroxyl groups 10 aryl, C6-C 10 aryl or aryl group or one or more R a-1 The C6-C substituent is substituted and "at least one of the substituents is a halogen or a C1-C6 alkyl group". 10 aryl; R 11-3 It is a C1-C6 alkoxy, halogen, or C1-C6 alkyl group; Option 23: In the quinazoline compounds of Formula I, R 11-3 It is a halogen or a C1-C6 alkyl group; R a-1 It can be independently a hydroxyl group, a halogen, or a C1-C6 alkyl group; Option 25: The quinazoline compounds shown in Formula I are compounds shown in Formulas I-I. ； Where G is C; R a for , , , , , , , , , ,or ; R b It is a halogen; R c For H; R d It is a halogen; Y 1 for ; for , , , , , , , or .

4. The quinazoline compound of formula I as described in claim 2, characterized in that, When R a C6-C substituted with one or more hydroxyl groups 10 When the aryl group is present, the R... a for ;" "Indicates that it is" "、" "or a mixture thereof; And / or, when R a For C6-C 10 When the aryl group is present, the C6-C 10 The aryl group is or ;" "Indicates that it is" "、" "or a mixture thereof; And / or, when R a For one or more R a-1 The C6-C substituent is substituted and "at least one of the substituents is a halogen or a C1-C6 alkyl group". 10 When the aryl group is present, the C6-C 10 The aryl group is or ;" "Indicates that it is" "、" "or a mixture thereof; And / or, R a-1 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl; And / or, R a-1 In this context, the halogen is F, Cl, Br, or I; And / or, R a-1 In this context, the C2-C6 ynyl group is ethynyl, propynyl, 1-butynyl, or 2-butynyl; And / or, R a-1 In the context of C3-C 12 The cycloalkyl group is C3-C 12 Monocycloalkyl, C3-C 12 Bridged cycloalkyl or C3-C 12 Spirocycloalkyl; And / or, R a-1 It is hydroxyl, methyl, fluorine, chlorine, ethyl, ethynyl, butynyl, cyclopropane or bicyclo[1,1,1]pentyl; And / or, R b R c and R d In this context, the halogen is fluorine, chlorine, bromine, or iodine; And / or, R A In this context, the halogen is F or Cl; And / or, R 11-3-1-2-1 and R 11-3-1-2-2 It can be independently H, methyl, ethyl, propyl, n-butyl, or tert-butyl; And / or, R 11-3-1 The C3-C6 alkyl group is cyclopropane, cyclobutane, cyclopentane, or cyclohexane; And / or, Y 1 In this context, the C1-C6 alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentoxy, isopentoxy, neopentoxy, n-hexyl, isohexyl, neohexyl, etc. , or ; And / or, R 11-3 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl; And / or, R 11-3 In the context of C3-C 12 The cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane.

5. The quinazoline compound of formula I as described in claim 4, or a pharmaceutically acceptable salt thereof, characterized in that, R a-1 In this context, the C1-C6 alkyl group is methyl or ethyl; And / or, R a-1 In this context, the halogen is either F or Cl; And / or, R a-1 In this context, the C2-C6 ynyl group is either ethynyl or butynyl; And / or, R a-1 In the context of C3-C 12 The cycloalkyl group is C3-C 12 Monocycloalkyl or C3-C 12 Bridged cycloalkyl; And / or, R 11-3-1 The C3-C6 alkyl group is cyclopropane; And / or, Y 1 In this context, the C1-C6 alkoxy groups are methoxy, n-propoxy, ethoxy, n-butoxy, isobutoxy, isopentoxy, neopentoxy, n-hexoxy, etc. , , or ; And / or, R 11-3 In this context, the C1-C6 alkyl group is methyl; And / or, R 11-3 In the context of C3-C 12 The cycloalkyl group is cyclopropane.

6. The quinazoline compound of formula I as described in claim 5, characterized in that, R a-1 In the context of C3-C 12 The cycloalkyl group is cyclopropane or bicyclo[1,1,1]pentane; And / or, Y 1 In the text, the C1-C6 alkoxy group is... or .

