Pan-kras inhibitors and their medical use

Abstract

The present application relates to compounds described by Formula (I), or stereoisomers, tautomers, deuterated analogs, or pharmaceutically acceptable salts thereof, methods of making them, pharmaceutical compositions containing them, and their use as medicaments to treat and / or prevent diseases mediated by KRAS.

Description

Pan-KRAS inhibitors and their medical applications Technical Field

[0001] The present invention relates to the field of medical technology, and specifically to a compound of formula (I), or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, as well as preparation methods and pharmaceutical compositions thereof, and their use as drugs for treating cancer. Background Art

[0002] Currently, drug development targeting KRAS mutations is a hot topic in new drug research. The KRAS gene is the most commonly mutated oncogene in human cancers. According to statistics, KRAS mutations occur in nearly 90% of pancreatic cancers, 30-40% of colon cancers, and over 30% of lung adenocarcinomas. However, because the KRAS protein lacks a suitable binding pocket for small molecule inhibitors, the development of small molecule drugs targeting KRAS has remained elusive for 40 years. Only in recent years, thanks to the tireless efforts of researchers, have KRAS G12C inhibitors finally been brought to market.

[0003] Since the discovery of KRAS G12C inhibitors, scientists have turned their attention to other KRAS mutants and to developing pan-KRAS (pan-KRAS) targeted therapies that can target multiple or even all KRAS mutants. Pan-KRAS targeted therapies have the potential to treat a wide range of patient populations, including cancers harboring KRAS G12D, G12V, G13D, G12R, G12A, and G12S mutations, as well as KRAS wild-type amplification, and cancers that are resistant to KRAS G12C inhibitors.

[0004] Given the importance of abnormal KRAS activation in cancer progression and the prevalence of KRAS gene mutations in human cancers, there is still a great unmet clinical need for the development of safe and effective pan-KRAS inhibitors.

[0005] Summary of the Invention

[0006] The purpose of the present invention is to provide a safe and effective pan-KRAS inhibitor, in particular an inhibitor for the treatment of tumors such as colorectal cancer, lung cancer, pancreatic cancer, bile duct cancer, and gastric cancer.

[0007] The present invention provides a compound represented by general formula (I), or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof:

[0008] in,

[0009] Indicates whether the bonds in the ring are single or double bonds;

[0010] Each X1 is the same or different and is independently selected from CR 10 , CR 10 R 10 、N、NR 10 , O, S or S(O) 1-2 ;

[0011] X2 is selected from O, S, S(O) 1-2 , N or NR 10 ;

[0012] X3 is selected from N or CR 10 ;

[0013] X4 selected from CR 10 or N;

[0014] X5 selected from CR 11 or N;

[0015] X6 selected from CR 12 or N;

[0016] X7 selected from CR 13 or N;

[0017] X8 selected from CR 14 or N;

[0018] X9 selected from CR 15 or N;

[0019] X 10 Selected from CR 16 or N;

[0020] X 11 Selected from C(R 17 )2, O or NR 17 ;

[0021] L is selected from

[0022] Ring A is selected from C 5-14 Cycloalkyl, 5-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl; wherein, the C 5-14 Cycloalkyl, 5-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more R a Substitution; or two R on the same atom a Formation C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0023] R1 is selected from H, hydroxyl, C 1-6 Hydroxyalkyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -C 0-3 Alkylene-N(R c )2. -C 0-3 Alkylene-C 2-6 Alkenyl, -C 0-3 Alkylene-C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group, -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-5-18 membered heteroaryl; wherein the hydroxyl group, C 1-6 Hydroxyalkyl, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -C 0-3 Alkylene-N(R c )2. -C 0-3 Alkylene-C 2-6 Alkenyl, -C 0-3 Alkylene-C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group, -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-5-18 membered heteroaryl is optionally further substituted by one or more R a Substitution, or two R on the same atom a Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0024] R2 is selected from H, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0025] R3 is selected from H, halogen, cyano, amino, nitro, C1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy or C 1-6 hydroxyalkyl;

[0026] Alternatively, R2 and R3 together with the atoms to which they are attached form a carbonyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b Substitution; or two R on the same atom b Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0027] R4 is selected from H, hydroxyl, C 1-6 Hydroxyalkyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-N(R c )2. -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group, -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-5-18 membered heteroaryl; wherein the hydroxyl group, C 1-6 Hydroxyalkyl, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-N(R c )2. -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group, -C 0-3 Alkylene-C 6-18 Aryl or -C0-3 Alkylene-5-18 membered heteroaryl is optionally further substituted by one or more R a Substitution; or two R on the same atom a Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0028] R 4a Selected from H, halogen, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy or C 1-6 Hydroxyalkyl; wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy or C 1-6 The hydroxyalkyl group is optionally further substituted with one or more R a Substitution; or two R on the same atom a Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0029] Or, two R 4a Together with the atoms to which they are attached, they form a carbonyl group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0030] R5 is selected from H, halogen, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy or C 1-6 hydroxyalkyl;

[0031] R6 is selected from H, halogen, hydroxy, cyano, C1-3 Alkoxy, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 Aryl; wherein the hydroxyl group, C 1-3 Alkoxy, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 The aryl group is optionally further substituted with one or more R a replace;

[0032] Alternatively, R5 and R6 together with the atoms to which they are attached form a carbonyl, C 3-8 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted by one or more R a replace;

[0033] R 5a and R 6a are independently H, halogen, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy or C 1-6 hydroxyalkyl;

[0034] Or, R 5a and R 6a Together with the atoms to which they are attached, they form a carbonyl group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0035] R7 is selected from the group consisting of absent, H, halogen, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-14 membered heterocyclyl or 5-10 membered heteroaryl;

[0036] R8 is selected from the group consisting of absent, H, halogen, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy or C 1-6 hydroxyalkyl;

[0037] Alternatively, R7 and R8 together with the atoms to which they are attached form a C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0038] Alternatively, two R8 atoms together with the atoms to which they are attached form a C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0039] M is selected from C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 1-6 heteroalkylene, -C(O)O-CH(R9)-, -C(O)NH-CH(R9)-, or 5-8 membered heteroarylene; R9 is selected from hydrogen or methyl;

[0040] When M is -C(O)O-CH(R9)- or -C(O)NH-CH(R9)-, CH(R9) therein is bonded to -C(R5R6)-; or

[0041] R6 and R9 together with the atoms to which they are attached form C 3-8 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0042] R 10 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group or C 1-6 alkyl halide;

[0043] Or, R 10 and R8 together with the atoms to which they are attached form C3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0044] Or, two R 10 Together with the atoms to which they are attached, they form a carbonyl group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0045] R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 are independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 1-6 alkyl halide;

[0046] Or, two R 17 Together with the atoms to which they are attached, they form a carbonyl group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0047] Or, R 13 and R 4a Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0048] Or, R 16 and R 5a Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0049] Or, R 17 and R 4a Together with the atoms to which it is attached, it forms C 3-8Cycloalkyl or 3-8 membered heterocyclic group; wherein said C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0050] Or, R 14 、R 15 、R 16 , R4 and R 4a Any two of them together with the atoms they are connected to form a C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally further substituted with one or more R b replace;

[0051] R a are independently selected from the group consisting of absent, H, hydroxy, oxo, amino, imino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -C 0-3 Alkylene-OR b 、-C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-S(O) 1-2 R b 、-C 0-3 Alkylene-S(R b )5、=C(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); wherein the amino, imino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-, -C 0-3Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace;

[0052] Each R b are independently H, halogen, hydroxy, oxo, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 1-6 Haloalkoxy or C 1-6 Haloalkyl; wherein the amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 1-6 Haloalkoxy or C 1-6 The haloalkyl group is optionally further substituted with one or more H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, amino, -NHC 1-3 Alkyl, -N(C 1-3 alkyl)2 substituted;

[0053] Each R c Each independently selected from H, hydroxy, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group or C 1-6 alkyl halide;

[0054] r is 1-3; preferably 1, 2 or 3;

[0055] s is 1-3, preferably 1, 2 or 3;

[0056] t is 0-4, preferably 0, 1, 2, 3 or 4, more preferably 0-3.

[0057] In some embodiments, formula (I) is selected from formula (I-1):

[0058] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a 、R 5a 、R 6a ,X1,X2,X3,X4,X5,X6,X7,X8,X9,X10 、X 11 , L, M, ring A, r, s, and t are as defined above in formula (I).

[0059] In some embodiments, formula (I) is selected from formula (II-1) or formula (II-2):

[0060] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 10 、R 4a 、R 5a 、R 6a ,X4,X5,X6,X7,X8,X9,X 10 、X 11 , L, ring A, s, and t are as defined above in formula (I).

[0061] In some embodiments, Formula (I) is selected from Formula (II-1a) or Formula (II-2a):

[0062] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a 、R 5a 、R 6a ,X4,X5,X6,X7,X8,X9,X 10 、X 11 , L, ring A, s, and t are as defined above in formula (I).

[0063] In some embodiments, Formula (I) is selected from Formula (IIIa-IIIc) or (IIIa'-IIIc'):

[0064] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a 、R 5a 、R 6a ,X4,X5,X6,X7,X8,X9,X 10 、X 11 , Ring A, s, and t are as defined above in formula (I).

[0065] In some embodiments, ring A in formula (I) is selected from C 6-18 Aryl or 5-18 membered heteroaryl; wherein, the C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more R a Substituted, the R a Selected from H, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C1-6 Halogenated alkoxy, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally further substituted with one or more R b Substituted, the R b Selected from H, halogen or C 1-6 alkyl.

[0066] In some embodiments, C in formula (I) 6-18 The aryl group is selected from a benzene ring.

[0067] In some embodiments, the 5-18 membered heteroaryl group in formula (I) is selected from a thiazole ring or an oxazole ring.

[0068] In some embodiments, X4 in formula (I) is selected from N.

[0069] In some embodiments, X5 in formula (I) is selected from CH or N.

[0070] In some embodiments, X6 in formula (I) is selected from CH or N.

[0071] In some embodiments, X7 in formula (I) is selected from CH or N.

[0072] In some embodiments, X8 in formula (I) is selected from CH or N.

[0073] In some embodiments, X9 in formula (I) is selected from CH or N.

[0074] In some embodiments, X in formula (I) 10 Selected from CH.

[0075] In some embodiments, X in formula (I) 11 Selected from O.

[0076] In some embodiments, Formula (I) is selected from Formula (IVa-IVc) or Formula (IVa'-IVc'):

[0077] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a 、R 5a 、R 6a , Ring A, s, and t are as defined above in formula (I).

[0078] In some embodiments, formula (I) is selected from formula (IVa-1 to IVc-1) or (IVa-1' to IVc-1'):

[0079] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a 、R 5a 、R 6a , Ring A, and t are as defined above in formula (I).

[0080] In some embodiments, Formula (I) is selected from Formula (Va-Vc) or Formula (Va'-Vc'):

[0081] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a 、R 5a 、R 6a , s, and t are as defined in the aforementioned formula (I).

[0082] In some embodiments, formula (I) is selected from formula (Va-1 to Vc-1) or formula (Va-1' to Vc-1'):

[0083] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a 、R 5a 、R 6a , t are as defined in the above formula (I).

[0084] In some embodiments, formula (I) is selected from the structure represented by formula (VI) or formula (VI'):

[0085] wherein R1 and R4 are as defined in the above formula (I).

[0086] In some embodiments, formula (I) is selected from the structure represented by formula (VI-1) or formula (VI'-1):

[0087] wherein R1 and R4 are as defined in the above formula (I).

[0088] In some embodiments, R1 in formula (I) is selected from C 1-6 Alkyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group, -C 0-3 Alkylene-N(R c )2. -C 0-3 Alkylene-C 2-6 Alkenyl or -C 0-3 Alkylene-C 2-6 Alkynyl; wherein the C 1-6 Alkyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C0-3 Alkylene-3-14 membered heterocyclic group, -C 0-3 Alkylene-N(R c )2. -C 0-3 Alkylene-C 2-6 Alkenyl or -C 0-3 Alkylene-C 2-6 The alkynyl group is optionally further substituted with one or more R a Replace, each R c Each independently selected from H, hydroxy, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 haloalkyl; said R a Selected from halogen, C 1-6 Alkyl, =C(R b )2、C 1-6 Halogenated alkyl, C 1-6 Alkoxy or -C 0-3 Alkylene-N(R b )2, the R b Selected from H, halogen or C 1-6 Alkyl; or two R on the same atom a Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group.

