Heterocyclic-substituted pyrimidopyran compounds and their use

Abstract

The present invention discloses piperazine-crosslinked ring-substituted pyrimidopyran compounds and their uses, particularly compounds represented by formula (I''), (I'), or (I), their stereoisomers, and pharmaceutically acceptable salts thereof. [C1] TIFF2026511123000399.tif84156

Description

[Technical Field]

[0001] This application is, CN202310290481.3, filed on March 23, 2023; CN202311634664.9, filed November 30, 2023; and We claim priority from CN202410309827.4, filed on March 18, 2024.

[0002] <Technical field> This disclosure relates to a class of crosslinked piperazine ring-substituted pyrimidopyran compounds and their uses, more specifically to compounds represented by formula (I''), formula (I'), or formula (I), their stereoisomers, and pharmaceutically acceptable salts thereof. [Background technology]

[0003] KRAS is the most common oncogenic mutant gene. KRAS mutations occur in approximately one in seven cancers. KRAS mutations / amplifications are most common in colorectal cancer (US: approximately 45%, China: approximately 49%), pancreatic cancer (US: approximately 90%, China: approximately 87%), and non-small cell lung cancer (US: approximately 35%, China: approximately 13%). G12D KRAS G12V and KRAS G12C It accounts for the largest proportion.

[0004] KRAS is a mouse sarcoma virus oncogenic gene and a key member of the RAS protein. When functioning normally, KRAS acts like a molecular switch regulating cell growth pathways. Following KRAS gene mutations, growth and proliferation signals can be transmitted independently to downstream pathways, unrelated to upstream growth factor receptor signaling, leading to uncontrolled cell growth and tumor progression. Simultaneously, whether or not the KRAS gene is mutated is an important indicator of tumor prognosis.

[0005] Currently, small molecules that directly target KRAS mutations are mainly KRAS G12Cis concentrated in the field. Among them, both AMG510 from Amgen and MRTX849 from Mirati Therapeutics have been approved for sale, and both show good therapeutic effects on tumor patients with G12C KRAS G12D mutations. In addition, MRTX1133, a small molecule drug targeting KRAS G12D mutations, entered phase I clinical trials and showed excellent antitumor properties in preclinical trials. However, there are still some problems with this class of compounds, and tumor patients with G12D KRAS

[0006] mutations have not yet benefited from precision medicine, and the continuous development of small molecule inhibitors targeting KRAS G12D is very important.

Summary of the Invention

Problems to be Solved by the Invention

[0007] In some aspects, the present disclosure provides a compound represented by formula (I''), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0008] In the formula,

[0009] R N is selected from H and C 1-3 alkyl, and C 1-3 alkyl is optionally substituted with 1, 2 or 3 F or Cl;

[0010] Ring A is selected from C6 aryl and 5-6 member heteroaryl;

[0011] Ring B is

Chemical formula

[0012] Ring B has 1, 2, 3, or 4 R 10 It is arbitrarily replaced with;

[0013] L is -C(R L1 R L2 )- Selected from, R L1 and R L2 These are H, D, and C, each independently. 1-3 Selected from alkyl groups;

[0014] R1 and R2 are each independently selected from oxo, H, F, Cl, Br, I, and CN;

[0015] Each R3 independently contains F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Each cycloalkyl group independently has 1, 2, 3, 4, or 5 R groups. a It is arbitrarily replaced with;

[0016] Each R a These are independently selected from D, F, Cl, Br, and I;

[0017] R4, R5, R6, R7, R 6’ and R 7’ These are, independently, oxo, H, F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 2-4 Alkenil, C1-3 Alkoxy, -C(=O)-R d -C(=O)-NR b1 R b2 , and =NO(C 1-3 Selected from alkyl, the C 1-3 Alkyl, C 2-4 Alkenyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R b It is arbitrarily replaced with;

[0018] Alternatively, R6 and R7, together with the carbon atoms to which they are bonded, form a 3- to 5-membered heterocycloalkyl group;

[0019] Each R b These are independently D, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkoxy and -C(=O)-NR b1 R b2 Selected from;

[0020] R8 consists of H, F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl and C 1-3 Selected from alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R a It is arbitrarily replaced with;

[0021] Alternatively, R8 and R 8’ Together with the carbon atoms to which they are bonded, C 3-5 Forming a cycloalkyl or 3-5 membered heterocycloalkyl, the C 3-5 Cycloalkyls and 3- to 5-membered heterocycloalkyls each independently have 1, 2, or 3 R 10 It is arbitrarily replaced with;

[0022] R9 is -C(=O)-NR b3 R b4 and -CH2R c Selected from;

[0023] Each R 10 is independently oxo, D, F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, di-C 1-3 alkylamino, -C(=O)-R d , -S-R d , -S(=O)-R d , -S(=O)2-R d , -NH-C(=O)-R d , C 6-10 aryl and 5- to 10-membered heteroaryl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 OH or F, the C 6-10 aryl and 5- to 10-membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4 or 5 R s1 ;

[0024] R[[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​and R b4 is, independently of each other, H, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl, and the C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R e2 ;

[0027] Alternatively, R b3 and R b4 together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocycloalkyl group, and the 3- to 6-membered heterocycloalkyl group is optionally substituted with 1, 2, 3 or 4 R e2 ;

[0028] R c is F, Cl, Br, I, OH, NH2, -(C=O)NR C1 R C2 , -O(C=O)NR C1 R C2 , -NR C0 (C=O)R C1 , and -NR C0 (C=O)NR C1 R C2 ;

[0029] R C0 、R C1 and R C2 are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl;

[0030] R d is C 1-3 alkyl;

[0031] R e1F, Cl, Br, I, OH, NH2, NO2, C 1-3 Alkyl, C 1-3 Alkylamino, di-C 1-3 Alkylamino, CN, C 1-3 Alkoxy, -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl), -(C=O)N(C 1-3 Alkyl)2, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls;

[0032] R e2 F, Cl, Br, I, OH, NH2, NO2, C 1-3 Alkyl, C 1-3 Alkylamino, di-C 1-3 Alkylamino, CN, C 1-3 Alkoxy, -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl), -(C=O)N(C 1-3 Alkyl)2, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, the C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Each aryl and 5-10 membered heteroaryl independently has 1, 2, 3, 4, or 5 R s1 It is arbitrarily replaced with C 1-3 Alkyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R s2 It is arbitrarily replaced with;

[0033] Alternatively, two or more R e2These, together with the carbon atoms to which they are bonded, form a C6 aryl group or a 5- or 6-membered heteroaryl group;

[0034] R s1 These are oxo, F, Cl, Br, I, OH, NH2, NO2, C 1-6 Alkyl, C 1-6 Alkylamino, di-C 1-6 Alkylamino, CN, C 1-6 Alkoxy, -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl) and -(C=O)N(C 1-3 Selected from alkyl)2;

[0035] R s2 F, Cl, Br, I, OH, NH2, C 1-6 Alkylamino, di-C 1-6 Alkylamino, CN, C 1-6 Alkoxy, -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl) and -(C=O)N(C 1-3 Selected from alkyl)2;

[0036] m is selected from 0, 1, 2, 3, 4, and 5;

[0037] however,

[0038] 1) Ring B is [ka] If that is the case, [ka] is one R 10 It is replaced with R 10F is R1, R2, R4, R5, R6, R7, R 6’ and R 7’ At least one of them is not H;

[0039] 2) Ring B is [ka] If that is the case, [ka] This is 1, 2, 3 or 4 R 10 It is arbitrarily substituted with R1, R2, R4, R5, R6, R7, R 6’ and R 7’ At least one of them is not H;

[0040] 3) The compound is [ka] isn't it.

[0041] In some embodiments, R N H is H.

[0042] In some embodiments, R N C is optionally substituted with 1, 2, or 3 F or Cl atoms. 1-3 It is alkyl.

[0043] This disclosure provides a compound represented by formula (I'), its stereoisomers, or pharmaceutically acceptable salts thereof. [ka]

[0044] During the ceremony,

[0045] Ring A is selected from C6 aryls and 5-6 membered heteroaryls;

[0046] Ring B is, [ka] Selected from;

[0047] Ring B has 1, 2, 3, or 4 R 10 It is arbitrarily replaced with;

[0048] L is -CH2-, and the -CH2- is optionally substituted with one or two D;

[0049] R1 and R2 are each independently selected from oxo, H, F, Cl, Br, I, and CN;

[0050] Each R3 independently contains F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Each cycloalkyl group independently has 1, 2, 3, 4, or 5 R groups. a It is arbitrarily replaced with;

[0051] Each R a These are independently selected from D, F, Cl, Br, and I;

[0052] R4, R5, R6, R7, R 6’ and R 7’ These are, independently, oxo, H, F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 2-4 Alkenil, C 1-3 Alkoxy, -C(=O)-R d -C(=O)-NRb1 R b2 , and =NO(C 1-3 Selected from alkyl, the C 1-3 Alkyl, C 2-4 Alkenyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R b It is arbitrarily replaced with;

[0053] Alternatively, R6 and R7, together with the carbon atoms to which they are bonded, form a 3- to 5-membered heterocycloalkyl group;

[0054] Each R b These are independently D, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkoxy and -C(=O)-NR b1 R b2 Selected from;

[0055] R8 consists of H, F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl and C 1-3 Selected from alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R a It is arbitrarily replaced with;

[0056] Alternatively, R8 and R 8’ Together with the carbon atoms to which they are bonded, C 3-5 Forming a cycloalkyl or 3-5 membered heterocycloalkyl, the C 3-5 Each cycloalkyl or 3- to 5-membered heterocycloalkyl group independently contains 1, 2, or 3 R groups. 10 It is arbitrarily replaced with;

[0057] R9 is -C(=O)-NR b1 R b2 and -CH2R c Selected from;

[0058] Each R 10These are independently oxo, D, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, -SR d -S(=O)-R d -S(=O)2-R d and -NH-C(=O)-R d Selected from, the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 OH groups;

[0059] R b1 and R b2 These are H and C, which are independent of each other. 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Each aryl and 5-10 membered heteroaryl independently has 1, 2, or 3 R e It is arbitrarily replaced with;

[0060] Alternatively, R b1 and R b2 These, together with the nitrogen atom to which they are bonded, form a 3- to 6-membered heterocycloalkyl group;

[0061] R c F, Cl, Br, I, OH, NH2, -O(C=O)NR C1 R C2 , -NR C0 (C=O)R C1 , and -NR C0 (C=O)NR C1 R C2 Selected from;

[0062] R C0 , R C1 and R C2 These are H and C, which are independent of each other. 1-6Alkyl, C 3-6 Selected from cycloalkyl and 3- to 6-membered heterocycloalkyl groups;

[0063] R d C 1-3 It is alkyl;

[0064] R e F, Cl, Br, I, OH, NH2, C 1-3 Alkylamino, di-C 1-3 Alkylamino, CN, C 1-3 Alkoxy, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls;

[0065] m is selected from 0, 1, 2, 3, 4, and 5;

[0066] however,

[0067] 1) Ring B is [ka] If that is the case, [ka] is one R 10 It is replaced with R 10 F is R1, R2, R4, R5, R6, R7, R 6’ and R 7’ At least one of them is not H;

[0068] 2) Ring B is [ka] If that is the case, [ka] This is 1, 2, 3 or 4 R 10 It is arbitrarily substituted with R1, R2, R4, R5, R6, R7, R6’ and R 7’ At least one of them is not H;

[0069] 3) The compound is [ka] isn't it.

[0070] This disclosure also provides a compound represented by formula (I'-1), its stereoisomers, or pharmaceutically acceptable salts thereof. [ka]

[0071] During the ceremony,

[0072] Ring A is a C6 aryl ring;

[0073] Ring B is, [ka] Selected from;

[0074] Ring B has 1, 2, 3, or 4 R 10 It is arbitrarily replaced with;

[0075] L is -CH2-, and the -CH2- is optionally substituted with one or two D;

[0076] R1 and R2 are each independently selected from oxo, H, F, Cl, Br, I, and CN;

[0077] Each R3 independently contains F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5Selected from cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Each cycloalkyl group independently has 1, 2, 3, 4, or 5 R groups. a It is arbitrarily replaced with;

[0078] Each R a These are independently selected from D, F, Cl, Br, and I;

[0079] R4, R5, R6, R7, R 6’ and R 7’ These are, independently, oxo, H, F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 2-4 Alkenil, C 1-3 Alkoxy, -C(=O)-R d -C(=O)-NR b1 R b2 , and =NO(C 1-3 Selected from alkyl, the C 1-3 Alkyl, C 2-4 Alkenyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R b It is arbitrarily replaced with;

[0080] Alternatively, R6 and R7, together with the carbon atoms to which they are bonded, form a 3- to 5-membered heterocycloalkyl group;

[0081] Each R b These are independently D, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkoxy and -C(=O)-NR b1 R b2 Selected from;

[0082] R8 consists of H, F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl and C1-3 Selected from alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R a It is arbitrarily replaced with;

[0083] Alternatively, R8 and R 8’ Together with the carbon atoms to which they are bonded, C 3-5 Forming a cycloalkyl or 3-5 membered heterocycloalkyl, the C 3-5 Each cycloalkyl or 3- to 5-membered heterocycloalkyl group independently contains 1, 2, or 3 R groups. 10 It is arbitrarily replaced with;

[0084] R9 is -C(=O)-NR b1 R b2 and -CH2R c Selected from;

[0085] Each R 10 These are independently oxo, D, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, -SR d -S(=O)-R d -S(=O)2-R d and -NH-C(=O)-R d Selected from, the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 OH groups;

[0086] R b1 and R b2 These are H and C, which are independent of each other. 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10Each aryl and 5-10 membered heteroaryl independently has 1, 2, or 3 R e It is arbitrarily replaced with;

[0087] Alternatively, R b1 and R b2 These, together with the nitrogen atom to which they are bonded, form a 3- to 6-membered heterocycloalkyl group;

[0088] R c F, Cl, Br, I, OH, NH2, -O(C=O)NR C1 R C2 , -NR C0 (C=O)R C1 , and -NR C0 (C=O)NR C1 R C2 Selected from;

[0089] R C0 , R C1 and R C2 These are H and C, which are independent of each other. 1-6 Alkyl, C 3-6 Selected from cycloalkyl and 3- to 6-membered heterocycloalkyl groups;

[0090] R d C 1-3 It is alkyl;

[0091] R e F, Cl, Br, I, OH, NH2, C 1-3 Alkylamino, di-C 1-3 Alkylamino, CN, C 1-3 Alkoxy, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls;

[0092] m is selected from 0, 1, 2, 3, 4, and 5;

[0093] however,

[0094] 1) Ring B is [ka] If that is the case, [ka] is one R 10 It is replaced with R 10 F is R1, R2, R4, R5, R6, R7, R 6’ and R 7’ At least one of them is not H;

[0095] 2) Ring B is [ka] If that is the case, [ka] This is 1, 2, 3 or 4 R 10 It is arbitrarily substituted with R1, R2, R4, R5, R6, R7, R 6’ and R 7’ At least one of them is not H;

[0096] 3) The compound is [ka] isn't it.

[0097] This disclosure also provides a compound represented by formula (I'-2), its stereoisomers, or pharmaceutically acceptable salts thereof. [ka]

[0098] During the ceremony,

[0099] Ring A is a 5-membered heteroaryl;

[0100] Ring B is, [ka] Selected from;

[0101] Ring B has 1, 2, 3, or 4 R 10 It is arbitrarily replaced with;

[0102] L is -CH2-, and the -CH2- is optionally substituted with one or two D;

[0103] R1 and R2 are each independently selected from oxo, H, F, Cl, Br, I, and CN;

[0104] Each R3 independently contains F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Each cycloalkyl group independently has 1, 2, 3, 4, or 5 R groups. a It is arbitrarily replaced with;

[0105] Each R a These are independently selected from D, F, Cl, Br, and I;

[0106] R4, R5, R6, R7, R 6’ and R 7’ These are, independently, oxo, H, F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 2-4 Alkenil, C 1-3 Alkoxy, -C(=O)-R d -C(=O)-NR b1 R b2, and =NO(C 1-3 Selected from alkyl, the C 1-3 Alkyl, C 2-4 Alkenyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R b It is arbitrarily replaced with;

[0107] Alternatively, R6 and R7, together with the carbon atoms to which they are bonded, form a 3- to 5-membered heterocycloalkyl group;

[0108] Each R b These are independently D, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkoxy and -C(=O)-NR b1 R b2 Selected from;

[0109] R8 consists of H, F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl and C 1-3 Selected from alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R a It is arbitrarily replaced with;

[0110] Alternatively, R8 and R 8’ Together with the carbon atoms to which they are bonded, C 3-5 Forming a cycloalkyl or 3-5 membered heterocycloalkyl, the C 3-5 Each cycloalkyl or 3- to 5-membered heterocycloalkyl group independently contains 1, 2, or 3 R groups. 10 It is arbitrarily replaced with;

[0111] R9 is -C(=O)-NR b1 R b2 and -CH2R c Selected from;

[0112] Each R 10 These are independently oxo, D, F, Cl, Br, I, OH, NH2, CN, C 1-3Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, -SR d -S(=O)-R d -S(=O)2-R d and -NH-C(=O)-R d Selected from, the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 OH groups;

[0113] R b1 and R b2 These are H and C, which are independent of each other. 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Each aryl and 5-10 membered heteroaryl independently has 1, 2, or 3 R e It is arbitrarily replaced with;

[0114] Alternatively, R b1 and R b2 These, together with the nitrogen atom to which they are bonded, form a 3- to 6-membered heterocycloalkyl group;

[0115] R c F, Cl, Br, I, OH, NH2, -O(C=O)NR C1 R C2 , -NR C0 (C=O)R C1 , and -NR C0 (C=O)NR C1 R C2 Selected from;

[0116] R C0 , R C1 and R C2 These are H and C, which are independent of each other. 1-6 Alkyl, C 3-6 Selected from cycloalkyl and 3- to 6-membered heterocycloalkyl groups;

[0117] R d C 1-3 It is alkyl;

[0118] R e F, Cl, Br, I, OH, NH2, C 1-3 Alkylamino, di-C 1-3 Alkylamino, CN, C 1-3 Alkoxy, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls;

[0119] m is selected from 0, 1, 2, 3, 4, and 5;

[0120] however,

[0121] 1) Ring B is [ka] If that is the case, [ka] is one R 10 It is replaced with R 10 F is R1, R2, R4, R5, R6, R7, R 6’ and R 7’ At least one of them is not H;

[0122] 2) Ring B is [ka] If that is the case, [ka] This is 1, 2, 3 or 4 R 10 It is arbitrarily substituted with R1, R2, R4, R5, R6, R7, R 6’ and R 7’ At least one of them is not H;

[0123] 3) The compound is [ka] isn't it.

[0124] In some embodiments of this disclosure, ring B is [ka] Selected from, ring B has 1, 2, 3 or 4 R 10 It is arbitrarily replaced.

[0125] In some embodiments of this disclosure, ring B is [ka] Ring B has 1, 2, 3 or 4 R 10 It is optionally substituted with. In some embodiments, ring B is unsubstituted. In some embodiments, ring B has 1 or 2 R 10 It is replaced by one R. In some embodiments, ring B is replaced by one R 10 It is replaced by two R 10 It has been replaced with.

[0126] In some embodiments of the present disclosure, the compound represented by formula (I'-1), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compounds of formula (I'-1-i) and (I'-2-i), their stereoisomers, or pharmaceutically acceptable salts thereof. [ka]

[0127] In some embodiments of the present disclosure, the compound represented by formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by formula (I'-1-i), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments of the present disclosure, the compound represented by formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by formula (I'-2-i), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments of this disclosure, ring B is [ka] Ring B has 1, 2, 3 or 4 R 10 It is optionally substituted with. In some embodiments, ring B is unsubstituted. In some embodiments, ring B has 1 or 2 R 10 It is replaced by one R. In some embodiments, ring B is replaced by one R 10 It is replaced by two R 10 It has been replaced with.

[0130] In some embodiments of the present disclosure, the compound represented by formula (I'-1), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compounds of formula (I'-1-ii) and (I'-2-ii), their stereoisomers, or pharmaceutically acceptable salts thereof. [ka]

[0131] In some embodiments of the present disclosure, the compound represented by formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by formula (I'-1-ii), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments of the present disclosure, the compound represented by formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by formula (I'-2-ii), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments of this disclosure, ring B is [ka] Selected from, ring B has 1, 2, 3 or 4 R 10 It is optionally substituted with. In some embodiments, ring B is unsubstituted. In some embodiments, ring B has 1 or 2 R 10 It is replaced by one R. In some embodiments, ring B is replaced by one R 10 It is replaced by two R 10 It has been replaced with.

[0134] In some embodiments of the present disclosure, the compound of formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compounds of formulas (I'-3), (I'-4), (I'-5), (I'-6), (I'-7), (I'-8), (I'-9), (I'-10), (I'-11), (I'-12), and (I'-13), their stereoisomers, or pharmaceutically acceptable salts thereof. [ka]

[0135] In some embodiments of the present disclosure, the compound represented by formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (I'-14) and (I'-15), their stereoisomers, or pharmaceutically acceptable salts thereof. [ka]

[0136] In some embodiments of this disclosure, ring A is phenyl, and the phenyl is substituted with at least one R3, each R3 independently being F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 2-4 Alkenil, C2-4 Alkinyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Each cycloalkyl group independently has 1, 2, 3, 4, or 5 R groups. a It is arbitrarily replaced.

[0137] In some embodiments of this disclosure, ring A is phenyl, and the phenyl is substituted with at least one R3, each R3 independently being F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected. In some embodiments of this disclosure, ring A is phenyl, and the phenyl is substituted with two R3s, each R3 independently being F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected. In some embodiments of this disclosure, ring A is phenyl, and the phenyl is substituted with three R3s, each R3 independently being F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected. In some embodiments of this disclosure, ring A is phenyl, and the phenyl is substituted with four R3s, each R3 independently being F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected.

[0138] In some embodiments of this disclosure, [ka] teeth, [ka] Selected from.

[0139] In some embodiments of this disclosure, [ka] teeth, [ka] Selected from.

[0140] In some embodiments of this disclosure, [ka] teeth [ka] That is the case.

[0141] In some embodiments of this disclosure, [ka] teeth, [ka] Selected from.

[0142] In some embodiments of this disclosure, ring A is a 5-6 membered heteroaryl group (e.g., pyridyl), and the 5-6 membered heteroaryl group is substituted with at least one R3, each R3 independently of F, Cl, Br, I, OH, NH2, CN, or C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Selected from cycloalkyl, the C 1-3Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Each cycloalkyl group independently has 1, 2, 3, 4, or 5 R groups. a It is arbitrarily replaced.

[0143] In some embodiments of this disclosure, ring A is a 5-6 membered heteroaryl group (e.g., pyridyl), and the 5-6 membered heteroaryl group is substituted with at least one R3, each R3 independently of F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected. In some embodiments of the present disclosure, ring A is a 5-6 membered heteroaryl group (e.g., pyridyl), the 5-6 membered heteroaryl group is substituted with two R3s, each R3 independently of F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected. In some embodiments of the present disclosure, ring A is a 5-6 membered heteroaryl group (e.g., pyridyl), the 5-6 membered heteroaryl group is substituted with three R3s, each R3 independently of F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected. In some embodiments of the present disclosure, ring A is a 5-6 membered heteroaryl group (e.g., pyridyl), the 5-6 membered heteroaryl group is substituted with four R3 groups, each R3 independently of F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected.

[0144] In some embodiments of the present disclosure, ring A is a five-membered heteroaryl group, which is substituted with at least one R3, each R3 independently of F, Cl, Br, I, OH, NH2, CN, or C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Each cycloalkyl group independently contains 1, 2, 3, 4, or 5 R atoms. a It is arbitrarily replaced.

[0145] In some embodiments of the present disclosure, ring A is selected from a five-membered heteroaryl group, the five-membered heteroaryl group being substituted with at least one R3, each R3 independently being F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected. In some embodiments of the present disclosure, ring A is a five-membered heteroaryl group, the five-membered heteroaryl group is substituted with two R3s, each R3 independently of F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected. In some embodiments of the present disclosure, ring A is a five-membered heteroaryl group, the five-membered heteroaryl group is substituted with three R3s, each R3 independently being F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected. In some embodiments of the present disclosure, ring A is a 5-membered heteroaryl, the 5-membered heteroaryl is substituted with 4 R3s, each R3 independently being F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected.

[0146] In some embodiments of this disclosure, ring A is a six-membered heteroaryl group, which is substituted with at least one R3, each R3 independently of F, Cl, Br, I, OH, NH2, CN, or C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Each cycloalkyl group independently has 1, 2, 3, 4, or 5 R groups. a It is arbitrarily replaced.

[0147] In some embodiments of this disclosure, ring A is a 6-membered heteroaryl group, the 6-membered heteroaryl group is substituted with at least one R3, each R3 independently of F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected. In some embodiments of the present disclosure, ring A is a 6-membered heteroaryl group, the 6-membered heteroaryl group is substituted with two R3s, each R3 independently being F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected. In some embodiments of the present disclosure, ring A is a 6-membered heteroaryl group, the 6-membered heteroaryl group is substituted with three R3s, each R3 independently being F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected. In some embodiments of the present disclosure, ring A is a 6-membered heteroaryl group, the 6-membered heteroaryl group is substituted with four R3s, each R3 independently being F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected.

[0148] In some embodiments of the present disclosure, the compound represented by formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compounds of formulas (I'-1'-i) and (I'-2'-i), their stereoisomers, or pharmaceutically acceptable salts thereof. [ka]

[0149] In some embodiments of the present disclosure, the compound represented by formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by formula (I'-1'-i), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments of the present disclosure, the compound represented by formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by formula (I'-2'-i), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments of the present disclosure, the compound represented by formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compounds of formulas (I'-1'-ii) and (I'-2'-ii), their stereoisomers, or pharmaceutically acceptable salts thereof. [ka]

[0152] In some embodiments of the present disclosure, the compound represented by formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by formula (I'-1'-ii), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments of the present disclosure, the compound represented by formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by formula (I'-2'-ii), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments of the present disclosure, the compound of formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compounds of formula (I'-3'), (I'-4'), (I'-5'), (I'-6'), (I'-7'), (I'-8'), (I'-9'), (I'-10'), (I'-11'), (I'-12'), and (I'-13'), their stereoisomers, or a pharmaceutically acceptable salt thereof. [ka] [ka]

[0155] In some embodiments of the present disclosure, the compound represented by formula (I'-1) of the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compounds of formulas (I'-14') and (I'-15'), their stereoisomers, or pharmaceutically acceptable salts thereof. [ka]

[0156] In some embodiments of this disclosure, ring A is selected from C6 aryls and 5-6 membered heteroaryls (e.g., heteroaryls comprising a ring containing 1-4 heteroatoms selected from O, N, and S) as described herein. In some embodiments of this disclosure, ring A is phenyl as described herein. In some embodiments of this disclosure, ring A is a 5-6 membered heteroaryl as described herein. In some embodiments of this disclosure, ring A is a 5 membered heteroaryl as described herein. In some embodiments of this disclosure, ring A is a 6 membered heteroaryl as described herein. In some embodiments of this disclosure, ring A is unsubstituted. In some embodiments of this disclosure, ring A is substituted as described herein. In some embodiments of this disclosure, ring A is substituted with at least one R3 (e.g., 2, 3, or 4 R3s) as described herein.

[0157] In some embodiments of this disclosure, L is -C(R L1 R L2 )- and R L1 and R L2 Each of these is independently selected from H and D.

[0158] In some embodiments of this disclosure, L is -C(R L1 R L2 )- and R L1 and R L2 Each of these is independently H.

[0159] In some embodiments of this disclosure, L is -C(R L1 R L2 )- and R L1 and R L2 At least one of them is C 1-3 It is alkyl.

[0160] In some embodiments of this disclosure, L is -CH2-, and the -CH2- is optionally replaced by one or two D.

[0161] In some embodiments of this disclosure, L is -CH2-. In some embodiments of this disclosure, L is -CD2-. In some embodiments of this disclosure, L is -CHD-.

[0162] In some embodiments of this disclosure, L is selected from -CH2- and -CD2-.

[0163] In some embodiments of this disclosure, R1 and R2 are each independently selected from oxo, H, F, Cl, Br, I, and CN.

[0164] In some embodiments of this disclosure, R1 and R2 are H.

[0165] In some embodiments of this disclosure, R1 is selected from oxo, H, F, Cl, Br, I, and CN. In some embodiments of this disclosure, R2 is selected from oxo, F, Cl, and CN.

[0166] In some embodiments of this disclosure, R2 is selected from oxo, H, F, Cl, Br, I, and CN. In some embodiments of this disclosure, R1 is selected from oxo, F, Cl, and CN.

[0167] In some embodiments of this disclosure, each R3 is independently F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)), C 1-3 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropyl(C3)), C 1-3 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-3Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino, or n-propylisopropylamino), C 2-4 Alkenyls (e.g., etenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), or butadienyl (C4)), C 2-4 Alkynnyl (e.g., ethynnyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), or 2-butynyl (C4)) and C 3-5 Selected from cycloalkyls (e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5)), the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Each cycloalkyl group independently has 1, 2, 3, 4, or 5 R groups. a It is arbitrarily replaced.

[0168] In some embodiments of this disclosure, each R3 is independently F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected.

[0169] Several embodiments of this disclosure, each R a R is independently selected from D, F, Cl, Br and I. In some embodiments of this disclosure, each R a These are independently selected from D, F, and I.

[0170] In some embodiments of this disclosure, m is selected from 0, 1, 2, 3, 4, and 5. In some embodiments of this disclosure, m is 0. In some embodiments of this disclosure, m is 1. In some embodiments of this disclosure, m is 2. In some embodiments of this disclosure, m is 3. In some embodiments of this disclosure, m is 4. In some embodiments of this disclosure, m is 5.

[0171] In some embodiments of this disclosure, m is 4.

[0172] Some embodiments of the present disclosure, R4, R5, R6, R7, R 6’ and R 7’ These are, independently, oxo, H, F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)), C 2-4 Alkenyls (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), or butadienyl (C4)), C 1-3 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropoxy(C3)), -C(=O)-R d -C(=O)-NR b1 R b2 , and =NO(C 1-3 Selected from alkyl, the C 1-3 Alkyl, C 2-4 Alkenyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R b It is arbitrarily replaced.

[0173] Some embodiments of the present disclosure, R4, R5, R6, R7, R 6’ and R 7’ H is H.

[0174] Some embodiments of the present disclosure, R4, R5, R6, R7, R 6’ and R 7’At least one of them is not H.

[0175] In some embodiments of this disclosure, R6 and R7, together with the carbon atoms to which they are bonded, form a 3- to 5-membered heterocycloalkyl group (for example, a 3- to 5-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from N, O, and S). In some embodiments of this disclosure, R6 and R7, together with the carbon atoms to which they are bonded, form a 3-membered heterocycloalkyl group containing 1 heteroatom selected from N, O, and S. In some embodiments of this disclosure, R6 and R7, together with the carbon atoms to which they are bonded, form a 3-membered heterocycloalkyl group containing 1 heteroatom selected from N and O. In some embodiments of this disclosure, R6 and R7, together with the carbon atoms to which they are bonded, form a 4-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from N, O, and S. In some embodiments of this disclosure, R6 and R7, together with the carbon atoms to which they are bonded, form a 4-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from N and O. In some embodiments of the present disclosure, R6 and R7, together with the carbon atoms to which they are bonded, form a four-membered heterocycloalkyl group containing one heteroatom selected from N and O. In some embodiments of the present disclosure, R6 and R7, together with the carbon atoms to which they are bonded, form a five-membered heterocycloalkyl group containing one or two heteroatoms selected from N, O, and S. In some embodiments of the present disclosure, R6 and R7, together with the carbon atoms to which they are bonded, form a five-membered heterocycloalkyl group containing one or two heteroatoms selected from N and O. In some embodiments of the present disclosure, R6 and R7, together with the carbon atoms to which they are bonded, form a five-membered heterocycloalkyl group containing one heteroatom selected from N and O.

[0176] Several embodiments of this disclosure, each R b These are independently D, F, Cl, Br, I, OH, NH2, CN, C1-3 Alkoxys (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropoxy(C3)) and -C(=O)-NR b1 R b2 Selected from. In some embodiments of this disclosure, each R b These are independently D, F, Cl, OH, NH2, CN, C 1-3 Alkoxys (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropoxy(C3)) and -C(=O)-NR b1 R b2 Selected from.

[0177] In some embodiments of this disclosure, R8 is H, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)) and C 1-3 Selected from alkoxys (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropoxy(C3)), the C 1-3 Alkyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R a It is arbitrarily replaced.

[0178] In some embodiments of this disclosure, R8 is H.

[0179] In some embodiments of this disclosure, R8 is F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)) and C 1-3 Selected from alkoxys (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropoxy(C3)), the C 1-3 Alkyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R a It is arbitrarily replaced.

[0180] In some embodiments of this disclosure, R8 is F, Cl, NH2, CN, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)) and C 1-3 Selected from alkoxys (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropoxy(C3)), the C 1-3 Alkyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R a It is arbitrarily replaced.

[0181] In some embodiments of this disclosure, R8 and R 8’ Together with the carbon atoms to which they are bonded, C 3-5 A cycloalkyl group (e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5)) or a 3- to 5-membered heterocycloalkyl group (e.g., a heterocycloalkyl group comprising a ring containing 1 to 3 heteroatoms selected from O, N, and S) is formed, and the C 3-5 Each cycloalkyl group or 3- to 5-membered heterocycloalkyl group independently contains 1, 2, or 3 R 10 It is arbitrarily replaced.

[0182] In some embodiments of this disclosure, R8 and R 8’ Together with the carbon atoms to which they are bonded, they form 1, 2, or 3 R 10 C is arbitrarily replaced by 3-5 It forms a cycloalkyl group (e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5)).

[0183] In some embodiments of this disclosure, R8 and R 8’ These, together with the carbon atoms to which they are bonded, form a 3-5 membered heterocycloalkyl group (for example, a 3-5 membered heterocycloalkyl group comprising a ring containing 1-2 heteroatoms selected from O, N, and S), and each of these 3-5 membered heterocycloalkyl groups independently contains 1, 2, or 3 R atoms. 10It is optionally replaced with R8 and R 8’ These, together with the carbon atoms to which they are bonded, form a three-membered heterocycloalkyl group containing one heteroatom selected from N, O, and S. In some embodiments of this disclosure, R8 and R 8’ These, together with the carbon atoms to which they are bonded, form a three-membered heterocycloalkyl group containing one heteroatom selected from N and O. In some embodiments of this disclosure, R8 and R 8’ These, together with the carbon atoms to which they are bonded, form a four-membered heterocycloalkyl group containing one or two heteroatoms selected from N, O, and S. In some embodiments of this disclosure, R8 and R 8’ These, together with the carbon atoms to which they are bonded, form a four-membered heterocycloalkyl group containing one or two heteroatoms selected from N and O. In some embodiments of this disclosure, R8 and R 8’ These, together with the carbon atoms to which they are bonded, form a four-membered heterocycloalkyl group containing one heteroatom selected from N and O. In some embodiments of this disclosure, R8 and R 8’ These, together with the carbon atoms to which they are bonded, form a five-membered heterocycloalkyl group containing one or two heteroatoms selected from N, O, and S. In some embodiments of this disclosure, R8 and R 8’ These, together with the carbon atoms to which they are bonded, form a five-membered heterocycloalkyl group containing one or two heteroatoms selected from N and O. In some embodiments of this disclosure, R8 and R 8’ These, together with the carbon atoms to which they are bonded, form a five-membered heterocycloalkyl group containing one heteroatom selected from N and O.