7. The quinazoline compound of formula I as described in claim 2, characterized in that, R a for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; And / or, Y 1 The R mentioned in 11 The substituted C1-C6 alkoxy groups are cis, trans, or a mixture thereof; And / or, in ring B, the 7-9 membered bridged heterocyclic alkyl group with "N heteroatom and 2 heteroatoms" is a 7-8 membered bridged heterocyclic alkyl group with "N heteroatom and 2 heteroatoms".

8. The quinazoline compound of formula I as described in claim 7, characterized in that, In ring B, the 7-9 membered bridged heterocyclic alkyl group described as having "N heteroatom and 2 heteroatoms" is... , , , , , , , , or .

9. The quinazoline compound of formula I as described in claim 7, characterized in that, In ring B, the 7-8 membered bridged heterocyclic alkyl group described as having "N heteroatom and two heteroatoms" is... , , , , or .

10. The quinazoline compound of formula I as described in claim 2, characterized in that, Y 1 for , , , , or ; And / or, middle, for , , , , , , , , , or .

11. The quinazoline compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The quinazoline compounds shown in Formula I are compounds shown in Formula IB. ； And / or, R b It is a halogen; And / or, R c For H; And / or, R d It is a halogen.

12. The quinazoline compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, wherein the quinazoline compound has any of the following structures: The " This indicates that the location contains a carbon atom with a chiral center. "Indicates that it is" "、" "or a mixture of them." 13. The quinazoline compound of formula I as described in claim 12, or a pharmaceutically acceptable salt thereof, characterized in that, The quinazoline compounds or their pharmaceutically acceptable salts have any of the following structures. 。 14. The quinazoline compound of formula I as described in claim 12, or a pharmaceutically acceptable salt thereof, characterized in that, The quinazoline compounds described herein are any of the following structures, wherein the symbol "" is used to indicate the structure of the quinazoline compound. The carbon atom in the figure represents a carbon atom with either an S or R configuration. The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 2.045 min. The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 3.463 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 20% phase B over 3.5 min at an isogradient; detector: UV 220 / 254 nm; retention time: 1.198 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 20% phase B over 4 min at an isogradient; detector: UV 220 / 254 nm; retention time: 1.880 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 3.0 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min at an isogradient; detector: UV 210 nm; retention time: 4.125 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 3.0 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min at an isogradient; detector: UV 210 nm; retention time: 2.126 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol (10 mmol / L ammonia); flow rate: 1 mL / min; elution with 50% phase B over 4 min using an isogradient; detector: UV 220 nm; retention time: 2.761 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol (10 mmol / L ammonia); flow rate: 1 mL / min; elution with 50% phase B over 4 min using an isogradient; detector: UV 220 nm; retention time: 1.705 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 3 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% of phase B over 4 min; detector: UV 230 nm; retention time: 2.80 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 3 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% phase B over 4 min; detector: UV 230 nm; retention time: 2.318 min. The HPLC conditions were as follows: chiral column: Cellulose-SB, 3 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 10% phase B over 3 min; detector: UV 220 nm; retention time: 1.911 min. The HPLC conditions were as follows: chiral column: Cellulose-SB, 3 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 10% phase B over 3 min; detector: UV 220 nm; retention time: 2.171 min. The HPLC conditions were as follows: chiral column: CHIRAL ARTCellulose-SB, 3 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 10% phase B over 3 min; detector: UV 220 nm; retention time: 2.148 min. The HPLC conditions were as follows: chiral column: CHIRAL ARTCellulose-SB, 3 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 10% phase B over 3 min; detector: UV 220 nm; retention time: 2.443 min. The HPLC conditions were as follows: chiral column: N-Lux 3 μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (0.1% diethylamine); flow rate: 4 mL / min; gradient: elution with 40% phase B over 7 min; detector: UV 220 nm; retention time: 3.698 min. The HPLC conditions were as follows: chiral column: N-Lux 3 μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (0.1% diethylamine); flow rate: 4 mL / min; gradient: elution with 40% phase B over 7 min; detector: UV 220 nm; retention time: 5.109 min.