[0089] In some embodiments, R1 in formula (I) is selected from

[0090] In some embodiments, R2 in formula (I) is selected from H.

[0091] In some embodiments, R3 in formula (I) is selected from H.

[0092] In some embodiments, R4 in formula (I) is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-3-14 membered heterocyclic group or -C 0-3 Alkylene-N(R c )2; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-3-14 membered heterocyclic group or -C 0-3 Alkylene-N(R c ) 2 optionally further represented by one or more R a Substituted, the R a are independently selected from the group consisting of absent, H, hydroxy, oxo, amino, imino, cyano, halogen, C 1-6 Alkyl, -C0-3 Alkylene-N(R b )2、C 1-6 Haloalkyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group; the amino, imino, C 1-6 Alkyl, -C 0-3 Alkylene-, C 1-6 Haloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group is optionally further substituted by one or more R b Replace, each R b independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 Halogenated alkyl.

[0093] In some embodiments, R4 in formula (I) is selected from

[0094] In some embodiments, R in formula (I) 4a Selected from H or C 1-6 alkyl.

[0095] In some embodiments, R5 in formula (I) is selected from H or C 1-3 alkyl.

[0096] In some embodiments, R6 in formula (I) is selected from H or C 1-3 alkyl.

[0097] In some embodiments, R in formula (I) 5a Selected from H or C 1-3 alkyl.

[0098] In some embodiments, R in formula (I) 6a Selected from H or C 1-3 alkyl.

[0099] In some embodiments, R7 in formula (I) is selected from H or C 1-3 Alkyl, preferably H.

[0100] In some embodiments, R8 in formula (I) is selected from H or C 1-3 Alkyl, preferably H.

[0101] In some embodiments, Ring A in Formula (I) is selected from wherein these groups are optionally further substituted by one or more Ra; or two Ra on the same atom form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with one or more Rb.

[0102] In some embodiments, the compound represented by formula (I) is selected from the following compounds:

[0103] The present invention relates to inhibitors of KRas wild type and / or various mutant forms of KRas, such as KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations. Specifically, the present invention relates to active compounds, pharmaceutical compositions and uses thereof that inhibit KRas wild type and / or KRas mutations such as G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H, preferably active compounds, pharmaceutical compositions and uses thereof that inhibit G12C, G12D, G12V.

[0104] The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of at least one compound represented by the aforementioned formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0105] The present invention also provides the use of the compound represented by the aforementioned formula (I), or its stereoisomers, tautomers, deuterated substances, or pharmaceutically acceptable salts or pharmaceutical compositions in the preparation of drugs.

[0106] The present invention further provides a preferred technical solution for the application:

[0107] Preferably, the application is application in the preparation of drugs for treating and / or preventing cancer.

[0108] Preferably, the application is for the preparation of a medicament for treating a disease mediated by KRAS. Preferably, the disease is cancer.

[0109] Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

[0110] The present invention also provides a method for treating and / or preventing a disease, comprising administering to a subject a therapeutically effective amount of at least one compound represented by the aforementioned formula (I), or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0111] The present invention also provides a method for treating and / or preventing a disease mediated by KRAS, comprising administering to a subject a therapeutically effective amount of at least one compound represented by the aforementioned formula (I), or a stereoisomer, tautomer, deuterated form, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0112] The present invention also provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of at least one compound represented by formula (I), or a stereoisomer, tautomer, deuterated compound, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0113] Preferably, in the above method, the KRAS-mediated disease is cancer.

[0114] Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

[0115] Unless otherwise indicated, general chemical terms used in the structural formulae have their usual meanings.

[0116] For example, the term "halogen," as used herein, refers to fluorine, chlorine, bromine, or iodine, unless otherwise indicated.

[0117] In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "alkyl" in 1-6 " refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain. The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane with two CH bonds replaced as the point of attachment of the alkylene to the rest of the compound. Similarly, C 1-3 The "C" in the alkylene 1-3 ” refers to an alkylene group containing 1, 2 or 3 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.

[0118] "Alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl groups, ie, -O-alkyl.

[0119] The term "haloalkyl" refers to an alkyl group in which one or more H groups have been replaced by a halogen atom.

[0120] The term "haloalkoxy" refers to the radical -O-haloalkyl.

[0121] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to C, and forms a sulfoxide group or a sulfone group or an N-oxide group when attached to a heteroatom.

[0122] In the present invention, unless otherwise specified, the term "aromatic ring", "aromatic ring" or "aromatic heterocycle" refers to a polyunsaturated carbon ring or heterocycle with aromatic characteristics (having (4n+2) delocalized π electrons, where n is an integer).

[0123] The term "aryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or condensed ring aromatic group containing carbon ring atoms. 6-12 Aryl, more preferably C 6-10 A monocyclic or bicyclic aromatic ring group. Preferably, it is phenyl or naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl group, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include but are not limited to benzocyclopentyl.

[0124] The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heterocyclic ring, wherein the heteroatom is selected from N, O and / or S. The heterocyclyl group may include a monocyclic or polycyclic ring (e.g., having 2, 3 or 4 fused rings, spirocyclic rings, bridged rings, etc.). The heterocyclyl group may be connected to the other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom. Preferably, the heterocyclyl group is a 3-14 membered group, wherein the "3-14 members" in the 3-14 membered heterocyclyl group refers to a heterocyclyl group composed of 3-14 C, N, O or S ring atoms; more preferably, a 3-8 membered heterocyclyl group. The nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. Examples of these heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclic group can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclic group.

[0125] The term "heteroaryl" in the present invention, unless otherwise specified, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. A 5-14-membered heteroaryl is preferred, wherein the "5-14 members" in the 5-14-membered heteroaryl refers to a heteroaryl group consisting of 5-14 ring atoms of C, N, O, or S. A 5-10-membered heteroaryl is more preferred; and a 5-6-membered heteroaryl is even more preferred. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolyl, or isoquinolyl. The heteroaryl group may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring.

[0126] The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. 3-12 Cycloalkyl, where "C 3-12" means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms. More preferred is a 3-10 membered cycloalkyl group; even more preferred is a 3-8 membered cycloalkyl group or a 5-6 membered cycloalkyl group. Cycloalkyl groups may include monocyclic and polycyclic rings (for example, having 2, 3 or 4 fused rings, spirocyclic rings, bridged rings, etc.). In some embodiments, cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group may also be fused to an aryl, heterocyclic or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl group.

[0127] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 5-14 members, more preferably 5-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, and more preferably a bicyclic or tricyclic group. Examples of bridged cycloalkyl groups include, but are not limited to

[0128] The term "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include but are not limited to halogen (F, Cl, Br or I), C 1-8 Alkyl, C 3-12 Cycloalkyl, -OR 1 、-SR 1 , =O, =S, -C(O)R1, -C(S)R 1 、=NR 1 、-C(O)OR 1 、-C(S)OR 1 、-NR 1 R 2 、-C(O)NR 1 R 2 , cyano, nitro, -S(O)2R 1 、-OS(O2)OR 1 、-OS(O)2R 1 、-OP(O)(OR 1 )(OR 2 ); where R 1 and R 2 Independently selected from -H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethylamino, methylthio, sulfonyl, and acetyl.

[0129] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0130] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.

[0131] When the compound provided by the present invention is an acid, its corresponding salt can be easily prepared from pharmaceutically acceptable nontoxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc and the like. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Nontoxic organic bases that can be derived into pharmaceutically acceptable salts include primary amines, secondary amines and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0132] When compound provided by the invention is a base, it is possible to conveniently prepare its corresponding salt from pharmaceutically acceptable nontoxic acid, including inorganic and organic acids. Such acid includes, as, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, tamoxifen, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0133] Prodrugs of the compounds of the present invention are included within the scope of protection of the present invention. Generally, such prodrugs are functional derivatives that are readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, ester salt, or other derivative of the compounds of the present invention, which, upon administration to a recipient, can directly or indirectly provide the compounds of the present invention or their pharmaceutically active metabolites or residues.

[0134] The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.

[0135] When the compound represented by formula (I) exists in tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0136] Substitution of compounds of formula (I) with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0137] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0138] In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient composition can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0139] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0140] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0141] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0142] The term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be therapeutic in terms of partial or complete stabilization or cure of a disease and / or side effects caused by the disease. As used herein, "treat" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., arresting its progression; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or its symptoms.

[0143] The term "effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0144] Synthesis scheme

[0145] in,

[0146] R 1 or R 2 Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-(3-14 membered heterocyclic) or -C 0-3 Alkylene-N(R c )2; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-(3-14 membered heterocyclic) or -C 0-3 Alkylene-N(R c ) 2 optionally further represented by one or more R a Substituted, the R a are independently selected from the group consisting of absent, H, hydroxy, oxo, amino, imino, cyano, halogen, C 1-6 Alkyl, -C 0-3 Alkylene-N(R b )2、C 1-6 Haloalkyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3Alkylene-(3-14 membered heterocyclic group); the amino, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclyl) is optionally further substituted with one or more R b Replace, each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0147] or R 1 and R 2 Together with the atoms to which it is attached, it forms a 3-14 membered heterocyclic group, which is optionally further substituted by one or more R a replace;

[0148] R 3 Selected from H, hydroxyl, C 1-6 Hydroxyalkyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -C 0-3 Alkylene-N(R c )2. -C 0-3 Alkylene-C 2-6 Alkenyl, -C 0-3 Alkylene-C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); wherein the C 1-6 Hydroxyalkyl, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -C 0-3 Alkylene-N(R c )2. -C 0-3 Alkylene-C 2-6 Alkenyl, -C 0-3 Alkylene-C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R a Substitution, or two R on the same atom a Formation C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 Cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace;

[0149] Each R b are independently H, halogen, hydroxy, oxo, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkoxy or C 1-6 haloalkyl; wherein said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkoxy or C 1-6 The haloalkyl group is optionally further substituted with one or more H, C 1-6 Alkoxy, -N(C 1-3 Alkyl)2;

[0150] Each R c Each independently selected from H, hydroxy, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Halogenated alkyl.

[0151] The compounds of formula (I) of the present invention can be synthesized according to the general methods in the above synthesis schemes. BRIEF DESCRIPTION OF THE DRAWINGS

[0152] Figure 1 is the HH NOESY spectrum of compound 1-6A.

[0153] Figure 2 is the absolute configuration diagram of the single crystal X-ray diffraction molecule of compound 83.

[0154] Figure 3 is the single crystal X-ray diffraction molecular structure ellipsoid diagram of compound 83.

[0155] FIG4 is a unit cell stacking projection diagram of single crystal X-ray diffraction of compound 83 along the c-axis direction. DETAILED DESCRIPTION

[0156] To make the above content clearer and more specific, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific embodiments of the present invention, technical means or methods not specifically described are conventional technical means or methods in the art.

[0157] Unless otherwise stated, all temperatures herein are in degrees Celsius.