[0184] In some embodiments of this disclosure, R9 is -C(=O)-NR b3 R b4 and -CH2R c Selected from. In some embodiments of this disclosure, R9 is -C(=O)-NR b3 Rb4 Selected from. In some embodiments of this disclosure, R9 is -CH2R c Selected from.

[0185] In some embodiments of this disclosure, R9 is -C(=O)-NR b1 R b2 That is the case.

[0186] Several embodiments of this disclosure, each R 10 These are independently oxo, D, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)), C 1-3 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropyl(C3)), C 1-3 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-3 Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino, or n-propylisopropylamino), -C(=O)-R d , -SR d -S(=O)-R d -S(=O)2-R d -NH-C(=O)-R d , C 6-10 Selected from aryls and 5-10 member heteroaryls, the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 OH or F groups, and the C 6-10 Each aryl and 5-10 membered heteroaryl independently has 1, 2, 3, 4, or 5 R s1 It is arbitrarily replaced.

[0187] In some embodiments of this disclosure, at least one R 10 These are oxo, D, F, Cl, Br, I, OH, NH2, CN, C1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)), C 1-3 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropyl(C3)), C 1-3 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-3 Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino, or n-propylisopropylamino), -SR d -S(=O)-R d -S(=O)2-R d and -NH-C(=O)-R d Selected from, the C 1-3 The alkyl group is optionally substituted with one, two, or three OH or F groups.

[0188] In some embodiments of this disclosure, at least one R 10 These are oxo, D, F, Cl, OH, NH2, CN, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)), C 1-3 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropyl(C3)), C 1-3 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-3 Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino, or n-propylisopropylamino), -SR d -S(=O)-R d -S(=O)2-R d and -NH-C(=O)-Rd Selected from, the C 1-3 The alkyl group is optionally substituted with one, two, or three OH or F groups.

[0189] In some embodiments of this disclosure, at least one R 10 These are oxo, F, Cl, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)), C 1-3 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropyl(C3)), C 1-3 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-3 Selected from alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino, or n-propylisopropylamino), C 1-3 The alkyl group is optionally substituted with one, two, or three OH or F groups.

[0190] In some embodiments of this disclosure, at least one R 10 is -C(=O)-R d , -SR d -S(=O)-R d -S(=O)2-R d , and -NH-C(=O)-R d Selected from.

[0191] In some embodiments of this disclosure, at least one R 10 C 6-10 Selected from aryls and 5-10 member heteroaryls, the C 6-10 Each aryl and 5-10 membered heteroaryl independently has 1, 2, 3, 4, or 5 R s1 It is arbitrarily replaced.

[0192] Some embodiments of this disclosure, R b1 and R b2 These are H and C, which are independent of each other. 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), m-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentyloxy (C5), hexyloxy (C6)), C 3-10 Cycloalkyl (e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6)), C 3-10 Cycloalkyls (e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6), cycloheptyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclodecyl (C) 10 ), octahydro-1H-indenyl(C9), decahydronaphthyl(C9) 10 ) or spiro[4.5]decyl(C 10 )), 3-10 membered heterocycloalkyls (for example, heterocycloalkyls comprising one or two 3-8 membered rings and one to five heteroatoms selected from N, O, and S), C 6-10 Selected from aryls (e.g., phenyl or naphthyl) and 5-10 membered heteroaryls (e.g., heteroaryls comprising one or two 5-membered or 6-membered rings and one to five heteroatoms selected from N, O, and S), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Each aryl and 5-10 membered heteroaryl independently has 1, 2, 3, or 4 R e1 It is arbitrarily replaced.

[0193] Some embodiments of this disclosure, R b1 and R b2 At least one of them is C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), m-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 3-6 Cycloalkyl (e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6)), C 1-6 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), isopropyl(C3), butoxy(C4), isobutoxy(C4), sec-butoxy(C4), tert-butoxy(C4), pentyloxy(C5), hexyloxy(C6)), C 3-10 Cycloalkyls (e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6), cycloheptyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclodecyl (C) 10 ), octahydro-1H-indenyl(C9), decahydronaphthyl(C9) 10 ) or spiro[4.5]decyl(C 10 )), 3-10 membered heterocycloalkyls (for example, heterocycloalkyls comprising one or two 3-8 membered rings and one to five heteroatoms selected from N, O, and S, which may be monocyclic or polycyclic, e.g., spirocyclic, bridging, or condensed polycyclic heterocycloalkyls), C 6-10 Selected from aryls (e.g., phenyl or naphthyl) and 5-10 membered heteroaryls (e.g., heteroaryls comprising one or two 5-membered or 6-membered rings and one to five heteroatoms selected from N, O, and S), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10Each aryl and 5-10 membered heteroaryl independently has 1, 2, 3, or 4 R e1 It is arbitrarily replaced.

[0194] Some embodiments of this disclosure, R b1 and R b2 At least one of them is C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), m-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 3-6 Cycloalkyls (e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6)) and C 1-6 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), isopropyl(C3), butoxy(C4), isobutoxy(C4), sec-butoxy(C4), tert-butoxy(C4), pentyloxy(C5), hexyloxy(C6)) are selected, and the C 1-6 Alkyl and C 1-6 Each alkoxy group independently has 1, 2, 3, or 4 R e1 It is arbitrarily substituted in the base.

[0195] Some embodiments of this disclosure, R b1 and R b2 At least one of them is C 3-10 Cycloalkyls (e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6), cycloheptyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclodecyl (C) 10 ), octahydro-1H-indenyl(C9), decahydronaphthyl(C9) 10 ) or spiro[4.5]decyl(C 10)), 3-10 membered heterocycloalkyls (for example, heterocycloalkyls comprising one or two 3-8 membered rings and one to five heteroatoms selected from N, O, and S, which may be monocyclic or polycyclic, e.g., spirocyclic, bridging, or condensed polycyclic heterocycloalkyls), C 6-10 Selected from aryls (e.g., phenyl or naphthyl) and 5-10 membered heteroaryls (e.g., heteroaryls comprising one or two 5-membered or 6-membered rings and one to five heteroatoms selected from N, O, and S), the C 3-10 Cycloalkyl, 3-10 member heterocycloalkyl, C 6-10 Each aryl and 5-10 membered heteroaryl independently has 1, 2, 3, or 4 R e1 It is arbitrarily replaced.

[0196] Some embodiments of this disclosure, R b1 and R b2 At least one of them is C 3-6 Selected from cycloalkyls (e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6)), 3-6 membered heterocycloalkyls, C6 aryls, and 5-6 membered heteroaryls (e.g., heteroaryls containing 1-3 heteroatoms selected from N, O, and S), each of the C3 cycloalkyl, 3-6 membered heterocycloalkyl, C6 aryl, and 5-6 membered heteroaryls independently contains 1, 2, 3, or 4 R atoms. e1 It is arbitrarily replaced.

[0197] Some embodiments of this disclosure, R b1 and R b2 These, together with the nitrogen atom to which they are bonded, form a 3-6 membered heterocycloalkyl group (for example, a heterocycloalkyl group comprising one or two 3-6 membered rings and one to four heteroatoms selected from N, O, and S), and the 3-6 membered heterocycloalkyl group has one, two, three, or four R atoms. e1 It is arbitrarily substituted in the base.

[0198] Some embodiments of this disclosure, R b3and R b4 H and C are independent of each other. 1-6 Alkyl, C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentyloxy (C5), hexyloxy (C6)), C 3-10 Cycloalkyls (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C) 10 ), cyclodecenyl (C 10 ), OctaHydro-1H-indenyl(C9), Decalinyl(C 10 ) or spiro[4.5]decyl(C 10 )), 3-10 membered heterocycloalkyls (for example, heterocycloalkyls comprising one or two 3-8 membered rings and one to five heteroatoms selected from N, O, and S), C 6-10 The alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group comprises 1, 2, 3, or 4 R atoms. e2 It is arbitrarily replaced.

[0199] Some embodiments of this disclosure, R b1 and R b2 At least one of them is C 1-6 Alkyl or C 1-6The alkyl or alkoxy is an alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), isopropoxy(C3), butoxy(C4), isobutoxy(C4), sec-butoxy(C4), tert-butoxy(C4), pentyloxy(C5), hexyloxy(C6)), and the alkyl or alkoxy has 1, 2, 3, or 4 R e2 It is arbitrarily replaced.

[0200] Some embodiments of this disclosure, R b1 and R b2 At least one of them is C 3-10 Cycloalkyls (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl(C9), decahydronaphthyl(C9) 10 ) or spiro[4.5]decyl(C 10 )), 3-10 membered heterocycloalkyls (for example, heterocycloalkyls comprising one or two 3-8 membered rings and one to five heteroatoms selected from N, O, and S, which may be monocyclic or polycyclic, e.g., spiropolycyclic, bridging polycyclic, or condensed polycyclic heterocycloalkyls), C 6-10 The aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., a heteroaryl comprising one or two 5-membered or 6-membered rings and one to five heteroatoms selected from N, O, and S), wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl has 1, 2, 3, or 4 R e2 It is arbitrarily replaced.

[0201] Some embodiments of this disclosure, R b1 and R b2 At least one of them is C 3-6 These are cycloalkyls (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6)), 3-6 membered heterocycloalkyls (e.g., heterocycloalkyls containing 1-3 heteroatoms selected from N, O, and S), C6 aryls, and 5-6 membered heteroaryls (e.g., heteroaryls containing 1-4 heteroatoms selected from N, O, and S), wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl has 1, 2, 3, or 4 R e2 It is arbitrarily replaced.

[0202] Some embodiments of this disclosure, R b3 and R b4 These, together with the nitrogen atom to which they are bonded, form a 3-6 member heterocycloalkyl group (for example, a heterocycloalkyl group containing 1-4 heteroatoms selected from N, O, and S), and the 3-6 member heterocycloalkyl group has 1, 2, 3, or 4 R e2 It is arbitrarily replaced.

[0203] Some embodiments of this disclosure, R c F, Cl, Br, I, OH, NH2, -(C=O)NR C1 R C2 -O(C=O)NR C1 R C2 , -NR C0 (C=O)R C1 , and -NR C0 (C=O)NR C1 R C2 Selected from. In some embodiments of this disclosure, R c F, Cl, OH, NH2, -O(C=O)NR C1 R C2 , -NR C0 (C=O)RC1 , and -NR C0 (C=O)NR C1 R C2 Selected from. In some embodiments of this disclosure, R c F, Cl, -O(C=O)NR C1 R C2 , -NR C0 (C=O)R C1 , and -NR C0 (C=O)NR C1 R C2 Selected from. In some embodiments of this disclosure, R c R is selected from F, Cl, OH, and NH2. In some embodiments of the present disclosure, R c is -O(C=O)NR C1 R C2 , -NR C0 (C=O)R C1 , and -NR C0 (C=O)NR C1 R C2 Selected from.

[0204] Some embodiments of this disclosure, R C0 , R C1 and R C2 These are H and C, which are independent of each other. 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), m-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 3-6 The selection is made from cycloalkyls (e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6)) and 3-6 membered heterocycloalkyls (e.g., heterocycloalkyls comprising one or two 3-6 membered rings and one to four heteroatoms selected from N, O, and S).

[0205] Some embodiments of this disclosure, R d C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)) is selected.

[0206] Some embodiments of this disclosure, R e1 F, Cl, Br, I, OH, NH2, NO2, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)), C 1-3 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-3 Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, ethyl-n-propylamino, ethyl-isopropylamino, or n-propyl-isopropylamino), CN, C 1-3 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropyloxy(C3)), -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl), -(C=O)N(C 1-3 Alkyl)2, C 3-10 Cycloalkyls (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C) 10 ), cyclodecenyl (C 10 ), OctaHydro-1H-indenyl(C9), Decalinyl(C 10 ) or spiro[4.5]decanil(C 10)), 3-10 membered heterocycloalkyls (for example, heterocycloalkyls comprising one or two 3-8 membered rings and one to five heteroatoms selected from N, O, and S, which may be monocyclic or polycyclic, e.g., spiropolycyclic, bridging polycyclic, or condensed polycyclic heterocycloalkyls), C 6-10 These are aryls (e.g., phenyl or naphthyl) and 5- to 10-membered heteroaryls (e.g., heteroaryls comprising one or two 5-membered or 6-membered rings and one to five heteroatoms selected from N, O, and S).

[0207] Some embodiments of this disclosure, R e1 F, Cl, Br, I, OH, NH2, NO2, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)), C 1-3 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-3 Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, ethyl-n-propylamino, ethyl-isopropylamino, or n-propyl-isopropylamino), CN, C 1-3 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropyloxy(C3)), -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl) or -(C=O)N(C 1-3 It is alkyl(2).

[0208] Some embodiments of this disclosure, R e1 F, Cl, Br, I, OH, NH2, NO2, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)), C 1-3Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-3 Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, ethyl-n-propylamino, ethyl-isopropylamino, or n-propyl-isopropylamino), CN or C 1-3 These are alkoxys (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropyloxy(C3)).

[0209] Some embodiments of this disclosure, R e1 is -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl) or -(C=O)N(C 1-3 It is alkyl(2).

[0210] Some embodiments of this disclosure, R e1 F, Cl, Br, I, OH, NH2, NO2, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)), C 1-3 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-3 Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino, or n-propylisopropylamino), CN, C 1-3 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropyl(C3)), C 3-10Cycloalkyls (e.g., cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6), cycloheptyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclodecyl (C) 10 ), octahydro-1H-indenyl(C9), decahydronaphthyl(C9) 10 ) or spiro[4.5]decyl(C 10 )), 3-10 membered heterocycloalkyls (for example, heterocycloalkyls comprising one or two 3-8 membered rings and one to five heteroatoms selected from N, O, and S, which may be monocyclic or polycyclic, e.g., spirocyclic, bridging, or condensed polycyclic heterocycloalkyls), C 6-10 The selection is made from aryls (e.g., phenyl or naphthyl) and 5-10 membered heteroaryls (e.g., heteroaryls comprising one or two 5-membered or 6-membered rings and one to five heteroatoms selected from N, O, and S).

[0211] Some embodiments of this disclosure, R e1 C 3-10 Cycloalkyls (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C) 10 ), cyclodecenyl (C 10 ), OctaHydro-1H-indenyl(C9), Decalinyl(C 10 ) or spiro[4.5]decanil(C 10)), 3-10 membered heterocycloalkyls (for example, heterocycloalkyls comprising one or two 3-8 membered rings and one to five heteroatoms selected from N, O, and S, which may be monocyclic or polycyclic, e.g., spiropolycyclic, bridging polycyclic, or condensed polycyclic heterocycloalkyls), C 6-10 These are aryls (e.g., phenyl or naphthyl) and 5- to 10-membered heteroaryls (e.g., heteroaryls comprising one or two 5-membered or 6-membered rings and one to five heteroatoms selected from N, O, and S).

[0212] Some embodiments of this disclosure, R e2 F, Cl, Br, I, OH, NH2, NO2, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)), C 1-3 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-3 Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino, or n-propylisopropylamino), CN, C 1-3 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropoxy(C3)), -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl), -(C=O)N(C 1-3 Alkyl)2, C 3-10Cycloalkyls (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C) 10 ), cyclodecenyl (C 10 ), OctaHydro-1H-indenyl(C9), Decalinyl(C 10 ) or spiro[4.5]decanyl(C 10 )), 3-10 membered heterocycloalkyls (for example, heterocycloalkyls comprising one or two 3-8 membered rings and one to five heteroatoms selected from N, O, and S, which may be monocyclic or polycyclic, e.g., spiropolycyclic, bridging polycyclic, or condensed polycyclic heterocycloalkyls), C 6-10 The aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., a heteroaryl comprising one or two 5-membered or 6-membered rings and one to five heteroatoms selected from N, O, and S), and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently comprises 1, 2, 3, 4, or 5 R s1 The alkyl and alkoxy groups are optionally substituted, and each of them independently has 1, 2, 3, 4, or 5 R groups. s2 It is arbitrarily replaced.

[0213] Some embodiments of this disclosure, R e2 F, Cl, Br, I, OH, NH2, NO2, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)), C 1-3 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-3Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino, or n-propylisopropylamino), CN, C 1-3 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropoxy(C3)), -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl) or -(C=O)N(C 1-3 The alkyl group is 2, and each alkyl group and alkoxy group independently has 1, 2, 3, 4, or 5 R s2 It is arbitrarily replaced.

[0214] Some embodiments of this disclosure, R e2 F, Cl, Br, I, OH, NH2, NO2, C 1-3 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or isopropyl (C3)), C 1-3 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-3 Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino, or n-propylisopropylamino), CN, or C 1-3 The alkyl and alkoxy groups are alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), or isopropoxy(C3)), and each alkyl and alkoxy group independently has 1, 2, 3, 4, or 5 R groups. s2 It is arbitrarily replaced.

[0215] Some embodiments of this disclosure, R e2 is -S(=O)2-(C1-3 alkyl), -(C=O)(C 1-3 alkyl), -(C=O)O(C 1-3 alkyl), -(C=O)NH(C 1-3 alkyl) or -(C=O)N(C 1-3 alkyl)2.

[0216] In some embodiments of the present disclosure, R e2 is F, Cl, Br, I, OH, NH2, NO2, C 1-3 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3) or isopropyl (C3)), C 1-3 alkylamino (e.g., methylamino, ethylamino, n-propylamino or isopropylamino), di-C 1-3 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino or n-propylisopropylamino), CN, C 1-3 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3) or isopropyloxy (C3)), C 3-10 cycloalkyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrieneyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decalinyl (C 10 ), or spiro[4.5]decyl (C 10)), 3-10 membered heterocycloalkyls (for example, heterocycloalkyls comprising one or two 3-8 membered rings and one to five heteroatoms selected from N, O, and S, which may be monocyclic or polycyclic, e.g., spiropolycyclic, bridging polycyclic, or condensed polycyclic heterocycloalkyls), C 6-10 The aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., a heteroaryl comprising one or two 5-membered or 6-membered rings and one to five heteroatoms selected from N, O, and S), and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently comprises 1, 2, 3, 4, or 5 R s1 The alkyl and alkoxy are optionally substituted, and each independently has 1, 2, 3, 4, or 5 R s2 It is arbitrarily replaced.

[0217] Some embodiments of this disclosure, R e2 C 3-10 Cycloalkyls (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C) 10 ), cyclodecenyl (C 10 ), OctaHydro-1H-indenyl(C9), Decalinyl(C 10 ) or spiro[4.5]decyl(C 10 )), 3-10 membered heterocycloalkyls (for example, heterocycloalkyls comprising one or two 3-8 membered rings and one to five heteroatoms selected from N, O, and S, which may be monocyclic or polycyclic, e.g., spiropolycyclic, bridging polycyclic, or condensed polycyclic heterocycloalkyls), C 6-10The aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., a heteroaryl comprising one or two 5-membered or 6-membered rings and one to five heteroatoms selected from N, O, and S), and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl each independently comprises 1, 2, 3, 4, or 5 R s1 It is arbitrarily replaced.

[0218] In some embodiments of this disclosure, two or more R e2 The groups, together with the carbon atoms to which they are bonded, form a C6 aryl group or a 5- or 6-membered heteroaryl group.

[0219] Some embodiments of this disclosure, R s1 These are oxo, F, Cl, Br, I, OH, NH2, NO2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-6 Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino, or n-propylisopropylamino), CN, C 1-6 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), isopropoxy(C3), butoxy(C4), isobutoxy(C4), sec-butoxy(C4), tert-butoxy(C4), pentyloxy(C5), hexyloxy(C6)), -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl) or -(C=O)N(C1-3 It is alkyl(2).

[0220] Some embodiments of this disclosure, R s1 These are oxo, F, Cl, Br, I, OH, NH2, NO2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-6 Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino, or n-propylisopropylamino), CN, or C 1-6 These are alkoxys (for example, methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentyloxy (C5), hexyloxy (C6)).

[0221] Some embodiments of this disclosure, R s1 C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-6Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino, or n-propylisopropylamino), CN, C 1-6 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), isopropyloxy(C3), butoxy(C4)), isobutoxy(C4), sec-butoxy(C4), tert-butoxy(C4), pentyloxy(C5), hexyloxy(C6)), -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl) or -(C=O)N(C 1-3 It is alkyl(2).

[0222] Some embodiments of this disclosure, R s1 These are oxo, F, Cl, Br, I, OH, NH2, NO2, -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl) or -(C=O)N(C 1-3 It is alkyl(2).

[0223] Some embodiments of this disclosure, R s1 is -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl) or -(C=O)N(C 1-3 It is alkyl(2).

[0224] Some embodiments of this disclosure, R s2 F, Cl, Br, I, OH, NH2, C 1-6Alkylamino (e.g., methylamino, ethylamino, n-propylamino or isopropylamino), di-C 1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino or n-propylisopropylamino), CN, C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentyloxy (C5), hexyloxy (C6)), -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl) or -(C=O)N(C 1-3 Alkyl)2.

[0225] In some embodiments of the present disclosure, R s2 is F, Cl, Br, I, OH, NH2, C 1-6 Alkylamino (e.g., methylamino, ethylamino, n-propylamino or isopropylamino), di-C 1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino or n-propylisopropylamino), CN or C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentyloxy (C5), hexyloxy (C6)).

[0226] In some embodiments of the present disclosure, R s2 is C1-6 Alkylamino (e.g., methylamino, ethylamino, n-propylamino, or isopropylamino), di-C 1-6 Alkylaminos (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-n-propylamino, ethylisopropylamino, or n-propylisopropylamino), CN, C 1-6 Alkoxy (e.g., methoxy(C1), ethoxy(C2), propoxy(C3), isopropoxy(C3), butoxy(C4), isobutoxy(C4), sec-butoxy(C4), tert-butoxy(C4), pentyloxy(C5), hexyloxy(C6)), -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl) or -(C=O)N(C 1-3 It is alkyl(2).

[0227] Some embodiments of this disclosure, R s2 F, Cl, Br, I, OH, NH2, -S(=O)2-(C 1-3 Alkyl), -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl) or -(C=O)N(C 1-3 It is alkyl(2).

[0228] Some embodiments of this disclosure, R s2 is -(C=O)(C 1-3 Alkyl), -(C=O)O(C 1-3 Alkyl), -(C=O)NH(C 1-3 Alkyl) or -(C=O)N(C 1-3 It is alkyl(2).

[0229] This disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [ka]

[0230] During the ceremony,

[0231] Ring A is C 6-10 Selected from aryls and 5-10 membered heteroaryls;

[0232] Ring B is, [ka] Selected from, [ka] Each of these independently comprises 1, 2, 3, or 4 R 10 It is arbitrarily replaced with;

[0233] L is -CH2-, and the -CH2- is optionally substituted with one or two D;

[0234] R1 and R2 are independently H, F, Cl, Br, I, and C. 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group independently has 1, 2, or 3 R groups. a It is arbitrarily replaced with;

[0235] Each R3 independently contains F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4 Alkinyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 2-4 Alkenil, C 2-4Alkinyl and C 3-5 Each cycloalkyl group independently has 1, 2, 3, 4, or 5 R groups. a It is arbitrarily replaced with;

[0236] R4, R5, R6, and R7 are each independently H, OH, NH2, CN, and C 1-3 Alkyl and C 1-3 Selected from alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R b It is arbitrarily replaced with;

[0237] R8 consists of H, F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl and C 1-3 Selected from alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy independently contains 1, 2, 3, 4, or 5 R a It is arbitrarily replaced with;

[0238] R9 is -C(=O)-NR b1 R b2 and -CH2R c Selected from;

[0239] Each R 10 These are independently D, F, Cl, Br, I, OH, NH2, C 1-3 Alkyl, C 1-3 Alkylamino and -NH-C(=O)-R d Selected from;

[0240] Each R a These are independently selected from D, F, Cl, Br, and I;

[0241] Each R b These are independently D, F, Cl, Br, I, OH, NH2, CN, and -C(=O)-NR b1 R b2 Selected from;

[0242] R b1and R b2 These are H and C, each independently. 1-3 Selected from alkyl groups;

[0243] R c It is selected from F, Cl, Br, I, OH, and NH2;

[0244] R d C 1-3 It is alkyl;

[0245] m is selected from 0, 1, 2, 3, 4, and 5.

[0246] In some embodiments of this disclosure, L is selected from -CH2- and -CD2-, and the other variables are as defined in this disclosure.

[0247] Some embodiments of this disclosure, each of the above R a These are independently selected from D, F, and Cl, and the other variables are as defined in this disclosure.

[0248] Some embodiments of this disclosure, each of the above R b These are independently selected from OH, CN, and -C(=O)-NH2, and the other variables are as defined in this disclosure.

[0249] In some embodiments of this disclosure, the above-mentioned R b1 and R b2 These are independently selected from H and CH3, and the other variables are as defined in this disclosure.

[0250] In some embodiments of this disclosure, the above R c is OH, and the other variables are as defined in this disclosure.

[0251] In some embodiments of this disclosure, the above R d CH3 is the other variable as defined in this disclosure.

[0252] In some embodiments of this disclosure, R1 is H, and the other variables are as defined in this disclosure.

[0253] In some embodiments of this disclosure, R2 is H, and the other variables are as defined in this disclosure.

[0254] In some embodiments of this disclosure, each of the above-mentioned R3 is independently F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, NHCH3, N(CH3)2, [ka] Selected from cyclopropyl and cyclobutyl; the CH3, CH2CH3, OCH3, OCH2CH3, NHCH3, N(CH3)2, [ka] Cyclopropyl and cyclobutyl each independently contain 1, 2, 3, 4, or 5 R a It is arbitrarily substituted with; other variables are as defined herein.

[0255] In some embodiments of this disclosure, the disclosure provides a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof. [ka]

[0256] During the ceremony,

[0257] Ring A is selected from C6 aryls and 5-membered heteroaryls;

[0258] Ring B is, [ka] and;

[0259] The other variables in equation (Ia) are as defined in equation (I).

[0260] In some embodiments of the present disclosure, in the compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, ring A is a C6 aryl compound.

[0261] In some embodiments of the present disclosure, in the compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, ring A is a five-membered heteroaryl group.

[0262] In some embodiments of this disclosure, the disclosure provides a compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof. [ka]

[0263] During the ceremony,

[0264] Ring A is selected from C6 aryls and 5-membered heteroaryls;

[0265] Ring B is, [ka] Selected from, [ka] Each of these independently comprises 1, 2, 3, or 4 R 10 It is arbitrarily replaced with;

[0266] The other variables in equation (Ib) are as defined in equation (I).

[0267] In some embodiments of the present disclosure, in the compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof, ring A is a C6 aryl compound.

[0268] In some embodiments of the present disclosure, in the compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof, ring A is a five-membered heteroaryl group.

[0269] In some embodiments of this disclosure, each R3 is independently F, OH, NH2, CF3, OCH3, [ka] and cyclopropyl are selected, and the other variables are as defined herein.

[0270] In some embodiments of this disclosure, ring A is phenyl, and the other variables are as defined herein.

[0271] In some embodiments of this disclosure, the above structural component: [ka] teeth, [ka] The variables are selected from the above, and the other variables are as defined in this disclosure.

[0272] In some embodiments of this disclosure, R5 is selected from H, OH, NH2, CN, CH3, CH2CH3, OCH3, and OCH2CH3, where each of CH3, CH2CH3, OCH3, and OCH2CH3 independently has 1, 2, 3, 4, or 5 R b The variables are arbitrarily substituted, and the other variables are as defined herein.

[0273] In some embodiments of this disclosure, R5 is selected from H, CH3, CH2CN, CH2OH, and CH2CONH2, and the other variables are as defined in this disclosure.

[0274] In some embodiments of this disclosure, R6 is selected from H and OH, and the other variables are as defined in this disclosure.

[0275] In some embodiments of this disclosure, R4 is H, and the other variables are as defined in this disclosure.

[0276] In some embodiments of this disclosure, R7 is H, and the other variables are as defined in this disclosure.

[0277] In some embodiments of this disclosure, R8 is selected from H and F, and the other variables are as defined in this disclosure.

[0278] In some embodiments of this disclosure, R9 is selected from -C(=O)-NH2, -C(=O)-NHCH3, -C(=O)-N(CH3)2, and -CH2OH, and the other variables are as defined in this disclosure.

[0279] Several embodiments of this disclosure, each R 10 These are independently selected from D, F, NH2, CH3, -N(CH3)2, and -NH-C(=O)-CH3, and the other variables are as defined in this disclosure.

[0280] In some embodiments of this disclosure, ring B is [ka] Selected from, [ka] Each of these independently comprises 1, 2, 3, or 4 R 10 The variables are arbitrarily substituted, and the other variables are as defined in this disclosure.

[0281] In some embodiments of this disclosure, ring B is [ka] The variables are selected from the above, and the other variables are as defined in this disclosure.

[0282] This disclosure also includes several embodiments resulting from any combination of the above variables.

[0283] This disclosure provides the compounds shown in Table 1 or pharmaceutically acceptable salts thereof.

[0284] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

[0285] This disclosure provides the compounds shown in Table 2 or pharmaceutically acceptable salts thereof.

[0286] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0287] This disclosure provides compounds shown in Table 2a or pharmaceutically acceptable salts thereof.

[0288] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6]

[0289] This disclosure provides the compounds shown in Table 3 or pharmaceutically acceptable salts thereof.

[0290] [Table 4-1] [Table 4-2]

[0291] This disclosure provides the compounds shown in Table 4 or pharmaceutically acceptable salts thereof.

[0292] [Table 5-1] [Table 5-2] [Table 5-3]

[0293] This disclosure provides the following compounds or pharmaceutically acceptable salts thereof. [ka] [ka] [ka]

[0294] In some embodiments of this disclosure, the compound or a pharmaceutically acceptable salt thereof is selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0295] This disclosure also provides the use of the aforementioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the treatment of KRAS mutation-related diseases or conditions.

[0296] This disclosure also provides uses for the aforementioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the treatment of KRAS mutation-related diseases or conditions.

[0297] This disclosure also provides the use of the aforementioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof for the treatment of KRAS mutation-related diseases or conditions.

[0298] This disclosure also provides the aforementioned compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof for use in the treatment of KRAS mutation-related diseases or conditions.

[0299] The disclosure also provides a method for treating a KRAS mutation-related disorder or condition, comprising administering the aforementioned compound, its stereoisomer, or a pharmaceutically acceptable salt thereof to a subject in need.

[0300] In some embodiments of this disclosure, the KRAS mutation is KRAS G12D It is a mutation.

[0301] This disclosure also provides the following biological testing methods. Test Method 1. GP2D cell p-ERK inhibition test

[0302] 1. Purpose

[0303] Using the HTRF method, KRAS G12D We screened for compounds that can effectively inhibit p-ERK in GP2D cells with mutations.

[0304] 2. Experimental Procedure

[0305] 1) GP2D cells were inoculated into a clear 96-well cell culture plate to create a cell suspension of 80 μL per well (containing 8,000 cells per well). The plate was placed in a CO2 incubator and incubated overnight at 37°C.

[0306] 2) Add 2 μL of the compound to 78 μL of cell culture medium and mix thoroughly; then add 20 μL of the compound solution to the corresponding wells of the cell plate. Return the cell plate to the CO2 incubator and incubate for a further 1 hour.

[0307] 3) After incubation, discard the cell supernatant and add 50 μL of 1× cell lysis buffer to each well. Incubate the plate at room temperature for 30 minutes with shaking.

[0308] 4) Phospho-ERK1 / 2 Eu Cryptate antibody and Phospho-ERK1 / 2 d2 antibody were diluted 20-fold with detection buffer.

[0309] 5) 16 μL of cell lysate supernatant was transferred to each well in a new 384-well white microplate. 2 μL of Phospho-ERK1 / 2 Eu Cryptate antibody dilution and 2 μL of Phospho-ERK1 / 2 d2 antibody dilution were added, and the plate was incubated at room temperature for at least 4 hours.

[0310] 6) After incubation, the HTRF was read using a multi-label analyzer at excitation: 320 nm, emission: 615 nm, and 665 nm.

[0311] 7) IC of the test compound 50 The result was calculated. Test Method 2. AGS cell p-ERK inhibition test

[0312] 1. Purpose

[0313] Using the HTRF method, KRAS G12D We screened for compounds that can effectively inhibit p-ERK in AGS cells with mutations.

[0314] 2. Experimental Procedure

[0315] 1) AGS cells were inoculated into a clear 96-well cell culture plate to create a cell suspension of 80 μL per well (containing 10,000 cells per well). The plate was placed in a CO2 incubator and incubated overnight at 37°C.

[0316] 2) After incubation, the cell supernatant was discarded, and 80 μL of culture medium containing 0.02% serum was added to each well. The cell plates were placed in a CO2 incubator and incubated overnight at 37°C.

[0317] 3) Add 2 μL of the compound to 78 μL of cell culture medium and mix thoroughly; then add 20 μL of the compound solution to the corresponding wells of the cell plate. Return the cell plate to the CO2 incubator and incubate for a further 3 hours.

[0318] 4) After incubation, discard the cell supernatant and add 50 μL of 1× cell lysis buffer to each well. Incubate the plate at room temperature for 30 minutes with shaking.

[0319] 5) Phospho-ERK1 / 2 Eu Cryptate antibody and Phospho-ERK1 / 2 d2 antibody were diluted 20-fold with detection buffer.

[0320] 6) 16 μL of cell lysate supernatant was transferred to each well in a new 384-well white microplate. Then, 2 μL of Phospho-ERK1 / 2 Eu Cryptate antibody dilution and 2 μL of Phospho-ERK1 / 2 d2 antibody dilution were added and incubated at room temperature for at least 4 hours.

[0321] 7) After incubation, the HTRF was read using a multi-label analyzer at excitation: 320 nm, emission: 615 nm, and 665 nm.

[0322] 8) Test compound IC 50 The result was calculated. Test Method 3. Anti-cell proliferation effect of the compound in the tumor cell line AsPC-1.

[0323] Objective of the experiment

[0324] In this study, the inhibitory effect of compounds on cell proliferation was investigated using KRAS. G12D This was investigated by detecting its effect on in vitro cell activity in the mutant tumor cell line AsPC-1.

[0325] Experimental materials

[0326] Cell line: AsPC-1; Tumor type: Pancreatic cancer; Growth characteristics: Adhesive growth; Culture method: RPMI 1640+10%FBS

[0327] Ultra Low Cluster 96-well plate (Corning-7007)

[0328] Greiner CELLSTAR 96-well plate (#655090)

[0329] Promega CellTiter-Glo 3D Luminescent Cell Viability Assay Kit(Promega-G9683)

[0330] 2104-10 EnVision Plate Reader, PerkinElmer

[0331] RPMI 1640, DMEM, PBS (phosphate-buffered saline), FBS (fetal bovine serum), Antibiotic-antimycotic, L-glutamine (L-Gln), DMSO (dimethyl sulfoxide)

[0332] Experimental method and process

[0333] cell culture

[0334] Tumor cell lines were cultured in a 37°C, 5% CO2 incubator according to the culture conditions specified in the culture method. Cells were periodically subcultured, and cells in the logarithmic growth phase were used for plating.