15. A quinazoline compound or a pharmaceutically acceptable salt thereof, characterized in that, The quinazoline compounds or their pharmaceutically acceptable salts have any of the following structures. 。 16. A quinazoline compound or a pharmaceutically acceptable salt thereof, characterized in that, The quinazoline compounds or their pharmaceutically acceptable salts have any of the following structures. 。 17. The quinazoline compound or a pharmaceutically acceptable salt thereof as described in claim 15, characterized in that, The quinazoline compounds or their pharmaceutically acceptable salts have any of the following structures. The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min at an isogradient; detector: UV 220 / 254 nm; retention time: 2.960 min. ； The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 30% phase B over 6 min; detector: UV 220 / 254 nm; retention time: 4.715 min. The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 2.813 min. The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane / dichloromethane = 3 / 1 (0.1% diethylamine); mobile phase B: isopropanol; flow rate: 1 mL / min. Isogradient elution with 30% B phase over 6 minutes; detector UV 220 nm; retention time: 1.965 minutes; Its origin and Made, The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% B phase over 6 min using an isogradient; detector: UV 254 nm; retention time: 2.198 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: isopropanol; flow rate: 1 mL / min; elution with 30% B phase over 6 min using an isogradient; detector: UV 254 nm; retention time: 3.411 min. The HPLC conditions were as follows: chiral column: CHIRAL ARTCellulose-SB, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 4.5 min; detector: UV 220 nm; retention time: 1.346 min. The HPLC conditions were as follows: chiral column: CHIRAL ARTCellulose-SB, 4.6 x 100 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 10% phase B over 4.5 min; detector: UV 220 nm; retention time: 2.438 min. The HPLC conditions were as follows: chiral column: XA-CHIRALPAK IG-3, 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid, mobile phase B: isopropanol (10 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% B phase over 6 min using an isogradient; detector: UV 220 nm; retention time: 4.214 min. The HPLC conditions were as follows: chiral column: XA-CHIRALPAK IG-3, 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid, mobile phase B: isopropanol (10 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 2.706 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 3.0 x 100 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 2 mL / min; isogradient elution with 30% phase B over 4 min; detector: UV 254 nm; retention time: 1.083 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IA-3, 3.0 x 100 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 2 mL / min; isogradient elution with 30% phase B over 4 min; detector: UV 254 nm; retention time: 2.010 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 40% phase B over 3.5 min; detector: UV 254 nm; retention time: 2.301 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; isogradient elution with 40% phase B over 4.5 min; detector: UV 254 nm; retention time: 1.465 min. The HPLC conditions were as follows: chiral column: N-Lux 3um Cellulose-4 (H17-388767), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (0.1% diethylamine); flow rate: 3.5 mL / min; isogradient elution with 48% phase B over 6 min; detector: UV 220 nm; retention time: 2.41 min. The HPLC conditions were as follows: chiral column: N-Lux 3um Cellulose-4 (H17-388767), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (0.1% diethylamine); flow rate: 3.5 mL / min; isogradient elution with 48% phase B over 6 min; detector: UV 220 nm; retention time: 3.66 min. The HPLC conditions were as follows: chiral column: N--CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 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 10% phase B over 6 min; detector: UV 220 nm; retention time: 4.514 min. The HPLC conditions were as follows: chiral column: N--CHIRALPAK IC-3 (Lot No. IC3SCK-VK002), 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 10% phase B over 6 min; detector: UV 220 nm; retention time: 4.948 min. The HPLC conditions were as follows: chiral column: N-CHIRALPAK IG-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: isopropanol (10 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 0.845 min. The HPLC conditions were as follows: chiral column: N-CHIRALPAK IG-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: isopropanol (10 mmol / L ammonia); flow rate: 2 mL / min; elution with 50% phase B over 6 min using an isogradient; detector: UV 220 nm; retention time: 1.905 min. The HPLC conditions were as follows: chiral column: N-CHIRALPAK IE-3 (Lot No. IF3SCK-SD016), 3 x 100 mm; 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; gradient: isogradient elution with 50% phase B over 8 min; detector: UV 220 nm; retention time: 4.857 min. The HPLC conditions were as follows: chiral column: N-CHIRALPAK IE-3 (Lot No. IF3SCK-SD016), 3 x 100 mm; 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 2 mL / min; gradient: isogradient elution with 50% phase B over 8 min; detector: UV 220 nm; retention time: 5.877 min. The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3 (Lot No. ID3SCK-TB004), 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% phase B over 4 min; detector: UV 220 nm; retention time: 1.822 min. The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3 (Lot No. ID3SCK-TB004), 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% phase B over 4 min; detector: UV 220 nm; retention time: 1.296 min. The HPLC conditions were as follows: chiral column: CHIRALART Cellulose-SB (Ser. No. 105CA80166), 4.6 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 over 4 min; detector: UV 230 nm; retention time: 2.055 min. The HPLC conditions were as follows: chiral column: CHIRALART Cellulose-SB (Ser. No. 105CA80166), 4.6 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 over 4 min; detector: UV 230 nm; retention time: 1.632 min. The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3 (Lot No. ID3SCK-TB004), 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% phase B over 4 min; detector: UV 230 nm; retention time: 1.878 min. The HPLC conditions were as follows: chiral column: CHIRALPAK ID-3 (Lot No. ID3SCK-TB004), 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; isogradient elution with 50% phase B over 4 min; detector: UV 230 nm; retention time: 1.217 min. The HPLC conditions were as follows: chiral column: N-CHIRALPAK IG-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 10% phase B over 6.5 min using an isogradient; detector: UV 230 nm; retention time: 4.553 min. The HPLC conditions were as follows: chiral column: N-CHIRALPAK IG-3, 3.0 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol (20 mmol / L ammonia); flow rate: 2 mL / min; elution with 10% phase B over 6.5 min using an isogradient; detector: UV 230 nm; retention time: 4.074 min. The HPLC conditions were as follows: chiral column: N-Lux 3um Cellulose-4 (H17-388767), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: ethanol (20 mmol / L ammonia); flow rate: 3.5 mL / min; isogradient elution with 35% phase B over 6.5 min; detector: UV 220 nm; retention time: 3.455 min. The HPLC conditions were as follows: chiral column: N-Lux 3um Cellulose-4 (H17-388767), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: ethanol (20 mmol / L ammonia); flow rate: 3.5 mL / min; isogradient elution with 35% phase B over 6.5 min; detector: UV 220 nm; retention time: 4.723 min. The HPLC conditions were as follows: chiral column: N-Lux 3 μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (0.1% diethylamine); flow rate: 4 mL / min; gradient: elution with 50% phase B over 6 min; detector: UV 254 nm; retention time: 1.349 min. The HPLC conditions were as follows: chiral column: N-Lux 3 μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (0.1% diethylamine); flow rate: 4 mL / min; gradient: elution with 50% phase B over 6 min; detector: UV 254 nm; retention time: 1.903 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; gradient: elution with 50% phase B over 4 min; detector: UV 254 nm; retention time: 0.617 min. The HPLC conditions were as follows: chiral column: CHIRALPAK IC-3, 4.6 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 mL / min; gradient: elution with 50% phase B over 4 min; detector: UV 254 nm; retention time: 1.334 min.