[0158] The following abbreviations are used in the examples:

[0159] EA: ethyl acetate;

[0160] PE: petroleum ether;

[0161] DCM: dichloromethane;

[0162] LiBH4: lithium borohydride;

[0163] THF: tetrahydrofuran;

[0164] MeOH: methanol;

[0165] EtOH: ethanol;

[0166] DMSO: dimethyl sulfoxide;

[0167] DMF: N,N-dimethylformamide;

[0168] ACN: acetonitrile;

[0169] TFA: trifluoroacetic acid;

[0170] TEA: triethylamine;

[0171] DIEA: N,N-diisopropylethylamine;

[0172] [Ir(COD)Cl]2: 1,5-cyclooctadiene iridium chloride dimer;

[0173] Dtbpy: 4,4′-di-tert-butyl-2,2′-bipyridine;

[0174] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium;

[0175] XpHos: 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl;

[0176] SpHos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl;

[0177] cataCXium A Pd G3: [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) methanesulfonate;

[0178] AgOTf: silver trifluoromethanesulfonate;

[0179] TBDPSCl: tert-butyldiphenylchlorosilane;

[0180] PdCl2(dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

[0181] BINAP: 1,1'-binaphthyl-2,2'-bis(diphenylphosphine);

[0182] NIS: iodosuccinimide;

[0183] B2pin2 or (Bpin)2: pinacol borate;

[0184] HOBt: 1-hydroxybenzotriazole;

[0185] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide;

[0186] TBAF: tetrabutylammonium fluoride;

[0187] DMAP: 4-dimethylaminopyridine;

[0188] HATU: benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0189] Noyori catalyst (ss): (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride;

[0190] ZnCl2: zinc chloride;

[0191] TsCl: p-toluenesulfonyl chloride;

[0192] CuBr2: copper bromide;

[0193] MeMgBr: methylmagnesium bromide.

[0194] Synthesis of intermediate M1:

[0195] Step 1: Synthesis of intermediate M1-1

[0196] Activated zinc powder (31.79 g), iodine (0.62 g), and 1 / 3 of (R)-N-Boc-3-iodoalanine methyl ester (30.00 g) were added to N,N-dimethylformamide (150.00 mL). Under nitrogen displacement, the reaction mixture was heated to 40°C and allowed to react for 1 hour. Two-thirds of (R)-N-Boc-3-iodoalanine methyl ester (60.00 g) was then added, and the internal temperature was rapidly raised to 55°C before being cooled to 40°C and allowed to react for 1 hour. After cooling, the supernatant was filtered through celite under nitrogen protection and washed three times with 20 mL of N,N-dimethylformamide. The combined filtrates yielded 210 mL of M1-1 in N,N-dimethylformamide, which was then used directly in the next step.

[0197] Step 2: Synthesis of intermediate M1

[0198] At room temperature, 2,4-dibromothiazole (70.93 g), Pd2(dba)3 (6.68 g), and XpHos (3.48 g) were added to a reaction flask. Under nitrogen protection, 210 mL of a solution of M1-1 in N,N-dimethylformamide was slowly added dropwise. The nitrogen was replaced three times, and the temperature was raised to 70°C, where the reaction was continued for 2 h. The reaction solution was slowly added to 1 L of saturated ammonium chloride, extracted three times with 500 mL of EA, washed once with 500 mL of saturated sodium chloride, and dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain a crude product, which was then separated by column chromatography (PE:EA = 95:5 to 80:20) to obtain the target intermediate M1 (47.64 g, 53.60% yield). ESI-MS m / z: 365.20, 367.22 [M+H] + .

[0199] Synthesis of intermediate M2:

[0200] Step 1: Synthesis of compound M2-2

[0201] To a solution of compound M2-1 (100 g) and imidazole (115 g) in DCM (2.5 L) at 0°C, TBDPSCl (244 g) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction, hydrochloric acid (2 N, 2.5 L) was added to neutralize the aqueous phase to acidity, followed by extraction twice with appropriate amounts of DCM. The combined organic phases were washed three times with sodium hydroxide (1 N, 3 L each), dried over anhydrous sodium sulfate, and concentrated to yield the target compound M2-2 (309 g, 102% yield, crude product).

[0202] Step 2: Synthesis of Compound M2-3

[0203] To a solution of compound M2-2 (200 g) in DCM (600 mL) was added DMF (0.43 mL) at room temperature. Oxalyl chloride (76 mL) was then slowly added dropwise to the stirred solution. The reaction mixture was transferred to a 40°C oil bath and stirred for 2 h. After completion of the reaction, the reaction system was concentrated to afford compound M2-3 (210 g, 99% yield), which was used directly in the next reaction.

[0204] Step 3: Synthesis of Compound M2-4

[0205] To a solution of compound M2-3 (210 g) in dichloromethane (800 mL) was added dropwise SnCl4 (560 mL, 1 M / THF) at 0°C under a nitrogen atmosphere. The reaction mixture was transferred to a -10°C cold bath and stirred for 30 minutes. A solution of 5-bromoindole (109.8 g) in DCM (560 mL) was then added dropwise to the reaction system. The reaction mixture was transferred to a -10°C cold bath and stirred for 15 minutes. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction and neutralize the reaction system to neutrality. The reaction system was stirred for 10 minutes, then concentrated to remove the dichloromethane. An appropriate amount of ethyl acetate was added for extraction and separation. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was slurried with ethyl acetate to obtain the target compound M2-4 (200 g, 67% yield).

[0206] Step 4: Synthesis of Compound M2-5

[0207] To a solution of compound M2-4 (194 g) in tetrahydrofuran (2 L) at 0°C under a nitrogen atmosphere, LiBH4 (23.7 g) was added portionwise. The reaction was then stirred in a 66°C oil bath for 20 h. After completion of the reaction, methanol was added dropwise to quench the reaction. Extraction was then performed with saturated brine and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was separated by column chromatography (elution with 0-10% EA / PE) to afford the target compound M2-5 (145 g, 77% yield).

[0208] Step 5: Synthesis of Compound M2-6

[0209] To a THF solution (500 mL) of compound M2-5 (100 g) was added TBAF (1 M, 500 mL), and the reaction system was stirred in a 50°C oil bath for 12 h. After completion of the reaction, the reaction system was concentrated, extracted with EA and water, and the organic phase was washed twice with water. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The concentrate was separated by column chromatography (elution with 0-35% EA / PE) to yield the target compound M2-6 (54 g, 100% yield).

[0210] Step 6: Synthesis of Compound M2-7

[0211] To a dichloromethane solution (300 mL) of compound M2-6 (54 g), triethylamine (80 mL), and DMAP (1.2 g) was added acetic anhydride (18 mL) dropwise at 0°C, and stirring was continued in an ice bath at 0°C for 10 min. After the reaction, an appropriate amount of water was added to the reaction system, and the organic phase was extracted and washed twice with water. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford compound M2-7 (62 g, 100% yield), which was used directly in the next reaction.

[0212] Step 7: Synthesis of Compound M2-8

[0213] To a 1L three-necked flask, M2-7 (40 g), (Bpin)2 (78.3 g), potassium acetate (30.3 g), PdCl2(dppf) (9.0 g), and 400 mL of toluene were added. The flask was purged with nitrogen three times and then placed in a 90°C oil bath and stirred for 2 h. After the reaction, the reaction mixture was concentrated and the concentrate was separated by column chromatography (elution with 0-25% EA / PE) to obtain the target compound M2-8 (36 g, 78% yield). ESI-MS m / z: 372.3 [M+H] + .

[0214] Step 8: Synthesis of Compound M2-9

[0215] To a 1L three-necked flask, M2-8 (36 g), intermediate M1 (47 g), potassium phosphate (51.5 g), PdCl2(dppf) (7.1 g), 210 mL of toluene, 70 mL of dioxane, and 70 mL of water were added. The flask was purged with nitrogen three times and then placed in a 70°C oil bath and stirred for 20 h. After the reaction, appropriate amounts of water and EA were added to the reaction system. After extraction and separation, the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by column chromatography (elution with 20-35% EA / PE) to obtain the target compound M2-9 (40 g, 78% yield). ESI-MS m / z: 530.3 [M+H] + .

[0216] Step 9: Synthesis of Compound M2-10

[0217] AgOTf (23.3 g) was added to a tetrahydrofuran solution (400 mL) of compound M2-9 (40 g) at 0°C, followed by a tetrahydrofuran solution (80 mL) of elemental iodine (19.2 g) dropwise, and the mixture was stirred in an ice bath at 0°C for 10 min. After the reaction, an appropriate amount of sodium thiosulfate solution was added to the system to quench the reaction. An appropriate amount of ethyl acetate was then added to the system for extraction and separation. The organic phase was washed once with water and once with saturated brine, then dried over anhydrous sodium sulfate and concentrated. The concentrate was separated by column chromatography (0-30% EA / PE elution) to obtain the target compound M2-10 (25 g, 51% yield). ESI-MS m / z: 656.3 [M+H] + .

[0218] Step 10: Synthesis of Compound M2-11

[0219] To a solution of compound M2-10 (25 g) in tetrahydrofuran (180 mL) / water (60 mL) at 0°C, lithium hydroxide (2.7 g) was added and the mixture was stirred at room temperature for 12 h. After the reaction, an appropriate amount of concentrated hydrochloric acid was added to the system to adjust the pH of the reaction system to approximately 5. An appropriate amount of ethyl acetate was then added for extraction and separation. The organic phase was washed once with water and once with saturated brine, then dried over anhydrous sodium sulfate and concentrated to yield the target compound M2-11 (23 g, 100% yield). ESI-MS m / z: 600.3 [M+H] + .

[0220] Step 11: Synthesis of Compound M2-12

[0221] To a DMF solution (130 mL) of compound M2-11 (26 g), (S)-tert-butylhexahydropyridazine-3-carboxylic acid methyl ester (10.2 g), and HATU (19.8 g) was added DIEA (25 mL) at 0°C. The reaction mixture was brought to room temperature and stirred for 2 h. After the reaction, appropriate amounts of EA and water were added to the system for extraction and separation. The aqueous phase was extracted twice with appropriate amounts of EA. The combined organic phases were washed once with saturated brine and dried over anhydrous sodium sulfate. The concentrate was separated by column chromatography (elution with 60% EA / PE) to obtain the target compound M2-12 (25 g, 79% yield). ESI-MS m / z: 726.4 [M+H] + .

[0222] Step 12: Synthesis of Compound M2-13

[0223] At 0°C, an aqueous solution of lithium hydroxide (2.1 g) (80 mL) was added dropwise to a THF solution (240 mL) of compound M2-12 (26 g). The reaction solution was brought to room temperature and stirred for 30 min. After the reaction was completed, an appropriate amount of concentrated hydrochloric acid was added to the system to adjust the pH of the reaction system to approximately 6. An appropriate amount of ethyl acetate was then added for extraction and separation. The organic phase was washed once with water and once with saturated brine, then dried over anhydrous sodium sulfate and concentrated to obtain the target compound M2-13 (25 g, 99% yield). ESI-MS m / z: 712.5 [M+H] + .

[0224] Step 13: Synthesis of Compound M2-14

[0225] To a dichloromethane solution (2 L) of compound M2-13 (25 g), HOBt (14.2 g), and DIEA (35 mL) was added EDCI (27.2 g) at 0°C. The reaction mixture was brought to room temperature and stirred for 4 h. After completion of the reaction, water was added to the system for extraction and separation. The organic phase was washed once with water and once with saturated brine, then dried over anhydrous sodium sulfate and concentrated. The concentrate was separated by column chromatography (0-50% EA / PE elution) to obtain the target compound M2-14 (18.3 g, 75% yield). ESI-MS m / z: 694.4 [M+H] + .

[0226] Step 14: Synthesis of Compound M2

[0227] M2-14 (10 g), Sphos (1.8 g), Pd2(dba)3 (1.6 g), potassium acetate (5.0 g), and 100 mL of toluene were added to a 250 mL three-necked flask. The flask was then purged with nitrogen three times and moved to a 0°C ice bath with stirring. Pinacol borane (15.7 mL) was then added to the reaction system, and the reaction system was placed in a 60°C oil bath and stirred for 4 h. After the reaction, an appropriate amount of saturated ammonium chloride was added to the reaction system to quench the reaction. EA was then added for extraction and separation. The organic phase was then washed twice with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was separated by column chromatography (0-40% EA / PE elution) to obtain the target compound M2 (9.7 g, 97% yield). ESI-MS m / z: 694.5 [M+H] + .