[0335] Cell plating

[0336] The cells were stained with trypan blue, and the number of viable cells was counted.

[0337] The cell concentration was adjusted to an appropriate level.

[0338] Cell line: AsPC-1; Density (per well): 7000 cells.

[0339] 135 μL of cell suspension was added to each well of a ULA culture plate, and the same volume of cell-free culture medium was added to a blank control well.

[0340] Immediately after plating, the ULA culture plate was centrifuged at 1000 rpm for 10 minutes at room temperature. Note: After centrifugation, care should be taken to avoid unnecessary stirring during subsequent operations.

[0341] The culture plates were incubated overnight in an incubator at 37°C, 5% CO2, and 100% relative humidity.

[0342] Preparation of 10X compound working solution and compound treatment of cells (Day 1)

[0343] After preparing a 10X compound working solution (DMSO 10X working solution), 15 μL of the 10X compound working solution was added to each well of the ULA culture plate. 15 μL of DMSO-cell culture medium mixture was added to the vehicle control and blank control.

[0344] The 96-well cell plates were returned to the incubator and cultured for 120 hours.

[0345] We observed the formation of cell spheres daily until the end of the experiment.

[0346] CellTiter-Glo luminescent cell viability assay (Day 5)

[0347] The following steps were performed according to the instructions for the Promega CellTiter-Glo 3D Luminescent Cell Viability Assay Kit (Promega #G9683).

[0348] 150 μL (equal to the volume of cell culture medium in each well) of CellTiter-Glo 3D Reagent was added to each well. The cell plate was wrapped in aluminum foil to protect it from light.

[0349] The culture plate was shaken on an orbital shaker for 5 minutes.

[0350] The mixture in the well was carefully pipetted up and down 10 times to ensure uniformity. Before proceeding to the next step, ensure that the cell spheres have completely dissociated.

[0351] Next, the solution in the ULA culture plate was transferred to a black-bottomed culture plate (#655090) and left at room temperature for 25 minutes to stabilize the luminescence signal.

[0352] A light emission signal was detected using the 2104 EnVision plate reader.

[0353] Data Analysis

[0354] The inhibition rate (IR) of the test compound was calculated using the following formula: IR(%) = (1 - (RLU compound - RLU blank control) / (RLU vehicle control - RLU blank control)) × 100%. The inhibition rates at various compound concentrations were calculated in Excel. Then, the inhibition curves were plotted using GraphPad Prism software, and the minimum inhibition rate, maximum inhibition rate, and IC50 were determined. 50 Related parameters, including [specific parameter], were calculated. Test Method 4. Pharmacokinetic studies of test compounds in CD-1 mice after oral and intravenous administration.

[0355] Objective of the experiment

[0356] The in vivo pharmacokinetics of the compound were tested in CD-1 mice administered orally and intravenously.

[0357] Experimental Procedure

[0358] The test compound was mixed with a 5% DMSO + 95% (10% HP-β-CD) aqueous solution, vortexed, and sonicated to prepare a 0.5 mg / mL clear solution (intravenously) or a 3 mg / mL clear solution (orally). The solution was then filtered through a micropore filter for subsequent use. Male CD-1 mice aged 7–10 weeks were selected and administered the candidate compound solution intravenously or orally. Whole blood was collected at specified intervals to prepare plasma. Drug concentrations were analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA).

[0359] Technical effects

[0360] The compounds disclosed herein are KRAS G12D It has good cell proliferation inhibitory activity against mutant cells, KRAS G12D It exhibits a significant inhibitory effect on p-ERK in mutant cells.

[0361] Related definitions

[0362] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. Certain terms or phrases should not be considered ambiguous or unclear in the absence of a specific definition, but should be understood in their conventional sense. Where trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0363] As used herein, the term “pharmaceutically acceptable” is intended to mean a compound, material, composition, and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of sound medical judgment, and that is commensurate with a reasonable benefit / risk ratio.

[0364] The term "pharmaceutically acceptable salt" means a salt of a compound disclosed herein, prepared by reacting a compound having certain substituents disclosed herein with a relatively non-toxic acid or base. If a compound disclosed herein has a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. If a compound disclosed herein has a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds disclosed herein have both basic and acidic functional groups and can be converted into any base addition salt or acid addition salt.

[0365] The pharmaceutically acceptable salts disclosed herein can be prepared from parent compounds containing an acidic or basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting a compound in free acid or base form with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof.

[0366] The compounds disclosed herein may exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic and other mixtures, such as enantiomers or diastereoisomers concentrated in a mixture, all of which are encompassed within the scope disclosed herein. Substituents such as alkyls may have additional chiral carbon atoms. All of these isomers and mixtures thereof are encompassed within the scope disclosed herein.

[0367] The compounds disclosed herein may contain unnatural proportions of atomic isotopes in one or more of the atoms constituting the compound. For example, the compound may contain tritium ( 3 H), Iodine-125( 125 I) or C-14 ( 14 They can be labeled with radioactive isotopes such as ¹¹C). In another example, hydrogen can be replaced with deuterium to form deuterated drugs. The bond between deuterium and carbon is more robust than the bond between ordinary hydrogen and carbon. Compared to undeuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, improved efficacy, and extended biological half-life. All variations in the isotopic composition of the compounds disclosed herein, whether radioactive or otherwise, are included within the scope of this disclosure.

[0368] The terms "optional" or "optional" mean that a subsequent event or condition may occur but is not required, and that the terms include instances in which such event or condition occurs and instances in which it does not occur.

[0369] The term "substituted" means that one or more hydrogen atoms on a particular atom are substituted by a substituent (including deuterium and hydrogen variants), provided that the valence of that atom is normal and the substituted compound is stable. If the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. The term "optionally substituted" means that an atom may or may not be substituted by a substituent, and unless otherwise specified, the type and number of substituents may be arbitrary to the extent chemically achievable.

[0370] If any variable (such as R) appears more than once in the composition or structure of a compound, the definition of the variable at each appearance is independent. Therefore, for example, if a group is substituted with 0 to 2 Rs, that group can be arbitrarily substituted with up to 2 Rs, and the definition of R at each appearance is independent. Furthermore, combinations of substituents and / or their variants are only permissible if the combination results in a stable compound.

[0371] When the number of linking groups is 0, as in -(CRR)0-, it means that the linking groups are single bonds.

[0372] If one of the variables is a single bond, it means that the two groups linked by the single bond are directly connected. For example, if L in ALZ represents a single bond, then the structure of ALZ is actually AZ.

[0373] If a listed linking unit does not indicate its linking direction, the linking direction is arbitrary. For example, [ka] If the linking group L in is -MW-, then -MW- is linked to rings A and B in the same direction as the reading order from left to right. [ka] It can be configured as follows, or it can be connected to ring A and ring B in the reverse direction of the reading order from left to right. [ka] It is also possible to construct such compounds. Combinations of linking groups, substituents, and / or their variants are permitted only if the combination can result in a stable compound.

[0374] Unless otherwise specified, if a group has one or more connectable sites, any one or more sites of the group can be connected to other groups via chemical bonds. If the connection positions of chemical bonds are variable and there are hydrogen atoms in the connectable sites, when a connectable site with hydrogen atoms is connected to a chemical bond, the number of hydrogen atoms in this site decreases in proportion to the increasing number of connected chemical bonds, and the group becomes a group with the corresponding valency. Chemical bonds between the described sites and other groups are linear solid bonds: [ka] , dashed line connection: [ka] , or wavy line: [ka] This can be represented by: For example, a linear solid bond in -OCH3 indicates that the group is connected to other groups via the oxygen atom within that group; [ka] The dashed linear bond in this diagram indicates that the group is connected to another group via the two ends of the nitrogen atom within that group; [ka] The dashed lines indicate that the group is connected to other groups via the 1- and 2-carbon atoms in the phenyl group; [ka] This means that any connectable site on the piperidinyl group has at least four modes of connection: [ka] This shows that they can be connected to other groups via one chemical bond; even if the H atom is drawn on the -N-, [ka] is still [ka] This involves a type of connection where, when one chemical bond is connected, one hydrogen atom is removed from that position, and the group becomes the corresponding monovalent piperidinyl group.

[0375] Unless otherwise specified, wedge-shaped solid line connections: [ka] and wedge-shaped dashed line connections: [ka] This indicates the absolute arrangement of the center of the solid; a solid line connects the points: [ka] and dashed line connections: [ka] The arrows indicate the relative arrangement of the center of the solid; the dashed lines indicate the relative arrangement of the center of the solid. [ka] This is a wedge-shaped solid line connection: [ka] Or a wedge-shaped dashed line connection: [ka] To indicate; or a wavy line: [ka] This is a combination of straight lines and solid lines: [ka] Or a dashed line connection: [ka] This indicates.

[0376] Unless otherwise specified, when a compound contains double bond structures such as carbon-carbon double bonds, carbon-nitrogen double bonds, and nitrogen-nitrogen double bonds, and each atom on the double bond is connected to two different substituents (in a double bond involving a nitrogen atom, the lone pair of electrons on the nitrogen atom is considered to be a substituent connected to it), the atoms on the double bond and their substituents in the compound are considered to be [ka] When expressed as such, it represents a mixture of two isomers of a compound.

[0377] Unless otherwise specified, the terms "tautomer" or "tautomer" mean that at room temperature, each isomer with different functional groups is in dynamic equilibrium and can rapidly convert to one another. When tautomerism is possible (e.g., in solution), a tautomeric chemical equilibrium can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers are tautomers that interconvert through the rearrangement of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypenta-3-en-2-one.

[0378] Unless otherwise indicated, the terms “one isomer concentrated,” “isomerically concentrated,” “one enantiomer concentrated,” or “enantiomerically concentrated” mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% or higher.

[0379] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference in the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is present in a 90% solution and the other is present in a 10% solution, the isomer or enantiomer excess (ee value) is 80%.

[0380] Unless otherwise specified, C n-n+m or C n -C n+m This includes any specific case of n ~ n + m carbon atoms (for example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 (including n~n+m), and also any range of n~n+m (for example, C 1-12 C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 and C 9-12(including, etc.). Similarly, n-membered to n+m-membered indicates that the number of atoms on the ring is n to n+m (for example, 3- to 12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings and 12-membered rings), and also includes any range of n to n+m (for example, 3- to 12-membered rings include 3- to 6-membered rings, 3- to 9-membered rings, 5- to 6-membered rings, 5- to 7-membered rings, 6- to 7-membered rings, 6- to 8-membered rings and 6- to 10-membered rings, etc.).

[0381] Unless otherwise specified, the term "halo" or "halogen" means a fluorine, chlorine, bromine, or iodine atom, either by itself or as part of another substituent.

[0382] Unless otherwise specified, "C 1-3 The term "alkyl" is used to describe a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl includes C 1-2 Alkyl, C 2-3 Alkyl compounds are included. They may be monovalent (methyl, etc.), divalent (methylene, etc.), or polyvalent (methenyl, etc.). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), and propyl (including n-propyl and isopropyl).

[0383] Unless otherwise specified, "C 1-6 The term "alkyl" is used to refer to a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl alkyl groups include C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 This includes C6 and C5 alkyl groups, etc.; they may be monovalent (methyl, etc.), divalent (methylene, etc.), or polyvalent (methine, etc.). 1-6Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), and hexyl.

[0384] Unless otherwise specified, "C 1-3 The term "alkoxy" refers to an alkyl group that has 1 to 3 carbon atoms bonded to the rest of the molecule via an oxygen atom. 1-3 The alkoxy group contains C 1-2 , C 2-3 This includes C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, and propoxy (including n-propoxy and isopropoxy).

[0385] Unless otherwise specified, "C 1-3 The term "alkylamino" is C 1-2 , including C3 and C2 alkylaminos -NH-C 1-3 Refers to alkyl. 1-3 Examples of alkylaminos include, but are not limited to, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, and -NHCH2(CH3)2.

[0386] Unless otherwise specified, "G-C" 1-3 The term "alkylamino" is di-C 1-2 , including di-C3 and di-C2 alkylaminos -N(C 1-3 Refers to alkyl(2). Di-C 1-3 Examples of alkylaminos include, but are not limited to, -N(CH3)2 and -N(CH3)CH2CH3.

[0387] Unless otherwise specified, "C 2-4The term "alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 4 carbon atoms having at least one carbon-carbon double bond, which may be located at any position in the group. 2-4 The alkenyl group contains C 2-3 , C4, C3 and C2 alkenyl groups are included, C 2-4 The alkenyl group may be monovalent, divalent, or polyvalent. 2-4 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, and butadienyl. Unless otherwise specified, "C 2-3 The term "alkenyl" is used to refer to a straight-chain or branched-chain hydrocarbon group consisting of 2 to 3 carbon atoms having at least one carbon-carbon double bond, which may be located at any position in the group. 2-3 Alkenyl groups include C3 and C2 alkenyl groups, 2-3 The alkenyl group may be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to, ethenyl and propenyl.

[0388] Unless otherwise specified, "C 2-4 "Alkynyl" refers to a linear or branched hydrocarbon group consisting of 2 to 4 carbon atoms having at least one carbon-carbon triple bond which may be located at any position within the group. 2-4 Examples of alkynyl groups include C 2-3 This includes C4, C3, and C2 alkynyl groups. These groups may be monovalent, divalent, or polyvalent. 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and butynyl.

[0389] Unless otherwise specified, "C 3-5 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system. 3-5 Cycloalkyl groups include C 3-4 and C 4-5 It may contain cycloalkyl groups, and may be monovalent, divalent, or polyvalent.3-5 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.

[0390] Unless otherwise specified, "C 3-10 "Cycloalkyl" refers to saturated cyclic hydrocarbon groups consisting of 3 to 10 carbon atoms, including monocyclic, bicyclic, and tricyclic ring systems. Bicyclic and tricyclic ring systems include spirocyclic, condensed, and bridging rings. 3-10 Cycloalkyl groups include C 3-8 , C 3-6 , C 3-5 , C 4-10 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 This includes, for example; it may be monovalent, divalent, or polyvalent. C 3-10 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and [2.2.2]bicyclooctane.

[0391] Unless otherwise specified, "C 3-10 "Carbocyclyl" refers to a saturated or partially saturated cyclic hydrocarbon group consisting of 3 to 10 carbon atoms, including monocyclic, bicyclic, and tricyclic ring systems. Bicyclic and tricyclic ring systems include spirocyclic, condensed, and bridging rings. 3-10 Carbocyclyl contains C 3-8 , C 3-6 , C 3-5 , C 4-10 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 This includes, for example; it may be monovalent, divalent, or polyvalent. C 3-10Examples of carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), and cyclodecyl (C) 10 ), cyclodecenyl (C 10 ), OctaHydro-1H-indenyl(C9), Decalinyl(C 10 ) or spiro[4.5]decyl(C 10 This includes, but is not limited to, these items.

[0392] Unless otherwise specified, the term “3-5 membered heterocycloalkyl,” when used alone or in combination with other terms, means a ring consisting of 3-5 ring atoms, of which 1, 2, 3, or 4 are independently selected heteroatoms from O, S, and N, the remainder being carbon atoms, the carbon atoms optionally oxidized (i.e., C(O)), the nitrogen atom optionally quaternized, and the nitrogen and sulfur heteroatoms optionally oxidized (i.e., NO and S(O)). p (wherein p is 1 or 2)) Refers to a saturated monocyclic group. Furthermore, with respect to such "3- to 5-membered heterocycloalkyls," the heteroatoms may occupy positions where the heterocycloalkyl is bonded to the rest of the molecule. Such 3- to 5-membered heterocycloalkyls include 4- to 5-membered, 4-membered, and 5-membered heterocycloalkyls, etc. Examples of 3- to 5-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) or tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.).

[0393] Unless otherwise specified, the term “3-6 membered heterocycloalkyl,” when used alone or in combination with other terms, means a ring of 3-6 ring atoms, of which 1, 2, 3, or 4 are independently heteroatoms selected from O, S, and N, the remainder being carbon atoms, the carbon atoms optionally oxidized (i.e., C(O)), the nitrogen atom optionally quaternized, and the nitrogen and sulfur heteroatoms optionally oxidized (i.e., NO and S(O)). p (wherein p is 1 or 2)) Refers to a saturated cyclic group. Includes monocyclic and bicyclic ring systems, with bicyclic ring systems including spirocyclic, fused, and bridging rings. Furthermore, with respect to "3-6 membered heterocycloalkyls," the heteroatom may occupy a position where the heterocycloalkyl is attached to the rest of the molecule. 3-6 membered heterocycloalkyls include 4-6 membered, 5-6 membered, 4-membered, 5-membered, and 6-membered heterocycloalkyls, etc. Examples of 3- to 6-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiadinyl, or hexahydropyridazinyl.

[0394] Unless otherwise specified, the term “3-10 membered heterocycloalkyl,” when used alone or in combination with other terms, means a ring molecule consisting of 3-10 ring atoms, where 1, 2, 3, or 4 of the ring atoms are independently heteroatoms selected from O, S, and N, the remainder being carbon atoms, the carbon atoms optionally oxidized (i.e., C(O)), the nitrogen atoms optionally quaternized, and the nitrogen and sulfur heteroatoms optionally oxidized (i.e., NO and S(O)).p (wherein p is 1 or 2)) Refers to a saturated cyclic group. This includes monocyclic, bicyclic, and tricyclic ring systems, with bicyclic and tricyclic ring systems including spirocyclic, fused, and bridging rings. Furthermore, with respect to the term "3-10 membered heterocycloalkyl," the heteroatom may occupy a position where the heterocycloalkyl group is bonded to the rest of the molecule. 3-10 membered heterocycloalkyl groups include 3-8 membered, 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4-membered, 5-membered, and 6-membered heterocycloalkyl groups, etc. Examples of 3- to 10-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranil (including tetrahydrofuran-2-yl, etc.), tetrahydropyranil, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanil, dithianil, isoxazolidinyl, isothiazolidinyl, hexahydropyridazinyl, homopiperadinyl, homopiperidinyl, or dioxepanil.

[0395] Unless otherwise specified, "C 6-10 aromatic ring” and “C 6-10 The term "aryl" is used interchangeably in this specification. 6-10 Aromatic ring or "C 6-10 The term "aryl" refers to a cyclic hydrocarbon group composed of 6 to 10 carbon atoms and having a conjugated π-electron system. It can be a monocyclic, fused bicyclic, or fused tricyclic ring system, with each ring being aromatic. It can be monovalent, divalent, or polyvalent. 6-10 The aryl group contains C 6-9 , C9, C 10 and C6 aryl group is included. 6-10 Examples of aryl groups include, but are not limited to, phenyl and naphthyl (including 1-naphthyl and 2-naphthyl).

[0396] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" may be used interchangeably. The term "5-10 membered heteroaryl" refers to a cyclic group having a conjugated pi-electron system, consisting of 5-10 ring atoms, where 1, 2, 3, or 4 ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms. It may be a monocyclic, fused bicyclic, or fused tricyclic ring system, each ring being aromatic, the nitrogen atom optionally quaternized, and the nitrogen and sulfur heteroatoms optionally oxidized (i.e., NO and S(O)). p(where p is 1 or 2). 5- to 10-membered heteroaryl groups can be bonded to the rest of the molecule via heteroatoms or carbon atoms. 5- to 10-membered heteroaryl groups include 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 5-membered, and 6-membered heteroaryl groups. Examples of 5- to 10-membered heteroaryls include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyrrolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (2-thiazolyl, 4-thiazolyl, and 5-thiazolyl) This includes, but is not limited to, lyl (including 2-furyl and 3-furyl), thienyl (including 2-thienyl and 3-thienyl), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl, pyrimidinyl (including 2-pyridinyl and 4-pyridinyl), benzothiazolyl (including 5-benzothiazolyl), prinyl, benzimidazolyl (including 2-benzimidazolyl), benzoxazolyl, indolyl (including 5-indolyl), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl), or quinolyl (including 3-quinolyl and 6-quinolyl).

[0397] Unless otherwise specified, the terms “5-6 membered heteroaromatic ring” and “5-6 membered heteroaryl” are used interchangeably herein. The term “5-6 membered heteroaryl” refers to a monocyclic group having a conjugated π-electron system and consisting of 5-6 ring atoms, where 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p (wherein p is 1 or 2)). The 5- to 6-membered heteroaryl group may be bonded to the rest of the molecule via a heteroatom or carbon atom. The 5- to 6-membered heteroaryl group includes both 5-membered heteroaryl groups and 6-membered heteroaryl groups. Examples of 5- to 6-membered heteroaryl groups include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyrrolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl) This includes, but is not limited to, lyazolyl (such as riazolyl), tetrazolyl, isoxazolyl (such as 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl), furyl (including 2-furyl and 3-furyl), thienyl (including 2-thienyl and 3-thienyl), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, or pyrimidinyl (including 2-pyridinyl and 4-pyridinyl).

[0398] The compounds of this disclosure can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments combining them with other chemical synthesis methods, and equivalents well known to those skilled in the art. Alternative embodiments include, but are not limited to, the examples of this disclosure.

[0399] The structures of the compounds disclosed herein can be confirmed using conventional methods well known to those skilled in the art. Where the disclosure relates to the absolute configuration of a compound, such absolute configuration can be confirmed using the prior art in the art. For example, single-crystal X-ray diffraction (SXRD) is performed using a Bruker D8 venture diffractometer, with CuKα light as the light source, and using the φ / ω scan mode to collect diffraction intensity data from a cultured single crystal. After collecting the relevant data, the crystal structure can be further analyzed using a direct method (Shelxs97) to confirm the absolute configuration.

[0400] The solvents used in this disclosure are commercially available. This disclosure uses the following abbreviations: NaOH represents sodium hydroxide; DMF represents N,N-dimethylformamide; THF represents tetrahydrofuran; 2-MeTHF represents 2-methyltetrahydrofuran; DCM represents dioxane; EA represents ethyl acetate; DIPEA represents N,N-diisopropylethylamine; DCM represents dichloromethane; m-CPBA represents m-chloroperbenzoic acid; Boc2O represents di-tert-butyl anhydride carbonate; LiAlH4 represents lithium aluminum tetrahydrogen; MNO2 represents manganese dioxide; NBS represents N-bromosuccinimide; TMP represents trimethylolpropane; n-BuLi represents n-butyllithium; TFA represents trifluoroacetic acid; Xphos Pd G4 represents (SP-4-3)-[dicyclohexyl[2',4',6'-tri(isopropyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium; AgNO3 represents silver nitrate; and NCS represents N-chlorosuccinimide.

[0401] The compounds were named according to conventional nomenclature in the art or using ChemDraw® software. Commercially available compounds were named according to the supplier's catalog name. [Modes for carrying out the invention]

[0402] The present disclosure will be described in detail below with reference to examples, but the examples are not intended to limit the present disclosure in any way. Although the present disclosure has been described in detail herein and specific embodiments have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0403] Example 1 [ka] [ka]

[0404] Process 1

[0405] Compound 1-1 was subjected to preparative supercritical liquid chromatography (SFC) (chromatography column: ChiralPak IH, 250*50 mm, 10 μm; mobile phase: A: supercritical carbon dioxide, B: [0.1% ammonia-ethanol]; B%: 20%-20%, run time 3.7 min) to obtain compound 1-1A. SFC analysis method (chromatography column: Chiralpak IH-3, 100×4.6 mm ID, 3 μm; mobile phase: A (supercritical carbon dioxide) and B (ethanol, containing 0.1% isopropylamine); gradient: B%=10-50%, 4 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 2000 psi). Compound 1-1A: Rt = 1.489 min and ee value 98.82%. 1 1H NMR (400 MHz, CDCl) 3) δ = 4.99 - 4.86 (m, 2H), 4.26 - 3.95 (m, 3H), 3.59 (m, 1H), 3.00 - 2.88 (m, 1H), 2.87 - 2.12 (m, 4H), 1.91 (s, 1H), 1.20 - 1.08 (m, 3H).

[0406] Process 2

[0407] Lithium aluminum tetrahydride (1.55 g, 40.15 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). The mixture was cooled to 0°C. Under nitrogen, a solution of compound 1-1A (2.8 g, 13.38 mmol) in anhydrous tetrahydrofuran (20 mL) was added. The reaction mixture was allowed to react at 70°C for 1 hour. At 0°C, 1.5 mL of water was added to the reaction mixture, followed by 1.5 mL of 15% NaOH solution and 4.5 mL of water. The mixture was stirred for 20 minutes. The reaction mixture was filtered. The filter cake was washed with 10 mL of tetrahydrofuran, and the filtrate was concentrated to obtain compound 1-2. 1 H NMR (400 MHz, CDCl3) δ = 4.99 - 4.86 (m, 2H), 4.26 - 3.95 (m, 3H), 3.59 (m, 1H), 3.00 - 2.88 (m, 1H), 2.74 - 2.27 (m, 4H), 1.91 (s, 1H), 1.20 - 1.08 (m, 3H).

[0408] Process 3

[0409] Compounds 1-3 (480 g, 2.53 mol) were weighed and DMF (2500 mL) was added. Then, 4-methoxybenzyl chloride (5.18 mol, 702.79 mL), potassium carbonate (872.82 g, 6.32 mol), and potassium iodide (419.35 g, 2.53 mol) were added. The mixture was reacted at 65°C for 2 hours. Water (1000 mL) was added, and the mixture was extracted with ethyl acetate (1000 mL x 3). The organic phase was concentrated under reduced pressure to obtain compound 1-4. MS m / z = 430.0 [M + H] + .

[0410] Process 4

[0411] Compound 2,2,6,6-tetramethylpiperidine (220.59 g, 1.56 mol, 265.13 mL) was weighed and THF (3000 mL) was added. n-butyllithium (2.5 M, 499.73 mL) was added at -5°C and the mixture was stirred for 0.5 hours. Then the temperature was lowered to -60°C and compounds 1-4 (280 g, 624.67 mmol) were added. The mixture was stirred for 0.5 hours and finally DMF (228.28 g, 3.12 mol, 240.30 mL) was added. The mixture was reacted for a further 0.5 hours. The reaction mixture was poured into water (1000 mL) and the pH was adjusted to 7 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (1000 mL x 3). The organic phase was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compounds 1-5.

[0412] Process 5

[0413] Compounds 1-5 (370 g, 807.30 mmol) were weighed. Toluene (1500 mL), dichlorobis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium (2.86 g, 4.04 mmol, 2.86 mL), and tributyl(1-propynyl)tin (265.69 g, 807.30 mmol) were added. The mixture was reacted under nitrogen at 120°C for 2 hours. The reaction solution was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 1-6. MS m / z = 418.1 [M + H] + .

[0414] Process 6

[0415] Compound 1-6 (450 g, 970.13 mmol) was weighed and DMF (100 mL) was added. N-bromosuccinimide (189.93 g, 1.07 mol) was added and the mixture was reacted at 25°C for 2 hours. Additional N-bromosuccinimide (17.27 g, 97.01 mmol) was added and the mixture was reacted for a further 3 hours. The reaction solution was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 1-7. MS m / z = 496.0 [M + H]+ .

[0416] Process 7

[0417] Compound 1-7 (55 g, 110.81 mmol) was weighed and DMF (300 mL) was added. Methyl fluorosulfonyl difluoroacetate (42.57 g, 221.61 mmol, 28.19 mL) and cuprous iodide (42.21 g, 221.61 mmol) were added, and the reaction mixture was reacted under nitrogen at 110°C for 2 hours. The mixture was quenched by adding 500 mL of water and extracted with ethyl acetate (600 mL x 3). The extracted organic phases were combined, washed sequentially with water (800 mL x 2) and saturated brine (800 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 1-8 was obtained by column chromatography (petroleum ether:ethyl acetate = 10:1). MS m / z = 485.9 [M + H] + .

[0418] Process 8

[0419] To a solution of sodium hydride (6.34 g, 158.61 mmol, 60% purity) in tetrahydrofuran (350 mL) at 0°C, methyl acetoacetate (158.61 mmol, 17.10 mL) was added dropwise. The mixture was allowed to react for 15 minutes. After cooling to -20°C, n-butyllithium (2.5 M, 63.44 mL) was added dropwise. After the addition was complete, the mixture was stirred for a further 15 minutes. Next, a solution of compound 1-8 (35 g, 72.10 mmol) in tetrahydrofuran (350 mL) was added. The mixture was allowed to react for 0.5 hours. The reaction was quenched by adding 200 mL of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (300 mL x 2). The extracted organic phases were combined, washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compounds 1-9 were obtained by column chromatography (petroleum ether:ethyl acetate = 10:1-1:1). MS m / z = 624.2 [M+Na] + .

[0420] Process 9

[0421] Compounds 1-9 (38 g, 63.17 mmol) were weighed, and dichloromethane (300 mL) was added, followed by N,N-dimethylformamide dimethyl acetal (9.03 g, 75.80 mmol). The mixture was reacted at 25°C for 16 hours. The mixture was cooled to 0°C, and boron trifluoride etherate (10.76 g, 75.80 mmol, 9.32 mL) was added. The system was stirred at 0°C for a further 1 hour. 200 mL of saturated sodium bicarbonate solution was added to the mixture. The organic phase was separated. The aqueous phase was extracted with 200 mL of dichloromethane. The extracted organic phases were combined, washed with 250 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compounds 1-10 were obtained by separation by column chromatography (petroleum ether:ethyl acetate = 10:1-1:1). MS m / z = 612.1 [M + H] + .

[0422] Step 10

[0423] Compounds 1-10 (30 g, 49.05 mmol) were weighed, tetrahydrofuran (300 mL) was added, followed by lithium tri-sec-butylborohydride (1 M, 53.96 mL) at -60°C. The mixture was reacted at -60°C for 1 hour, quenched with 200 mL of water, and extracted with ethyl acetate (300 mL x 2). The extracted organic phases were combined, washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compounds 1-11 were obtained by column chromatography (petroleum ether:ethyl acetate = 10:1-5:1). MS m / z = 614.1 [M + H] + .

[0424] Step 11

[0425] Compound 1-11 (20 g, 32.59 mmol) was weighed and ethanol (200 mL) was added. Then, 2-methyl-2-thioisourea sulfate (27.22 g, 97.78 mmol) and sodium carbonate (6.91 g, 65.19 mmol) were added and the mixture was reacted at 50°C for 13 hours. The reaction mixture was concentrated to dryness. 40 mL of water was added and the mixture was extracted with ethyl acetate (50 mL x 2). The extracted organic phases were combined, washed with 60 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain compound 1-12. MS m / z = 654.3 [M + H] + .

[0426] Step 12

[0427] Compound 1-12 (21 g, 32.13 mmol) was weighed and DMF (200 mL) was added. Then, N,N-diisopropylethylamine (12.46 g, 96.38 mmol, 16.79 mL) and N-phenylbis(trifluoromethanesulfonyl)imide (13.77 g, 38.55 mmol) were added. The mixture was reacted at 25°C for 1 hour. 300 mL of water was added to the mixture and the mixture was extracted with ethyl acetate (300 mL x 3). The mixture was sequentially washed with water (2 x 400 mL) and saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 1-13 was obtained by column chromatography (petroleum ether:ethyl acetate = 10:1). Compound 1-13B was obtained by preparative SFC separation (chromatography column: DAIEL CHIRALPAK IG (250mm*50mm, 10μm); mobile phase: [supercritical carbon dioxide - ethanol (0.1% ammonia)]; ethanol (0.1% ammonia) percentage: 25%-25%). Chiral SFC analysis (chromatography column: ChiralPak IG-3 (100mm*4.6mm, 3μm); mobile phase: [supercritical carbon dioxide - ethanol (0.05% diethylamine)]; ethanol (0.05% diethylamine) percentage: 5%-40%) revealed compound 1-13B with an Rt of 3.055 mins and an ee value of 99%.

[0428] Step 13

[0429] Compound 1-13B (200 mg, 254.53 μmol) and Compound 1-14A (174.74 mg) were added to N,N-dimethylformamide (2 mL), followed by the addition of N,N-diisopropylethylamine (131.58 mg, 1.02 mmol). The resulting reaction mixture was heated to 105°C under nitrogen and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain Compound 1-14. MS m / z = 906.3 [M + H] + .

[0430] Step 14

[0431] Compound 1-14 (120 mg, 132.45 μmol) was dissolved in dichloromethane (2 mL), followed by the addition of m-chloroperbenzoic acid (29.58 mg, 145.70 μmol, 85% purity). The resulting reaction mixture was stirred under nitrogen at 20°C for 2 hours. The reaction mixture was diluted with 30 mL of dichloromethane and then washed with 5 mL of saturated sodium bicarbonate solution and 5 mL of saturated brine. The organic phase was dried and concentrated under reduced pressure to obtain compound 1-15. MS m / z = 922.7 [M + H] + .

[0432] Step 15

[0433] Sodium tert-butoxide (23.97 mg, 249.46 μmol) and compound 1-2 (38.22 mg, 249.46 μmol) were added to tetrahydrofuran (1.5 mL) and stirred at 20°C for 0.5 hours. Next, a solution of compound 1-15 (115 mg, 124.73 μmol) in tetrahydrofuran (1 mL) was added to the mixture and stirred for a further 1 hour. The reaction mixture was adjusted to pH 7 with 0.5 M hydrochloric acid, followed by the addition of 20 mL of ethyl acetate and 10 mL of water. The mixture was dissolved while stirring. The aqueous layer was separated. The organic phase was washed with 2 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 1-16. MS m / z = 10¹¹.5 [M + H] + .

[0434] Process 16

[0435] Compound 1-16 (120.00 mg, 118.68 μmol) was dissolved in tetrahydrofuran (2 mL). The resulting solution was cooled to 0°C, and lithium aluminum tetrahydride (1 M, 118.68 μL) was added dropwise. The reaction mixture was stirred for 0.5 hours. The reaction solution was carefully quenched with 0.2 mL of water, followed by the addition of 0.5 g of anhydrous sodium sulfate, and the mixture was stirred for 2 minutes. The mixture was filtered through a Celite pad, and the filter cake was rinsed with 20 mL of tetrahydrofuran. The filtrate was collected and concentrated under reduced pressure to obtain compound 1-17. MS(ESI)m / z = 983.4[M+H] + .

[0436] Process 17

[0437] Compound 1-17 (120 mg, 122.06 μmol) was added to trifluoroacetic acid (2 mL) and stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by high-performance liquid chromatography (HPLC column: Xtimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile): 10%-40%) and concentrated under reduced pressure to obtain the hydrochloride salt of compound 1. MS m / z = 643.3 [M + H] + . Example 2 [ka]

[0438] Process 1

[0439] Compound 2-1 (2.3 g, 4.77 mmol) was dissolved in dioxane (30 mL), and then hydrochloric acid (1 M, 14.30 mL) was added. The resulting reaction mixture was stirred under nitrogen at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and 20 mL of water and 50 mL of ethyl acetate were added to the residue and stirred until completely dissolved. The aqueous phase was separated. The organic phase was washed with 10 mL of 0.5 M hydrochloric acid. The aqueous phases were combined, the pH was adjusted to 10 with 20% sodium carbonate solution, and then extracted with dichloromethane (20 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain compound 2-2.