18. A pharmaceutical composition comprising a quinazoline compound of Formula I as described in any one of claims 1-14 or a pharmaceutically acceptable salt thereof, a quinazoline compound of formula I as described in any one of claims 15-17 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients.

19. The use of a quinazoline compound of Formula I as described in any one of claims 1-14, or a pharmaceutically acceptable salt thereof, a quinazoline compound of formula I as described in any one of claims 15-17, or a pharmaceutical composition as described in claim 18, in the preparation of a KRAS mutant protein inhibitor; wherein the KRAS mutant protein is a KRAS G12D mutant protein.

20. The use of a quinazoline compound of Formula I as described in any one of claims 1-14, a pharmaceutically acceptable salt thereof, a quinazoline compound of formula I as described in any one of claims 15-17, or a pharmaceutical composition as described in claim 18 in the preparation of a medicament; wherein the medicament is for the prevention and / or treatment of cancer mediated by KRAS mutations, and the KRAS mutant protein is a KRAS G12D mutant protein.

21. The application as described in claim 20, wherein the cancer is a blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

22. The use of a quinazoline compound of Formula I as described in any one of claims 1-14, a pharmaceutically acceptable salt thereof, a quinazoline compound of formula I as described in any one of claims 15-17, or a pharmaceutical composition as described in claim 18 in the preparation of a medicament; wherein the medicament is a medicament for the prevention and / or treatment of cancer.

23. The application as described in claim 22, wherein the cancer is a blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

Images