[0228] Synthesis of intermediate M3:

[0229] Step 1: Synthesis of Compound M3-1

[0230] Compound (S)-(+)-1,3-butanediol (5.00 g), triethylamine (11.60 mL), and 4-DMAP (0.14 g) were sequentially added to a DCM (60.00 mL) solution. Under nitrogen protection, the mixture was cooled to -20°C and TsCl (11.63 g) dissolved in DCM (60.00 mL) was slowly added dropwise over 2 hours. The mixture was then incubated at -25 to -20°C for 3 hours before returning to room temperature for 18 hours. After completion of the reaction, the mixture was quenched with 100 mL of water, extracted three times with 50 mL of DCM, and washed twice with 50 mL of saturated sodium chloride. The organic phases were combined, concentrated, and dried to obtain the crude product. The crude product was separated by column chromatography (PE:EA = 95:5 to 80:20) to afford the target compound M3-1 (9.50 g, 70.09% yield) as a colorless liquid. ESI-MS m / z:245.32[M+H] + .

[0231] Step 2: Synthesis of Compound M3

[0232] At room temperature, compound M3-1 (9.50 g), 4-DMAP (0.24 g), and imidazole (6.62 g) were added to DCM (80.00 mL). Tert-butyldimethylsilyl chloride (8.79 g) was then slowly added under N2 protection and allowed to react at room temperature for 2 h. After completion of the reaction, 100 mL of water was added to the reaction solution to quench the reaction. The mixture was then extracted with 3 50 mL of DCM and washed with 2 50 mL of saturated sodium chloride. The combined organic phases were concentrated to obtain a crude product, which was separated by column chromatography (PE:EA = 95:5 to 80:20) to obtain the target compound M3 (13.80 g, 98.97% yield) as a colorless liquid. ESI-MS m / z: 359.43 [M+H] + .

[0233] Synthesis of intermediate M4:

[0234] Step 1: Synthesis of compound M4-1

[0235] 3-Bromo-5-fluoro-pyridine-2-carbonitrile (25.00 g, 124.38 mmol), benzyl-1-piperazine carbonate (30.14 g, 136.82 mmol), and DMF (150.00 mL) were added to a 500 ml three-necked flask under nitrogen protection. Triethylamine (25.93 mL, 186.57 mmol) was added dropwise at 0°C. The mixture was allowed to react for 2 h at room temperature, then poured into ice water and stirred for 30 min. The mixture was filtered, washed with water, and dried. The solid was slurried with PE to obtain compound M4-1 (46.50 g, 93.17%). ESI-MS m / z: 402.23, [M+H] + .

[0236] Step 2: Synthesis of compound M4-2

[0237] Compound M4-1 (46.50 g, 115.89 mmol) and tetrahydrofuran (465.00 mL) were added to a 1 L three-necked flask under nitrogen protection. Methylmagnesium bromide (108.16 mL, 3.00 mol / L, 324.48 mmol) was added dropwise at -25°C. The mixture was reacted at -20°C for 2 h, then poured into an icy aqueous ammonium chloride solution. The pH was adjusted to 3 with 1N HCl and stirred for 10 min. The pH was adjusted to 8 with sodium carbonate. The mixture was extracted with EA, washed with brine, dried, and separated by column chromatography (PE:EA=4:1) to obtain compound M4-2 (44.00 g, 90.77%). ESI-MS m / z: 419.26, [M+H] + .

[0238] Step 3: Synthesis of Compound M4-3

[0239] Triethylamine (23.26 mL, 167.35 mmol) was added to a 100 ml three-necked flask under nitrogen protection. Formic acid (7.70 g, 167.35 mmol) was added dropwise at 0°C. After the addition was complete, Noyori catalyst (ss) (1.06 g, 1.67 mmol) was added. The mixture was stirred at 0°C for 10 min, and compound M4-2 (14.00 g, 33.47 mmol) was added. The reaction was allowed to proceed at room temperature for 48 h, and the mixture was dried by spin drying. EA was added, the mixture was washed with brine, dried, and then dried by spin drying. Compound M4-3 (14.00 g, 75.00%) was obtained by column chromatography with a PE:EA ratio of 2:1. ESI-MS m / z: 421.32, [M+H] + .

[0240] Step 4: Synthesis of Compound M4-4

[0241] To a 250 mL three-necked flask, compound M4-3 (4000.00 mg, 9.52 mmol), 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate (9837.02 mg, 28.55 mmol), DMSO (100.00 mL), and THF (20.00 mL) were added sequentially. The mixture was cooled in an ice-water bath, and sodium tert-butoxide (2286.46 mg, 23.79 mmol) was added portionwise. The ice-water bath was removed, and the reaction was stirred at room temperature. After completion of the reaction as monitored by LC-MS, the reaction solution was added to ethyl acetate and a cold saturated aqueous solution of ammonium chloride, quenched, and then extracted with ethyl acetate. The organic phases were combined, washed with brine, separated, and concentrated to give the crude product, which was separated and purified by silica gel column chromatography (PE-PE / EA = 75 / 25) to obtain the target compound M4-4 (2630 mg, slightly yellow oil). ESI-MS m / z:592.27,594.27[M+H]+.

[0242] Step 5: Synthesis of Compound M4-5

[0243] Compound M4-4 (6159.00 mg, 10.39 mmol) and tetrabutylammonium fluoride (50.00 mL) (1.0 mol / L THF) were added to a 250 mL single-necked flask. The mixture was stirred at room temperature overnight under nitrogen protection. After completion of the reaction, the reaction solution was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution, and brine. The mixture was separated and the organic phase was concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (PE / EA = 90 / 10 to 75 / 25) to obtain the target product M4-5 (4820 mg, light brown viscous substance). ESI-MS m / z: 478.09, 480.06, [M+H] + .

[0244] Step 6: Synthesis of Compound M4-6

[0245] To a 250 mL single-necked flask, compound M4-5 (4820.00 mg, 10.08 mmol), DCM (75.00 mL), DIEA (4.16 mL, 25.19 mmol), and DMAP (123.10 mg, 1.01 mmol) were added sequentially. TosCl (2305.07 mg, 12.09 mmol) was added portionwise and stirred at room temperature. After 1 hour of reaction, DMAP (1354.05 mg, 11.08 mmol) and TosCl (2305.07 mg, 12.09 mmol) were added and the reaction continued with stirring. After the reaction was completed as monitored by LC-MS, the reaction mixture was diluted with dichloromethane and washed sequentially with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution, and brine. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (PE / EA=90 / 10 to 75 / 25) to obtain the target compound M4-6 (4650 mg, slightly yellowish brown viscous material). ESI-MS m / z: 632.16, 634.14, [M+H] + .

[0246] Step 7: Synthesis of Compound M4-7

[0247] To a 250 mL three-necked flask were added compound M4-6 (4650.00 mg, 7.35 mmol), M2 (5099.10 mg, 7.35 mmol), toluene (75.00 mL), dioxane (25.00 mL), water (25.00 mL), K2CO3 (2539.95 mg, 18.38 mmol), and [PdCl2(dppf)]CH2Cl2 (600.31 mg, 0.74 mmol) in sequence. The mixture was reacted under nitrogen in an oil bath at 60-65°C. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, and then with saturated aqueous ammonium chloride solution. The organic phase was separated and concentrated to give the crude product, which was then purified by silica gel column chromatography (DCM / MeOH = 500 / 15) to give the target compound M4-7 (8320 mg, slightly yellow foamy solid).

[0248] Step 8: Synthesis of Compound M4-8

[0249] To a 500 mL single-necked flask, compound M4-7 (8228.00 mg, 7.35 mmol), DMF (100.00 mL), and Cs2CO3 (4790.01 mg, 14.70 mmol) were added sequentially. The mixture was placed under nitrogen and heated in an oil bath at 60-65°C. After completion of the reaction as monitored by LC-MS, the reaction mixture was filtered, the filtrate collected, cooled in an ice-water bath, and ice water was added dropwise to precipitate an off-white solid powder. The filter cake was collected by filtration, dissolved in ethyl acetate, and washed sequentially with water and brine. The organic phase was separated and concentrated to obtain the crude product, which was separated and purified by silica gel column chromatography (DCM / MeOH = 50 / 1) to obtain the target compound M4-8 (6760 mg, slightly yellow foamy solid). ESI-MS m / z: 947.61, [M+H] + .

[0250] Step 9: Synthesis of Compound M4

[0251] To a 500 mL single-necked flask, compound M4-8 (6760.00 mg, 7.14 mmol) and MeOH (110.00 mL) were added sequentially. The atmosphere was purged with nitrogen, and Pd(OH)2 / C (4009.14 mg, 10%, 2.85 mmol) was added. The atmosphere was then purged with nitrogen and replaced with a hydrogen balloon. The hydrogen atmosphere was maintained and the reaction was stirred at room temperature. After completion of the reaction as monitored by LC-MS, the reaction mixture was filtered, the filtrate collected, concentrated to dryness, and purified by silica gel column chromatography (DCM to DCM / MeOH = 85 / 15) to obtain the target compound M4 (4270 mg, beige foamy solid). ESI-MS m / z: 813.54, [M+H] + .

[0252] Synthesis of intermediate M5:

[0253] Step 1: Synthesis of compound M5-1

[0254] 5-Bromo-3-fluoro-2-pyridinecarbonitrile (25.00 g) and N-methylpiperazine (13.70 g) were added sequentially to DMF (125.00 mL). Triethylamine (22.50 mL) was then slowly added in portions under N2 protection and in an ice-water bath. The mixture was allowed to react at room temperature for 2 h. After the reaction, the mixture was slowly added in portions to 500 mL of ice water. A white solid precipitated, which was then slurried with 3 500 mL of water, filtered, and dried in vacuo to obtain the target compound M5-1 (30.60 g, 87.50% yield). ESI-MS m / z: 281.2, 283.2 [M+H] + .

[0255] Step 2: Synthesis of compound M5-2

[0256] Compound M5-1 (30.60 g) was added to THF (300.00 mL). Methylmagnesium bromide (108.90 mL, 3.00 mol / L) was then slowly added in portions under N2 protection, maintaining the temperature at -25 to -15°C. The reaction was allowed to proceed at -20 to -10°C for 2 h. After completion, the reaction solution was slowly added to 800 mL (1 M HCl) to quench the reaction. Saturated sodium bicarbonate was then added to adjust the pH to 8-9, and the mixture was extracted with DCM (200 mL x 3). The organic phases were combined, washed with saturated sodium chloride, and concentrated to obtain the crude product. The crude product was isolated and purified by column chromatography (DCM:MeOH = 97:3 to 88:12) to obtain the target compound M5-2 (17.90 g, 55.16% yield). ESI-MS m / z: 298.2, 300.2 [M+H] + .

[0257] Step 3: Synthesis of Compound M5

[0258] Compound M5-2 (7.80 g) was added to THF (80.00 mL) and MeOH (20.00 mL). NaBH4 (1.29 g) was then slowly added in portions under N2 protection in an ice-water bath. The reaction was continued in an ice-water bath at 0-10°C for 1 h. After completion of the reaction, 100 mL of 1M HCl was added to quench the reaction (approximately 25% of the complex was quenched). The target product was then heated to reflux to dissociate. Saturated sodium carbonate solution was added to adjust the pH to 9-10, followed by extraction with 60 mL of EA (4 portions). The organic phases were combined, washed with saturated sodium chloride, and concentrated to yield the crude product. The crude product was then isolated by column chromatography (DCM:MeOH = 97:3 to 88:12) to afford target compound M5 (7.00 g, 89.14% yield). ESI-MS m / z: 300.2, 302.2 [M+H] + .

[0259] Synthesis of intermediate M6:

[0260] Step 1: Synthesis of compound M6-1

[0261] Compound 3-bromo-5-fluoro-pyridine-2-carbonitrile (99.0 g, 492.5 mmol) and potassium carbonate (102.1 g, 738.8 mmol) were added to 600 mL of DMF and cooled to 0°C. Ethylpiperazine (67.5 g, 591.1 mmol) was then slowly added and stirred at room temperature for 1 hour. After completion of the reaction, as monitored by LC-MS, the reaction solution was poured into 3 L of crushed ice. A solid precipitated with stirring and was filtered. The solid was washed with water (500 mL x 3) and then dissolved in 1000 mL of DCM, washed three times with brine, dried over anhydrous sodium sulfate, concentrated, and used directly in the next reaction. The target compound M6-1 (132.9 g) was obtained. ESI-MS m / z: 295.05, 297.05 [M+H] + .