[0440] Process 2

[0441] Compound 2-2 (1.2 g, 4.77 mmol) was mixed with 20 mL of dichloromethane, followed by the addition of Boc2O (2.08 g, 9.53 mmol). The mixture was stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 2-3. 1 H NMR (400 MHz, CDCl3) δ: 9.55 - 9.47 (m, 1H), 4.40-4.00 (m, 2H), 3.95 - 3.55 (m, 1H), 3.30 - 2.90 (m, 2H), 2.25 - 1.91 (m, 2H), 1.78 (s, 2H), 1.47 (s, 18H).

[0442] Process 3

[0443] Potassium tert-butoxide (830.68 mg, 7.40 mmol) was added to ethylene glycol dimethyl ether (25 mL). The resulting mixture was cooled to -78°C, and then p-toluenesulfonyl methyl isocyanide (794.91 mg, 4.07 mmol) was added. After the addition, the reaction mixture was stirred for 30 minutes. Next, a solution of compound 2-3 (1.26 g, 3.70 mmol) in ethylene glycol dimethyl ether (25 mL) was added dropwise. After the addition, the mixture was stirred for 30 minutes. The cooling bath was removed. The mixture was heated to room temperature (20°C) and stirred for 30 minutes. Finally, 40 mL of methanol was added, and the resulting reaction mixture was heated to 90°C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 2-4. 1 H NMR (400MHz, CDCl3) δ: 4.22 (s, 1H), 3.65 - 3.55 (m, 2H), 3.30-2.62 (m, 4H), 1.99 - 1.89 (m, 2H), 1.65 - 1.30 (m, 20H).

[0444] Process 4

[0445] Compound 2-4 (375 mg, 1.07 mmol) was dissolved in dichloromethane (2 mL), followed by the addition of trifluoroacetic acid (1.22 g, 10.67 mmol). The resulting reaction mixture was stirred under nitrogen at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and 20 mL of ethyl acetate was added to the residue. Then, 1 mL of 4 M hydrogen chloride / ethyl acetate solution was added, and the mixture was concentrated under reduced pressure to obtain the hydrochloride salt of compound 2-5.

[0446] Process 5

[0447] Compound 1-13B (350 mg, 445.44 μmol) and the hydrochloride salt of compound 2-5 (299.51 mg) were added to N,N-dimethylformamide (3 mL), followed by the addition of N,N-diisopropylethylamine (460.56 mg, 3.56 mmol). The mixture was heated to 105°C under nitrogen with stirring for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was dissolved in 50 mL of ethyl acetate and washed with saturated brine (10 mL x 2). The organic phase was dried and concentrated under reduced pressure to obtain compound 2-6. MS m / z = 787.2 [M + H] + .

[0448] Process 6

[0449] Compound 2-6 (368 mg, 467.67 μmol) and N,N-diisopropylethylamine (120.89 mg, 935.34 μmol) were added to dichloromethane (3 mL), followed by the addition of Boc2O (153.10 mg, 701.51 μmol). The resulting reaction mixture was stirred under nitrogen at 20°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 2-7. MS m / z = 887.4 [M + H] + .

[0450] Process 7

[0451] Compound 2-7 (220 mg, 248.03 μmol) was dissolved in dichloromethane (2 mL), followed by the addition of m-chloroperbenzoic acid (50.35 mg, 248.03 μmol, 85% purity). The resulting reaction mixture was stirred under nitrogen at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 2-8. MS m / z = 903.6 [M + H] + .

[0452] Process 8

[0453] Compound 1-2 (75.68 mg, 493.91 μmol) was dissolved in THF (2 mL), followed by the addition of sodium tert-butoxide (47.47 mg, 493.91 μmol). The reaction mixture was stirred under nitrogen at 20°C for 1 hour. Next, a solution of compound 2-8 (223 mg, 246.96 μmol) in tetrahydrofuran (1 mL) was added. After the addition, the reaction mixture was stirred at 20°C for 0.5 hours. The reaction solution was dissolved in 10 mL of ethyl acetate and washed with 5 mL of saturated brine. The organic phase was dried and filtered. The filtrate was concentrated under reduced pressure to obtain compound 2-9. MS m / z = 992.5 [M + H] + .

[0454] Process 9

[0455] Trifluoroacetic acid (2 mL) was added to compound 2-9 (214 mg, 215.70 μmol), and the resulting reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatography column: Xtimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile): 10%-40%), and concentrated under reduced pressure to obtain the hydrochloride salt of compound 2. MS m / z = 652.2 [M + H] + . Example 3 [ka] [ka]

[0456] Process 1

[0457] A 1 M, 21 mL solution of borane in tetrahydrofuran was slowly added dropwise to a solution of compound 3-1 (1.7 g, 5.18 mmol) in anhydrous THF (20 mL) under nitrogen at 0°C. The mixture was then stirred at 25°C for 12 hours. Next, a 5% NaOH solution (26.31 mmol, 21 mL) was added dropwise at 0°C, followed by the dropwise addition of hydrogen peroxide (4.88 g, 43.04 mmol, 4.14 mL, 30% purity). The mixture was reacted at 25°C for 2 hours. The reaction mixture was quenched by slowly adding 50 mL of saturated sodium sulfite solution and extracted with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 3-2. MS m / z = 347.2 [M + H] + .

[0458] Process 2

[0459] To a solution of compound 3-2 (1 g, 2.89 mmol) in anhydrous dioxane (10 mL), hydrochloric acid / dioxane solution (4 M, 10 mL) was added, and the mixture was reacted at 20°C for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound 3-3.

[0460] Process 3

[0461] Compound 3-4A (750 mg, 3.04 mmol) was dissolved in anhydrous DCM (10 mL). Then, triethylamine (584 mg, 5.77 mmol) and the hydrochloride salt of compound 3-3 (921 mg) were added, and the reaction was carried out at 20°C for 1 hour. The resulting dichloromethane solution of compound 3-4 was used directly in the next step. MS m / z = 457.2 [M+1] + .

[0462] Process 4

[0463] To 10 mL of a dichloromethane solution of compounds 3-4 obtained in step 3, triethylsilyl chloride (871 mg, 5.78 mmol) and imidazole (590 mg, 8.67 mmol) were added, respectively. The mixture was reacted at 25°C for 12 hours. The reaction solution was diluted with 10 mL of water and extracted with 10 mL of dichloromethane. The organic phase was washed with 10 mL of brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain compounds 3-5. MS m / z = 571.3 [M+1] + .

[0464] Process 5

[0465] Compound 3-5 (1.43 g, 2.50 mmol) was slowly added at 0°C to a solution of lithium aluminum hydride (2.5 M, 2.00 mL) in tetrahydrofuran at 0°C. The reaction was allowed to proceed at 25°C for 5 hours. Then, ethyl acetate (10 mL) was added dropwise to quench the reaction. The resulting suspension was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain compound 3-6. MS m / z = 529.3 [M+1] + .

[0466] Process 6

[0467] Compound tetramethylpiperidine (460 mg, 3.26 mmol) was dissolved in anhydrous tetrahydrofuran (1.0 mL), cooled to -40°C under nitrogen, and then n-butyllithium (2.5 M, 1.3 mL) was added dropwise. The reaction mixture was stirred for 0.5 hours. Compound 3-6 (430 mg, 813 μmol) was dissolved in anhydrous tetrahydrofuran (0.5 mL) and added dropwise to the reaction flask at -60°C. After the addition was complete, the reaction mixture was stirred for 0.5 hours. Finally, a solution of compound 1-8 (486 mg, 1.00 mmol) in anhydrous tetrahydrofuran (0.5 mL) was added to the reaction mixture at -60°C. The mixture was then warmed to 20°C and stirred for 2.5 hours. The reaction was quenched by adding 20 mL of water and extracted with ethyl acetate (20 mL). The organic phase was washed with 20 mL of brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) and separated by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compounds 3-7. MS m / z = 1014.5 [M + H] + .

[0468] Process 7

[0469] Compound 3-7 (70 mg, 69.0 μmol) was dissolved in anhydrous toluene (1.5 mL), and cyanomethylenetri-n-butylphosphine (150 mg, 621.50 μmol) was added. After nitrogen purging, the reaction mixture was stirred at 110°C for 12 hours. The reaction solution was cooled and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 3-8. MS m / z = 996.5 [M + H] + .

[0470] Process 8

[0471] Compound 3-8 (22.5 mg, 22.58 μmol) was dissolved in anhydrous dichloromethane (0.5 mL). Meta-chloroperbenzoic acid (5 mg, 24.63 μmol, 85% purity) was added, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by adding 4 mL of saturated sodium sulfite solution, and extracted with dichloromethane (20 mL x 3). The organic phase was washed with 20 mL of brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 3-9. MS m / z = 10¹².6 [M + H] + .

[0472] Process 9

[0473] Compound 3-9 (19 mg, 18.8 μmol) was dissolved in anhydrous toluene (0.5 mL). Sodium tert-butoxide (7.22 mg, 75.1 μmol), 4 Å molecular sieve (10 mg), and compound 3-10A (12 mg, 75.08 μmol) were added. The reaction mixture was stirred at 100 °C for 12 hours. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (ethyl acetate:methanol = 10:1) to obtain compound 3-10. MS m / z = 1107.7 [M + H] + .

[0474] Step 10

[0475] Compound 3-10 (17 mg, 15.35 μmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (chromatography column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 18%-48%) to obtain the trifluoroacetic acid salts of compounds 3A and 3B.

[0476] Trifluoroacetate of compound 3A (single compound or mixture), MS m / z = 635.3 [M + H] + . 1 H NMR (CD3OD, 400 MHz) δ 6.94 (d, J = 8.50 Hz, 1 H), 5.71 - 5.50 (m, 1 H), 5.17 (br dd, J = 10.94, 4.06 Hz, 1 H), 4.80 (br d, J = 13.63 Hz, 2 H), 4.62 - 4.48 (m, 3 H), 4.17 - 3.73 (m, 7 H), 3.54 - 3.36 (m, 3 H), 3.31 - 3.25 (m, 1 H), 2.93 (br dd, J = 18.01, 3.75 Hz, 1 H), 2.77 - 2.48 (m, 3H), 2.46 - 2.28 (m, 3 H), 2.26 - 2.12 (m, 1 H), 2.04 (s, 3 H), 1.96 (dd, J = 14.01, 4.13 Hz, 1 H).

[0477] Trifluoroacetate of compound 3B (single compound or mixture), MS m / z = 635.2 [M + H] + . 1 H NMR (CD3OD, 400 MHz) δ 6.93 (d, J = 8.50 Hz, 1 H), 5.69 - 5.49 (m, 1 H), 5.30 (d, J = 13.88 Hz, 1 H), 5.18 (br dd, J = 11.19, 3.56 Hz, 1 H), 4.87 - 4.78 (m, 2 H), 4.69 - 4.50 (m, 3 H), 4.29 (br d, J = 13.26 Hz, 1 H), 4.20 - 3.87 (m, 6 H), 3.63 (br d, J = 14.51 Hz, 1 H), 3.53 - 3.42 (m, 1 H), 3.35 (br s, 1 H), 2.93 (br dd, J = 17.70, 3.56 Hz, 1 H), 2.77 - 2.51 (m, 3 H), 2.47 - 2.28 (m, 3 H), 2.26 - 2.12 (m, 1 H), 2.04 (s, 3 H), 1.83 (dd, J = 13.88, 4.25 Hz, 1 H). Example 4 [ka] [ka]

[0478] Process 1

[0479] Compound 1-13B (240 mg, 305.44 μmol) and compound 4-1A (97.26 mg, 458.16 μmol) were dissolved in DMF (5 mL). DIPEA (916.33 μmol, 159.61 μL) was added, and the mixture was stirred at 100°C for 1 hour. The mixture was extracted with 30 mL of ethyl acetate. The organic phase was washed with 50 mL of brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 4-1. MS m / z = 848.5 [M + H] + .

[0480] Process 2

[0481] Compound 4-1 (200 mg, 235.86 μmol) was dissolved in dichloromethane (5 mL). Meta-chloroperbenzoic acid (40.70 mg, 235.86 μmol, 85% purity) was added, and the mixture was stirred at 25°C for 1 hour. The reaction solution was extracted with 5 mL of dichloromethane. The organic phase was washed with 10 mL of saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 4-2. MS m / z = 864.3 [M + H] + .

[0482] Process 3

[0483] Compound 4-3 (610 mg, hydrochloride) was dissolved in acetonitrile (10 mL), and potassium carbonate (1.46 g, 10.6 mmol) and potassium iodide (35.1 mg, 212 μmol) were added. The reaction mixture was reacted at 25°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1), and then separated by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compounds 4-4A and 4-4B. Compound 4-4A (petroleum ether:ethyl acetate = 1:1, R f The MS m / z value for (=0.21) is 216.0[M+1] + Compound 4-4B (petroleum ether:ethyl acetate = 1:1, R f The MS m / z value for (=0.12) is 216.1[M+1] + That was the case.

[0484] Compound 4-4A: 1 H NMR (400 MHz, CDCl3) δ ppm 3.75 (s, 3H), 3.54 (dd, J = 6.5, 9.0 Hz, 1H), 3.33 (tt, J = 6.4, 10.6 Hz, 1H), 3.13 (td, J = 6.4, 10.8 Hz, 1H), 2.86 - 2.75 (m, 2H), 2.52 (t, J = 9.6 Hz, 1H), 2.30 - 2.18 (m, 1H), 2.15 (s, 3H), 1.99 - 1.81 (m, 3H), 1.61 (dd, J = 11.3, 12.6 Hz, 1H);Compound 4-4B: 1 H NMR (400 MHz, CDCl3) δ ppm 3.67 (s, 3H), 3.28 - 3.08 (m, 2H), 3.06 - 2.92 (m, 2H), 2.56 (td, J = 7.4, 9.5 Hz, 1H), 2.37 - 2.17 (m, 2H), 2.09 (dd, J = 6.9, 13.2 Hz, 1H), 2.04 (s, 3H), 1.79 - 1.69 (m, 2H), 1.67 - 1.56 (m, 1H).

[0485] Process 4

[0486] Compound 4-4A (102 mg, 474 μmol) was dissolved in THF (5.0 mL). Lithium aluminum tetrahydride (2.5 M, 0.3 mL) was added dropwise at 0°C. The reaction mixture was heated to 25°C and allowed to react for 1 hour. Then, water (0.03 mL), 15% sodium hydroxide aqueous solution (0.03 mL), and water (0.1 mL) were added dropwise at 0°C, and the mixture was stirred for 0.5 hours. The mixture was filtered. The filtered cake was washed with 10 mL of ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain compound 4-5A. MS m / z = 188.1 [M+1] + .

[0487] Process 5

[0488] Compound 4-2 (120 mg, 139 μmol), compound 4-5A (89 mg, 475 μmol), 4 Å molecular sieve (120 mg), and sodium tert-butoxide (80 mg, 832 μmol) were added to toluene (15 mL) and heated at 100°C for 6 hours. The reaction mixture was filtered. The filtered cake was washed with 10 mL of ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 4-6A. MS m / z = 987.4 [M+1] + .

[0489] Process 6

[0490] Compound 4-6A (81 mg, 82.0 μmol) was dissolved in dichloromethane (10.0 mL), and trifluoroacetic acid (3.07 g, 26.9 mmol, 2 mL) was added. The reaction mixture was reacted at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 15%-45%) to obtain the trifluoroacetate salt of compound 4A. MS m / z = 647.3 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.94 (d, J = 8.5 Hz, 1H), 5.21 (br dd, J = 3.9, 11.1 Hz, 1H), 4.79 - 4.49 (m, 4H), 4.47 - 4.32 (m, 1H), 4.24 - 4.02 (m, 3H), 3.86 (br d, J = 13.9 Hz, 1H), 3.76 - 3.65 (m, 2H), 3.65 - 3.55 (m, 1H), 3.54 - 3.46 (m, 1H), 3.41 - 3.35 (m, 1H), 3.20 - 3.08 (m, 1H), 3.01 - 2.89 (m, 1H), 2.71 (br dd, J = 6.5, 13.4 Hz, 1H), 2.41 - 2.19 (m, 8H), 2.19 - 1.90 (m, 8H).

[0491] Process 7

[0492] Compound 4-4B (51 mg, 237 μmol) was dissolved in THF (3.0 mL). Lithium aluminum tetrahydride (2.5 M, 0.15 mL) was added dropwise at 0°C. The reaction mixture was heated to 25°C and allowed to react for 1 hour. Then, water (0.02 mL), 15% NaOH aqueous solution (0.02 mL), and water (0.06 mL) were added dropwise at 0°C, and the mixture was stirred for 0.5 hours. The mixture was filtered. The filtered cake was washed with 10 mL of ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain compound 4-5B. MS m / z = 188.2 [M+1] + .

[0493] Process 8

[0494] Compound 4-2 (100 mg, 116 μmol), compound 4-5B (41 mg, 219 μmol), 4 Å molecular sieve (70 mg), and sodium tert-butoxide (80 mg, 832 μmol) were added to toluene (15 mL) and heated at 100°C for 6 hours. The reaction mixture was filtered. The filtered cake was washed with 10 mL of ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain compound 4-6B. MS m / z = 987.4 [M+1] + .

[0495] Process 9

[0496] Compound 4-6B (70 mg, 70.9 μmol) was dissolved in dichloromethane (10.0 mL), and trifluoroacetic acid (3.07 g, 26.9 mmol, 2 mL) was added. The reaction mixture was reacted at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (chromatography column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 15%-45%) to obtain the trifluoroacetate salt of compound 4B. MS m / z = 647.3 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.94 (d, J = 8.5 Hz, 1H), 5.21 (br dd, J = 4.1, 10.6 Hz, 1H), 4.78 - 4.64 (m, 4H), 4.54 (br d, J = 11.8 Hz, 1H), 4.42 - 4.32 (m, 1H), 4.21 - 4.11 (m, 2H), 3.88 - 3.54 (m, 6H), 3.40 - 3.34 (m, 2H), 2.96 (br dd, J = 4.0, 17.9 Hz, 1H), 2.55 - 2.37 (m, 2H), 2.36 - 1.89 (m, 14H). Example 5 [ka]

[0497] Process 1

[0498] Compound 5-1 (10.0 g, 43.5 mmol) was dissolved in DMF (4 mL), followed by the addition of potassium carbonate (15.0 g, 109 mmol) and p-methoxybenzyl chloride (16.3 g, 104 mmol, 14.2 mL). The reaction mixture was allowed to react at 80°C for 12 hours. After the reaction mixture cooled to room temperature, 200 mL of ethyl acetate was added to the reaction mixture. The mixture was washed with 200 mL of water and 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 30:1) to obtain compound 5-2. 1 H NMR (400 MHz, CDCl3) δ ppm 7.48 (t, J = 1.31 Hz, 1H), 7.41 (dd, J = 2.38, 1.13 Hz, 1H), 7.13 (d, J = 8.50 Hz, 4H), 7.06 - 7.02 (m, 1H), 6.92 - 6.83 (m, 4H), 4.56 (s, 4H), 3.86 (s, 3H) 3.81 (s, 6H).

[0499] Process 2

[0500] Compound 5-2 (17.5 g, 37.2 mmol) was dissolved in anhydrous THF (200 mL). Then, LiAlH4 (2.5 M, 30 mL) was added at 0°C, followed by reaction at 25°C for 1 hour. The reaction mixture was cooled to room temperature, and under a nitrogen stream, 2.85 mL of H2O, 2.85 mL of 15% NaOH aqueous solution, and 8.6 mL of H2O were slowly added dropwise. The resulting solid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5-3. 1 H NMR (400 MHz, CDCl3) δ ppm 7.03 (d, J = 8.63 Hz, 4H), 6.82 - 6.67 (m, 6H), 6.57 (s, 1H), 4.44 (s, 6H), 3.71 (s, 6H).

[0501] Process 3

[0502] Compound 5-3 (15.0 g, 33.9 mmol) was dissolved in THF (150 mL). The atmosphere was replaced with nitrogen three times, and MnO2 (60.0 g, 690 mmol) was added. After reacting at 75°C for 12 hours, the reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain compound 5-4. 1 H NMR (400 MHz, CDCl3) δ ppm 9.79 (s, 1H), 7.16 - 7.09 (m, 6H), 6.92 - 6.86 (m, 5H), 4.59 (s, 4H), 3.81 (s, 6H).

[0503] Process 4

[0504] Compound 5-4 (7.20 g, 16.4 mmol), 1-propynyltri-n-butyltin (5.38 g, 16.4 mmol), and dichlorobis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium(II) (57.9 mg, 81.8 μmol) were dissolved in anhydrous toluene (170 mL). The atmosphere was purged three times with nitrogen, and the mixture was reacted at 110 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 5-5. MS m / z = 400.3 [M + H] + , 1 H NMR (400 MHz, CDCl3) δ ppm 9.82 (s, 1H), 7.21 (s, 1H), 7.18 - 7.15 (m, 1H), 7.12 (d, J = 8.63 Hz, 4H), 7.03 - 7.01 (m, 1H), 6.87 (d, J = 8.63 Hz, 4H), 4.58 (s, 4H), 3.81 (s, 6H), 2.02 (s, 3H).

[0505] Process 5

[0506] Compound 5-5 (4.60 g, 11.5 mmol) was dissolved in anhydrous DMF (50 mL), and NBS (2.25 g, 12.7 mmol) was added. The mixture was reacted at room temperature for 0.5 hours. Water (150 mL) was added to the organic phase, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phase was washed three times with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 5-6. MS m / z = 478.2 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 10.31 (s, 1H), 7.24 (d, J = 3.38 Hz, 1H), 7.10 (d, J = 8.63 Hz, 4H), 7.05 (d, J = 3.38 Hz, 1H), 6.89 - 6.83 (m, 4H), 4.55 (s, 4H), 3.80 (s, 6H), 2.09 (s, 3H).

[0507] Process 6

[0508] Compounds 5-6 (5.30 g, 11.1 mmol), cuprous iodide (4.22 g, 22.2 mmol), and methyl 2,2-difluoro-2-fluorosulfonyl acetate (8.09 g, 42.1 mmol) were dissolved in DMF (50 mL). The atmosphere was purged three times with nitrogen, and the mixture was reacted at 110°C for 2.5 hours. The reaction solution was cooled, filtered through Celite, and water (150 mL) was added to the organic phase. The mixture was extracted three times with 150 mL of ethyl acetate. The organic phase was washed three times with saturated brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain compound 5-7. MS m / z = 468.2 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 10.30 (q, J = 2.71 Hz, 1H), 7.25 (d, J = 2.75 Hz, 1H), 7.10 (d, J = 8.63 Hz, 4H), 7.00 (d, J = 2.88 Hz, 1H), 6.90 - 6.85 (m, 4H), 4.60 (s, 4H), 3.81 (s, 6H), 2.05 (d, J = 4.13 Hz, 3H).

[0509] Process 7

[0510] TMP (2.45 g, 17.4 mmol, 2.94 mL) was dissolved in THF (20 mL). The atmosphere was purged with nitrogen three times. The temperature was lowered to -40°C, and n-BuLi (2.5 M, 6.71 mL) was slowly added dropwise. After the addition was complete, the mixture was reacted at -40°C for 30 minutes. Next, the reaction system was cooled to -60°C, and the solution of 5-7A (2.20 g, 5.78 mmol) in THF (20 mL) was slowly added dropwise to the reaction mixture. After reacting at -40°C for 15 minutes, compound 5-7 (3.94 g, 6.94 mmol) was gradually added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (100 mL) and extracted twice with ethyl acetate (100 mL). The organic phase was washed twice with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compounds 5-8. MS m / z = 848.4 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 7.15 - 6.99 (m, 5H), 6.79 (d, J = 8.63 Hz, 4H), 6.75 (br d, J = 2.38 Hz, 1H), 5.39 (br d, J = 8.63 Hz, 1H), 4.84 - 4.40 (m, 5H), 4.38 - 4.12 (m, 5H), 3.72 (s, 6H), 3.42 - 3.11 (m, 2H), 3.06 - 2.86 (m, 1H), 2.70 - 2.51 (m, 1H), 2.40 (s, 3H), 2.36 - 2.23 (m, 1H), 1.94 (s, 2H), 1.85 - 1.74 (m, 3H), 1.66 (br d, J = 9.13 Hz, 1H), 1.42 (s, 9H).

[0511] Process 8

[0512] Compound 5-8 (324 mg, 390 μmol) was dissolved in anhydrous toluene (23 mL), and tributylcyanomethylene phosphate (1.30 g, 5.40 mmol) was added. The mixture was then purged three times with nitrogen and reacted at 110°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1), separated by preparative high-performance liquid chromatography (Phenomenex luna C18 150*25 mm*10 μm column; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile): 55%-85%), and concentrated under reduced pressure to obtain the hydrochloride salt of compound 5-9. MS m / z = 830.5 [M+H] + .

[0513] Process 9

[0514] Compound 5-9 (324 mg, hydrochloride) was dissolved in anhydrous dichloromethane (3 mL), and m-chloroperbenzoic acid (83.2 mg, 410 μmol, purity 85%) was added. The mixture was reacted at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure. Sodium bicarbonate (10 mL) and sodium sulfite (10 mL) were added to quench the mixture. The mixture was extracted twice with DCM (50 mL), washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 5-10. MS m / z = 846.5 [M + H] + .

[0515] Step 10

[0516] Compounds 5-10 (280 mg, 331 μmol) were dissolved in anhydrous toluene (20 mL). 4 Å molecular sieves (150 mg, 2.34 mmol), compounds 1-2 (203 mg, 1.32 mmol), and sodium tert-butoxide (127 mg, 1.32 mmol) were added, and the mixture was reacted at 100°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) and separated by preparative high-performance liquid chromatography (Phenomenex luna C18 150*30 mm*10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; (acetonitrile): 48%-78%). The mixture was then concentrated under reduced pressure to obtain the formate of compound 5-11. MS m / z = 935.7 [M+H] + Next, the residue was subjected to preparative SFC separation (chiral column: DAIEL CHIRALCEL OD (250mm*30mm, 10μm); mobile phase: [supercritical carbon dioxide - acetonitrile / isopropanol (0.1% ammonia)]; acetonitrile / isopropanol (0.1% ammonia): 45%-45%), and concentrated under reduced pressure to obtain compounds 5-11A and 5-11B. After analytical SFC (chiral column: DAIEL CHIRALCEL OD-3 (50mm*4.6mm, 3μm); mobile phase: [supercritical carbon dioxide - methanol (0.05% diethylamine)]; methanol (0.05% diethylamine)%: 40%), the Rt of compound 5-11A was 0.657 min, the ee value was 99%; MS m / z = 935.6 [M+H]. + The Rt of compound 5-11B was 1.848 min, the ee value was 99%, and the MS m / z = 935.5 [M+H]. + That was the case.

[0517] Step 11

[0518] Compound 5-11A (105 mg, 112 μmol) was dissolved in TFA (1 mL) and reacted at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was separated by preparative HPLC (chromatographic column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 12%-42%) and lyophilized to obtain the trifluoroacetate salt of compound 5A. MS m / z = 595.4 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.96 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 5.34 - 5.28 (m, 2H), 5.11 (dd, J = 2.8, 10.8 Hz, 1H), 4.99 - 4.92 (m, 1H), 4.82 - 4.75 (m, 1H), 4.57 (d, J = 1.6 Hz, 2H), 4.44 - 4.30 (m, 2H), 4.21 - 4.11 (m, 2H), 3.96 - 3.83 (m, 2H), 3.81 - 3.66 (m, 2H), 3.33 (br s, 1H), 3.24 (td, J = 7.2, 11.6 Hz, 1H), 3.05 (br s, 1H), 3.03 - 2.98 (m, 1H), 2.87 - 2.74 (m, 2H), 2.41 - 2.32 (m, 1H), 2.30 - 2.19 (m, 2H), 2.18 - 2.05 (m, 4H), 2.05 - 1.93 (m, 4H).

[0519] Compound 5-11B (110 mg, 118 μmol) was dissolved in TFA (1 mL) and reacted at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was separated by preparative HPLC (chromatography column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 12%-42%) and lyophilized to obtain the trifluoroacetate salt of compound 5B. MS m / z = 595.4 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.97 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 5.30 (br d, J = 8.0 Hz, 2H), 5.11 (br dd, J = 10.8, 2.8 Hz, 1H), 4.98 - 4.94 (m, 1H), 4.84 - 4.77 (m, 1H), 4.66 - 4.55 (m, 2H), 4.46 (br d, J = 14.0 Hz, 1H), 4.34 (br d, J = 14.0 Hz, 1H), 4.17 (br d, J = 16.0 Hz, 2H), 3.96 - 3.85 (m, 2H), 3.82 - 3.68 (m, 2H), 3.37 (br d, J = 14.0 Hz, 1H), 3.23 (td, J = 7.2, 11.6 Hz, 1H), 3.03 (br d, J = 16.4 Hz, 2H), 2.89 - 2.75 (m, 2H), 2.42 - 2.33 (m, 1H), 2.28 - 2.20 (m, 2H), 2.20 - 2.09 (m, 4H), 2.06 - 1.93 (m, 4H). Example 7 [ka]

[0520] Process 1

[0521] Compound 7-1 (1.20 g, 1.26 mmol) was dissolved in anhydrous toluene (12.0 mL), followed by the addition of tributyl(trimethylsilylethynyl)tin (2.94 g, 7.58 mmol) and dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (537 mg, 758 μmol). The reaction was carried out at 110 °C for 20 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 7-1. MS m / z = 10¹¹.6 [M+1] + .

[0522] Process 2

[0523] Compound 7-2 (1.00 g, 989 μmol) was dissolved in anhydrous tetrahydrofuran (10.0 mL), followed by the addition of tetrabutylammonium fluoride (1 M, 989 μL). The mixture was reacted at 25°C for 4 hours. 30.0 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL). The organic phase was dried and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 7-2. MS m / z = 939.6 [M+1] + .

[0524] Process 3

[0525] Compound 7-2 (310 mg, 330.12 μmol) was dissolved in anhydrous acetone (5 mL), followed by the addition of AgNO3 (350 mg, 2.06 mmol) and NCS (220.41 mg, 1.65 mmol). The reaction was carried out at 25°C for 10 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 7-3. MS m / z = 973.4 [M+1] + .

[0526] Process 4

[0527] Compound 7-3 (12.0 mg, 12.3 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (153 mg, 1.35 mmol, 0.1 mL) was added. The mixture was reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 18%-48%), and lyophilized to obtain the trifluoroacetate salt of compound 7. MS m / z = 633.2 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ ppm 7.00 (d, J = 8.5 Hz, 1H), 5.33 - 5.30 (m, 2H), 5.21 - 5.18 (m, 1H), 4.85 (s, 4H), 4.76 - 4.71 (m, 1H), 4.54 (s, 2H), 4.35 - 4.30 (m, 2H), 4.17 - 4.12 (m, 2H), 3.93 (d, J = 14.0 Hz, 1H), 3.86 - 3.70 (m, 2H), 3.68 - 3.64 (m, 1H), 3.07 - 2.88 (m, 2H), 2.82 - 2.73 (m, 1H), 2.37 - 2.29 (m, 1H), 2.28 - 2.18 (m, 2H), 2.17 - 2.05 (m, 4H), 2.01 - 1.92 (m, 1H). Example 8 [ka]

[0528] Process 1

[0529] Compound 1-13B (100 mg, 127 μmol), compound 8-1 (63.4 mg, 280 μmol), and triethylamine (509 μmol, 70.9 μL) were dissolved in DMF (1.00 mL). The atmosphere was purged three times with nitrogen, and the mixture was reacted at 50°C for 6 hours. 10.0 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20.0 mL). The organic phase was washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 8-2. MS m / z = 862.4 [M + H] + .

[0530] Process 2

[0531] Compound 8-2 (60.0 mg, 69.6 μmol) was dissolved in anhydrous dichloromethane (1.00 mL). Meta-chloroperbenzoic acid (15.5 mg, 76.6 μmol, purity 85.0%) was added gradually at 0°C. The mixture was reacted at room temperature for 1 hour. 10.0 mL of sodium bicarbonate solution and 10.0 mL of sodium sulfite solution were added to the reaction solution, and the mixture was extracted three times with dichloromethane (30.0 mL). The organic phase was washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 8-3. MS m / z = 878.3 [M + H] + .

[0532] Process 3

[0533] Compound 8-3 (35.0 mg, 39.9 μmol) was dissolved in anhydrous toluene (1.00 mL). Compound 1-2 (12.2 mg, 79.7 μmol), sodium tert-butoxide (15.3 mg, 159 μmol), and 4 Å molecular sieve (18.0 mg) were added. After replacing the atmosphere with nitrogen, the mixture was reacted at 100°C for 6 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (pure ethyl acetate) to obtain compound 8-4. MS m / z = 967.4 [M + H] + .

[0534] Process 4

[0535] Compound 8-4 (30.0 mg, 31.0 μmol) was dissolved in anhydrous dichloromethane (0.5 mL), and trifluoroacetic acid (1.35 mmol, 100 μL) was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was then separated by preparative high-performance liquid chromatography (Phenomenex luna C18 150*25 mm*10 μm column; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 16%-46%). After lyophilization, the trifluoroacetic acid salts of compounds 8A and 8B were obtained.

[0536] Trifluoroacetate of compound 8A: MS m / z = 627.3 [M + H] + , 1 H NMR (400 MHz, CD3OD) δ ppm 6.92 (d, J = 8.5 Hz, 1H), 5.31 (br d, J = 8.5 Hz, 2H), 5.19 (br dd, J = 3.6, 11.8 Hz, 1H), 4.97 - 4.93 (m, 1H), 4.73 (br d, J = 14.6 Hz, 1H), 4.65 - 4.45 (m, 2H), 4.34 (br d, J = 14.4 Hz, 1H), 4.14 (br d, J = 5.5 Hz, 1H), 4.03 - 3.89 (m, 3H), 3.81 - 3.70 (m, 1H), 3.42 - 3.34 (m, 1H), 3.29 - 3.23 (m, 1H), 3.22 - 3.15 (m, 1H), 3.07 - 2.91 (m, 3H), 2.81 (br d, J = 16.0 Hz, 1H), 2.36 (br dd, J = 5.9, 11.4 Hz, 2H), 2.31 - 2.10 (m, 5H), 2.06 - 1.93 (m, 4H), 1.15 (d, J = 6.0 Hz, 3H).