[0262] Step 2: Synthesis of compound M6-2

[0263] Compound M6-1 (134.0 g, 453.9 mmol) was dissolved in 2100 mL of tetrahydrofuran and cooled to -30°C. MeMgBr (453 ml, 1362 mmol) was then added dropwise. After complete addition, the mixture was kept at 0-5°C for 4 h. After completion of the reaction, the reaction solution was quenched by adding 2.5 L of 1N dilute hydrochloric acid and stirred for half an hour. Solid sodium bicarbonate was then added to adjust the pH to 7-8. Ethyl acetate (1000 ml x 2) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, the target compound M6-2 (132.0 g), which was used directly in the next step. ESI-MS m / z: 312.02, 314.11 [M+H] +。

[0264] Step 3: Synthesis of Compound M6

[0265] Triethylamine (868 mL, 6246 mmol) was added to a 2000 ml three-necked flask under nitrogen. The temperature was lowered to 0°C, and then formic acid (31.4 g, 832 mmol) was slowly added. (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (10.5 g, 16.6 mmol) was added. The reaction was allowed to proceed at 40°C for 15 min. The temperature was then lowered to room temperature, and compound M6-2 (130 g, 416 mmol) was added. The reaction was continued at room temperature for 64 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with DCM, washed sequentially with water and brine, and the organic phase was concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain the target compound M6 (109 g). ESI-MS m / z: 314.03, 316.07 [M+H]. + .

[0266] Synthesis of intermediate M7:

[0267] Step 1: Synthesis of compound M7-1

[0268] To a 3 L three-necked flask, 3-((tert-butyldimethylsilyl)oxy)-propanol (200.00 g, 1050.67 mmol), dichloromethane (1000.00 mL), triethylamine (292.08 mL, 2101.34 mmol), and 4-dimethylaminopyridine (6.42 g, 52.53 mmol) were added in sequence. p-Toluenesulfonyl chloride (210.32 g, 1103.20 mmol) was added portionwise at 0°C and stirred at room temperature for 5 hours. TLC monitored the reaction completion. The reaction solution was diluted with dichloromethane and quenched with saturated NH4Cl solution. The organic layer was washed with water, saturated brine, and finally dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and allowed to cool to precipitate solid impurities. Petroleum ether was added and filtered, and the filter cake was rinsed with petroleum ether. The filtrate was concentrated under reduced pressure to obtain the desired product M7-1 (327.00 g).

[0269] Step 2: Synthesis of compound M7-2

[0270] To a 3 L three-necked flask, add M7-1 (367.00 g, 1065.18 mmol) and tetrahydrofuran (1000.00 mL) in sequence. Concentrated hydrochloric acid (44.38 mL, 12.00 mol / L, 532.59 mmol) was added dropwise at 0°C. Stir at room temperature for 1 hour. LC-MS monitored the reaction completion. The reaction mixture was quenched by pouring into ice water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure and purified by column chromatography to obtain the desired product, M7-2 (180.00 g).

[0271] Step 3: Synthesis of Compound M7-3

[0272] To a 3L three-necked flask, add M7-2 (151.20g, 656.59mmol), dichloromethane (800.00mL), and N,N-diisopropylethylamine (173.62mL, 1050.54mmol) in sequence. Under nitrogen, cool the temperature to 0°C and add chloromethyl ether (97.47mL, 1050.54mmol) dropwise. Stir at room temperature for 2 hours. LC-MS monitoring indicates residual starting material. Additional N,N-diisopropylethylamine (32.55mL, 196.98mmol) and chloromethyl ether (18.27mL, 196.98mmol) are added. Stir at room temperature for 1 hour. LC-MS monitoring indicates completion of the reaction. The reaction solution is diluted with dichloromethane and quenched by pouring into water. The organic layer is washed with water and twice with saturated brine. The organic layer is then concentrated under reduced pressure. The mixture is then dissolved in ethyl acetate, washed three times with saturated brine, and dried over anhydrous sodium sulfate. Activated carbon (40 g) was added to the organic layer and stirred for 1 hour. The mixture was filtered and the filter cake was rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the target product M7-3 (169.1 g).

[0273] Step 4: Synthesis of Compound M7-4

[0274] To a 500 mL three-necked flask, intermediate M6 (17.70 g, 56.33 mmol), dimethyl sulfoxide (130.00 mL), tetrahydrofuran (26.00 mL), and M7-3 (16.24 g, 56.33 mmol) were added in sequence. Sodium tert-butoxide (8.12 g, 84.49 mmol) was added in batches at 10°C and stirred at room temperature for 5 hours. LC-MS monitoring indicated residual starting material, and additional M7-3 (21.12 g, 73.23 mmol) and sodium tert-butoxide (7.04 g, 73.23 mmol) were added. Stir at room temperature for 12 hours. LC-MS monitoring indicated that the reaction was complete, and the reaction solution was poured into ice water to quench. Extraction was performed twice with ethyl acetate, and the organic layer was washed three times with saturated brine and dried over anhydrous sulfuric acid. Concentration under reduced pressure gave the target product M7-4 (30.0 g). ESI-MS m / z: 430.2 [M+H] + .

[0275] Step 5: Synthesis of Compound M7-5

[0276] To a 500 mL single-necked flask, add M7-4 (30.00 g, 69.71 mmol) and methanol (150.00 mL) in sequence. Add hydrochloric acid (4 M in dioxane) (90.00 mL) at 0°C and stir at room temperature for 4 hours. LC-MS monitoring showed that the reaction was complete, and the mixture was concentrated under reduced pressure. Water and dichloromethane were added for back extraction. The aqueous layer was adjusted to pH 8-9 with saturated NaHCO3 and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the target product M7-5 (21.7 g). ESI-MS m / z: 372.2 [M+H] + .

[0277] Step 6: Synthesis of Compound M7

[0278] To a 500 mL three-necked flask, add M7-5 (20.70 g, 55.60 mmol), dichloromethane (100.00 mL), 4-dimethylaminopyridine (0.34 g, 2.78 mmol), and triethylamine (15.46 mL, 111.20 mmol) in sequence. Add p-toluenesulfonyl chloride (13.78 g, 72.28 mmol) in portions at 0°C and stir at room temperature for 4 hours. LC-MS monitoring of the reaction completion was performed, and the reaction solution was diluted with dichloromethane. Wash with water, wash the organic layer with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure and purify by column chromatography to obtain the target product M7 (21.9 g). ESI-MS m / z: 526.2 [M+H] + .

[0279] Synthesis of intermediate M8:

[0280] Step 1: Synthesis of compound M8-1

[0281] Compound (-)-methyl-D-BATA-hydroxyisobutyrate (5.00 g) and imidazole (5.76 g) were sequentially added to a DCM (50.00 mL) solution. Under N2 protection, the temperature was lowered to -0°C, and TBSCL (7.66 g) was slowly added dropwise. The mixture was then reacted at room temperature for 4 h. After completion of the reaction, 100 mL of ammonium chloride was added to quench the reaction mixture. The mixture was then extracted with ethyl acetate and washed with 50 mL of saturated sodium chloride. The crude product was then dried and separated by column chromatography to yield the target compound M8-1 (9.70 g, 98.62% yield) as a colorless liquid. ESI-MS m / z: 233.15 [M+H] + .

[0282] Step 2: Synthesis of compound M8-2

[0283] Compound M8-1 (4.0 g) was dissolved in THF (40 ml). DIBAL-H (51.64 ml, 1 M / n-hexane) was added dropwise at -40°C. After completion of the addition, the mixture was stirred at -40°C for 3 hours. Water (20 ml) was added to quench the reaction. The aqueous phase was extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate and separated by column chromatography to obtain the target compound M8-2 (2.28 g, 64.81% yield). ESI-MS m / z: 205.38 [M+H] + .

[0284] Step 3: Synthesis of Compound M8

[0285] At room temperature, compound M8-2 (2.28 g) and 4-DMAP (2.18 g) were added to DCM (80.00 mL). Tert-butyldimethylsilyl chloride (2.76 g) was then slowly added under N2 protection. The reaction mixture was allowed to react overnight at room temperature. The reaction mixture was quenched with 100 mL of water. The mixture was then extracted three times with 50 mL of DCM and washed twice with 50 mL of saturated sodium chloride. The combined organic phases were concentrated to yield the crude product, which was then separated by column chromatography to yield the target compound M8 (3.26 g, 81.50% yield). ESI-MS m / z: 359.57 [M+H] + .

[0286] Synthesis of intermediate M9:

[0287] Step 1: Synthesis of compound M9-1

[0288] To a 3 L three-necked flask, M7-2 (5.70 g, 24.75 mmol), dichloromethane (80.00 mL), and N,N-diisopropylethylamine (8.62 mL, 49.50 mmol) were added sequentially. Under nitrogen, the temperature was lowered to 0°C and chloromethyl methyl ether (2.23 mL, 29.70 mmol) was added dropwise. Stir at room temperature for 5 hours. Upon completion of the reaction as monitored by LC-MS, the reaction solution was diluted with dichloromethane and quenched by pouring into water. The reaction mixture was washed twice with saturated brine. The organic layer was concentrated under reduced pressure and purified by column chromatography to yield the desired product, M9-1 (3.6 g).

[0289] Step 2: Synthesis of compound M9-2

[0290] Compound M6 (8.00 g, 26.65 mmol) and compound M9-1 (14.62 g, 53.30 mmol) were dissolved in DMSO (50.00 mL) and THF (10.00 mL) under nitrogen atmosphere. The temperature was lowered to 10°C, and t-BuONa (6.40 g, 66.62 mmol) was added. The mixture was allowed to react at 10°C for 2 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the organic phase was concentrated to obtain the crude product. The crude product was then separated and purified by silica gel column chromatography to obtain the target compound M9-2 (14.1 g). ESI-MS m / z: 401.13, 402.22 [M+H] + .

[0291] Step 3: Synthesis of Compound M9

[0292] Compound M9-2 (6.00 g, 14.91 mmol), B2Pin2 (5.68 g, 22.37 mmol), [PdCl2(dppf)]CH2Cl2 (1.22 g, 1.49 mmol), and potassium acetate (4.39 g, 44.74 mmol) were dissolved in toluene (60.00 mL) under nitrogen atmosphere at 100°C for 3 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, separated, and concentrated to yield the crude target compound M9 (13 g). ESI-MS m / z: 463.32, 464.33 [M+H] + .

[0293] Synthesis of intermediate M10:

[0294] Step 1: Synthesis of compound M10-1

[0295] DMSO (14.69 mL, 207.12 mmol) was dissolved in DCM (350.00 mL) and cooled to -78°C. Oxalyl chloride (8.76 mL, 103.56 mmol) in DCM (20.00 mL) was then slowly added (ensuring the temperature was below -60°C during addition). The reaction was allowed to proceed at -78°C for 30 min. (R)-N-Boc-2-hydroxymethylmorpholine in DCM (50.00 mL) was then slowly added and the reaction was allowed to proceed at -78°C for 2 h. TEA (38.39 mL, 276.16 mmol) was then slowly added (ensuring the temperature was below -60°C during addition). The reaction was allowed to proceed at -78°C for 30 min, and the reaction was then slowly warmed to room temperature. The mixture was extracted with DCM and saturated aqueous sodium bicarbonate, then with DCM and saturated aqueous sodium chloride. The mixture was dried over anhydrous sodium sulfate, and concentrated to afford the crude target compound M10-1 (16 g), which was used directly in the next step.

[0296] Step 2: Synthesis of compound M10-2

[0297] Compound M10-1 (14.50 g, 67.36 mmol) and (±)-Z-α-phosphonoglycine trimethyl ester (26.78 g, 80.84 mmol) were dissolved in ACN (300.00 mL). The temperature was cooled to 10°C, and TMG (16.94 mL, 134.73 mmol) was added. The mixture was reacted at 10°C for 30 minutes, then warmed to room temperature for 2 hours. The mixture was directly concentrated and purified by wet-loading column chromatography to obtain the target compound M10-2 (26 g).

[0298] Step 3: Synthesis of compound M10-3

[0299] Compound M10-2 (26.00 g, 61.84 mmol) was dissolved in MeOH (300.00 mL), and Pd / C (6.58 g, 61.84 mmol) was added. A few drops of HOAc (0.18 mL, 3.09 mmol) were added to accelerate the reaction. The atmosphere was replaced with hydrogen five times and the reaction was continued at 65°C overnight. LC-MS indicated the reaction was complete. The mixture was filtered and concentrated to afford the crude target compound M10-3 (24 g). ESI-MS m / z: 288.17, 289.29 [M+H] + .

[0300] Step 4: Synthesis of compound M10-4

[0301] Compound M10-3 (24.00 g, 83.24 mmol) was dissolved in 1,4-dioxane (150.00 mL) and H2O (150.00 mL). The temperature was lowered to 0°C, and K2CO3 (34.51 g, 249.71 mmol) and Cbz-CL (17.57 mL, 124.85 mmol) were added. The mixture was allowed to react at room temperature for 3 h. LC-MS indicated the reaction was complete. The mixture was quenched with saturated ammonium chloride and extracted with EA and water. The mixture was dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product. The product was then separated and purified by silica gel column chromatography to obtain the target compound M10-4 (28 g). ESI-MS m / z: 422.21, 423.19 [M+H] + .

[0302] Step 5: Synthesis of Compound M10

[0303] Compound M10-4 (26.00 g, 61.54 mmol) was dissolved in DCM (80.00 mL), and then HCl (4M / dioxane) (80.00 mL) was added. The mixture was allowed to react at room temperature for 30 min. LC-MS indicated the reaction was complete. The mixture was concentrated under reduced pressure, extracted with sodium bicarbonate and DCM, and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, which was then separated and purified by silica gel column chromatography to obtain the target compound M10 (12.8 g). ESI-MS m / z: 322.15, 323.18 [M+H] + .

[0304] Synthesis of intermediate M11:

[0305] Step 1: Synthesis of compound M11-1

[0306] To a 250 mL three-necked flask, 2-(3-oxocyclobutyl)acetic acid (4.5 g, 35.12 mmol), (S)-4-benzyl-2-oxazolidinone (7.47 g, 42.15 mmol), 4-dimethylaminopyridine (0.43 g, 3.51 mmol), triethylamine (14.65 mL, 105.36 mmol), and DCM (90.00 mL) were added in sequence. Under nitrogen protection, the mixture was cooled in an ice-water bath, and 2-chloro-1-methylpyridinium iodide (15.25 g, 59.71 mmol) was slowly added in batches. The reaction was allowed to react at room temperature for 2 h. After the reaction was completed as monitored by LC-MS, the reaction solution was slowly added to 100 mL of water to quench the reaction, and then extracted with 60 mL of DCM*3. The combined organic phases were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude compound M11-1. The target product M11-1 (10.00 g, light yellow liquid) was separated and purified by silica gel column chromatography. ESI-MS m / z: 288.42 [M+H] + .

[0307] Step 2: Synthesis of compound M11-2

[0308] To a 250 mL three-necked flask, M11-1 (10.00 g, 34.81 mmol), glacial acetic acid (3.98 mL, 69.61 mmol), and THF (90.00 mL) were added in sequence. Under nitrogen protection, the mixture was cooled in an ice-water bath. Sodium borohydride (1.05 g, 27.84 mmol) was slowly added in batches and the mixture was kept in an ice-water bath for 2.5 h. After the reaction was completed as monitored by LC-MS, 20 mL of saturated ammonium chloride was added dropwise to quench the reaction. The mixture was then extracted with 60 mL of EA*3 and washed with saturated sodium bicarbonate. The organic phases were combined and concentrated to obtain a crude product, which was then subjected to column chromatography to obtain the target product M11-2 (10.00 g, light yellow liquid). ESI-MS m / z: 290.41 [M+H]+ .

[0309] Step 3: Synthesis of compound M11-3

[0310] Compound M11-2 (10.00 g, 34.56 mmol), DIEA (8.57 mL, 51.84 mmol), and DMAP (3.38 g, 27.65 mmol) were sequentially added to anhydrous DCM (90.00 mL). Under nitrogen protection, the temperature was lowered to 0°C, and TsCl (7.91 g, 41.48 mmol) was slowly added. The mixture was then allowed to warm to room temperature and allowed to react for 3 h. After completion of the reaction, 100 mL of water was added to quench the reaction mixture, followed by extraction with 3 50 mL of DCM and washing with 2 50 mL of saturated sodium chloride. The combined organic phases were concentrated to yield the crude product, which was then separated and purified by silica gel column chromatography to yield the desired product, M11-3 (14.10 g, light yellow liquid). ESI-MS m / z: 444.52 [M+H]. + .

[0311] Step 4: Synthesis of compound M11-4

[0312] To a 250 mL single-necked flask, M11-3 (14.00 g, 31.56 mmol), lithium bromide (5.47 g, 63.12 mmol), and NMP (140.00 mL) were added in sequence. The mixture was reacted at 90°C for 3 h under nitrogen protection. After the reaction was completed as monitored by LC-MS, the reaction solution was directly and slowly added to 60 mL of ice water to quench the reaction. The mixture was then extracted with 50 mL of EA*3, and the combined organic phases were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product of compound M11-4, which was separated and purified by silica gel column chromatography to obtain the target product M11-4 (11.00 g, light yellow liquid). ESI-MS m / z: 353.24, 355.21 [M+H] + .

[0313] Step 5: Synthesis of Compound M11-5

[0314] To a 250 mL three-necked flask, M11-4 (7.50 g, 21.29 mmol), N,N-dimethylpropylene urea (5.15 mL, 42.59 mmol), and THF (120.00 mL) were added in sequence. Under nitrogen protection, LDA (2M in THF / hexane) (13.84 mL, 27.68 mmol) was slowly added dropwise at -78 °C. The reaction was kept warm for 1 h. Then, di-tert-butyl azodicarboxylate (5.88 g, 25.55 mmol) dissolved in THF (10.00 mL) was added and the reaction was continued at -78 to -65 °C for 2 h. After the reaction was completed, the reaction solution was slowly added to 200 mL of ice water to quench the reaction. The mixture was then extracted with 100 mL of EA (3 times). The combined organic phases were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product of compound M11-5. The crude product was separated and purified by silica gel column chromatography to obtain the target product M11-5 (12.00 g, white solid). ESI-MS m / z: 583.52 [M+H] + .

[0315] Step 6: Synthesis of Compound M11-6

[0316] To a 500 mL three-necked flask, M11-5 (11.50 g, 19.74 mmol) and THF (200.00 mL) were added sequentially. Under nitrogen protection, LDA (2M in THF / hexane) (13.82 mL, 27.64 mmol) was slowly added dropwise and the mixture was allowed to warm to room temperature for 4 h. After completion of the reaction as monitored by LC-MS, 100 mL of water was slowly added to the reaction solution to quench the reaction. Lithium hydroxide monohydrate (2.48 g, 59.22 mmol) was then added and stirring continued at room temperature for 1 h. 1 M HCl was then added to adjust the pH to 5-6. The mixture was then extracted with 50 mL of EA (3 volumes). The combined organic phases were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The concentrated organic phase was concentrated to obtain crude compound M11-5, which was then purified by silica gel column chromatography to obtain the target product M11-6 (2.20 g). ESI-MS m / z: 343.27 [M+H] + .

[0317] Step 7: Synthesis of Compound M11-7

[0318] To a 100 mL three-necked flask, M11-6 (2.20 g, 6.43 mmol) and MeOH (30.00 mL) were added sequentially. Under nitrogen protection, trimethylsilylated diazomethane (16.06 mL, 2.00 mol / L, 32.13 mmol) was slowly added in an ice-water bath, and the mixture was allowed to warm to room temperature for 1 h. After completion of the reaction, as monitored by LC-MS, 0.3 mL of acetic acid was slowly added to the reaction solution to quench the reaction. Saturated sodium bicarbonate was then added to adjust the pH to 8-9, and then extracted with 50 mL of EA*3. The combined organic phases were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The concentrated organic phase was concentrated to obtain the crude compound M11-7, which was separated and purified by silica gel column chromatography to obtain the target product M11-7 (0.78 g, light yellow liquid). ESI-MS m / z: 357.43 [M+H] + .

[0319] Step 8: Synthesis of Compound M11-8

[0320] M11-7 (0.78 g, 2.28 mmol) and DCM (9.00 mL) were added to a 100 mL single-necked flask in sequence. Under nitrogen protection, trifluoroacetic acid (3.00 mL) was slowly added in an ice-water bath, and then the temperature was returned to room temperature for 8 h. After the reaction was completed, the reaction solution was concentrated to remove the solvent, and then 10 mL of methyl tert-butyl ether was slowly added to the reaction solution. A white solid was precipitated by ultrasound, and then 10 mL of n-hexane was added to fully crystallize. The target product M11-8 (0.41 g, white solid) was obtained by filtration and drying. ESI-MS m / z: 157.24 [M+H] + .

[0321] Step 9: Synthesis of Compound M11-9

[0322] To a 100 mL single-necked flask, M2-11 (600.00 mg, 1.00 mmol), N,N-diisopropylethylamine (0.83 mL, 5.00 mmol), and DMF (15.00 mL) were added sequentially. The mixture was stirred at room temperature for 10 min under nitrogen protection. HATU (951.45 mg, 2.50 mmol) was added at 0°C and the reaction was continued at this temperature for 20 min. M11-8 (384.6 mg, 1.00 mmol) was then added and the temperature was returned to 25°C for 1 h. After completion of the reaction as monitored by LC-MS, the reaction solution was directly added slowly to 20 mL of ice water to quench the reaction. The mixture was then extracted with 20 mL of EA*3. The combined organic phases were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The concentrated organic phase was concentrated to give the crude compound M11-9, which was then separated and purified by silica gel column chromatography to obtain the target product M11-9 (704.00 mg, light yellow solid). ESI-MS m / z:738.21[M+H]+ .

[0323] Step 10: Synthesis of Compound M11-10

[0324] To a 100 mL single-necked flask, M11-9 (0.88 g, 2.98 mmol) and THF (12.00 mL) were added sequentially. Under nitrogen protection, an aqueous solution of lithium hydroxide monohydrate (0.13 g, 2.98 mmol) dissolved in water (4.00 mL) was slowly added in an ice-water bath. The mixture was kept in an ice-water bath for 1 h. After the reaction was completed as monitored by LC-MS, 1 M HCl was added to adjust the pH to 5-6. The mixture was then extracted with 50 mL of EA (3 volumes). The combined organic phases were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The concentrated organic phase was concentrated to give the crude compound M11-5, which was then separated and purified by silica gel column chromatography to give the target product M11-10 (0.5 g, white foamy solid). ESI-MS m / z: 724.65 [M+H] + .

[0325] Step 11: Synthesis of Compound M11-11

[0326] To a 100 mL single-necked flask, M11-10 (470.00 mg, 0.64 mmol), N-methylimidazole (159.97 mg, 1.95 mmol), DMF (5.00 mL), and acetonitrile (3.00 mL) were added sequentially under nitrogen protection. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (23.29 mg, 0.08 mmol) was slowly added in batches at room temperature and the reaction was continued for 0.5 h. After the reaction was completed as monitored by LC-MS, the reaction solution was directly added slowly to 20 mL of ice water to quench the reaction, and then extracted with 20 mL of EA*3. The combined organic phases were washed with saturated sodium chloride and saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude compound M11-11, which was separated and purified by silica gel column chromatography to obtain the target product M11-11 (200.00 mg, white solid). ESI-MS m / z:706.65[M+H] + .