[0537] Trifluoroacetate of Compound 8B, MS m / z = 627.3 [M+H] + , 1 H NMR (400 MHz, CD3OD) δ ppm 6.93 (d, J = 8.5 Hz, 1H), 5.31 (br d, J = 8.0 Hz, 2H), 5.10 - 4.99 (m, 2H), 4.75 (s, 1H), 4.57 (s, 2H), 4.33 (br d, J = 14.3 Hz, 1H), 4.21 - 4.09 (m, 1H), 3.98 - 3.84 (m, 3H), 3.82 - 3.71 (m, 1H), 3.45 (br dd, J = 11.2, 17.7 Hz, 1H), 3.28 - 3.18 (m, 2H), 3.15 - 3.01 (m, 2H), 2.92 - 2.77 (m, 2H), 2.40 - 2.11 (m, 7H), 2.03 - 1.92 (m, 4H), 1.02 (d, J = 6.3 Hz, 3H). Example 9 [ka] [ka]

[0538] Process 1

[0539] Compound 1-13B (49.0 mg, 62.4 μmol) and Compound 9-1 (48.0 mg, 187 μmol) were dissolved in dichloromethane (1.00 mL). N,N-diisopropylethylamine (54.3 μL) was added, and the reaction mixture was reacted at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain Compound 9-2. MS m / z = 892.4 [M+1] +Next, preparative SFC separation was performed (chiral column: (s,s)WHELK-O1 (250mm*30mm, 10μm); mobile phase: [supercritical carbon dioxide - acetonitrile / isopropanol (0.1% ammonia)]; acetonitrile / isopropanol (0.1% ammonia): 50%-50%). After concentration under reduced pressure, compounds 9-2A and 9-2B were obtained. Analytical SFC: (chiral column: (s,s)WHELK-O1 (50mm*4.6mm, 3.5μm); mobile phase: [supercritical carbon dioxide - isopropanol (0.05% diethylamine)]; isopropanol (0.05% diethylamine)%: 40%), compound 9-2A, Rt=1.768 min, ee value 99%; MS m / z=892.4[M+H] + Compound 9-2B, Rt=2.286 min, ee value 99%, MS m / z=892.4[M+H] + .

[0540] Process 2

[0541] Compound 9-2A (30.0 mg, 33.6 μmol) was dissolved in dichloromethane (1.00 mL), and m-chloroperbenzoic acid (8.19 mg, 40.4 μmol, purity 85.0%) was added. The reaction mixture was reacted at 25°C for 2 hours. The reaction mixture was quenched with saturated sodium sulfite solution. The organic phase was recovered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 9-3A. m / z = 908.4 [M+1] + .

[0542] Referring to step 2, compound 9-3B was obtained by using compound 9-2B as the starting material instead of compound 9-2A. m / z = 908.4 [M+1] + .

[0543] Process 3

[0544] Compound 9-3A (12.0 mg, 13.2 μmol), compound 1-2 (6.07 mg, 39.7 μmol), sodium tert-butoxide (3.81 mg, 39.7 μmol), and 4 Å molecular sieve (12.0 mg) were added to toluene (1.00 mL). The reaction mixture was reacted at 110 °C for 12 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 9-4A. MS m / z = 997.6 [M+1] + .

[0545] Referring to step 3, compound 9-4B was obtained by using compound 9-3B as the starting material instead of compound 9-3A. MS m / z = 997.6 [M+1] + .

[0546] Process 4

[0547] Compound 9-4A (10.0 mg, 10.0 μmol) was dissolved in dichloromethane (1.00 mL), and trifluoroacetic acid (0.30 mL) was added. The reaction mixture was reacted at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 15%-45%) to obtain the trifluoroacetate of 9A. MS m / z = 657.4 [M+1] + , 1 H NMR (400 MHz, CD3OD) δ ppm 6.97 - 6.92 (m, 1H), 5.33 (br d, J = 7.8 Hz, 2H), 5.28 - 5.17 (m, 1H), 4.76 - 4.72 (m, 1H), 4.56 (s, 2H), 4.41 - 4.28 (m, 2H), 4.22 - 4.15 (m, 1H), 3.99 - 3.91 (m, 1H), 3.79 - 3.63 (m, 5H), 3.52 - 3.48 (m, 3H), 3.35 (br d, J = 1.8 Hz, 1H), 3.31 - 3.23 (m, 3H), 3.09 - 2.79 (m, 3H), 2.40 - 2.10 (m, 6H), 2.04 (s, 3H), 2.01 - 1.88 (m, 2H).

[0548] Compound 9-4B (13.0 mg, 13.0 μmol) was dissolved in dichloromethane (1.00 mL), and trifluoroacetic acid (0.30 mL) was added. The reaction mixture was reacted at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (chromatography column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 15%-45%) to obtain the trifluoroacetate of 9B. MS m / z = 657.5 [M+1] + , 1 H NMR (400 MHz, CD3OD) δ ppm 6.94 (d, J = 8.5 Hz, 1H), 5.33 (br d, J = 7.6 Hz, 2H), 5.26 - 5.18 (m, 1H), 4.78 - 4.73 (m, 1H), 4.57 (s, 2H), 4.39 - 4.28 (m, 2H), 4.17 - 4.12 (m, 1H), 3.94 (br d, J = 14.4 Hz, 1H), 3.85 - 3.63 (m, 5H), 3.50 (s, 3H), 3.41 - 3.34 (m, 2H), 3.31 - 3.21 (m, 2H), 3.09 - 2.78 (m, 3H), 2.41 - 2.12 (m, 6H), 2.04 (s, 3H), 2.02 - 1.91 (m, 2H). Example 10 [ka]

[0549] Process 1

[0550] Compound 1-13B (49.0 mg, 62.4 μmol) and compound 10-1 (48.0 mg, 187 μmol) were dissolved in dichloromethane (1.00 mL). N,N-diisopropylethylamine (40.3 mg, 312 μmol, 54.3 μL) was added, and the reaction mixture was reacted at 25°C for 12 hours. The reaction mixture was directly concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 10-2. MS m / z = 894.4 [M+1] + .

[0551] Process 2

[0552] Compound 10-2 (50.0 mg, 55.9 μmol) was dissolved in dichloromethane (1.00 mL), and m-chloroperbenzoic acid (13.6 mg, 67.1 μmol, purity 85.0%) was added. The reaction mixture was reacted at 25°C for 1 hour. The reaction mixture was quenched with saturated sodium sulfite solution, and the aqueous phase was extracted with dichloromethane (10.0 mL × 2). The organic phase was recovered and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 10-3. m / z = 910.3 [M+1] + .

[0553] Process 3

[0554] Compound 10-3 (30.0 mg, 32.9 μmol), Compound 1-2 (15.2 mg, 98.9 μmol), sodium tert-butoxide (9.50 mg, 98.9 μmol), and 4 Å molecular sieve (30.0 mg) were added to toluene (1.00 mL). The reaction mixture was reacted at 110 °C for 12 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 10-4. MS m / z = 999.6 [M+1] + .

[0555] Process 4

[0556] Compound 10-4 (25.0 mg, 25.0 μmol) was dissolved in dichloromethane (1.00 mL), and trifluoroacetic acid (0.30 mL) was added. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was concentrated to obtain the crude product. The crude product was then purified by preparative HPLC (chromatography column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 12%-42%) to obtain the trifluoroacetate of compound 10. MS m / z = 659.3 [M+1] + , 1 H NMR (400 MHz, CD3OD) δ ppm 6.92 (d, J = 8.5 Hz, 1H), 5.54 - 5.52 (m, 1H), 5.31 (br d, J = 7.6 Hz, 2H), 5.23 - 5.13 (m, 1H), 4.94 - 4.90 (m, 1H), 4.85 - 4.63 (m, 5H), 4.62 - 4.25 (m, 4H), 4.23 - 4.11 (m, 1H), 3.97 - 3.67 (m, 4H), 3.40 - 3.33 (m, 1H), 3.28 - 3.22 (m, 1H), 3.10 - 2.89 (m, 2H), 2.80 (br d, J = 15.9 Hz, 1H), 2.44 - 2.33 (m, 2H), 2.27 - 2.11 (m, 5H), 2.02 (s, 3H), 1.98 - 1.91 (m, 1H). Example 11 [ka]

[0557] Process 1

[0558] Compound 11-1 was subjected to preparative SFC separation (chiral column: DAIEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [supercritical carbon dioxide - acetonitrile / isopropanol (0.1% ammonia)]; acetonitrile / isopropanol (0.1% ammonia): 30%-30%). After concentration under reduced pressure, compounds 11-1A and 11-1B were obtained. Analytical SFC: (chiral column: DAIEL CHIRALPAK AD (50 mm*4.6 mm, 3 μm); mobile phase: [supercritical carbon dioxide - isopropanol (0.05% diethylamine)]; isopropanol (0.05% diethylamine) %: 5%-40%), compound 11-1A, Rt=1.308 min, ee value 99%; MS m / z=503.2 [M+Na] + Compound 11-1B, Rt=1.499 min, ee value 99%, MS m / z=503.2[M+Na] + .

[0559] Process 2

[0560] Compound 11-1A (238 mg, 495 μmol) was dissolved in acetic acid (4.00 mL) and reacted at 25°C for 12 hours. After that, the acetic acid was removed by concentrating under reduced pressure to obtain the acetate salt of compound 11-2A.

[0561] Referring to step 2, compound 11-1B was used as the raw material instead of compound 11-1A to obtain the acetate of compound 11-2B.

[0562] Process 3

[0563] Compound 1-13B (200 mg, 254 μmol) and compound 11-2A (182 mg, acetate) were dissolved in dichloromethane (3.00 mL). N,N-diisopropylethylamine (1.27 mmol, 222 μL) was added, and the reaction mixture was reacted at 25°C for 12 hours. The reaction mixture was directly concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 11-3A. MS m / z = 874.4 [M+1] + .

[0564] Referring to step 3, compound 11-3B was obtained by using the acetate of compound 11-2B as the starting material instead of the acetate of compound 11-2A. MS m / z = 874.4 [M+1] + .

[0565] Process 4

[0566] Compound 11-3A (180 mg, 206 μmol) was dissolved in dichloromethane (3.00 mL), and m-chloroperbenzoic acid (43.9 mg, 216 μmol, purity 85.0%) was added. The reaction mixture was allowed to react at 25°C for 2 hours. 10.0 mL of sodium bicarbonate solution and 10.0 mL of sodium sulfite solution were added to the reaction mixture. The aqueous phase was extracted with dichloromethane (30.0 mL × 2). The organic phase was recovered and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 11-4A.

[0567] Referring to step 4, compound 11-4B was obtained by using compound 11-3B as the starting material instead of compound 11-3A.

[0568] Process 5

[0569] Compound 11-4A (140 mg, 157 μmol), Compound 1-2 (48.2 mg, 315 μmol), sodium tert-butoxide (60.5 mg, 629 μmol), and 4 Å molecular sieve (70.0 mg) were added to toluene (3.00 mL). The reaction mixture was reacted at 110 °C for 12 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain Compound 11-5A. MS m / z = 979.5 [M+1] + .

[0570] Referring to step 4, compound 11-5B was obtained by using compound 11-4B as the starting material instead of compound 11-4A. MS m / z = 979.5 [M+1] + .

[0571] Process 6

[0572] Compound 11-5A (72.0 mg, 73.5 μmol) was dissolved in dichloromethane (1.00 mL), and trifluoroacetic acid (0.20 mL) was added. The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was concentrated to obtain the crude product. The crude product was then purified by preparative HPLC (chromatography column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 16%-46%) to obtain the trifluoroacetate of 11A. MS m / z = 639.3 [M + H] + , 1 H NMR (400 MHz, CD3OD) δ ppm 6.92 (d, J = 8.6 Hz, 1H), 6.15 (dd, J = 11.2, 17.7 Hz, 1H), 5.61 - 5.46 (m, 2H), 5.31 (br d, J = 7.5 Hz, 2H), 5.25 - 5.17 (m, 1H), 5.09 - 4.97 (m, 1H), 4.77 - 4.72 (m, 2H), 4.55 (s, 2H), 4.39 - 4.22 (m, 3H), 3.98 - 3.70 (m, 3H), 3.55 (d, J = 13.6 Hz, 1H), 3.28 - 3.21 (m, 2H), 3.09 - 2.90 (m, 2H), 2.79 (br d, J = 16.3 Hz, 1H), 2.40 - 2.05 (m, 8H), 2.02 (s, 3H).

[0573] Compound 11-5B (64.0 mg, 65.4 μmol) was dissolved in dichloromethane (1.00 mL), and trifluoroacetic acid (0.20 mL) was added. The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was concentrated to obtain the crude product. The crude product was then purified by preparative HPLC (chromatography column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 16%-46%) to obtain the trifluoroacetate of 11B. MS m / z = 639.3 [M + H] + ,1 H NMR (400 MHz, CD3OD) δ ppm 6.92 (d, J = 8.5 Hz, 1H), 6.18 (dd, J = 11.2, 17.7 Hz, 1H), 5.66 - 5.48 (m, 2H), 5.31 (br d, J = 7.4 Hz, 2H), 5.20 (br dd, J = 4.1, 10.9 Hz, 1H), 4.95 - 4.91 (m, 1H), 4.78 - 4.71 (m, 2H), 4.55 (s, 2H), 4.45 - 4.16 (m, 3H), 3.98 - 3.62 (m, 4H), 3.27 - 3.22 (m, 2H), 3.09 - 2.88 (m, 2H), 2.79 (br d, J = 16.3 Hz, 1H), 2.56 - 2.03 (m, 8H), 2.02 (s, 3H). Example 12 [ka]

[0574] Process 1

[0575] Compound 4-2 (100 mg, 115 μmol), compound 12-1A (83.0 mg, 463 μmol), sodium tert-butoxide (44.5 mg, 463 μmol), and 4 Å molecular sieve (100.0 mg) were added to toluene (5.00 mL). The reaction mixture was reacted at 110 °C for 12 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 12-1. MS m / z = 979.5 [M+1] + .

[0576] Process 2

[0577] Compound 12-1 (90.0 mg, 91.90 μmol) was dissolved in dichloromethane (1.00 mL), and trifluoroacetic acid (0.30 mL) was added. The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was concentrated to obtain the crude product. The crude product was then purified by preparative HPLC (chromatography column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 16%-46%) to obtain the trifluoroacetate of compound 12. MS m / z = 639.4 [M + H] + , 1 H NMR (400 MHz, D2O) δ ppm 7.12 (d, J = 8.5 Hz, 1H), 5.33 - 5.26 (m, 2H), 5.05 - 4.94 (m, 2H), 4.36 - 4.19 (m, 4H), 3.99 - 3.87 (m, 3H), 3.62 - 3.25 (m, 5H), 3.21 - 2.85 (m, 4H), 2.31 - 2.07 (m, 6H), 2.06 - 2.01 (m, 3H), 1.96 - 1.86 (m, 1H), 0.87 - 0.72 (m, 4H). Example 13 [ka]

[0578] Process 1

[0579] Compound 4-2 (50.0 mg, 57.9 μmol), compound 13-1A (26.6 mg, 174 μmol), and sodium tert-butoxide (27.8 mg, 289 μmol) 4 Å molecular sieve (50.0 mg) were added to toluene (2.00 mL). The reaction mixture was reacted at 110 °C for 12 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 13-1. MS m / z = 953.5 [M+1] +Compound 13-1 was subjected to preparative SFC separation (chiral column: (s,s)WHELK-O1 (250mm*30mm, 10μm); mobile phase: [supercritical carbon dioxide - acetonitrile / isopropanol (0.1% ammonia)]; acetonitrile / isopropanol (0.1% ammonia): 38%-38%), and concentrated under reduced pressure to obtain compounds 13-1A and 13-1B. Analytical SFC: (chiral column: (s,s)WHELK-O1 (50mm*4.6mm, 3.5μm); mobile phase: [supercritical carbon dioxide - isopropanol (0.05% diethylamine)]; isopropanol (0.05% diethylamine)%: 40%), compound 13-1A, Rt=1.495 min, ee value 99%; MS m / z=953.5[M+H] + Compound 13-1B, Rt=1.716 min, ee value 95%, MS m / z=953.5[M+H] + .

[0580] Process 2

[0581] Compound 13-1A (17.0 mg, 17.8 μmol) was dissolved in dichloromethane (1.00 mL), and trifluoroacetic acid (0.30 mL) was added. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was concentrated to obtain the crude product. The crude product was then purified by preparative HPLC (chromatography column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 10%-40%) to obtain the trifluoroacetate of 13A. MS m / z = 613.4 [M + H] + , 1 H NMR (400 MHz, CD3OD) δ ppm 6.92 (d, J = 8.5 Hz, 1H), 5.41 - 5.27 (m, 2H), 5.18 (br dd, J = 3.8, 10.8 Hz, 1H), 4.77 - 4.70 (m, 1H), 4.68 - 4.50 (m, 2H), 4.32 (br d, J = 14.4 Hz, 1H), 4.22 - 4.10 (m, 2H), 3.88 - 3.63 (m, 4H), 3.48 - 3.32 (m, 4H), 3.27 (br d, J = 12.1 Hz, 1H), 3.03 - 2.88 (m, 3H), 2.53 - 2.40 (m, 1H), 2.32 - 2.09 (m, 6H), 2.04 - 2.01 (m, 3H), 2.01 - 1.93 (m, 1H).

[0582] Compound 13-1B (20.0 mg, 21.0 μmol) was dissolved in dichloromethane (1.00 mL), and trifluoroacetic acid (0.30 mL) was added. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was concentrated to obtain the crude product. The crude product was then purified by preparative HPLC (chromatography column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 10%-40%) to obtain the trifluoroacetate of 13B. MS m / z = 613.5 [M+H] + , 1 H NMR (400 MHz, CD3OD) δ ppm 6.94 (d, J = 8.5 Hz, 1H), 5.44 - 5.30 (m, 2H), 5.20 (dd, J = 3.8, 11.3 Hz, 1H), 4.79 - 4.73 (m, 1H), 4.70 - 4.56 (m, 2H), 4.39 (br d, J = 14.0 Hz, 1H), 4.22 - 4.13 (m, 2H), 3.88 - 3.69 (m, 4H), 3.47 - 3.34 (m, 4H), 3.32 - 3.27 (m, 1H), 3.01 - 2.94 (m, 3H), 2.53 - 2.40 (m, 1H), 2.32 - 2.12 (m, 6H), 2.04 (s, 3H), 2.02 - 1.94 (m, 1H). Example 14 [ka]

[0583] Process 1

[0584] Compound 14-1 (5.00 g, 20.6 mmol) was dissolved in DMF (50.0 mL), followed by the addition of triphenylphosphonium difluoroacetate (19.0 g, 53.4 mmol). The reaction mixture was allowed to react at 80°C for 2 hours. 300 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (200 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:1-3:1) to obtain compound 14-2. 1 H NMR (400 MHz, CDCl3) 5.00 - 4.76 (m, 1H), 3.82 - 3.65 (m, 4H), 3.61 - 3.45 (m, 1H), 2.71 - 2.55 (m, 2H), 1.49 - 1.38 (m, 9H).

[0585] Process 2

[0586] Compound 14-2 (2.80 g, 10.1 mmol) was dissolved in tetrahydrofuran (3.00 mL), and lithium diisopropylamide (2.00 M, 10.1 mL) was added. The mixture was reacted at -60°C for 1 hour. Then, 1-chloro-3-iodopropane (10.3 g, 50.5 mmol, 1.55 mL) was added, and the mixture was reacted at -60°C for 1 hour, followed by 25°C for 12 hours. 50.0 mL of ammonium chloride solution was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50.0 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 50:1-10:1) to obtain compound 14-3. MS m / z = 376.1 [M + Na] + .

[0587] Process 3

[0588] Compound 14-3 (3.20 g, 9.04 mmol) was dissolved in acetonitrile (1.00 mL), and hydrochloric acid / dioxane (2.00 M, 5.00 mL) was added. The mixture was reacted at 25°C for 12 hours. The mixture was concentrated under reduced pressure, and the solvent was removed to obtain the hydrochloride salt of compound 14-4. MS m / z = 254.1 [M + H] + .

[0589] Process 4

[0590] Compound 14-4 (2.50 g, hydrochloride) was dissolved in acetonitrile (25.0 mL). Potassium carbonate (5.95 g, 43.1 mmol) and potassium iodide (143 mg, 862 μmol) were added. The mixture was reacted at 25°C for 12 hours. The mixture was filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 50:1-20:1) to obtain compound 14-5. MS m / z = 218 [M + H] + .

[0591] Process 5

[0592] Compound 14-5 (300 mg, 1.38 mmol) was dissolved in THF (3.00 mL), and lithium aluminum tetrahydrogen (2.50 M, 1.10 mL) was added. The mixture was then reacted at 0°C for 1 hour. To the reaction solution, 0.11 mL of water, 0.11 mL of 15% sodium hydroxide solution, and 0.33 mL of water were added. The reaction solution was filtered and concentrated to obtain compound 14-6. MS m / z = 190.1 [M + H] + .

[0593] Process 6

[0594] Compound 14-6 (300 mg, 1.59 mmol) was dissolved in anhydrous dichloromethane (3.00 mL). Imidazole (432 mg, 6.34 mmol), 4-dimethylaminopyridine (19.37 mg, 159 μmol), and tert-butyldiphenylsilyl chloride (872 mg, 3.17 mmol, 812 μL) were added, and the mixture was reacted at 25°C for 12 hours. The reaction solution was concentrated to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 25%-55%) to obtain compound 14-7. MS m / z = 428.3 [M + H] + Compound 14-7 was subjected to preparative SFC separation (chiral column: DAIEL CHIRALCEL OX (250mm*50mm, 10μm); mobile phase: [supercritical carbon dioxide - methanol (0.1% ammonia)]; methanol (0.1% ammonia): 10%-10%), and concentrated under reduced pressure to obtain compounds 14-7A and 14-7B. Analytical SFC: (chiral column: DAIEL CHIRALCEL OX (50mm*4.6mm, 3μm); mobile phase: [supercritical carbon dioxide - methanol (0.05% diethylamine)]; methanol (0.05% diethylamine): 5%-40%), compound 14-7A, Rt=1.165 min, ee value 99%; MS m / z=428.2[M+H] + Compound 14-7B, Rt=1.233 min, ee value 95%, MS m / z=428.2[M+H]+ .

[0595] Process 7

[0596] Compound 14-7A (126 mg, 295 μmol) was dissolved in dioxane (2.00 mL), and hydrochloric acid (12 M, 0.50 mL) was added. The mixture was reacted at 95°C for 12 hours, and then dissolved by adding 2 mL of water. The mixture was extracted with ethyl acetate (10 mL), and the aqueous phase was freeze-dried to obtain the hydrochloride salt of compound 14-8A. MS m / z = 190.1 [M + H] + .

[0597] Referring to step 7, compound 14-7B was used as the starting material instead of compound 14-7A to obtain the hydrochloride salt of compound 14-8B. MS m / z = 190.1 [M + H] + .

[0598] Process 8

[0599] Compound 4-2 (120 mg, 139 μmol), compound 14-8A (62.7 mg, hydrochloride), sodium tert-butoxide (66.7 mg, 695 μmol), and 4 Å molecular sieve (30.0 mg) were added to toluene (3.00 mL). The reaction solution was incubated at 100 °C for 6 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography (pure ethyl acetate) to obtain compound 14-9A. MS m / z = 989.7 [M+1] + .

[0600] Referring to step 8, compound 14-9B was obtained by using compound 14-8B as the starting material instead of compound 14-8A. MS m / z = 989.6 [M + H] + .

[0601] Process 9

[0602] Compound 14-9A (63.0 mg, 63.7 μmol) was dissolved in dichloromethane (4.00 mL), and trifluoroacetic acid (1.00 mL) was added. The reaction mixture was allowed to react at 25°C for 12 hours. The reaction mixture was concentrated to obtain the crude product. The crude product was then purified by preparative HPLC (chromatography column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 16%-46%) to obtain the trifluoroacetate of 14A. MS m / z = 649.2 [M + H] + , 1 H NMR (400 MHz, MeOD) δ ppm 6.92 (d, J = 8.5 Hz, 1H), 5.19 (br dd, J = 3.9, 11.1 Hz, 1H), 4.96 - 4.90 (m, 1H), 4.84 - 4.78 (m, 1H), 4.77 - 4.70 (m, 2H), 4.66 - 4.58 (m, 1H), 4.32 (br d, J = 14.0 Hz, 1H), 4.15 (br dd, J = 3.0, 13.6 Hz, 2H), 3.97 - 3.63 (m, 4H), 3.57 - 3.39 (m, 2H), 3.36 - 3.33 (m, 1H), 3.09 - 2.87 (m, 3H), 2.49 - 2.05 (m, 7H), 2.04 - 1.93 (m, 4H).

[0603] Compound 14-9B (88.0 mg, 89.0 μmol) was dissolved in dichloromethane (4.00 mL), and trifluoroacetic acid (1.00 mL) was added. The reaction mixture was allowed to react at 25°C for 12 hours. The reaction mixture was concentrated to obtain the crude product. The crude product was then purified by preparative HPLC (chromatography column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 16%-46%) to obtain the trifluoroacetate of 14B. MS m / z = 649.2 [M+H] + , 1 H NMR (400 MHz, MeOD) δ ppm 6.92 (d, J = 8.5 Hz, 1H), 5.19 (br dd, J = 4.1, 11.3 Hz, 1H), 4.93 - 4.88 (m, 2H), 4.80 - 4.70 (m, 2H), 4.59 (d, J = 12.4 Hz, 1H), 4.30 (br d, J = 14.1 Hz, 1H), 4.15 (br dd, J = 2.1, 14.3 Hz, 2H), 3.95 - 3.62 (m, 4H), 3.58 - 3.38 (m, 2H), 3.30 - 3.24 (m, 1H), 3.09 - 2.87 (m, 3H), 2.47 - 2.07 (m, 7H), 2.05 - 1.94 (m, 4H). Example 15 [ka]

[0604] Process 1

[0605] Compound 14-5 (500 mg, 2.30 mmol) was dissolved in 2-MeTHF (5.00 mL), and sodium bis(2-methoxyethoxy)aluminum hydride (2.66 g, 9.21 mmol, 2.57 mL, 70% purity) was added. The mixture was reacted at 10°C for 2.5 hours, then at room temperature for 12 hours. 10.0 mL of water was added to the reaction mixture, and the mixture was concentrated to remove dimethyltetrahydrofuran. The mixture was then freeze-dried to obtain compound 15-1. MS m / z = 172.1 [M + H] + .

[0606] Process 2

[0607] Compound 15-1 (261 mg, 1.52 mmol) was dissolved in anhydrous dichloromethane (3.00 mL). Imidazole (415 mg, 6.10 mmol), 4-dimethylaminopyridine (18.6 mg, 152 μmol), and tert-butyldiphenylsilyl chloride (838 mg, 3.05 mmol, 780 μL) were added, and the mixture was reacted at 45°C for 12 hours. The reaction solution was concentrated to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 35%-65%) to obtain compound 15-2. MS m / z = 410.3 [M + H] + Compound 15-2 was subjected to preparative SFC separation (chiral column: DAIEL CHIRALPAK IG (250mm*50mm, 10μm); mobile phase: [supercritical dichloromethane-methanol (0.1% ammonia)]; methanol (0.1% ammonia): 18%-18%), and concentrated under reduced pressure to obtain compounds 15-2-1 and 15-2-2. Analytical SFC: (chiral column: Chiralcel OX-3 (50mm*4.6mm, 3μm); mobile phase: [supercritical carbon dioxide-ethanol (0.05% diethylamine)]; ethanol (0.05% diethylamine) %: 5%-40%), compound 15-2-1, Rt=1.18 min, ee value 99%; MS m / z=410.2 [M+H] + Compound 15-2-2, Rt=1.46 min, ee value 97%, MS m / z=410.2[M+H] + .

[0608] Compound 15-2-1 was subjected to chiral preparative HPLC separation (chiral column: DAIEL CHIRALCEL OX (250 mm*50 mm, 10 μm); mobile phase: [n-hexane-ethanol (0.1% ammonia)]; ethanol (0.1% ammonia): 10%-10%), and concentrated under reduced pressure to obtain compounds 15-2A and 15-2B. Analytical SFC: (chiral column: Chiralcel OX-3 (50 mm*4.6 mm, 3 μm); mobile phase: [supercritical carbon dioxide-ethanol (0.05% diethylamine)]; ethanol (0.05% diethylamine): 5%-40%), compound 15-2A, Rt=1.18 min, ee value 99%; MS m / z=410.2 [M+H] + Compound 15-2B, Rt=1.21 min, ee value 99%, MS m / z=410.2[M+H] + .

[0609] Process 3

[0610] Compound 15-2A (160 mg, 391 μmol) was dissolved in dioxane (4.00 mL), and hydrochloric acid (12 M, 1.00 mL) was added. The mixture was reacted at 95°C for 12 hours. The mixture was dissolved by adding 5 mL of water and extracted with ethyl acetate (3.0 mL). The aqueous phase was freeze-dried to obtain the hydrochloride salt of compound 15-3A. MS m / z = 172.1 [M + H] + .

[0611] Referring to step 3, compound 15-2B was used as the starting material instead of compound 15-2A to obtain the hydrochloride salt of compound 15-3B. MS m / z = 172.1 [M + H] + .

[0612] Process 4

[0613] Compound 4-2 (100 mg, 116 μmol), compound 15-3A (48.1 mg, hydrochloride), sodium tert-butoxide (55.6 mg, 579 μmol), and 4 Å molecular sieve (50.0 mg) were added to toluene (3.00 mL). The reaction solution was reacted at 100 °C for 6 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (pure ethyl acetate) to obtain compound 15-4A. MS m / z = 971.4 [M+1] + .

[0614] Referring to step 4, compound 15-4B was obtained by using the hydrochloride salt of compound 15-3B as the starting material instead of the hydrochloride salt of compound 15-3A. MS m / z = 971.4 [M + H] + .

[0615] Process 5

[0616] Compound 15-4A (71.0 mg, 73.1 μmol) was dissolved in dichloromethane (5.00 mL), and trifluoroacetic acid (1.00 mL) was added. The reaction mixture was allowed to react at 25°C for 12 hours. The reaction mixture was concentrated to obtain the crude product. The crude product was then purified by preparative HPLC (chromatography column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (0.1% ammonia)-acetonitrile]; acetonitrile: 35%-65%) to obtain compound 15A. MS m / z = 631.3 [M+H] + , 1 H NMR (400 MHz, MeOD) δ ppm 6.99 - 6.71 (m, 2H), 5.14 (br dd, J = 4.1, 11.5 Hz, 1H), 4.81 - 4.76 (m, 2H), 4.20 - 4.09 (m, 3H), 3.61 - 3.38 (m, 4H), 3.26 - 3.00 (m, 4H), 2.90 - 2.58 (m, 5H), 2.25 - 2.10 (m, 1H), 2.07 - 1.60 (m, 10H).

[0617] Compound 15-4B (61.0 mg, 62.8 μmol) was dissolved in dichloromethane (5.00 mL), and trifluoroacetic acid (1.00 mL) was added. The reaction mixture was allowed to react at 25°C for 12 hours. The reaction mixture was directly concentrated to obtain the crude product. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile: 10%-40%) to obtain the trifluoroacetate salt of compound 15B. MS m / z = 631.3 [M + H] + , 1 H NMR (400 MHz, MeOD) δ ppm 7.27 - 6.84 (m, 2H), 5.19 (br dd, J = 3.5, 11.0 Hz, 1H), 4.79 - 4.50 (m, 4H), 4.34 (br d, J = 14.3 Hz, 1H), 4.15 (br dd. 2.04 - 1.92 (m, 4H). Example 16 [ka] [ka]

[0618] Process 1

[0619] Under nitrogen, a solution of lithium bistrimethylsilylamide in tetrahydrofuran (569.72 mL, 569.72 mmol, 1 M) was slowly added dropwise at -70°C to a solution of compound 16-1 (100.00 g, 379.81 mmol) in tetrahydrofuran (1000 mL). The mixture was reacted at -70°C for 1 hour. 4-bromo-1-butene (128.19 g, 949.53 mmol) was added dropwise to the reaction mixture at -70°C, and the mixture was heated to 20°C with stirring for 12 hours. The reaction was quenched by adding 1000 mL of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (700 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain compound 16-2. MS m / z = 318.0 [M + H] + .

[0620] Process 2

[0621] Compound 16-2 (96.00 g, 302.48 mmol) was dissolved in dichloromethane (1000 mL), and m-chloroperbenzoic acid (135.10 g, 665.45 mmol, 85% purity) was added. The reaction mixture was stirred under nitrogen at 20°C for 12 hours. The reaction was quenched by adding saturated sodium sulfite aqueous solution (1500 mL), and washed with saturated sodium bicarbonate aqueous solution (1000 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain compound 16-3. MS m / z = 334.1 [M + H] + .

[0622] Process 3

[0623] Palladium / carbon (16.64 g, 156.40 mmol, purity 10%) was added to a solution of compound 16-3 (79.00 g, 236.97 mmol) in methanol (1500 mL). The mixture was reacted under a hydrogen atmosphere (15 psi) at 20°C for 16 hours. The filtrate was filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 20:1-9:1) to obtain compounds 16-4A (developing solvent: dichloromethane:methanol = 15:1, Rf = 0.5) and 16-4B (developing solvent: dichloromethane:methanol = 15:1, Rf = 0.3), respectively. Compound 16-4A: MS m / z = 200.0 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 3.71 (s, 3H), 3.60 (dd, J = 12.0 Hz, 4.0 Hz,1H), 3.41 (dd, J = 12.0 Hz, 4.0 Hz,1H), 3.13 - 3.05 (m, 1H), 2.99 - 2.94 (m, 1H), 2.73 - 2.67 (m, 1H), 2.36 - 2.31 (m, 1H), 2.24 - 2.20 (m, 1H), 1.93 - 1.79 (m, 5H), 1.74 - 1.66 (m, 1H).Compound 16-4B:MS m / z = 200.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 3.90 (dd, J = 12.0 Hz, 8.0 Hz,1H), 3.79 (dd, J = 12.0 Hz, 5.2 Hz,1H), 3.73 (s, 3H), 3.49 - 3.42 (m, 1H), 3.11 - 3.07 (m, 1H), 2.76 - 2.69 (m, 1H), 2.58 - 2.52 (m, 1H), 2.29 - 2.21 (m, 1H), 1.89 - 1.80 (m, 4H), 1.67 - 1.54 (m, 2H).

[0624] Process 4

[0625] Compound 16-4B (21.00 g, 105.40 mmol) was dissolved in dichloromethane (200 mL). Imidazole (15.07 g, 221.33 mmol) was added at 0°C and the mixture was stirred for 10 minutes. Then, tert-butyldiphenylsilyl chloride (37.66 g, 137.02 mmol) was added. The mixture was heated to 20°C and stirred for 7 hours. The mixture was filtered, concentrated under reduced pressure, and separated by column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain compound 16-5 (MS m / z = 438.0 [M + H]). + Compounds 16-5C and 16-5D were obtained by chiral preparative HPLC (chromatography column: Regis(S,S)Whelk-O 1, 25×250 mm 10 μm; mobile phase: A: n-hexane, B: ethanol; B%: 2%). SFC analysis (chromatography column: Regis(s,s)WHELK-01 (4.6 mm I.D * 150 mm L, 5 μm); mobile phase: [supercritical carbon dioxide - methanol (0.05% diethylamine)]; gradient: methanol (0.05% diethylamine)%: 5%-40%, 4 min), compound 16-5C, Rt=3.640 min, ee value 97.06%, MS m / z=438.0[M+H] + Compound 16-5D, Rt=3.826 min, ee value 97.88%, MS m / z=438.0[M+H] + .

[0626] Process 5

[0627] Compound 16-5C (12.00 g, 27.42 mmol) was dissolved in a hydrogen chloride / 1,4-dioxane solution (100 mL, 4 M) and stirred at 50°C for 16 hours. The reaction solution was concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol = 7:1) to obtain compound 16-6C. MS m / z = 200.0 [M + H] + .

[0628] Referring to step 5, compound 16-6D was obtained by using compound 16-5D as the starting material instead of compound 16-5C. MS m / z = 200.0 [M + H] + .

[0629] Process 6

[0630] Compound 16-6C (1.00 g, 5.02 mmol) was dissolved in 10 mL of a mixed solvent (acetonitrile:water = 100:0.75). Chromium trioxide (150.56 mg, 1.51 mmol) and periodic acid (2.86 g, 12.55 mmol) were added at 0°C. The mixture was heated to 20°C, and the reactants were stirred under nitrogen for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 16-7C. MS m / z = 214.0 [M + H] + .

[0631] Referring to step 6, compound 16-7D was obtained by using compound 16-6D as the starting material instead of compound 16-6C. MS m / z = 214.0 [M + H] + .

[0632] Process 7

[0633] Compound 16-7C (0.20 g, 0.94 mmol) was dissolved in N,N-dimethylformamide (5 mL). N-ethyl-4-methoxybenzylamine (154.98 mg, 0.94 mmol), N,N-diisopropylethylamine (606.12 mg, 4.69 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added sequentially. The reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 16-8C. MS m / z = 361.0 [M + H] + .

[0634] Referring to step 7, compound 16-8D was obtained by using compound 16-7D as the starting material instead of compound 16-7C. MS m / z = 361.0 [M + H] + .

[0635] Process 8

[0636] Compound 16-8C (150 mg, 0.42 mmol) was dissolved in anhydrous methanol (3 mL). The mixture was cooled to 0°C, and sodium borohydride (50 mg, 1.25 mmol) and sodium methoxide / methanol solution (7.49 mg, 41.62 μmol, 30% purity) were added sequentially. The reaction mixture was stirred at room temperature for 8 hours. The reaction was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL x 3). The extracted organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 16-9C. MS m / z = 333.3 [M + H] + .

[0637] Referring to step 8, compound 16-9D was obtained by using compound 16-8D as the starting material instead of compound 16-8C. MS m / z = 333.3 [M + H] + .

[0638] Process 9

[0639] Compound 16-9C (0.10 g, 0.30 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL) and cooled to 0°C. Sodium hydride (60.16 mg, 1.50 mmol, 60% purity) was added. After stirring at 0°C for 30 minutes, compound 4-2 (264.70 mg, 0.30 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aqueous solution of ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL x 3). The extracted organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 16-10C. MS m / z = 1132.5 [M + H] + .

[0640] Referring to step 9, compound 16-10D was obtained by using compound 16-9D as the starting material instead of compound 16-9C. MS m / z = 1132.5 [M + H] + .

[0641] Step 11

[0642] Compound 16-10C (0.20 g, 0.18 mmol) was added to trifluoroacetic acid (4 mL) and stirred at 60°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Waters Xbridge, 250 × 19 mm, 5 mm; mobile phase: [water (0.1% ammonia)-acetonitrile]; gradient: (acetonitrile): 55%-70%) and lyophilized to obtain compound 16C. MS m / z = 672.5 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.16 - 5.14 (m, 1H), 4.81 - 4.78 (m, 1H), 4.67 - 4.63 (m, 1H), 4.16 - 4.13 (m, 2H), 4.09 - 4.08 (m, 1H), 3.75 - 3.72 (m, 1H), 3.54 - 3.51 (m, 3H), 3.43 - 3.40 (m, 1H), 3.28 - 3.17 (m, 3H), 3.06 - 3.03 (m, 1H), 2.91 - 2.83 (m, 2H), 2.78 - 2.72 (m, 1H), 2.12 - 2.08 (m, 2H), 2.02 - 1.91 (m, 11H), 1.76 - 1.66 (m, 2H), 1.14 (t, J = 8.0 Hz, 3H).

[0643] Compound 16-10D (0.16 g, 0.14 mmol) was added to trifluoroacetic acid (4 mL) and stirred at 60°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Waters Xbridge, 250 × 19 mm, 5 mm; mobile phase: [water (0.1% ammonia)-acetonitrile]; gradient: (acetonitrile): 55%-70%), and lyophilized to obtain compound 16D. MS m / z = 672.5 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.17 - 5.12 (m, 1H), 4.84 - 4.78 (m, 1H), 4.66 - 4.63 (m, 1H), 4.18 - 4.12 (m, 2H), 4.05 - 4.03 (m, 1H), 3.74 - 3.71 (m, 1H), 3.53 - 3.50 (m, 3H), 3.43 - 3.40 (m, 1H), 3.28 - 3.17 (m, 3H), 3.05 - 3.02 (m, 1H), 2.92 - 2.82 (m, 2H), 2.78 - 2.71 (m, 1H), 2.13 - 2.07 (m, 2H), 2.01-1.82 (m, 11H), 1.76 - 1.66 (m, 2H), 1.14 (t, J = 8.0 Hz, 3H).

[0644] It was confirmed that 16C and 16D have the following structures. [ka] Example 17 [ka]

[0645] Process 1

[0646] Compound 16-7C (0.90 g, 4.22 mmol) was dissolved in N,N-dimethylformamide (10 mL). N,N-diisopropylethylamine (2.73 g, 21.10 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.21 g, 8.44 mmol), and morpholine (735.43 mg, 8.44 mmol) were added sequentially. The mixture was reacted at 25°C for 12 hours. Water (10 mL) was added to the reaction solution, and then it was extracted with ethyl acetate (20 mL x 3). The extracted organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 17-1C. MS m / z = 283.2 [M + H] + .

[0647] Referring to step 1, compound 17-1D was obtained by using compound 16-7D as the starting material instead of compound 16-7C. MS m / z = 283.2 [M + H] + .

[0648] Process 2

[0649] Compound 17-1C (20.00 mg, 70.84 μmol) was dissolved in methanol (0.5 mL). Sodium methoxide (38.27 μg, 0.71 μmol) and sodium borohydride (8.04 mg, 212.51 μmol) were added at 0°C, and the reaction was carried out at 25°C for 16 hours. The reaction was quenched by adding saturated ammonium chloride (10 mL). The product was extracted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 17-2C. MS m / z = 255.3 [M + H] + .

[0650] Referring to step 2, compound 17-2D was obtained by using compound 17-1D as the starting material instead of compound 17-1C. MS m / z = 255.3 [M + H] + .

[0651] Process 3

[0652] Compound 17-2C (66.00 mg, 259.51 μmol) was dissolved in tetrahydrofuran (10 mL). Sodium hydride (31.14 mg, 1.30 mmol, 60% purity) was added at 0°C and the mixture was stirred for 0.5 hours. Finally, compound 4-2 (228.36 mg, 259.51 μmol) was added and the mixture was reacted at 25°C for 2 hours. The reaction was quenched by adding water (10 mL), and the mixture was extracted with ethyl acetate (20 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 0:1) to obtain compound 17-3C. MS m / z = 1054.9 [M + H] + .

[0653] Referring to step 3, compound 17-3D was obtained by using compound 17-2D as the starting material instead of compound 17-2C. MS m / z = 1054.9 [M + H] + .

[0654] Process 4

[0655] Compound 17-3C (0.20 g, 189.72 μmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The mixture was reacted at 25°C for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Waters SunFire, 250 × 19 mm, 5 μm; mobile phase: [water (0.1% formic acid)-acetonitrile]; gradient: (acetonitrile): 40%-75%), and lyophilized to obtain the formate of compound 17C. MS m / z = 714.6 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.29 (s, 1H), 6.91 (d, J = 8.0 Hz, 1H), 5.18 (dd, J = 8.0, 4.0 Hz, 1H), 4.82 (s, 1H), 4.71 (d, J = 16.0 Hz, 1H), 4.30 - 4.22 (m, 3H), 4.12 (d, J = 12.0 Hz, 2H), 4.04 (dd, J = 12.0, 4.0 Hz, 1H), 3.78 - 3.57 (m, 9H), 3.52 - 3.46 (m, 1H), 3.25 (d, J = 12.0Hz, 2H), 2.94 - 2.87 (m, 2H), 2.76 - 2.70 (m, 1H), 2.31 - 2.24 (m, 2H), 2.12 - 2.09 (m, 3H), 2.02 (s, 3H), 1.99 - 1.83 (m, 6H), 1.74 - 1.66 (m, 1H).

[0656] Compound 17-3D (0.10 g, 94.86 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at 25°C for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Waters Xbridge, 250*19 mm, 5 mm; mobile phase: [water (0.1% ammonia)-acetonitrile]; gradient: (acetonitrile): 55%-70%), and lyophilized to obtain compound 17D. MS m / z = 714.6 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.14 (dd, J = 12.0,4.0 Hz, 1H), 4.80 (d, J = 12.0 Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.37 (d, J = 8.0 Hz, 1H), 4.11 - 4.05 (m, 2H), 3.80 - 3.76 (m, 1H), 3.74 - 3.60 (m, 4H), 3.58 - 3.48 (m, 6H), 3.42 - 3.39 (m, 2H), 3.21 (dd, J = 16.0, 12.0 Hz, 1H), 3.03 (d, J = 12 Hz, 1H), 2.87 - 2.76 (m, 2H), 2.58 - 2.52 (m, 1H), 2.22 - 2.11 (m, 1H), 2.01 - 1.98 (m, 5H), 1.94 - 1.88 (m, 1H), 1.85 - 1.80 (m, 4H), 1.79-1.66 (m, 3H), 1.61-1.54 (m, 1H).

[0657] Compounds 17C and 17D were confirmed to have the following structures. [ka] Example 18 [ka]

[0658] Process 1

[0659] Compound 16-7C (0.15 g, 703.47 μmol) was dissolved in dichloromethane (10 mL). N,N-diisopropylethylamine (3.52 mmol, 612.65 μL), N-(2,4-dimethoxybenzyl)-2-methoxyethylamine (316.96 mg, 1.41 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (534.96 mg, 1.41 mmol) were added. The mixture was reacted at 25°C for 1 hour. The organic phase was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 18-1C. MS m / z = 421.4 [M + H] + .

[0660] Referring to step 1, compound 18-1D was obtained by using compound 16-7D as the starting material instead of compound 16-7C. MS m / z = 421.4 [M + H] + .

[0661] Process 2

[0662] Compound 18-1C (0.27 g, 642.10 μmol) was dissolved in tetrahydrofuran (3 mL), and sodium borohydride (485.84 mg, 12.84 mmol) and lithium chloride (27.22 mg, 642.10 μmol) were added. The mixture was reacted at 50°C for 16 hours. After cooling to room temperature, the reaction was quenched with water (3 mL). The mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and concentrated under reduced pressure to obtain compound 18-2C. MS m / z = 393.3 [M + H] + .

[0663] Referring to step 2, compound 18-2D was obtained by using compound 18-1D as the starting material instead of compound 18-1C. MS m / z = 393.3 [M + H] + .

[0664] Process 3

[0665] Compound 18-2C (0.18 g, 321.03 μmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0°C. Sodium hydride (17.12 mg, 428.04 μmol, 60% purity) was added and the mixture was reacted at 0°C for 0.5 hours. Compound 4-2 (188.33 mg, 214.02 μmol) was added and the mixture was reacted at 25°C for 0.5 hours. The reaction was quenched with saturated ammonium chloride aqueous solution (15 mL) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, concentrated under reduced pressure, and separated by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 18-3C. MS m / z = 1192.8 [M + H] + .

[0666] Referring to step 3, compound 18-3D was obtained by using compound 18-2D as the starting material instead of compound 18-2C. MS m / z = 1192.8 [M + H] + .

[0667] Process 4

[0668] Compound 18-3C (0.20 g, 167.74 μmol) was dissolved in trifluoroacetic acid (10 mL) and reacted at 50°C for 0.5 hours. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then separated by preparative HPLC (chromatographic column: Waters Xbridge, 250 × 19 mm, 5 mm; mobile phase: water (0.1% ammonia)-acetonitrile; gradient: acetonitrile: 55%-70%). After lyophilization, compound 18C was obtained. MS m / z = 702.6 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.15 (dd, J = 12.0, 4.0 Hz, 1H), 4.78 (s, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.17 - 4.06 (m, 3H), 3.77 (dd, J = 8.0, 4.0 Hz, 1H), 3.53 (d, J = 12.0 Hz, 3H), 3.49 - 3.36 (m, 5H), 3.34 (s, 3H), 3.21 (dd, J = 16.0, 12.0 Hz, 1H), 3.04 (d, J = 12.0 Hz, 1H), 2.95 - 2.91 (m, 1H), 2.85 (dd, J = 16.0, 4.0 Hz, 1H), 2.78 - 2.69 (m, 1H), 2.13 - 2.06 (m, 2H), 2.04 - 1.96 (m, 5H), 1.94 - 1.89 (m, 4H), 1.85 - 1.82 (m, 2H), 1.76 - 1.66 (m, 2H).

[0669] Compound 18-3D (0.15 g, 125.80 μmol) was weighed. Dichloromethane (2.5 mL) and trifluoroacetic acid (2.5 mL) were added, and the mixture was reacted at 25°C for 0.5 hours. The organic phase was concentrated under reduced pressure, and the crude product was separated by preparative HPLC (chromatographic column: Waters Xbridge, 250 × 19 mm, 5 mm; mobile phase: [water (0.1% ammonia)-acetonitrile]; gradient: (acetonitrile): 55%-70%). After lyophilization, compound 18D was obtained. MS m / z = 702.6 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.15 (dd, J = 12.0, 4.0 Hz, 1H), 4.78 (s, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.15 (t, J = 12.0 Hz, 2H), 4.05 (d, J = 12.0 Hz, 1H), 3.78 - 3.75 (m, 1H), 3.53 (d, J = 8.0 Hz, 3H), 3.49 - 3.36 (m, 5H), 3.34 (s, 3H), 3.21 (dd, J = 16.0, 12.0Hz, 1H), 3.04 (d, J = 12.0 Hz, 1H), 2.95 - 2.90 (m, 1H), 2.84 (dd, J = 16.0, 4.0 Hz, 1H), 2.76 - 2.70 (m, 1H), 2.15 - 2.07 (m, 2H), 2.01 - 1.94 (m, 5H),1.95 - 1.87 (m, 4H), 1.86-1.80 (m, 2H), 1.76-1.66 (m, 2H).

[0670] Compounds 18C and 18D were confirmed to have the following structures. [ka] Example 19 [ka]

[0671] Process 1

[0672] Compound 16-7C (0.40 g, 1.86 mol) was weighed and dichloromethane (6 mL) was added. Isopropylamine (166.33 mg, 2.81 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.43 g, 3.75 mmol), and N,N-diisopropylethylamine (0.73 g, 5.63 mol) were also added. The mixture was reacted at 25°C for 3 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was concentrated under reduced pressure to obtain compound 19-1C. MS m / z = 255.0 [M + H] + .

[0673] Referring to Step 1, compound 19-1D was obtained by using compound 16-7D as the starting material instead of compound 16-7C. MS m / z = 255.0 [M + H] + .

[0674] Process 2

[0675] Compound 19-1C (0.10 g, 0.39 mmol) was weighed and anhydrous tetrahydrofuran (3 mL) was added under nitrogen. The mixture was cooled to 0°C and lithium aluminum tetrahydrogen solution in tetrahydrofuran (1.18 mmol, 0.47 ml, 2.5 M) was added. The mixture was reacted at 25°C for 15 minutes. At 0°C, the reaction was quenched by adding 0.2 mL of water to the reaction solution and then 0.2 mL of 15% NaOH solution. The reaction mixture was stirred for 10 minutes and filtered. The filtrate was washed with 5 mL of tetrahydrofuran. The filtrate was concentrated to obtain compound 19-2C. MS m / z = 227.1 [M + H] +

[0676] Referring to step 2, compound 19-2D was obtained by using compound 19-1D as the starting material instead of compound 19-1C. MS m / z = 227.1 [M + H] + .

[0677] Process 3

[0678] Compound 19-2C (50.0 mg, 0.22 mmol) was weighed and anhydrous tetrahydrofuran (5 mL) was added. Sodium hydride (15.91 mg, 0.66 mmol, 60%) was added under ice bath at 0°C. The mixture was stirred at 25°C for 30 minutes and compound 4-2 (0.20 g, 0.22 mmol) was added. The reaction mixture was reacted at 25°C for 1 hour. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 19-3C. MS m / z = 1026.8 [M + H] + .

[0679] Referring to step 3, compound 19-3D was obtained by using compound 19-2D as the starting material instead of compound 19-2C. MS m / z = 1026.8 [M + H] + .

[0680] Process 4

[0681] Compound 19-3C (50 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was reacted at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Waters SunFire, 250 × 19 mm, 5 μm; mobile phase: [water (0.05% formic acid)-acetonitrile]; (acetonitrile): 45%-75%), and lyophilized to obtain the formate of compound 19C. MS m / z = 686.5 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.45 (s, 1.52 H), 6.91 (d, J = 8.4 Hz, 1 H), 5.20 - 5.16 (m, 1 H), 4.84 - 4.79 (m, 1 H), 4.70 (d, J = 13.7 Hz, 1 H), 4.33 (d, J = 11.2 Hz, 1 H), 4.26 - 4.10 (m, 2 H), 4.08 - 3.97 (m, 4 H), 3.76 - 3.73 (m, 1 H), 3.58 (d, J = 13.4 Hz, 1 H), 3.27 - 3.21 (m, 3 H), 3.03 - 3.01 (m, 1 H), 2.93 - 2.88 (m, 1 H), 2.26 - 2.06 (m, 8 H), 2.01 - 1.94 (m, 5 H), 1.92 - 1.87 (m, 2 H), 1.17 (dd, J = 6.6, 1.5 Hz, 6 H).

[0682] Compound 19-3D (50 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was reacted at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Waters SunFire, 250 × 19 mm, 5 μm; mobile phase: [water (0.05% formic acid)-acetonitrile]; (acetonitrile): 45%-75%), and lyophilized to obtain the formate of compound 19D. MS m / z = 686.5 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.36 (s, 1.59 H), 6.81 (d, J = 8.4 Hz, 1 H), 5.10 - 5.07 (m, 1 H), 4.81 - 4.78 (m, 1 H), 4.61 (d, J = 13.6 Hz, 1 H), 4.22 - 4.08 (m, 3 H), 3.94 - 3.88 (m, 4 H), 3.63 (d, J = 13.6 Hz, 1 H), 3.48 (d, J = 13.2 Hz, 1 H), 3.17 - 3.03 (m, 3 H), 2.91 - 2.78 (m, 2 H), 2.15 - 1.99 (m, 6 H), 1.98 - 1.92 (m, 6 H), 1.84 - 1.76 (m, 3 H), 1.07 (d, J = 6.6 Hz, 6 H).

[0683] Compounds 19C and 19D were confirmed to have the following structures. [ka] Example 20 [ka]

[0684] Process 1

[0685] Compound 16-7C (100 mg, 468.98 μmol) was dissolved in N,N-dimethylformamide (2 mL). 2-Chloro-1-methylpyridinium iodide (179.72 mg, 703.47 μmol), triethylamine (142.37 mg, 1.41 mmol), and tert-butylamine (51.45 mg, 703.47 μmol) were added, and the mixture was reacted at 25°C for 2 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The extracted organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 20-1C was obtained by separation by column chromatography (petroleum ether:ethyl acetate = 1:1). MS m / z = 269.0 [M + H] + .

[0686] Referring to Step 1, compound 20-1D was obtained by using compound 16-7D as the starting material instead of compound 16-7C. MS m / z = 269.0 [M + H] + .

[0687] Process 2

[0688] Compound 20-1C (300 mg, 1.12 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and cooled to 0°C under nitrogen. A 2 M solution of lithium borohydride in tetrahydrofuran (1.12 mL) was added dropwise, and the mixture was heated to 50°C with stirring for 8 hours. The reaction was quenched by adding 3 mL of water, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 20-2C. MS m / z = 241.1 [M + H] + .

[0689] Referring to step 2, compound 20-2D was obtained by using compound 20-1D as the starting material instead of compound 20-1C. MS m / z = 241.1 [M + H] + .

[0690] Process 3

[0691] Compound 20-2C (81.90 mg, 340.93 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and cooled to 0°C. Sodium hydride (20.50 mg, 853.75 μmol, 60% purity) was slowly added, and the mixture was heated to 25°C with stirring for 0.5 hours. Compound 4-2 (200 mg, 227.28 μmol) was then added, and the mixture was reacted at 25°C for 2 hours. The reaction was quenched by adding 3 mL of water, and the mixture was extracted with ethyl acetate (5 mL x 3). The extracted organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 20-3C was obtained by separation by column chromatography (petroleum ether:ethyl acetate = 1:1). MS m / z = 1040.8 [M + H] + .

[0692] Referring to step 3, compound 20-3D was obtained by using compound 20-2D as the starting material instead of compound 20-2C. MS m / z = 1040.8 [M + H] + .

[0693] Process 4

[0694] Compound 20-3C (100 mg, 96.14 μmol) was dissolved in anhydrous dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was reacted at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Xtimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% formic acid)-acetonitrile]; acetonitrile: 10%-40%), and lyophilized to obtain the formate of compound 20C. MS m / z = 700.6 [M + H] + , 1 H NMR (400 MHz, CD3OD) δ ppm 8.51 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.20 - 5.15 (m, 1H), 4.82 (d, J = 13.6 Hz, 1H), 4.69 (d, J = 13.6 Hz, 1H), 4.27 - 4.14 (m, 3H), 3.88 (s, 3H), 3.68 (d, J = 13.2 Hz, 1H), 3.54 (d, J = 13.2 Hz, 1H), 3.28 - 3.15 (m, 2H), 3.10 - 3.04 (m, 1H), 2.95 - 2.86 (m, 2H), 2.21 - 2.12 (m, 3H), 2.02 - 1.76 (m, 12H), 1.36 (s, 9H).

[0695] Compound 20-3D (150 mg, 144.21 μmol) was dissolved in dichloromethane (4.5 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Xtimate C18 150*40 mm*5 μm; mobile phase: [water (0.1% ammonium bicarbonate)-acetonitrile]; (acetonitrile): 35%-53%), and lyophilized to obtain compound 20D. MS m / z = 700.6 [M + H] + , 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.4 Hz, 1H), 5.17 - 5.12 (m, 1H), 4.80 (d, J = 13.6 Hz, 1H), 4.65 (d, J = 13.6 Hz, 1H), 4.18 - 4.12 (m, 2H), 4.05 (d, J = 16.0 Hz, 1H), 3.71 - 3.68 (m, 1H), 3.54 - 3.51 (m, 3H), 3.43 - 3.40 (m, 1H), 3.25 - 3.18 (m, 1H), 3.04 (d, J = 16.0Hz, 1H), 2.93 - 2.71 (m, 3H), 2.14 - 2.09 (m, 2H), 2.06 - 2.01 (m, 4H), 1.92-1.83 (m, 7H), 1.74 - 1.96 (m, 2H), 1.35 (s, 9H).

[0696] Compounds 20C and 20D were confirmed to have the following structures. [ka] Example 21 [ka]

[0697] Process 1

[0698] Compound 16-7C (150 mg, 703.47 μmol) was dissolved in N,N-dimethylformamide (2 mL). 4-aminotetrahydrofuran (106.73 mg, 1.06 mmol), N-methylimidazole (173.27 mg, 2.11 μmol), and tetramethylchlorouronium hexafluorophosphate (296.07 mg, 1.06 mmol) were added, and the mixture was reacted at 25°C for 3 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The extracted organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Separation by column chromatography (dichloromethane:methanol = 20:1) yielded compound 21-1C. MS m / z = 297.1 [M + H] + .

[0699] Referring to Step 1, compound 21-1D was obtained by using compound 16-7D as the starting material instead of compound 16-7C. MS m / z = 297.1 [M + H] + .

[0700] Process 2

[0701] Compound 21-1C (300 mg, 1.01 mmol) was dissolved in anhydrous methanol (5 mL). Sodium methoxide (21.90 mg, 404.91 μmol) and sodium borohydride (191.50 mg, 5.06 mmol) were added, and the mixture was reacted at 50°C for 24 hours. The reaction was quenched by adding 3 mL of saturated ammonium chloride aqueous solution. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 21-2C was obtained by separation by column chromatography (dichloromethane:methanol = 10:1). MS m / z = 269.2 268.5 [M + H] + .

[0702] Referring to step 2, compound 21-2D was obtained by using compound 21-1D as the starting material instead of compound 21-1C. MS m / z = 269.2 [M + H] + .

[0703] Process 3

[0704] Compound 21-2C (100 mg, 372.65 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and cooled to 0°C. Sodium hydride (44.70 mg, 1.12 mmol, 60% purity) was slowly added. The mixture was heated to 25°C and stirred for 0.5 hours. Compound 4-2 (163.90 mg, 186.32 μmol) was then added and the mixture was reacted at 25°C for 2 hours. The reaction was quenched by adding 3 mL of water and extracted with ethyl acetate (5 mL x 3). The extracted organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 21-3C was obtained by separation by column chromatography (dichloromethane:methanol = 20:1). MS m / z = 1068.5 [M + H] + .

[0705] Referring to step 3, compound 21-3D was obtained by using compound 21-2D as the starting material instead of compound 21-2C. MS m / z = 1068.5 [M + H] + .

[0706] Process 4

[0707] Compound 21-3C (114 mg, 106.72 μmol) was dissolved in anhydrous dichloromethane (0.9 mL), and trifluoroacetic acid (0.3 mL) was added. The mixture was reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatography column: Xtimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% formic acid)-acetonitrile]; (acetonitrile): 10%-60%), and lyophilized to obtain the formate of compound 21C. MS m / z = 728.5 [M + H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (s, 1.38H), 7.97 (d, J = 7.7 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.02 (s, 2H), 5.05 - 5.01 (m, 1H), 4.75 (d, J = 13.7 Hz, 1H), 4.57 (d, J = 13.7 Hz, 1H), 3.94 - 3.90 (m, 3H), 3.83 - 3.79 (m, 3H), 3.64 (s, 2H), 3.54 - 3.51 (m, 1H), 3.44 - 3.41 (m, 1H), 3.35 - 3.30 (m, 4H), 3.09 - 3.02 (m, 1H), 2.98 (d, J = 12.5 Hz, 1H), 2.82 - 2.77 (m, 1H), 2.75 - 2.70 (m, 1H), 2.66 - 2.59 (m, 1H), 2.03 (s, 3H), 1.97 - 1.80 (m, 6H), 1.80 - 1.52 (m, 8H), 1.47 - 1.37 (m, 2H).

[0708] Compound 21-3D (200 mg, 187.23 μmol) was dissolved in anhydrous dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The mixture was reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Xtimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% formic acid)-acetonitrile]; (acetonitrile): 10%-60%), and lyophilized to obtain the formate of compound 21D. MS m / z = 728.5 [M + H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (s, 0.56H), 7.96 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.01 (s, 2H), 5.04 - 5.00 (m, 1H), 4.74 (d, J = 13.7 Hz, 1H), 4.54 (d, J = 13.7 Hz, 1H), 4.05 - 3.92 (m, 4H), 3.85 - 3.79 (m, 4H), 3.64 - 3.51 (m, 2H), 3.46 (d, J = 13.3 Hz, 1H), 3.40 - 3.35 (m, 3H), 3.14 - 3.06 (m, 2H), 2.87 - 2.68 (m, 2H), 2.67 - 2.52 (m, 1H), 2.03 (s, 3H), 1.91 - 1.53 (m, 14H), 1.46 - 1.38 (m, 2H).

[0709] Compounds 21C and 21D were confirmed to have the following structures. [ka] Example 22 [ka]

[0710] Process 1

[0711] 2,4-Dimethoxybenzaldehyde (500 mg, 3.01 mmol) was added to anhydrous tetrahydrofuran (5 mL), followed by the addition of cyclopropylamine (6.02 mmol, 416.97 μL) and glacial acetic acid (18.00 mg, 300.89 μmol). The mixture was reacted at 25°C for 2 hours. Sodium borohydride (567.20 mg, 9.03 mmol) was added to the reaction system, and the mixture was stirred at 25°C for 16 hours. The mixture was quenched with water (5 mL) and extracted with dichloromethane (10 mL x 3). The extracted organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 22-1C. MS m / z = 208.2 [M + H] + .

[0712] Process 2

[0713] Compound 16-7C (140 mg, 656.56 μmol) was dissolved in anhydrous dichloromethane (6 mL). N,N-diisopropylethylamine (3.28 mmol, 571.80 μL), compound 22-1C (176.90 mg, 853.54 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (499.31 mg, 1313.14 μmol) were added. The reaction was allowed to proceed at 25°C for 16 hours. The mixture was quenched by adding water (5 mL) and extracted with ethyl acetate (10 mL x 3). The extracted organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 22-2C. MS m / z = 403.2[M+H] + .

[0714] Referring to step 2, compound 22-2D was obtained by using compound 16-7D as the starting material instead of compound 16-7C. MS m / z = 403.2 [M + H] + .

[0715] Process 3

[0716] Compound 22-2C (170 mg, 422.38 μmol) was dissolved in anhydrous tetrahydrofuran (3 mL) and anhydrous methanol (3 mL). Sodium borohydride (79.90 mg, 2.11 mmol) and lithium chloride (17.90 mg, 422.38 μmol) were added, and the mixture was reacted at 50°C for 2 hours. The mixture was quenched by adding water (0.5 mL) and filtered. The filtrate was concentrated under reduced pressure to obtain compound 22-3C. MS m / z = 375.2 [M + H] + .

[0717] Referring to step 3, compound 22-3D was obtained by using compound 22-2D as the starting material instead of compound 22-2C. MS m / z = 375.2 [M + H] + .

[0718] Process 4

[0719] Compound 22-3C (104 mg, 277.72 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and sodium hydride (33.30 mg, 833.17 μmol, 60% purity) was added. The mixture was reacted at 0°C for 0.5 hours. Then, compound 4-2 (150.00 mg, 170.46 μmol) was added, and the mixture was reacted at 25°C for 1 hour. The mixture was quenched by adding saturated ammonium chloride aqueous solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The extracted organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 22-4C. MS m / z = 1174.5 [M + H] + .

[0720] Referring to step 4, compound 22-4D was obtained by using compound 22-3D as the starting material instead of compound 22-3C. MS m / z = 1174.5 [M + H] + .

[0721] Process 5

[0722] Compound 22-4C (150.00 mg, 127.73 μmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 50°C for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was separated by preparative HPLC (chromatographic column: Xtimate C18 150*40 mm*5 μm; mobile phase: [water (0.1% ammonia)-acetonitrile]; gradient: (acetonitrile): 35%-60%) and lyophilized to obtain compound 22C. MS m / z = 684.6 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.4 Hz, 1H), 5.14 (dd, J = 11.6 Hz, 4.8 Hz, 1H), 4.79 (d, J = 13.6 Hz, 1H), 4.64 (d, J = 13.6 Hz, 1H), 4.14 - 4.04 (m, 3H), 3.68 (dd, J = 8.0 Hz, 5.2 Hz, 1H), 3.52 - 3.49 (m, 3H), 3.42 - 3.38 (m, 1H), 3.21 (dd, J = 17.6 Hz, 11.2 Hz, 1H), 3.03 (d, J = 12.4 Hz, 1H), 2.88 - 2.84 (m, 2H), 2.73 - 2.65 (m, 2H), 2.11 - 2.05 (m, 2H), 2.01 - 1.97 (m, 5H), 1.94 - 1.81 (m, 6H), 1.76 - 1.64 (m, 2H), 0.75 - 0.71 (m, 2H), 0.53 - 0.48 (m, 2H).

[0723] Compound 22-4D (100.00 mg, 85.16 μmol) was dissolved in trifluoroacetic acid (3 mL) and reacted at 50°C for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was separated by preparative high-performance liquid chromatography (chromatography column: Xtimate C18 150*40 mm*5 μm; mobile phase: [water (0.1% ammonia)-acetonitrile]; gradient: (acetonitrile): 35%-70%). The mixture was then lyophilized to obtain compound 22D. MS m / z = 684.5 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.4 Hz, 1H), 5.14 (dd, J = 11.6, 4.8 Hz, 1H), 4.79 (d, J = 13.6 Hz, 1H), 4.64 (d, J = 13.6 Hz, 1H), 4.16 - 4.12 (m, 2H), 4.03 (d, J = 10.4 Hz, 1H), 3.68 (dd, J = 8.0 Hz, 5.2 Hz, 1H), 3.53 - 3.50 (m, 3H), 3.42 - 3.39 (m, 1H), 3.21 (dd, J = 17.6 Hz, 11.2 Hz, 1H), 3.03 (d, J = 12.4 Hz, 1H), 2.88 - 2.81 (m, 2H), 2.78 - 2.66 (m, 2H), 2.12 - 2.06 (m, 2H), 2.01 - 1.97 (m, 5H), 1.95 - 1.81 (m, 6H), 1.77 - 1.66 (m, 2H), 0.76 - 0.72 (m, 2H), 0.52 - 0.48 (m, 2H).

[0724] Compounds 22C and 22D were confirmed to have the following structures. [ka] Example 23 [ka]

[0725] Process 1

[0726] Compound 16-7C (0.20 g, 937.96 μmol) was dissolved in dimethylformamide (2 mL). N,N-diisopropylethylamine (606.12 mg, 4.69 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (713.28 mg, 1.88 mmol), and N-[(2,4-dimethoxyphenyl)methyl]cyclobutanamine (207.56 mg, 937.96 μmol) were added sequentially. The mixture was reacted at 25°C for 12 hours. Water (10 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL x 3). The mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 23-1C. MS m / z = 417.4 [M + H] +

[0727] Referring to Step 1, compound 23-1D was obtained by using compound 16-7D as the starting material instead of compound 16-7C. MS m / z = 417.4 [M + H] + .

[0728] Process 2

[0729] Compound 23-1C (0.20 g, 480.18 μmol) was dissolved in methanol (2 mL). Sodium methoxide (2.59 mg, 48.02 μmol) and sodium borohydride (90.83 mg, 2.40 mmol) were added at 0°C, and the mixture was reacted at 25°C for 16 hours. The reaction was quenched by adding saturated ammonium chloride (10 mL), and the mixture was extracted with ethyl acetate (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 23-2C. MS m / z = 389.3 [M + H] +

[0730] Referring to step 2, compound 23-2D was obtained by using compound 23-1D as the starting material instead of compound 23-1C. MS m / z = 389.3 [M + H]+ .

[0731] Process 3

[0732] Compound 23-2C (50.00 mg, 128.70 μmol) was dissolved in tetrahydrofuran (1 mL). Sodium hydride (51.48 mg, 1.29 mmol, 60% purity) was added at 0°C and the mixture was stirred for 0.5 hours. Finally, compound 4-2 (113.25 mg, 128.70 μmol) was added, and the mixture was reacted at 25°C for 2 hours. The reaction was quenched by adding water (10 mL), and the mixture was extracted with ethyl acetate (20 mL). The mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 0:1) to obtain compound 23-3C. MS m / z = 1188.7 [M + H] + .

[0733] Referring to step 3, compound 23-3D was obtained by using compound 23-2D as the starting material instead of compound 23-2C. MS m / z = 1188.7 [M + H] + .