[0327] Step 12: Synthesis of Compound M11

[0328] To a 50 mL three-necked flask, M11-11 (200.00 mg, 0.28 mmol), Sphos-Pd-G2 (10.22 mg, 0.01 mmol), potassium acetate (97.35 mg, 0.99 mmol), toluene (4.50 mL) and 1,4-dioxane (1.50 mL) were added in sequence, and then 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.33 mL, 2.27 mmol) was added under N2 protection and in an ice-water bath. The temperature was returned to room temperature and the reaction was carried out for 3 h. After the reaction was completed as monitored by LC-MS, 10 mL of saturated ammonium chloride was slowly added to the reaction solution to quench the reaction. The mixture was then extracted with 3 20 mL of EA. The combined organic phases were washed with saturated sodium chloride and saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain crude compound M11, which was then purified by silica gel column chromatography to obtain the target product M11 (80.00 mg, white solid). ESI-MS m / z: 706.69 [M+H] + .

[0329] Synthesis of intermediate M11-8:

[0330] Step 1: Synthesis of compound M11-8-1

[0331] To a 5000mL four-necked flask, methyl 3-butenoate (98.00g, 978.87mmol), ethylene glycol dimethyl ether (500.00mL), methyl tert-butyl ether (2500.00mL), and Zn(Cu) (189.32g, 1468.30mmol) were added sequentially. The atmosphere was replaced with nitrogen, the temperature was cooled in a cold water bath, and trichloroacetyl chloride (373.78g, 2055.62mmol) was added dropwise at 20-25°C. Stirring was continued overnight. The reaction solution was filtered and washed with MTBE (400mL x 3). The filtrate was concentrated to dryness. The concentrate was purified by column chromatography (PE-PE / EA = 16 / 1). 297.5g of a light yellow-brown liquid, crude compound M11-8-1, was obtained and used directly in the next reaction.

[0332] Step 2: Synthesis of compound M11-8-2

[0333] To a 5000mL three-necked flask, compound M11-8-1 (295.50g, 69.9% content, 978.73mmol), methanol (1500.00mL), water (1500.00mL), and ammonium chloride (261.76g, 4893.66mmol) were added in sequence. The mixture was cooled in an ice-water bath, maintaining the temperature at 10-25°C. Zn / zinc powder (192.00g, 2936.20mmol) was added portionwise. After addition, the reaction was stirred periodically for 5 hours and then allowed to stand overnight. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to remove the methanol to obtain a concentrate, which was dissolved in 250mL of water. The mixture was extracted with ethyl acetate (200mL x 3). The organic phases were combined and washed with saturated brine (300mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 109.5g of a light brown liquid, which was the crude product of compound M11-8-2 and used directly in the next reaction.

[0334] Step 3: Synthesis of compound M11-8-3

[0335] To a 2000mL three-necked flask, compound M11-8-2 (108.00g, 759.75mmol) and ethanol (800.00mL) were added sequentially. Under nitrogen, cooled in an ice-water bath, and sodium borohydride (12.93g, 341.89mmol) was added portionwise at 0-5°C. After addition, the reaction was maintained at 0-5°C. After monitoring the reaction for completion, 100mL of saturated aqueous ammonium chloride was slowly added to quench the reaction solution. The reaction solution was then concentrated to remove the organic solvent. 300mL of water was added to the concentrated residue, and the mixture was extracted with ethyl acetate (250mL x 3). The organic phases were combined, washed with 250mL of saturated aqueous sodium bicarbonate, separated, dried over anhydrous sodium sulfate, and spin-dried to obtain 89.3g of the liquid, which is compound M11-8-3.

[0336] Step 4: Synthesis of compound M11-8-4

[0337] To a 1000mL three-necked flask, compound M11-8-3 (30.20g, 209.48mmol), tetrahydrofuran (500.00mL), triphenylphosphine (65.94g, 251.37mmol), and p-nitrobenzoic acid (42.01g, 251.37mmol) were added sequentially. Diethyl azodicarboxylate (43.78g, 251.37mmol) was then added dropwise. Stirring was continued. After the reaction was complete, the reaction solution was concentrated. When solid precipitated, MTBE was added and the concentration was continued (100mL x 2). 300mL of MTBE was then added and the mixture was stirred for 10 minutes. 150mL of PE was then added and the mixture was stirred for 1 hour. Filter, drain, and elute the residue with a 1 / 1 mixture of MTBE and PE. The filtrate was collected. The filtrate was dried and purified by column chromatography to obtain 49.5 g of a slightly yellow solid, which was compound M11-8-4. ESI-MS m / z: 294.09 [M+H] + .

[0338] Step 5: Synthesis of compound M11-8-5

[0339] Compound M11-8-4 (50.50 g, 172.19 mmol), methanol (500.00 mL), tetrahydrofuran (250.00 mL), water (60.00 mL), and potassium carbonate (23.80 g, 172.19 mmol) were added to a 500 mL three-necked flask in sequence. After the addition was complete, the reaction was stirred and continued. The reaction solution was filtered and the filtrate was concentrated to obtain a concentrated residue. 400 mL of cold water was added to the concentrated residue, and then dichloromethane was added for extraction and separation. 250 mL * 3; the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated. Column chromatography was performed to obtain 21.8 g of a colorless liquid, which was compound M11-8-5.

[0340] Step 6: Synthesis of compound M11-8-6

[0341] To a 1000mL three-necked flask, compound M11-8-5 (43.00g, 298.26mmol) and DCM / dichloromethane (450.00mL) were added sequentially. The mixture was cooled to below 5°C in an ice-water bath. DMAP / 4-dimethylaminopyridine (3.64g, 29.83mmol) and imidazole (22.34g, 328.09mmol) were then added. TBSCl / tert-butyldimethylsilyl chloride (47.20g, 313.18mmol) was then added. After addition, the mixture was kept at 0-5°C and stirred for 3 hours. After monitoring the reaction, the mixture was washed with 300mL of water and 200mL of saturated sodium chloride solution, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate. Filtered, the desiccant was removed, and the filtrate was concentrated to dryness to obtain 77g of a slightly yellow liquid, compound M11-8-6.

[0342] Step 7: Synthesis of compound M11-8-7

[0343] To a 100mL three-necked flask, compound M11-8-6 (2.60g, 10.06mmol), tetrahydrofuran (10.00mL), methanol (10.00mL), and water (10.00mL) were added in sequence. The mixture was cooled in an ice-water bath, and lithium hydroxide monohydrate (0.63g, 15.09mmol) was added, with continued stirring. After the reaction was complete, 20mL of water was added to the reaction mixture, which was then incubated in a water bath at 35-40°C. The reaction mixture was concentrated to remove THF and methanol. An additional 20mL of water was added, and the mixture was extracted with 30mL of ethyl acetate and separated. The organic phase was discarded. The aqueous phase was collected and 1N dilute hydrochloric acid was added dropwise to adjust the pH to approximately 3-4. The mixture was extracted with ethyl acetate, separated, and extracted with 30mL of 2 extractions. The organic phases were combined and dried over anhydrous sodium sulfate. Filtered and concentrated, the filtrate afforded 2.2g of a colorless liquid, compound M11-8-7.

[0344] Step 8: Synthesis of compound M11-8-8

[0345] To a 2000 mL three-necked flask, compound M11-8-7 (57.30 g, 234.45 mmol), (S)-4-benzyl-2-oxazolidinone (45.70 g, 257.89 mmol), 4-dimethylaminopyridine (2.86 g, 23.44 mmol), triethylamine (97.76 mL, 703.35 mmol), and dichloromethane (860.00 mL) were added sequentially. The mixture was cooled in a cold water bath and the temperature was maintained at 20-25°C. CMPI / 2-chloro-1-methylpyridinium iodide (71.88 g, 281.34 mmol) was added portionwise. The reaction was maintained at 20-25°C for 2 h. TLC monitoring indicated complete conversion of the starting material. The reaction was quenched with 500 mL of water and extracted with 400 mL of DCM (2x), followed by washing with 500 mL of saturated sodium chloride (2x). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The mixture was separated and purified by column chromatography to obtain 79.2 g of a slightly yellow viscous substance, which was compound M11-8-8. ESI-MS m / z: 404.2 [M+H] + .

[0346] Step 9: Synthesis of compound M11-8-9

[0347] To a 2L three-necked flask, add compound M11-8-8 (76.20g, 188.81mmol) and tetrahydrofuran (750.00mL) sequentially. Cool to below -78°C in a dry ice-ethanol bath under nitrogen. Add lithium diisopropylamide (2M in THF / hexane) (122.72mL, 2.00mol / L, 245.45mmol) dropwise. Continue stirring and incubate. After 1 hour, add di-tert-butyl azodicarboxylate (52.17g, 226.57mmol) dissolved in tetrahydrofuran (100.00mL). Continue incubating at -78°C for another 1 hour until complete. Add the reaction mixture to 1000mL of cold ammonium chloride solution and stir for 10 minutes. Extract with ethyl acetate and separate the layers into 500mL x 3 volumes. Combine the organic phases, wash with saturated brine, and separate the layers into 500mL x 2 volumes. The organic phase was dried over anhydrous sodium sulfate. Filtered and desiccant removed; the filtrate was concentrated and silica gel was added to prepare sand. Purification was performed by column chromatography (PE-PE / EA = 88:12). Concentration afforded 105.8 g of a white foamy solid, compound M11-8-9. ESI-MS m / z: 634.3 [M+H] + .

[0348] Step 10: Synthesis of compound M11-8-10

[0349] Compound M11-8-9 (95.00 g, 149.88 mmol) and methanol (400.00 mL) were added to a 1 L three-necked flask in sequence. Under nitrogen protection, ytterbium trifluoromethanesulfonate (9.30 g, 14.99 mmol) was added at room temperature and the mixture was stirred and kept warm for 50 h. The reaction was completed. The reaction solution was concentrated to dryness and purified by column chromatography to obtain 52.00 g of a white foamy solid, which was compound M11-8-10. ESI-MS m / z: 175.2 [M+H] + .

[0350] Step 11: Synthesis of compound M11-8-11

[0351] In a 2000mL three-necked flask, compound M11-8-10 (42.00g, 112.17mmol), tetrahydrofuran (630.00mL), triethylamine (46.77mL, 336.51mmol) were added in sequence, cooled in a water bath, Ms2O / methanesulfonic anhydride (25.40g, 145.82mmol) was added, and the mixture was returned to room temperature for 0.5h. TLC monitoring showed that the raw material was completely converted. The reaction solution was washed with 400mL of water and 400mL of saturated brine in sequence, and the liquid was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 50.0g of a light yellow oil, which was compound M11-8-11, ESI-MS m / z: 453.2[M+H]+ .

[0352] Step 12: Synthesis of Compound M11-7

[0353] To a 1000 mL single-necked flask, compound M11-8-11 (50.00 g, 110.49 mmol), N,N-dimethylacetamide (500.00 mL), and cesium carbonate (90.00 g, 276.23 mmol) were added in sequence. The mixture was heated in an oil bath at 60-65°C under nitrogen for 1-1.5 h. After completion of the reaction, the reaction solution was added to 500 g of ice water and stirred. Ethyl acetate was then added for extraction and the mixture was separated into 400 mL x 3 volumes. The organic phases were combined, washed with saturated sodium chloride (300 mL x 5), separated, and dried over anhydrous sodium sulfate. The organic phase was separated and purified by column chromatography to obtain 27.5 g of a light yellow-brown viscous product, which was compound M11-7. ESI-MS m / z: 357.43 [M+H] + .

[0354] Step 13: Synthesis of Compound M11-8

[0355] Compound M11-7 (27.50 g, 77.16 mmol) was added to dichloromethane (82.50 mL). Trifluoroacetic acid (82.50 mL) was then slowly added under N2 protection in an ice-water bath. The reaction was allowed to proceed at 25°C for 4 h, completing the reaction. The reaction mixture was subjected to rotary evaporation at 30°C to remove most of the solvent. A large amount of trifluoroacetic acid was removed using an oil pump. 100 mL of MTBE was then added, and the solid was ultrasonically precipitated. 100 mL of n-hexane was then added to slurry the mixture, followed by filtration. The solid was then drained to yield 18.4 g of compound M11-8. ESI-MS m / z: 157.24 [M+H] + .