[0734] Process 4

[0735] Compound 23-3C (17 mg, 14.31 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.3 mL) was added. The mixture was reacted at 25°C for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Waters Xbridge, 250 × 19 mm, 5 mm; mobile phase: [water (0.1% ammonia)-acetonitrile]; gradient: (acetonitrile): 55%-70%), and lyophilized to obtain compound 23C. MS m / z = 698.5 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.15 (dd, J = 12.0, 4.0 Hz, 1H), 4.84 - 4.79 (m, 1H), 4.62 (d, J = 16.0 Hz, 1H), 4.34 - 4.26 (m, 1H), 4.16 - 4.06 (m, 3H), 3.74 - 3.70 (m, 1H), 3.51 - 3.48 (m, 3H), 3.44 - 3.41 (m, 1H), 3.25 - 3.13 (m, 1H), 3.04 (d, J = 12.0Hz, 1H), 2.89 - 2.82 (m, 2H), 2.76 - 2.70 (m, 1H), 2.32 - 2.26 (m, 2H), 2.12 - 2.06 (m, 2H), 2.04 - 1.89 (m, 11H), 1.85 - 1.83 (m, 2H), 1.77 - 1.71 (m, 4H).

[0736] Compound 23-3D (40 mg, 33.66 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at 25°C for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (Waters Xbridge, 250 × 19 mm, 5 mm; mobile phase: [water (0.1% ammonia)-acetonitrile]; gradient: (acetonitrile): 55%-70%), and lyophilized to obtain compound 23D. MS m / z = 698.5 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.15 (dd, J = 12.0, 4.0 Hz, 1H), 4.83 - 4.78 (m, 1H), 4.65 (d, J = 16.0 Hz, 1H), 4.34 - 4.26 (m, 1H), 4.18 - 4.12 (m, 2H), 4.04 (d, J = 8.0 Hz, 1 H), 3.73 - 3.69 (m, 1H), 3.53 (d, J = 12.0 Hz, 3H), 3.43 - 3.41 (d, J = 8.0 Hz, 1H), 3.25 - 3.18 (m, 1H), 3.04 (d, J = 12.0 Hz, 1H), 2.91 - 2.82 (m, 2H), 2.76-2.70 (m, 1H), 2.33 - 2.26 (m, 2H), 2.11 - 2.07 (m, 2H), 2.01 - 1.90 (m, 11H), 1.85 - 1.83 (m, 2H), 1.78-1.68 (m, 4H).

[0737] Compounds 23C and 23D were confirmed to have the following structures. [ka] Example 24 [ka]

[0738] Process 1

[0739] Compound 4-1 (280 mg, 0.33 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (376 mg, 3.30 mmol) was added. The resulting reaction solution was stirred under nitrogen at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure, and 3 mL of ethyl acetate was added to the residue. Then, hydrogen chloride / ethyl acetate solution (4 M, 1 mL) was added. The reaction mixture was stirred at 25°C for 1 hour, and the mixture was concentrated under reduced pressure to obtain the hydrochloride salt of compound 24-1.

[0740] Process 2

[0741] 160 mg of the hydrochloride salt of compound 24-1 and triethylamine (159.50 mg, 1.58 mol) were added to dichloromethane (5 mL). Then, di-tert-butyl dicarbonate (1.38 g, 6.30 mmol) and 4-dimethylaminopyridine (38.51 mg, 0.33 mmol) were added. The resulting reaction mixture was stirred under nitrogen at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 24-2. MS m / z = 808.6 [M + H] + .

[0742] Process 3

[0743] Compound 24-2 (240 mg, 0.30 mmol) was dissolved in tetrahydrofuran (5 mL), and m-chloroperbenzoic acid (61.52 mg, 0.35 mmol, 85% purity) was added. The resulting reaction mixture was stirred under nitrogen at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 24-3. MS m / z = 824.5 [M + H] + .

[0744] Process 4

[0745] Compound 16-7C (180 mg, 0.84 mmol) was dissolved in N,N-dimethylformamide (4 mL). Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (641.95 mg, 1.69 mmol) and N,N-diisopropylethylamine (218.42 mg, 1.69 mmol) were added, and the reaction mixture was stirred at 25°C for 30 minutes. 3-Oxetanamine hydrochloride (92.09 mg, 1.26 mmol) was added to the mixture, and the resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 24-4C was obtained by separation by column chromatography (dichloromethane:methanol = 20:1). MS m / z = 269.18 [M + H] + .

[0746] Referring to step 4, compound 24-4D was obtained by using compound 16-7D as the starting material instead of compound 16-7C. MS m / z = 269.18 [M + H] + .

[0747] Process 5

[0748] Compound 24-4C (100 mg, 0.37 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium borohydride (69.98 mg, 1.85 mmol) and lithium chloride (78.42 mg, 1.85 mmol) were added. The mixture was reacted under nitrogen at 25°C for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 24-5C was obtained by separation by column chromatography (dichloromethane:methanol = 10:1). MS m / z = 241.22 [M + H] + .

[0749] Referring to step 5, compound 24-5D was obtained by using compound 24-4D as the starting material instead of compound 24-4C. MS m / z = 241.22 [M + H] + .

[0750] Process 6

[0751] Compound 24-5C (70 mg, 0.29 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of sodium hydride (12 mg, 0.29 mmol, 60% purity). The reaction mixture was stirred under nitrogen at 25°C for 0.5 hours. Next, a solution of compound 24-3 (210 mg, 0.29 mmol) in tetrahydrofuran (1 mL) was added. After the addition, the reaction mixture was stirred at 25°C for 2 hours. The reaction solution was dissolved in 10 mL of ethyl acetate and washed with saturated brine (5 mL). The organic phase was dried and filtered. The filtrate was concentrated under reduced pressure. Compound 24-6C was obtained by separation by column chromatography (dichloromethane:methanol = 20:1). MS m / z = 900.6 [M-100+1] + .

[0752] Referring to step 6, compound 24-6D was obtained by using compound 24-5D as the starting material instead of compound 24-5C. MS m / z = 900.6 [M-100+1] + .

[0753] Process 7

[0754] Compound 24-6C (10 mg, 10.00 μmol) was dissolved in dichloromethane (3 mL), followed by the addition of zinc bromide (5 mg, 20.00 μmol). The mixture was stirred under nitrogen at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Waters SunFire, 250 × 19 mm, 5 μm; mobile phase: [water (0.1% formic acid)-acetonitrile]; (acetonitrile): 10%-40%), and lyophilized to obtain the formate of compound 24C. MS m / z = 700.4 [M + H] + , 1 H NMR (400 MHz, CD3OD) δ ppm 8.39 (s, 2H), 6.92 (d, J = 8.4 Hz, 1H), 5.19 (dd, J = 11.2, 4.4 Hz, 1H), 4.94 (q, J = 6.4 Hz, 1H), 4.88 (d, J = 6.8 Hz, 3H), 4.72 (d, J = 13.8 Hz, 1H), 4.59 (q, J = 5.8 Hz, 2H), 4.41 (d, J = 6.8 Hz, 3H), 4.27 (d, J = 13.8 Hz, 1H), 4.11 (d, J = 12.8 Hz, 2H), 3.78 (d, J = 13.6 Hz, 1H), 3.65 (d, J = 13.2 Hz, 1H), 3.49 - 3.36 (m, 1H), 3.27 (d, J = 11.6 Hz, 2H), 3.13 (s, 1H), 2.93 (dd, J = 18.2, 4.4 Hz, 1H), 2.37 - 2.19 (m, 5H), 2.14 - 2.05 (m, 4H), 2.03 - 1.99 (m, 4H), 1.97 - 1.91 (m, 2H).

[0755] Compound 24-6D (30 mg, 30.00 μmol) was dissolved in dichloromethane (3 mL), followed by the addition of zinc bromide (14 mg, 30.00 μmol). The mixture was stirred under nitrogen at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatography column: Waters SunFire, 250 × 19 mm, 5 μm; mobile phase: [water (0.1% formic acid)-acetonitrile]; (acetonitrile): 10%-40%), and lyophilized to obtain the formate of compound 24D. MS m / z = 700.5 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.46 (s, 3H), 6.92 (d, J = 8.4 Hz, 1H), 5.19 (dd, J = 11.0, 4.0 Hz, 1H), 4.98 - 4.92 (m, 1H), 4.91 - 4.89 (m, 2H), 4.72 (d, J = 13.6 Hz, 2H), 4.60 - 4.57 (m, 2H), 4.37 - 4.23 (m, 3H), 4.21 - 4.15 (m, 1H), 4.07 (d, J = 12.6 Hz, 2H), 3.76 (d, J = 14.6 Hz, 1H), 3.63 (d, J = 13.6 Hz, 1H), 3.27 (d, J = 13.2 Hz, 3H), 3.01 - 2.96 (m, 1H), 2.95 - 2.86 (m, 1H), 2.33 - 2.13 (m, 5H), 2.13 - 2.03 (m, 4H), 2.02 (s, 3H), 1.99 - 1.85 (m, 3H).

[0756] Compounds 24C and 24D were confirmed to have the following structures. [ka] Example 25 [ka]

[0757] Process 1

[0758] Compound 16-3 (8.00 g, 24.00 mmol) was dissolved in methanol (30 mL), and 10% palladium-carbon (1.5 g) was added. The reaction mixture was stirred under a hydrogen atmosphere at 25°C for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain compound 25-1. MS m / z = 200.2 [M + H] +

[0759] Process 2

[0760] Periodic acid (12.30 g, 53.95 mmol) was dissolved in acetonitrile (0.075% water) (50.0 mL). Chromium trioxide (647.40 mg, 6.47 mmol) was slowly added at 0°C and the mixture was stirred for 10 minutes. Compound 25-1 was dissolved in acetonitrile (50.0 mL) and slowly added to the mixture at 0°C. After addition, the mixture was slowly warmed to room temperature and stirred for 10 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 25-2. MS m / z = 214.2 [M + H] +

[0761] Process 3

[0762] Compound 25-2 (0.90 g, 4.22 mmol) was dissolved in N,N-dimethylformamide (20 mL). Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.41 g, 6.33 mmol) and N,N-diisopropylethylamine (2.73 g, 21.10 mmol) were added, and the reaction mixture was stirred at room temperature for 30 minutes. Dimethylamine hydrochloride (1.72 g, 21.10 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (35 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to preparative high-performance liquid chromatography (chromatography column: Waters Xbridge, 250*19mm, 5mm; mobile phase: [water (0.1% aqueous ammonia)-acetonitrile]; gradient: (acetonitrile): 10%-40%) to obtain compounds 25-3A and 25-3B. LC-MS analysis was performed (chromatography column: Waters Xbridge C18 (50mm × 4.6mm × 3.5μm); mobile phase: [A: water (0.1% ammonia) B: acetonitrile]; gradient: B%: 0-10%, 0.2 min; 20-95%, 1.8 min; 95-95%, 0.7 min; 95-10%, 0.1 min; 10-10%, 0.7 min). For compound 25-3A, Rt = 1.780 min, MS m / z = 241.2 [M+H]. +For compound 25-3B, Rt = 1.833 mins, MS m / z = 241.2 [M + H] + .

[0763] Process 4

[0764] Compound 25-3A (0.13 g, 540.99 μmol) was dissolved in methanol (5 mL). Sodium borohydride (61.40 mg, 1.62 mmol) and 30% sodium methoxide in methanol (2.92 mg, 54.10 μmol) were added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. After completion, the reaction was quenched with saturated ammonium chloride solution (10 mL) and extracted with dichloromethane (10 mL). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 25-4A was obtained by separation by column chromatography (dichloromethane:methanol = 10:1). MS m / z = 213.1 [M + H] + .

[0765] Referring to step 4, compound 25-4B was obtained by using compound 25-3B as the starting material instead of compound 25-3A. MS m / z = 213.1 [M + H] + .

[0766] Process 5

[0767] Compound 25-4A (50.00 mg, 235.53 μmol) was dissolved in tetrahydrofuran (2 mL) and cooled to 0°C. NaH (16.96 mg, 706.59 μmol, 60% purity) was added and the mixture was stirred for 1 hour. Compound 4-2 (50.00 mg, 235.53 μmol) was added to the above mixture and the resulting mixture was stirred at 25°C for 1 hour. The resulting mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 25-5A was obtained by separation by column chromatography (dichloromethane:methanol = 10:1). MS m / z = 10¹².8 [M + H] + .

[0768] Referring to step 5, compound 25-5B was obtained by using compound 25-4B as the starting material instead of compound 25-4A. MS m / z = 10¹² [M + H] + .

[0769] Process 6

[0770] Compound 25-5A (0.14 g, 138.32 μmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at 25°C for 1 hour. The reaction mixture was concentrated and TFA was removed. The crude product was separated by preparative HPLC (chromatographic column: Waters Xbridge, 250 × 19 mm, 5 mm; [water (0.1% ammonia)-acetonitrile]; gradient: acetonitrile: 30%-70%). Mobile phase A: water (0.1% ammonia) and B: (acetonitrile); gradient: B%=30%-70%). After lyophilization, compound 25A was obtained. MS m / z = 672.6 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.13 - 5.09 (m, 1H), 4.78 - 4.67 (m, 2H), 4.54 (d, J = 8.0 Hz, 1H), 4.35 - 4.28 (m, 1H), 4.26 - 4.23 (m, 1H), 4.13 - 4.09 (m, 1H), 3.91 - 3.88 (m, 1H), 3.27 - 3.19 (m, 2H), 3.16 - 3.10 (m, 4H), 2.94 - 2.88 (m, 4H), 2.79 - 2.66 (m, 4H), 2.22 - 2.15 (m, 2H), 2.11 - 1.89 (m, 11H), 1.78 - 1.75 (m, 1H), 1.72 - 1.66 (m, 1H).

[0771] Compound 25-5B (60.00 mg, 59.28 μmol) was dissolved in trifluoroacetic acid (1 mL) and stirred at 25°C for 1 hour. The reaction mixture was concentrated and TFA was removed. The crude product was separated by preparative HPLC (chromatographic column: Waters Xbridge, 250 × 19 mm, 5 mm; [water (0.1% ammonia)-acetonitrile]; gradient: acetonitrile: 30%-70%). Mobile phase A: water (0.1% ammonia) and B: (acetonitrile); gradient: B%=30%-70%). After lyophilization, compound 25B was obtained. MS m / z = 672.1 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.13 - 5.10 (m, 1H), 4.78 - 4.67 (m, 2H), 4.52 - 4.47 (m, 1H), 4.32 - 4.28 (m, 1H), 4.26 - 4.21 (m, 1H), 4.15 - 4.10 (m, 1H), 3.91 - 3.87 (m, 1H), 3.27 - 3.22 (m, 2H), 3.15 - 3.13 (m, 3H), 2.93 - 2.92 (m, 3H), 2.80 - 2.72 (m, 4H), 2.67 - 2.66 (m, 1H), 2.54 - 2.50 (m, 1H), 2.18 - 2.04 (m, 3H), 2.02 - 1.89 (m, 7H), 1.83 - 1.74 (m, 4H), 1.62 - 1.55 (m, 1H). Example 26 [ka]

[0772] Process 1

[0773] Compound 25-2 (1.00 g, 4.69 mmol) was dissolved in N,N-dimethylformamide (20 mL). N,N-diisopropylethylamine (2.12 g, 16.41 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.67 g, 7.03 mmol), and 2,4-dimethoxybenzylamine (1.02 g, 6.10 mmol) were added sequentially. The mixture was reacted at 25°C for 2 hours. Water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (40 mL x 3). The mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 2:3) to obtain compound 26-1. MS m / z = 363.5 [M + H] + .

[0774] Process 2

[0775] Compound 26-1 (50.00 mg, 137.96 μmol) was dissolved in ethanol (1 mL), and tetrahydrofuran (0.6 mL), lithium chloride (11.70 mg, 275.92 μmol), and sodium borohydride (10.44 mg, 275.92 μmol) were added sequentially. The mixture was reacted at 50°C for 3 hours. The mixture was cooled to room temperature, and DCM (20 mL) was added. The mixture was washed with saturated brine (3 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 26-2. MS m / z = 335.3 [M + H] + .

[0776] Process 3

[0777] Compound 26-2 (30.00 mg, 89.71 μmol) was dissolved in tetrahydrofuran (3 mL). Sodium tert-butoxide (43.11 mg, 44.85 μmol) was added, and the mixture was stirred for 0.5 hours. Finally, compound 4-2 (77.51 mg, 89.71 μmol) was added. The reaction mixture was stirred at 25°C for 1 hour. Water (3 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL). The mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 1:4) to obtain compound 26-3. MS m / z = 1134.6 [M + H] + .

[0778] Process 4

[0779] Compound 26-3 (50.00 mg, 44.08 μmol) was dissolved in trifluoroacetic acid (1 mL) and reacted at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatography column: Waters SunFire, 250*19 mm, 5 μm; mobile phase: [water (0.1% formic acid)-acetonitrile]; gradient: (acetonitrile): 40%-75%) and lyophilized to obtain the formate of compound 26. MS m / z = 644.1 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.38 (brs, 1H), 6.91 (d, J = 8.5 Hz, 1H), 5.20 - 5.12 (m, 1H), 4.82 - 4.66 (m, 4H), 4.47 (d, J = 6.4 Hz, 1H), 4.27 (q, J = 10.8 Hz, 2H), 3.58 (d, J = 12.5 Hz, 1H), 3.52 - 3.41 (m, 1H), 3.26 - 3.15 (m, 4H), 2.91 - 2.77 (m, 2H), 2.38 - 2.28 (m, 2H), 2.20 - 2.09 (m, 2H), 2.07 - 1.93 (m, 9H), 1.86 - 1.71 (m, 2H). Example 27 [ka] [ka] [ka] [ka]

[0780] Process 1

[0781] Periodic acid (1.71 g, 7.54 mmol) was dissolved in 15 mL of mixed solvent (acetonitrile:water = 100:0.75). Chromium trioxide (89.54 mg, 0.90 mmol) was added at 0°C and the mixture was stirred for 15 minutes. Compound 16-4A (0.60 g, 3.02 mmol) was dissolved in acetonitrile (15 mL) and slowly added to the above mixed solution at 0°C. After addition, the mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 27-1A. MS m / z = 214.0 [M + H] + .

[0782] Referring to Step 1, compound 27-1B was obtained by using compound 16-4B as the starting material instead of compound 16-4A. MS m / z = 214.0 [M + H] + .

[0783] Process 2

[0784] Compound 27-1A (0.20 g, 0.94 mmol) was dissolved in N,N-dimethylformamide (5 mL). 2,4-dimethoxy-N-methylbenzylamine (254.92 mg, 1.41 mmol), N,N-diisopropylethylamine (605.63 mg, 4.69 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (606.57 mg, 1.60 mmol) were added sequentially. The mixture was reacted at room temperature for 1 hour. 25 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed sequentially with water (10 mL x 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 27-2-P1 was obtained by separation using column chromatography (dichloromethane:methanol = 20:1). MS m / z = 377.1 [M + H] + .

[0785] Compound 27-2-P1 was subjected to preparative SFC separation (chromatography column: DAIEL CHIRALPAK® AS-10, 25*250 mm, 10 μm; mobile phase: A: supercritical carbon dioxide, B: [0.05% ammonia methanol-ethanol]; B%: 80%-20%) to obtain compounds 27-2A and 27-2B. After analytical SFC (chromatography column: DAIEL CHIRALPAK® AS-10 (4.6 mm I.D * 150 mm L, 5 μm); mobile phase: [A: supercritical carbon dioxide, B: ethanol (0.05% diethylamine)]; gradient: B%: 5%-40%, 4 min), the Rt of compound 27-2A was 2.824 min, the ee value was 99.05%, and the MS m / z = 377.1 [M+H]. + The Rt value for compound 27-2B was 3.327 mins, the ee value was 99.10%, and the MS m / z value was 377.1 [M+H]. + .

[0786] Referring to step 2, compound 27-2-P2 was obtained by using compound 27-1B as the starting material instead of compound 27-1A. MS m / z = 377.1 [M + H] + .

[0787] Compound 27-2-P2 was subjected to preparative SFC separation (chromatography column: DAIEL CHIRALPAK® AS-10, 25*250 mm, 10 μm; mobile phase: A: supercritical carbon dioxide, B: [0.05% ammonia methanol-ethanol]; B%: 80%-20%) to obtain compounds 27-2C and 27-2D. After analytical SFC (chromatography column: DAIEL CHIRALPAK® AS-10 (4.6 mm I.D*150 mm L, 5 μm); mobile phase: [A: supercritical carbon dioxide, B: ethanol (0.05% diethylamine)]; gradient: B%: 5%-40%, 4 min), the Rt of compound 27-2C was 2.891 min, the ee value was 95.80%, and the MS m / z = 377.1 [M+H]. + The Rt value for compound 27-2D was 3.327 mins, the ee value was 96.34%, and the MS m / z value was 377.1 [M+H]. + .

[0788] Process 3

[0789] Compound 27-2A (80.00 mg, 0.21 mmol) was dissolved in methanol (5 mL). Sodium methoxide-methanol solution (7.66 mg, 0.04 mmol, 30% purity) and sodium borohydride (24.2 mg, 0.63 mmol) were added, and the reaction mixture was stirred at 25°C for 16 hours. The mixture was quenched by adding 3 mL of saturated ammonium chloride solution and extracted with dichloromethane (5 mL x 3). The extracted organic phases were combined, washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (dichloromethane:ethyl acetate = 20:1) to obtain compound 27-3A. MS m / z = 349.1 [M + H] + .

[0790] Referring to step 3, compound 27-3B was obtained by using compound 27-2B as the starting material instead of compound 27-2A. MS m / z = 349.1 [M + H] + .

[0791] Referring to step 3, compound 27-3C was obtained by using compound 27-2C as the starting material instead of compound 27-2A. MS m / z = 349.1 [M + H] + .

[0792] Referring to step 3, compound 27-3D was obtained by using compound 27-2D as the starting material instead of compound 27-2A. MS m / z = 349.1 [M + H] + .

[0793] Process 4

[0794] Compound 27-3A (60.00 mg, 0.17 mmol) was dissolved in tetrahydrofuran (5 mL). Sodium hydride (34.48 mg, 0.85 mmol, 60% purity) was added at 0°C and the mixture was stirred for 0.5 hours. Next, a solution of compound 4-2 (164.56 mg, 0.19 mmol) in tetrahydrofuran (1 mL) was added to the system, and the mixture was heated to 25°C and stirred for a further 1 hour. The reaction was quenched by adding 6 mL of saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (5 mL x 2). The extracted organic phases were combined, washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 27-4A. MS m / z = 1148.5 [M + H] + .

[0795] Referring to step 4, compound 27-4B was obtained by using compound 27-3B as the starting material instead of compound 27-3A. MS m / z = 1148.5 [M + H] + .

[0796] Referring to step 4, compound 27-4C was obtained by using compound 27-3C as the starting material instead of compound 27-3A. MS m / z = 1148.5 [M + H] + .

[0797] Referring to step 4, compound 27-4D was obtained by using compound 27-3D as the starting material instead of compound 27-3A. MS m / z = 1148.5 [M + H] + .

[0798] Process 5

[0799] Compound 27-4A (0.10 g, 87.15 μmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatography column: Waters Xbridge, 250 × 19 mm, 5 μm; mobile phase: [water (0.1% ammonia)-acetonitrile]; (acetonitrile): 50%-70%), and lyophilized to obtain compound 27A. MS m / z = 658.6 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.18 - 5.10 (m, 1H), 4.78 (s, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.23 (d, J = 12.0 Hz, 1H), 4.16 - 4.07 (m, 2H), 3.57 - 3.48 (m, 3H), 3.45 - 3.38 (m, 1H), 3.29 - 3.17 (m, 2H), 3.10 - 3.01 (m, 2H), 2.89 - 2.81 (m, 1H), 2.73 (s, 3H), 2.67 - 2.60 (m, 1H), 2.31 - 2.23 (m, 1H), 2.15 - 2.08 (m, 1H), 2.04 - 1.96 (m, 4H), 1.95 - 1.87 (m, 4H), 1.86 - 1.79 (m, 2H), 1.76 - 1.65 (m, 3H).

[0800] Compound 27-4B (80.00 mg, 69.71 μmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatography column: Waters Xbridge, 250*19 mm, 5 μm; mobile phase: [water (0.1% ammonia)-acetonitrile]; (acetonitrile): 50%-70%), and lyophilized to obtain compound 27B. MS m / z = 658.5 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.21 - 5.09 (m, 1H), 4.80 (d, J = 12.0 Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.25 (d, J = 9.0 Hz, 1H), 4.16 - 4.06 (m, 2H), 3.57 - 3.48 (m, 3H), 3.44 - 3.38 (m, 1H), 3.30 - 3.15 (m, 2H), 3.10 - 3.01 (m, 2H), 2.89 - 2.80 (m, 1H), 2.73 (s, 3H), 2.68 - 2.60 (m, 1H), 2.31 - 2.21 (m, 1H), 2.19 - 2.09 (m, 1H), 2.01 - 1.96 (m, 4H), 1.94 - 1.78 (m, 6H), 1.77 - 1.64 (m, 3H).

[0801] Compound 27-4C (90.00 mg, 78.36 μmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatography column: Waters Xbridge, 250*19 mm, 5 μm; mobile phase: [water (0.1% ammonia)-acetonitrile]; (acetonitrile): 50%-70%), and lyophilized to obtain compound 27C. MS m / z = 658.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.19 - 5.10 (m, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.18 - 4.10 (m, 2H), 4.10 - 4.05 (m, 1H), 3.76 - 3.71 (m, 1H), 3.57 - 3.48 (m, 3H), 3.45 - 3.38 (m, 1H), 3.26 - 3.16 (m, 1H), 3.04 (d, J = 12.7 Hz, 1H), 2.92 - 2.81 (m, 2H), 2.75 (s, 3H), 2.75 - 2.68 (m, 1H), 2.14 - 2.05 (m, 2H), 2.04 - 1.97 (m, 5H), 1.96 - 1.80 (m, 6H), 1.76 - 1.64 (m, 2H).

[0802] Compound 27-4D (95.00 mg, 82.28 μmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatography column: Waters Xbridge, 250*19 mm, 5 μm; mobile phase: [water (0.1% ammonia)-acetonitrile]; (acetonitrile): 50%-70%), and lyophilized to obtain compound 27D. MS m / z = 658.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.18 - 5.11 (m, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.19 - 4.10 (m, 2H), 4.07 - 4.01 (m, 1H), 3.76 - 3.71 (m, 1H), 3.56 - 3.48 (m, 3H), 3.45 - 3.38 (m, 1H), 3.26 - 3.17 (m, 1H), 3.03 (d, J = 12.6 Hz, 1H), 2.92 - 2.81 (m, 2H), 2.75 (s, 3H), 2.75 - 2.69 (m, 1H), 2.15 - 2.06 (m, 2H), 2.05 - 1.97 (m, 5H), 1.96 - 1.80 (m, 6H), 1.76 - 1.65 (m, 2H).

[0803] Compounds 27C and 27D were confirmed to have the following structures. [ka]

[0804] Process 1

[0805] Compound 28-1 (1 g, 4.04 mmol) was weighed and anhydrous tetrahydrofuran (10 mL) was added under nitrogen. The mixture was cooled to -76°C in a dry ice bath and lithium bis(trimethylsilyl)amide (12.12 mL, 12.12 mmol, 1 M) was slowly added. The mixture was stirred at -76°C for 40 minutes. A solution of 4-bromobutene (654.48 mg, 4.84 mmol) in anhydrous tetrahydrofuran (5 mL) was added and the mixture was stirred for a further 60 minutes. The reaction was quenched by the addition of saturated ammonium chloride aqueous solution (10 mL) and extracted with ethyl acetate (15 mL x 3). The extracted organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 28-2 was obtained by separation by column chromatography (ethyl acetate:petroleum ether = 1:7). MS m / z = 302.2 [M + H] +

[0806] Process 2

[0807] Compound 28-2 (500 mg, 1.66 mmol) was weighed. Dichloromethane (3 mL) and hydrochloric acid / 1,4-dioxane solution (3 mL) were added, and the mixture was reacted at room temperature for 30 minutes. The reaction solution was directly concentrated to obtain the hydrochloride salt of compound 28-3. MS m / z = 202.1 [M + H] +

[0808] Process 3

[0809] Compound 28-3 (500 mg, hydrochloride) was weighed and anhydrous tetrahydrofuran (10 mL) was added. Sodium hydride (148.80 mg, 3.72 mmol, 60% purity) was added under ice bath at 0°C. The mixture was stirred at 0°C for 1 hour. Benzyl chloroformate (634.59 mg, 3.72 mmol) was added gradually and stirred at 40°C for 16 hours. The reaction was quenched with water (15 mL) and extracted with ethyl acetate (20 mL x 3). The extracted organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 28-4 was obtained by separation by column chromatography (ethyl acetate:petroleum ether = 1:8). MS m / z = 336.2 [M + H] + .

[0810] Process 4

[0811] Compound 28-4 (300 mg, 0.89 mmol) was weighed and dichloromethane (5 mL) was added. m-chloroperbenzoic acid (307.17 mg, 1.78 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Saturated sodium sulfite aqueous solution (1 mL) was added to the reaction solution and stirred for 5 minutes. Water (10 mL) was added. The mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 28-5 was obtained by separation by column chromatography (ethyl acetate:petroleum ether = 1:6). MS m / z = 352.2 [M + H] + .

[0812] Process 5

[0813] Compound 28-5 (1 g, 2.85 mmol) was weighed and anhydrous methanol (10 mL) was added. 10% palladium-carbon (100 mg) was added, and the atmosphere was replaced with hydrogen three times. The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered directly, the filter cake was washed with methanol (10 mL), and the filtrate was concentrated under reduced pressure. Separation by column chromatography (dichloromethane:methanol = 50:1) revealed compound 28-6A (eluent: DCM / MeOH = 15:1, Rf = 0.5) (MS m / z = 218.1 [M + H]). + ) and compound 28-6B (developing solvent: DCM / MeOH=15:1, Rf=0.3) (MS m / z=218.1[M+H] + ) was obtained.

[0814] Compound 28-6A: 1 H NMR (400 MHz, DMSO-d6) δ ppm 5.39 - 5.21 (m, 1 H), 4.37 (d, J = 8.0 Hz, 1H), 3.58 (s, 3H), 3.39 - 3.35 (m, 1H), 3.29 - 3.21 (m, 2H), 2.99 - 2.86 (m, 1H), 2.82 - 2.77 (m, 1H), 2.61 - 2.52 (m, 1H), 2.09 - 1.91 (m, 3H), 1.84 - 1.78 (m, 1H), 1.68 - 1.60 (m, 1H).

[0815] Compound 28-6B: 1 H NMR (400 MHz, DMSO-d6) δ ppm 5.27 - 5.10 (m, 1H), 4.64 (d, J = 8.0 Hz, 1H), 3.59 (s, 3H), 3.58 - 3.54 (m, 1H), 3.51 - 3.46 (m, 1H), 3.25 - 3.18 (m, 1H), 3.09 - 2.95 (m, 2H), 2.69 - 2.60 (m, 1H), 2.02 - 1.70 (m, 4H), 1.59 - 1.48 (m, 1H).

[0816] Process 6

[0817] Compound 28-6A (200.00 mg, 920.65 mmol) was weighed. Acetonitrile (2 mL) and water (0.014 mL) were added. The mixture was cooled to 0°C, and periodic acid (662.87 mg, 2.30 mmol) and chromium trioxide (27.62 mg, 1.84 mmol) were added. The reaction was allowed to proceed at room temperature for 4 hours. The reaction mixture was filtered. The filtered cake was washed with 10 mL of dichloromethane, and the filtrate was concentrated to obtain compound 28-7A (MS m / z = 232.1 [M + H]). + ) was obtained.

[0818] Referring to step 6, compound 28-7B was obtained by using compound 28-6B as the starting material instead of compound 28-6A. MS m / z = 232.1 [M + H] + .

[0819] Process 7

[0820] Compound 28-7A (120 mg, 518.99 μmol) was dissolved in N,N-dimethylformamide (3 mL). N-methyl-3,4-dimethylbenzylamine (92.94 mg, 622.79 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (394.67 mg, 1.04 mmol), and N,N-diisopropylethylamine (201.22 mg, 1.56 mmol) were added, and the mixture was reacted at 25°C for 4 hours. The mixture was extracted with ethyl acetate (20 mL x 2). The extracted organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 28-8A was obtained by column chromatography (petroleum ether:ethyl acetate = 10:1-1:1). MS m / z = 395.2 [M + H] + .

[0821] Referring to step 7, compound 28-8B was obtained by using compound 28-7B as the starting material instead of compound 28-7A. MS m / z = 395.2 [M + H] + .

[0822] Process 8

[0823] Compound 28-8A (20.00 mg, 55.18 μmol) was dissolved in methanol (0.5 mL), and sodium borohydride (4.18 mg, 110.36 μmol) and sodium methoxide (29.81 μg, 0.55 μmol) were added. The reaction was carried out at 25°C for 4 hours. The mixture was extracted with ethyl acetate (20 mL x 2). The extracted organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 28-9A. MS m / z = 367.3 [M + H] + .

[0824] Referring to step 8, compound 28-9B was obtained by using compound 28-8B as the starting material instead of compound 28-8A. MS m / z = 367.3 [M + H] + .

[0825] Process 9

[0826] Compound 28-9A (20 mg, 54.58 μmol) was dissolved in anhydrous tetrahydrofuran (0.5 mL) and cooled to 0°C. Sodium hydride (2.62 mg, 109.16 μmol, 60% purity) was added under nitrogen. The mixture was reacted at room temperature for 1 hour. The reaction was quenched by adding 5 mL of saturated ammonium chloride solution and extracted with ethyl acetate (10 mL x 2). The extracted organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 28-10A was obtained by purification by preparative thin-layer chromatography (dichloromethane:methanol = 20:1). MS m / z = 1166.5 [M + H] + .

[0827] Referring to step 9, compound 28-10B was obtained by using compound 28-9B as the starting material instead of compound 28-9A. MS m / z = 1166.5 [M + H] + .

[0828] Step 10

[0829] Compound 28-10A (20 mg, 17.63 μmol) was added to dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL), and the reaction mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Xtimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% formic acid)-acetonitrile]; gradient: (acetonitrile): 10%-40%), and lyophilized to obtain the formate of compound 28A. MS m / z = 676.5 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.52 (brs, 1H), 6.91 (d, J = 8.0 Hz, 1H), 5.49 - 5.27 (m, 1H), 5.17 (dd, J = 11.6, 4.5 Hz, 1H), 4.82 - 4.79 (m, 1H), 4.69 (d, J = 16.0 Hz, 1H), 4.39 (d, J = 12.0 Hz, 1H), 4.30 - 4.19 (m, 2H), 3.91 (s, 2H), 3.71 - 3.64 (m, 1H), 3.59 - 3.42 (m, 2H), 3.29 - 3.12 (m, 3H), 3.04 - 2.85 (m, 2H), 2.73 (s, 3H), 2.44 - 2.29 (m, 2H), 2.23 - 2.15 (m, 2H), 2.07 - 1.98 (m, 6H), 1.97 - 1.75 (m, 3H).

[0830] Compound 28-10B (20 mg, 17.63 μmol) was added to dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL), and the reaction mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Xtimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; gradient: (acetonitrile): 10%-40%), and lyophilized to obtain the hydrochloride salt of compound 28B. MS m / z = 676.5 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.42 - 5.25 (m, 1H), 5.18 - 5.11 (m, 1H), 4.79 (d, J = 13.5 Hz, 1H), 4.64 (d, J = 16.0 Hz, 1H), 4.23 (d, J = 8.0 Hz, 1H), 4.20 - 4.11 (m, 2H), 3.75 (t, J = 5.6 Hz, 1H), 3.52 (d, J = 12.0 Hz, 3H), 3.42 (d, J = 12.0 Hz, 1H), 3.26 - 3.12 (m, 2H), 3.10 - 2.99 (m, 2H), 2.88 - 2.80 (m, 1H), 2.73 (s, 3H), 2.45 - 2.35 (m, 1H), 2.24 - 2.07 (m, 2H), 2.06 - 1.96 (m, 7H), 1.87 - 1.77 (m, 2H), 1.68 (t, J = 8.9 Hz, 1H). Example 29 [ka]

[0831] Process 1

[0832] To a solution of compound 1-2 (50.00 mg, 326.33 μmol) in methanol (2 mL), palladium / carbon (16.64 mg, purity 10%) was added, and the mixture was reacted under a hydrogen atmosphere (15 psi) at 20°C for 16 hours. The reaction mixture was filtered. The filtrate was concentrated to dryness by nitrogen blowdown to obtain compound 29-1. MS m / z = 156.15 [M + H] +

[0833] Process 2

[0834] Potassium tert-butoxide (257.54 mg, 2.68 mmol) was added at 0°C to a solution of compound 29-1 (52.00 mg, 334.97 μmol) in tetrahydrofuran (4 ml) and stirred for 1 hour. Compound 4-2 (347.28 mg, 401.97 μmol) was added to the above mixture and the resulting mixture was stirred at 25°C for 1 hour. The reaction was quenched by adding 5 mL of saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (2 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 29-2. MS m / z = 955.2 [M + H] +

[0835] Process 3

[0836] Compound 29-2 (0.11 g, 115.17 μmol) was dissolved in trifluoroacetic acid (1 mL). The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (chromatography column: Waters Xbridge, 250*19 mm, 5 μm; mobile phase: [water (0.1% formic acid)-acetonitrile]; gradient: (acetonitrile): 45%-75%) to obtain the formate of compound 29. MS m / z = 615.2 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.53 (s, 0.71H), 6.93 (d, J = 12.0 Hz, 1H), 5.18 - 5.15 (m, 1H), 4.80 - 4.73 (m, 3H), 4.62 - 4.60 (m, 1H), 4.49 - 4.43 (m, 3H), 3.78 - 3.72 (m, 1H), 3.52 - 3.36 (m, 2H), 3.30 - 3.17 (m, 2H), 3.02 - 2.99 (m, 1H), 2.91- 2.87 (m, 2H), 2.83 - 2.75 (m, 2H), 2.62 - 2.42 (m, 1H), 2.35 - 2.26 (m, 1H), 2.21 - 2.18 (m, 3H), 2.10 - 2.06 (m, 2H), 2.04 (m, 5H), 1.90 - 1.70 (m, 1H), 1.20 - 1.15 (m, 3H). Example 30 [ka]

[0837] Process 1

[0838] Compound 30-1 (10 g, 40.44 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to -78°C. Lithium hexamethyldisilazide (1 M, 52.58 mmol, 52.58 mL) was then added, and the mixture was stirred at -78°C for 0.5 hours. Allyl bromide (5.87 g, 48.53 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Saturated ammonium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, concentrated under reduced pressure, and separated by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 30-2. MS m / z = 288.2 [M + H] +

[0839] Process 2

[0840] Compound 30-2 (200 mg, 696.07 μmol) was dissolved in tetrahydrofuran (1 mL). Water (1 mL) was added and the mixture was thoroughly stirred. N-bromosuccinimide (123.89 mg, 696.07 μmol) was added in three separate additions. Saturated sodium bicarbonate aqueous solution (3 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The mixture was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain compound 30-3. MS m / z = 384.2 [M + H] +

[0841] Process 3

[0842] Compound 30-3 (400 mg, 1.04 mmol) was dissolved in dichloromethane (3 mL) and cooled to 0°C. Trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 30-4. MS m / z = 284.2 [M + H] +

[0843] Process 4

[0844] Compound 30-4 (295.78 mg, 1.04 mmol) was dissolved in acetonitrile (4 mL). Potassium carbonate (719.38 mg, 5.21 mmol) was added, and the mixture was heated to 80°C and stirred for 3 hours. After cooling to room temperature, the mixture was filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 30-5. MS m / z = 204.3 [M + H] +

[0845] Process 5

[0846] Compound 30-5 (500 mg, 2.46 mmol) was dissolved in chloromethane. Dess-Martin periodinane (3.13 g, 7.38 mmol) was added at 0°C and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution (10 mL), the mixture was filtered, and extracted with ethyl acetate (5 mL x 3). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 30-6. MS m / z = 202.1 [M + H] +

[0847] Process 6

[0848] Compound 30-6 (240 mg, 1.19 mmol) was dissolved in toluene (5 mL), and ethylene glycol (0.37 g, 5.96 mmol) was added. p-toluenesulfonic acid monohydrate (22.69 mg, 0.12 mmol) was added, and the mixture was heated to 90°C and stirred for 16 hours. After cooling to room temperature, saturated sodium bicarbonate aqueous solution (5 mL) was added. The mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 30-7. MS m / z = 246.1 [M + H] + .

[0849] Process 7

[0850] Compound 30-7 (100 mg, 0.41 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0°C. Lithium aluminum tetrahydrogen (15.48 mg, 0.41 mmol) was added, and the mixture was slowly returned to room temperature and stirred for 1 hour. The reaction was quenched by sequentially adding water (0.02 mL), 15% aqueous sodium hydroxide solution (0.02 mL), and water (0.06 mL). The mixture was stirred at room temperature for 0.5 hours, filtered, and concentrated under reduced pressure to obtain compound 30-8. MS m / z = 218.2 [M + H] + .

[0851] Process 8

[0852] Compound 30-8 (60 mg, 0.28 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL) and cooled to 0°C. Sodium hydride (55.23 mg, 1.38 mmol, 60% purity) was added. After stirring at 0°C for 30 minutes, compound 4-2 (264.70 mg, 0.30 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 30-9. MS m / z = 1017.7 [M + H] + .

[0853] Process 9

[0854] Compound 30-9 (0.10 g, 0.098 mmol) was added to 10 mL of a mixed solvent (trifluoroacetic acid:dichloromethane = 1:3) at 0°C and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (Waters Xbridge, 250 × 19 mm, 5 μm; mobile phase: [water (0.1% ammonia)-acetonitrile]; gradient: (acetonitrile): 55%-70%) and concentrated under reduced pressure to obtain compound 30. MS m / z = 677.5 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.96 (d, J = 8.0 Hz, 1H), 5.42 - 5.28 (m, 1H), 5.20 - 5.17 (m, 1H), 4.85 - 4.47 (m, 2H), 4.62 - 4.60 (m, 1H), 4.46 - 4.41 (m, 1H), 4.35 - 4.27 (m, 2H), 4.03 - 3.92 (m, 4H), 3.55 - 3.38 (m, 3H), 3.31 - 3.18 (m, 3H), 3.08 - 2.99 (m, 1H), 2.92 - 2.84 (m, 3H), 2.59 - 2.49 (M, 1H), 2.43 - 2.35 (m, 1H), 2.31 - 2.16 (m, 2H), 2.12 - 2.01 (m, 7H). Example 31 [ka]

[0855] Process 1

[0856] Compound 31-1 (20 mg, 57.87 μmol) was dissolved in anhydrous tetrahydrofuran (3 mL), cooled to 0°C, and sodium hydride (4.63 mg, 115.75 μmol, 60% purity) was added. The mixture was stirred at 0°C for 30 minutes. Compound 4-2 (50 mg, 57.87 μmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The extracted organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 31-2. MS m / z = 973.7 [M + H] + .

[0857] Process 2

[0858] Compound 31-2 (40 mg, 41.11 μmol) was added to trifluoroacetic acid (4 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (chromatography column: Waters Xbridge, 250*19 mm, 5 μm; mobile phase: [water (0.1% ammonia)-acetonitrile]; gradient: (acetonitrile): 55%-70%). After drying, compound 31 was obtained. MS m / z = 633.5 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.91 (d, J = 8.0 Hz, 1H), 5.47 - 5.45 (m, 0.5H), 5.34 - 5.31 (m, 0.5H), 5.17 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 4.80 (s, 1H), 4.67 (d, J = 12.0 Hz, 1H), 4.57 (s, 1H), 4.25 (d, J = 12.0 Hz, 2H), 4.12 (d, J = 12.0 Hz, 1H), 3.89 - 3.85 (m, 2H), 3.69-3.62 (m, 1H), 3.58 - 3.53 (m, 1H), 3.47 - 3.37 (m, 1H), 3.21 - 3.15 (m, 1H), 3.07 - 2.83 (m, 3H), 2.47 (dd, J = 20.0 Hz, 16.0 Hz, 1H), 2.25 - 2.15 (m, 2H), 2.08 - 1.93 (m, 7H), 1.88 - 1.70 (m, 3H), 1.16 (d, J = 8.0 Hz, 3H). Example 32 [ka]

[0859] Process 1

[0860] Compound 30-5 (110.00 mg, 0.54 mmol) was weighed. Dichloromethane (5 mL) was added. Tert-butyldimethylsilyl chloride (162.76 mg, 1.08 mmol) and imidazole (110.16 mg, 1.62 mmol) were added, and the mixture was reacted at room temperature for 16 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 32-1. MS m / z = 318.2 [M + H] + .

[0861] Process 2

[0862] Compound 32-1 (85 mg, 0.27 mmol) was weighed and anhydrous tetrahydrofuran (3 mL) was added under nitrogen. The mixture was cooled to 0°C and lithium aluminum tetrahydrogen (0.54 mmol, 0.22 mL, 2.5 M) was added. The mixture was reacted at room temperature for 15 minutes. The reaction was quenched by adding 0.2 mL of water to the reaction solution at 0°C and then adding 0.2 mL of 15% sodium hydroxide solution. The mixture was stirred for 10 minutes and filtered. The filtrate was washed with 5 mL of tetrahydrofuran. The filtrate was concentrated to obtain compound 32-2. MS m / z = 290.2 [M + H] +

[0863] Process 3

[0864] Compound 32-2 (64 mg, 0.22 mmol) was weighed and anhydrous tetrahydrofuran (5 mL) was added. Sodium hydride (15.91 mg, 0.66 mmol, 60% purity) was added under ice bath conditions, and the mixture was stirred at room temperature for 30 minutes. Compound 4-2 (195.41 mg, 0.22 mmol) was added, and the mixture was reacted at room temperature for 1 hour. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phase was concentrated under reduced pressure and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 32-3. MS m / z = 1089.5 [M + H] + .

[0865] Process 4

[0866] Compound 32-3 (50 mg, 0.05 mmol) was weighed. Dichloromethane (2 mL) and trifluoroacetic acid (1 mL) were added, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then separated by preparative HPLC (chromatographic column: Waters Xbridge, 250 × 19 mm, 5 μm; mobile phase: [water (0.1% hydrochloric acid) - acetonitrile]; gradient: (acetonitrile): 10%-40%) to obtain the hydrochloride salt of compound 32. MS m / z = 635.3 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.94 (d, J = 8.0 Hz, 1H), 5.57 (d, J = 48.0 Hz, 1H), 5.23 (d, J = 12.0 Hz, 1H), 5.0 - 5.04 (m, 1H), 4.99 - 4.90 (m, 4H), 4.76 (t, J = 4.0 Hz, 1H), 4.23 (d, J = 28.0 Hz, 2H), 4.12 - 3.95 (m, 3H), 3.73 - 3.51 (m, 4H), 3.35 - 3.43 (m, 1H), 3.07 - 3.03 (m, 1H), 2.85 - 2.76 (m, 1H), 2.67 - 2.41 (m, 3H), 2.22 - 2.05 (m, 4H), 2.02 (s, 3H). Example 33 [ka] [ka]

[0867] Process 1

[0868] At 0°C, tert-butyldiphenylsilyl chloride (1.50 g, 4.83 mmol) was added dropwise to a solution of compound 28-6A (700 mg, 3.22 mmol) and imidazole (658.09 mg, 9.67 mmol) in dichloromethane (20 mL). The mixture was heated to 20°C and stirred for 4 hours. The reaction was quenched by adding 30 mL of saturated ammonium chloride aqueous solution. The mixture was extracted with dichloromethane (15 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 33-1A. MS m / z = 456.3 [M + H] + .

[0869] Referring to Step 1, compound 33-1B was obtained by using compound 28-6B as the starting material instead of compound 28-6A. MS m / z = 456.3 [M + H] + .

[0870] Process 2

[0871] Lithium aluminum tetrahydride (37.58 mg, 0.99 mmol) was slowly added at 0°C to a solution of compound 33-1A (300 mg, 0.66 mmol) in tetrahydrofuran (5 mL). The reaction was stirred at 0°C for 0.5 hours. The reaction was quenched by the addition of 100 mg of sodium sulfate decahydrate. The quenched reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The compounds were separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 33-2A. MS m / z = 428.3 [M + H] + .

[0872] Referring to step 2, compound 33-2B was obtained by using compound 33-1B as the starting material instead of compound 33-1A. MS m / z = 428.3 [M + H] + .

[0873] Process 3

[0874] Sodium hydride (46.84 mg, 1.17 mmol, 60% purity) was slowly added at 0°C to a solution of compound 33-2A (100.00 mg, 0.23 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at 0°C for 0.5 hours. Next, a solution of compound 4-2 (205.49 mg, 0.24 mmol) in tetrahydrofuran (1 mL) was added to the system, and the mixture was heated to 25°C and stirred for a further 1 hour. The reaction was quenched by adding saturated ammonium chloride aqueous solution (6 mL), and extracted with ethyl acetate (6 mL x 2). The extracted organic phases were combined, washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 33-3A was obtained by separation by column chromatography (petroleum ether:ethyl acetate = 3:1). MS m / z = 1227.5 [M + H] + .

[0875] Referring to step 3, compound 33-3B was obtained by using compound 33-2B as the starting material instead of compound 33-2A. MS m / z = 1227.5 [M + H] + .

[0876] Process 4

[0877] Compound 33-3A (220 mg, 0.18 mmol) was dissolved in tetrahydrofuran (4 mL), to which a solution of tetrabutylammonium fluoride in tetrahydrofuran (0.54 mL, 0.54 mmol, 1 M) was added at 20°C. The reaction mixture was stirred at 20°C for 4 hours. Ethyl acetate (20 mL) was added to the system, and the mixture was washed with water (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 33-4A was obtained by separation by column chromatography (dichloromethane:methanol = 20:1). MS m / z = 989.7 [M + H] + .

[0878] Referring to step 4, compound 33-4B was obtained by using compound 33-3B as the starting material instead of compound 33-3A. MS m / z = 989.7 [M + H] + .

[0879] Process 5

[0880] Compound 33-4A (100 mg, 0.10 mmol) was added to trifluoroacetic acid (3 mL) and stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatography column: Waters Xbridge, 250 × 19 mm, 5 μm; mobile phase: [water (0.1% ammonia)-acetonitrile]; (acetonitrile): 40%-70%), dried, and compound 33A was obtained. MS m / z = 649.5 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.36 (dt, J = 56.0, 4.0 Hz, 1H), 5.14 (dd, J = 12.0, 4.0 Hz, 1H), 4.81 - 4.77 (m, 1H), 4.66 - 4.62 (m, 1H), 4.23 - 4.13 (m, 2H), 4.11 - 4.04 (m, 1H), 3.59 - 3.40 (m, 7H), 3.25 - 3.16 (m, 1H), 3.08 - 2.92 (m, 2H), 2.91 - 2.80 (m, 2H), 2.49 - 2.38 (m, 1H), 2.24 - 2.16 (m, 1H), 2.09 - 1.99 (m, 5H), 1.96 - 1.77 (m, 4H), 1.74 - 1.63 (m, 2H).

[0881] Compound 33-4B (140 mg, 0.14 mmol) was added to trifluoroacetic acid (5 mL) and stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatographic column: Waters Xbridge, 250 × 19 mm, 5 μm; mobile phase: [water (0.1% ammonia)-acetonitrile]; (acetonitrile): 40%-70%), dried, and compound 33B was obtained. MS m / z = 649.5 [M + H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.26 (dt, J = 52.0, 4.0 Hz, 1H), 5.14 (dd, J = 8.0, 4.0 Hz, 1H), 4.82 - 4.77 (m, 1H), 4.68 - 4.61 (m, 1H), 4.35 - 4.29 (m, 1H), 4.22 - 4.15 (m, 2H), 3.84 - 3.77 (m, 1H), 3.73 - 3.67 (m, 1H), 3.57 - 3.49 (m, 3H), 3.46 - 3.34 (m, 2H), 3.25 - 3.02 (m, 4H), 2.89 - 2.81 (m, 1H), 2.49 - 2.39 (m, 1H), 2.08 - 1.92 (m, 6H), 1.91 - 1.79 (m, 4H), 1.77 - 1.64 (m, 2H). Example 34 [ka]

[0882] Process 1

[0883] Compound 34-1 (40 mg, 0.23 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and cooled to 0°C. Sodium hydride (9.03 mg, 0.23 mmol, 60% purity) was added. Af...

Claims

1. A compound represented by formula (I''), or its stereoisomer, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, R Ｎ H and C １－３ Selected from alkyl groups, the above C １－３ The alkyl group is optionally substituted with one, two, or three F or Cl atoms; Ring A is C ６ Selected from aryls and 5-6 member heteroaryls; Ring B is, 【Chemistry 2】 Selected from; Ring B has 1, 2, 3, or 4 R １０ It is arbitrarily replaced with; L is selected from -C(R Ｌ１ R Ｌ２ ), and R Ｌ１ and R Ｌ２ are each independently selected from H, D, and C １－３ alkyl; R １ and R ２ Each is independently selected from oxo, H, F, Cl, Br, I, and CN; Each R ３ These are independently F, Cl, Br, I, OH, NH ２ , CN, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Alkylamino, D-C １－３ Alkylamino, C ２－４ Alkenil, C ２－４ Alkinyl and C ３－５ Selected from cycloalkyl, the above C １－３ Alkyl, C １－３ Alkoxy, C １－３ Alkylamino, D-C １－３ Alkylamino, C ２－４ Alkenil, C ２－４ Alkinyl and C ３－５ Each cycloalkyl group independently has 1, 2, 3, 4, or 5 R groups. ａ It is arbitrarily replaced with; Each R ａ These are independently selected from D, F, Cl, Br, and I; R ４ , R ５ , R ６ , R ７ , R ６’ and R ７’ These are, independently, oxo, H, F, Cl, Br, I, OH, NH ２ , CN, C １－３ Alkyl, C ２－４ Alkenil, C １－３ Alkoxy, -C(=O)-R ｄ , -C(=O)-NR ｂ１ R ｂ２ , and = NO(C １－３ Selected from alkyl, and the above C １－３ Alkyl, C ２－４ Alkenyl and C １－３ Each alkoxy independently contains 1, 2, 3, 4, or 5 R ｂ It is arbitrarily replaced with; Alternatively, R ６ and R ７ These, together with the carbon atoms to which they are bonded, form a 3- to 5-membered heterocycloalkyl group; Each R ｂ These are independently D, F, Cl, Br, I, OH, NH ２ , CN, C １－３ Alkoxy and -C(=O)-NR ｂ１ R ｂ２ Selected from; R ８ are H, F, Cl, Br, I, OH, NH ２ , CN, C １－３ Alkyl and C １－３ Selected from alkoxy, the above C １－３ Alkyl and C １－３ Each alkoxy independently contains 1, 2, 3, 4, or 5 R ａ It is arbitrarily replaced with; Alternatively, R ８ and R ８’ Together with the carbon atoms to which they are bonded, C ３－５ Forming a cycloalkyl or 3-5 membered heterocycloalkyl, the above C ３－５ Cycloalkyls and 3- to 5-membered heterocycloalkyls each independently have 1, 2, or 3 R １０ It is arbitrarily replaced with; R ９ is -C(=O)-NR ｂ３ R ｂ４ and -CH ２ R ｃ Selected from; Each R １０ These are independently oxo, D, F, Cl, Br, I, OH, NH ２ , CN, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Alkylamino, D-C １－３ Alkylamino, -C(=O)-R ｄ , -S-R ｄ , -S (=O) -R ｄ , -S (=O) ２ -R ｄ , -NH-C(=O)-R ｄ , C ６－１０ Selected from aryls and 5-10 member heteroaryls, the above C １－３ The alkyl group is optionally substituted with 1, 2, or 3 OH or F groups, and the above C ６－１０ Each aryl and 5- to 10-membered heteroaryl independently has 1, 2, 3, 4, or 5 R ｓ１ It is arbitrarily replaced with; R ｂ１ and R ｂ２ each independently is selected from H, C １－６ alkyl, C １－６ alkoxy, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl and 5- to 10-membered heteroaryl, and the above-mentioned C １－６ alkyl, C １－６ alkoxy, C ３－１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl and 5- to 10-membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R ｅ１ ; Alternatively, R ｂ１ and R ｂ２ These, together with the nitrogen atom to which they are bonded, form a 3-6 member heterocycloalkyl group, and the above 3-6 member heterocycloalkyl group has 1, 2, 3 or 4 R ｅ１ It is arbitrarily substituted in the base; R ｂ３ and R ｂ４ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Alkoxy, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5-10 member heteroaryls, the above C １－６ Alkyl, C １－６ Alkoxy, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Each aryl and 5- to 10-membered heteroaryl independently has 1, 2, 3, or 4 R ｅ２ It is arbitrarily replaced with; Alternatively, R ｂ３ and R ｂ４ These, together with the nitrogen atom to which they are bonded, form a 3-6 member heterocycloalkyl group, and the above 3-6 member heterocycloalkyl group has 1, 2, 3 or 4 R ｅ２ It is arbitrarily substituted in the base; R ｃ is F, Cl, Br, I, OH, NH ２ , -(C=O)NR Ｃ１ R Ｃ２ , -O(C=O)NR Ｃ１ R Ｃ２ , -NR Ｃ０ (C=O)R Ｃ１ , and -NR Ｃ０ (C=O)NR Ｃ１ R Ｃ２ Selected from; R Ｃ０ , R Ｃ１ and R Ｃ２ These are H and C, which are independent of each other. １－６ Alkyl, C ３－６ Selected from cycloalkyl and 3- to 6-membered heterocycloalkyl groups; R ｄ C １－３ Selected from alkyl groups; R ｅ１ is F, Cl, Br, I, OH, NH ２ NO ２ , C １－３ Alkyl, C １－３ Alkylamino, D-C １－３ Alkylamino, C, C １－３ Alkoxy, -S (=O) ２ - (C １－３ Alkyl), -(C=O)(C １－３ Alkyl), -(C=O)O(C １－３ Alkyl), -(C=O)NH(C １－３ Alkyl), -(C=O)N(C １－３ Alkyl) ２ , C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; R ｅ２ is F, Cl, Br, I, OH, NH ２ NO ２ , C １－３ Alkyl, C １－３ Alkylamino, D-C １－３ Alkylamino, C, C １－３ Alkoxy, -S (=O) ２ - (C １－３ Alkyl), -(C=O)(C １－３ Alkyl), -(C=O)O(C １－３ Alkyl), -(C=O)NH(C １－３ Alkyl), -(C=O)N(C １－３ Alkyl) ２ , C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5-10 member heteroaryls, the above C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Each aryl and 5- to 10-membered heteroaryl independently has 1, 2, 3, 4, or 5 R ｓ１ It is arbitrarily replaced with the above C １－３ Alkyl and C １－３ Each alkoxy independently contains 1, 2, 3, 4, or 5 R ｓ２ It is arbitrarily replaced with; Alternatively, two or more R ｅ２ Together with the carbon atoms to which they are bonded, C ６ Forming an aryl group or a 5- or 6-membered heteroaryl group; R ｓ１ , oxo, F, Cl, Br, I, OH, NH ２ NO ２ , C １－６ Alkyl, C １－６ Alkylamino, D-C １－６ Alkylamino, C, C １－６ Alkoxy, -S (=O) ２ - (C １－３ Alkyl), -(C=O)(C １－３ Alkyl), -(C=O)O(C １－３ Alkyl), -(C=O)NH(C １－３ Alkyl) and -(C=O)N(C １－３ Alkyl) ２ Selected from; R ｓ２ is F, Cl, Br, I, OH, NH ２ , C １－６ Alkylamino, D-C １－６ Alkylamino, C, C １－６ Alkoxy, -S (=O) ２ - (C １－３ Alkyl), -(C=O)(C １－３ Alkyl), -(C=O)O(C １－３ Alkyl), -(C=O)NH(C １－３ Alkyl) and -(C=O)N(C １－３ Alkyl) ２ Selected from; m is selected from 0, 1, 2, 3, 4, and 5; however, 1) Ring B is 【Transformation 3】 If selected from the above, 【Chemistry 4】 is one R １０ It is replaced with R １０ F is R １ , R ２ , R ４ , R ５ , R ６ , R ７ , R ６’ and R ７’ At least one of them is not H; 2) Ring B is 【Transformation 5】 If selected from the above, 【Transformation 6】 is 1, 2, 3 or 4 R １０ It is arbitrarily replaced in R １ , R ２ , R ４ , R ５ , R ６ , R ７ , R ６’ and R ７’ At least one of them is not H; 3) The above compound is 【Transformation 7】 isn't it).

2. R Ｎ The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein is H.

3. R Ｎ However, C is optionally substituted with one, two, or three F or Cl groups. １－３ A compound according to claim 1, which is an alkyl group, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. The compound represented by formula (I'), or its stereoisomer, or its pharmaceutically acceptable salt: 【Transformation 8】 (In the formula, Ring A is C ６ Selected from aryls and 5-6 member heteroaryls; Ring B is, 【Chemistry 9】 Selected from; Ring B has 1, 2, 3, or 4 R １０ It is arbitrarily replaced with; L is -CH ２ - Selected from the above -CH ２ - is arbitrarily replaced by one or two D; R １ and R ２ Each is independently selected from oxo, H, F, Cl, Br, I, and CN; Each R ３ These are independently F, Cl, Br, I, OH, NH ２ , CN, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Alkylamino, D-C １－３ Alkylamino, C ２－４ Alkenil, C ２－４ Alkinyl and C ３－５ Selected from cycloalkyl, the above C １－３ Alkyl, C １－３ Alkoxy, C １－３ Alkylamino, D-C １－３ Alkylamino, C ２－４ Alkenil, C ２－４ Alkinyl and C ３－５ Each cycloalkyl group independently has 1, 2, 3, 4, or 5 R groups. ａ It is arbitrarily replaced with; Each R ａ These are independently selected from D, F, Cl, Br, and I; R ４ , R ５ , R ６ , R ７ , R ６’ and R ７’ These are, independently, oxo, H, F, Cl, Br, I, OH, NH ２ , CN, C １－３ Alkyl, C ２－４ Alkenil, C １－３ Alkoxy, -C(=O)-R ｄ , -C(=O)-NR ｂ１ R ｂ２ , and = NO(C １－３ Selected from alkyl, and the above C １－３ Alkyl, C ２－４ Alkenyl and C １－３ Each alkoxy independently contains 1, 2, 3, 4, or 5 R ｂ It is arbitrarily replaced with; Alternatively, R ６ and R ７ These, together with the carbon atoms to which they are bonded, form a 3- to 5-membered heterocycloalkyl group; Each R ｂ These are independently D, F, Cl, Br, I, OH, NH ２ , CN, C １－３ Alkoxy and -C(=O)-NR ｂ１ R ｂ２ Selected from; R ８ are H, F, Cl, Br, I, OH, NH ２ , CN, C １－３ Alkyl and C １－３ Selected from alkoxy, the above C １－３ Alkyl and C １－３ Each alkoxy independently contains 1, 2, 3, 4, or 5 R ａ It is arbitrarily replaced with; Alternatively, R ８ and R ８’ Together with the carbon atoms to which they are bonded, C ３－５ Forming a cycloalkyl or 3-5 membered heterocycloalkyl, the above C ３－５ Cycloalkyls and 3- to 5-membered heterocycloalkyls each independently have 1, 2, or 3 R １０ It is arbitrarily replaced with; R ９ is -C(=O)-NR ｂ１ R ｂ２ and -CH ２ R ｃ Selected from; Each R １０ These are independently oxo, D, F, Cl, Br, I, OH, NH ２ , CN, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Alkylamino, D-C １－３ Alkylamino, -S-R ｄ , -S (=O) -R ｄ , -S (=O) ２ -R ｄ and -NH-C(=O)-R ｄ Selected from the above C １－３ The alkyl group is optionally substituted with one, two, or three OH groups; R ｂ１ and R ｂ２ These are H and C, which are independent of each other. １－６ Alkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5-10 member heteroaryls, the above C １－６ Alkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Each aryl and 5- to 10-membered heteroaryl independently has 1, 2, or 3 R ｅ１ It is arbitrarily replaced with; Alternatively, R ｂ１ and R ｂ２ These, together with the nitrogen atom to which they are bonded, form a 3- to 6-membered heterocycloalkyl group; R ｃ is F, Cl, Br, I, OH, NH ２ , -O(C=O)NR Ｃ１ R Ｃ２ , -NR Ｃ０ (C=O)R Ｃ１ , and -NR Ｃ０ (C=O)NR Ｃ１ R Ｃ２ Selected from; R Ｃ０ , R Ｃ１ and R Ｃ２ These are H and C, which are independent of each other. １－６ Alkyl, C ３－６ Selected from cycloalkyl and 3- to 6-membered heterocycloalkyl groups; R ｄ C １－３ Selected from alkyl groups; R ｅ１ is F, Cl, Br, I, OH, NH ２ , C １－３ Alkylamino, D-C １－３ Alkylamino, C, C １－３ Alkoxy, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; m is selected from 0, 1, 2, 3, 4, and 5; however, 1) Ring B is 【Chemistry 10】 If selected from the above, 【Chemistry 11】 is one R １０ It is replaced with R １０ F is R １ , R ２ , R ４ , R ５ , R ６ , R ７ , R ６’ and R ７’ At least one of them is not H; 2) Ring B is 【Chemistry 12】 If selected from the above, 【Chemistry 13】 is 1, 2, 3 or 4 R １０ It is arbitrarily replaced in R １ , R ２ , R ４ , R ５ , R ６ , R ７ , R ６’ and R ７’ At least one of them is not H; 3) The above compound is 【Chemistry 14】 isn't it).

5. Ring A is C ６ A compound according to any one of claims 1 to 4, selected from aryl compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. A compound according to any one of claims 1 to 4, wherein ring A is selected from a five-membered heteroaryl group, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

7. Ring B has 1, 2, 3, or 4 R １０ It is arbitrarily replaced with 【Chemistry 15】 A compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from among.

8. Ring B has 1, 2, 3 or 4 R １０ It is arbitrarily replaced with 【Chemistry 16】 A compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

9. A compound according to claim 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compound of formula (I'-1-i), or its stereoisomer, or its stereoisomer: 【Chemistry 17】 。

10. A compound according to claim 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compound of formula (I'-2-i), its stereoisomer, or a pharmaceutically acceptable salt thereof: [Chemistry 18] 。

11. Ring B has 1, 2, 3 or 4 R １０ It is arbitrarily replaced with 【Chemistry 19】 The compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compound of formula (I'-1-ii), or its stereoisomer, or its stereoisomer: 【Chemistry 20】 。

13. A compound according to claim 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compound of formula (I'-2-ii), or its stereoisomer, or its stereoisomer: 【Chemistry 21】 。

14. Ring B has 1, 2, 3 or 4 R １０ It is arbitrarily replaced with 【Chemistry 22】 A compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from among.

15. A compound according to claim 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compounds of formulas (I'-3), (I'-4), (I'-5), (I'-6), (I'-7), (I'-8), (I'-9), (I'-10), (I'-11), (I'-12), and (I'-13), or their stereoisomers, or their pharmaceutically acceptable salts: 【Chemistry 23-1】 【Chemistry 23-2】 。

16. R ４ , R ５ , R ６ , R ７ , R ６’ and R ７’ A compound according to any one of claims 7 to 13 and 15, wherein H is selected from H, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compounds of formulas (I'-14) and (I'-15), or their stereoisomers, or their pharmaceutically acceptable salts: 【Chemistry 24】 。

18. Ring A is phenyl, and at least one R ３ It is replaced by each R ３ However, independently, F, OH, NH ２ CF ３ , OCH ３ , 【Chemistry 25】 A compound according to any one of claims 1 to 5 and 7 to 17, selected from and cyclopropyl, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Request Item 19】 【Chemistry 26】 but 【Chemistry 27】 A compound according to any one of claims 1 to 5 and 7 to 17, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above. 【Request Item 20】 【Chemistry 28】 but 【Chemistry 29】 A compound according to any one of claims 1 to 5 and 7 to 17, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

21. A compound according to claim 19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compound of formula (I'-1'-i), or its stereoisomer, or its stereoisomer: 【Transformation 30】 。

22. A compound according to claim 19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compound of formula (I'-1'-ii), or its stereoisomer, or its stereoisomer: 【Chemistry 31】 。

23. A compound according to claim 19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compound of formula (I'-2'-i), or its stereoisomer, or its stereoisomer: 【Chemistry 32】 。

24. A compound according to claim 19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compound of formula (I'-2'-ii), or its stereoisomer, or its stereoisomer: 【Transformation 33】 。

25. A compound according to claim 19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compounds of formulas (I'-3'), (I'-4'), (I'-5'), (I'-6'), (I'-7'), (I'-8'), (I'-9'), (I'-10'), (I'-11'), (I'-12'), and (I'-13'), or their stereoisomers, or their pharmaceutically acceptable salts: 【Chemistry 34-1】 【Chemistry 34-2】 。

26. R ４ , R ５ , R ６ , R ７ , R ６’ and R ７’ The compound according to claim 25, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each of the atoms is H.

27. A compound according to claim 19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compounds of formulas (I'-14') and (I'-15'), or their stereoisomers, or pharmaceutically acceptable salts thereof: 【Chemistry 35】 。

28. L is -C(R Ｌ１ R Ｌ２ ) - and R Ｌ１ and R Ｌ２ However, each is independently selected from H and D, and is a compound according to any one of claims 1 to 27, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

29. L is -C(R Ｌ１ R Ｌ２ ) - and R Ｌ１ and R Ｌ２ However, each is independently selected from H, and is a compound according to any one of claims 1 to 27, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

30. L is -C(R Ｌ１ R Ｌ２ ) - and R Ｌ１ and R Ｌ２ At least one of them is C １－３ A compound according to any one of claims 1 to 27, selected from alkyl groups, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

31. R １ and R ２ A compound according to any one of claims 1 to 30, wherein H is selected from H, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

32. A compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from Table 1.

33. A compound according to claim 32, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from Table 2 and Table 2a.

34. Use of a compound according to any one of claims 1 to 33, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product for treating a disease or condition associated with KRAS mutation.

35. A compound according to any one of claims 1 to 33, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition associated with KRAS mutation.

36. A method for treating a disease or symptom associated with KRAS mutation, comprising administering a compound according to any one of claims 1 to 33, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need.

37. The above KRAS mutation is KRAS Ｇ１２Ｄ A mutation, the use according to claim 34, the compound according to claim 35, or the method according to claim 36.

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