[0356] Synthesis of intermediate M12

[0357] Step 1: Synthesis of compound M12-1

[0358] Compound 3-bromo-5-methyl-pyridine-2-carbonitrile (5 g, 25.38 mmol) was dissolved in carbon tetrachloride (100 mL), and N-bromosuccinimide (4.52 g, 25.38 mmol) and azobisisobutyronitrile (0.42 g, 2.54 mmol) were added. The mixture was heated to 80°C for reaction. After the reaction was complete, the reaction solution was diluted with EA and water, extracted twice with EA, and purified by column chromatography to obtain compound M12-1 (5.94 g). ESI-MS m / z: 274.97 [M+H] + .

[0359] Step 2: Synthesis of compound M12-2

[0360] Compound M12-1 (5.94 g, 21.53 mmol) and methylpiperazine (3.23 g, 32.29 mmol) were dissolved in acetonitrile (60 mL), and N,N-diisopropylethylamine (10.67 mL, 64.58 mmol) was added and reacted at room temperature for 2 h. After the reaction was complete, the mixture was directly mixed with silica gel and purified by column chromatography to obtain compound M12-2 (2.82 g). ESI-MS m / z: 295.15 [M+H] + .

[0361] Step 3: Synthesis of compound M12-3

[0362] Compound M12-2 (2.82 g, 9.55 mmol) was dissolved in tetrahydrofuran (30 mL), the temperature was lowered to -20°C, and methylmagnesium bromide (9.55 mL, 3.00 mol / L, 28.66 mmol) was slowly added dropwise. The reaction mixture was allowed to stand at room temperature until the reaction was complete. After the reaction was complete, the reaction solution was added to icy dilute hydrochloric acid at pH 3-4 and stirred for ten minutes. The imine intermediate was completely converted to ketone. The pH was adjusted to 9 with saturated sodium carbonate and the mixture was extracted twice with EA. The mixture was dried, filtered, and spin-dried to obtain compound M12-3 (2.8 g). The crude product was used directly in the next step. ESI-MS m / z: 312.16 [M+H] + .

[0363] Step 4: Synthesis of compound M12-4

[0364] Compound M12-3 (2.80 g, 8.97 mmol) was dissolved in triethylamine (30 mL) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium (II) chloride (0.23 g, 0.36 mmol) and formic acid (1.65 g, 35.87 mmol) were added. The mixture was allowed to react at room temperature for 6 h. After the reaction was complete, the mixture was directly added to silica gel and purified by column chromatography to obtain compound M12-4 (2.7 g). ESI-MS m / z: 314.18 [M+H] + .

[0365] Step 5: Synthesis of Compound M12-5

[0366] Compound M12-4 (2.6 g, 8.27 mmol) and compound M7-3 (4.77 g, 16.55 mmol) were dissolved in dimethyl sulfoxide (20 mL) and tetrahydrofuran (4 mL). The temperature was lowered to 0°C, sodium tert-butoxide (1.59 g, 16.55 mmol) was added, and the reaction was allowed to return to room temperature for 3 h. After the reaction was complete, the temperature was lowered to 0°C, quenched with saturated ammonium chloride, extracted twice with EA, washed three times with saturated brine, dried, filtered, and spin-dried to obtain compound M12-5 (3.6 g). The crude product was used directly in the next step. ESI-MS m / z: 430.26 [M+H] + .

[0367] Step 6: Synthesis of Compound M12

[0368] Compound M12-5 (3.60 g, 8.36 mmol) was dissolved in methanol (10 mL) and hydrochloric acid (4 M in dioxane) (10 mL) was added. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction solution was spin-dried and the compound was dissolved in DCM and water. The DCM was extracted twice and discarded. The aqueous phase was freed with saturated sodium carbonate and extracted three times with EA. The mixture was dried, filtered, and spin-dried to obtain compound M12 (2.6 g). ESI-MS m / z: 373.39 [M+H] + .

[0369] Synthesis of intermediate M13:

[0370] Step 1: Synthesis of compound M13-1:

[0371] The intermediate oxazole (2.1 g) was added to a 100 mL three-necked flask, followed by anhydrous THF (13 mL) and DMPU (10.4 mL). The temperature was lowered to -78°C under N2 protection, and LiHMDS (67 mL, 1 mol / L in THF) was slowly added dropwise. The reaction was maintained at -75°C for 1.0 h. Iodine (15.4 g) was added portionwise, and the reaction was maintained at -75°C for 30 min before being transferred to room temperature for 8.0 h. After the reaction, the solution was diluted with saturated aqueous sodium thiosulfate (20 mL) and extracted with Et2O. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (PE:EA = 9:1) to afford M13-1 (6.54 g, 67.3% yield). ESI-MS m / z: 321.1 [M+H] + .

[0372] Step 2: Synthesis of compound M13:

[0373] Compound M13-1 (4.0 g), Pd2(dba)3 (626 mg), X-Phos (978 mg), and anhydrous DMF (20 mL) were added to a 250 mL three-necked flask. The atmosphere was replaced with N2 three times, and finally, M1-1 (61.56 mL, a 0.33 mol / L DMF solution) was added. The temperature was raised to 70°C and the reaction mixture was reacted for 2.5 h. After the reaction was completed, the mixture was cooled to room temperature, and EA and water were added to the reaction mixture for extraction. The aqueous phase was extracted twice more with EA. The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE:EA = 3:1) to obtain the target compound M13 (1.52 g, 31% yield). ESI-MS m / z: 396.3 [M+H] + .

[0374] Example 1: Synthesis of (1S,2S)-2-methyl-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-(4-methylpiperazin-1-yl)-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazino[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinocycloundecane-4-yl)cyclopropane-1-carboxamide

[0375] Step 1: Synthesis of compound 1-1

[0376] Compound 3-((tert-Butyldimethylsilyl)oxy)-propanol (3.00 g), triethylamine (3.29 mL), and 4-DMAP (0.19 g) were sequentially added to a DCM (40.00 mL) solution. Under nitrogen protection, the temperature was lowered to 0°C, and TsCl (3.91 g) was slowly added. The mixture was then allowed to warm to room temperature and allowed to react for 13 h. After completion of the reaction, 100 mL of water was added to quench the reaction mixture. The mixture was then extracted three times with 50 mL of DCM and washed twice with 50 mL of saturated sodium chloride. The combined organic phases were concentrated to obtain the crude product, which was then separated by column chromatography (PE:EA = 95:5 to 80:20) to afford the target compound 1-1 (4.00 g, 73.66% yield) as a colorless liquid. ESI-MS m / z: 345.4 [M+H] + .

[0377] Step 2: Synthesis of compound 1-2

[0378] Compound 1-1 (1.72 g) and compound M5 (0.75 g) were added to DMSO (10.00 mL) and THF (2.00 mL). Under N2 protection, a solution of sodium tert-butoxide (0.60 g) in THF (2.00 mL) was slowly added at room temperature. The mixture was allowed to react for 5 h. After completion of the reaction, 30 mL of water was added to quench the reaction mixture. The mixture was then extracted three times with 30 mL of EA. The organic phases were combined, washed with saturated sodium chloride, and concentrated to obtain a crude product. The crude product was separated by column chromatography (DCM:EA = 90:10 to 10:90) to obtain the target compound 1-2 (0.80 g, 67.77% yield). ESI-MS m / z: 472.5, 474.5 [M+H] + .

[0379] Step 3: Synthesis of Compound 1-3

[0380] Compound 1-2 (0.80 g) and TBAF (1.86 mL, 1.00 mol / L) were added to THF (10.00 mL) and reacted at 50°C under N2 protection for 1 h. After the reaction, 30 mL of water was added to the reaction solution to quench the reaction. The mixture was then extracted five times with 30 mL of DCM. The organic phases were combined, washed with saturated sodium chloride, and concentrated to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 97:3 to 90:10) to obtain the target compound 1-3 (0.60 g, 98.92% yield). ESI-MS m / z: 358.3, 360.3 [M+H] + .

[0381] Step 4: Synthesis of Compounds 1-4

[0382] Compound 1-3 (600.00 mg), triethylamine (0.35 mL), and 4-DMAP (20.50 mg) were sequentially added to a DCM (10.00 mL) solution under N2 protection. The temperature was lowered to 0°C, and TsCl (415.1 mg) was slowly added. The mixture was then allowed to warm to room temperature and allowed to react for 12 h. After completion of the reaction, 100 mL of water was added to quench the reaction mixture. The mixture was then extracted three times with 50 mL of DCM and washed twice with 50 mL of saturated sodium chloride. The combined organic phases were concentrated to yield the crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 90:10) to afford the target compound 1-4 (450.00 mg, 52.43% yield). ESI-MS m / z: 512.4, 514.4 [M+H] + .

[0383] Step 5: Synthesis of Compound 1-5

[0384] Compound 1-4 (265.97 mg), intermediate M2 (300.00 mg), PdCl2(dppf) (31.61 mg), and K2CO3 (149.43 mg) were added to toluene (4.50 mL), 1,4-dioxane (1.50 mL), and water (1.00 mL). The mixture was then reacted at 65°C under nitrogen for 2 h. After completion, the reaction mixture was quenched with 30 mL of water. The mixture was then extracted three times with 30 mL of DCM and washed twice with 30 mL of saturated sodium chloride. The combined organic phases were concentrated to obtain the crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 90:10) to afford the target compound 1-5 (270.00 mg, 62.48% yield). ESI-MS m / z: 1000.2 [M+H] + .

[0385] Step 6: Synthesis of compounds 1-6A and 1-6B

[0386] Compound 1-5 (270.00 mg) and Cs2CO3 (176.04 mg) were added to DMF (30.00 mL) and reacted at 90°C under N2 protection for 0.5 h. After completion, the reaction mixture was quenched with 50 mL of water. The mixture was then extracted three times with 40 mL of DCM and washed four times with 30 mL of saturated sodium chloride. The combined organic phases were concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 90:10) to afford the target compound 1-6 (170.00 mg, 68.48% yield). ESI-MS m / z: 828.1 [M+H] + .

[0387] The preparation and separation conditions were as follows: chromatographic column: Phenome (21.2×150 mm, 5 μm); mobile phase: A: 0.05% TFA / H 2 O, B: ACN; gradient: 39%-42%; flow rate: 20 ml / min.

[0388] Compound 1-6A: Retention time: 5.45-5.95 min (55.00 mg, 32.34% yield). ESI-MS m / z: 828.1 [M+H] + ; 1H NMR (500MHz, CDCl3) δ8.60(d,J=1.6Hz,1H),8.42(d,J=3.0Hz,1H),7.58(dd,J =8.5,1.7Hz,1H),7.32-7.27(m,2H),7.09(d,J=2.9Hz,1H),5.58(t,J=9.4Hz,1 H),5.48(d,J=10.4Hz,1H),4.61-4.56(m,1H),4.38-4.32(m,1H),4.26-4.17( m,2H),4.09–3.95(m,2H),3.87–3.73(m,3H),3.41(d,J=14.8Hz,1H),3.35-3.3 1(m,5H),3.20(d,J=14.4Hz,1H),3.05(dd,J=14.9,8.8Hz,1H),2.68(td,J=12 .9,3.0Hz,1H),2.62-3.58(m,4H),2.43(d,J=14.4Hz,1H),2.36(s,3H),2.32–2 .29(m,1H),2.22–2.18(m,1H),1.99-1.92(m,2H),1.84-1.76(m,1H),1.62-1. 56(m,1H),1.51(d,J=6.5Hz,3H),1.51–1.41(m,9H),0.97(s,3H),0.41(s,3H).

[0389] Compound 1-6B: sample retention time: 6.15-6.9 min (30.00 mg, 17.64% yield). 1H NMR (500MHz, CDCl3) δ8.61(s,1H),8.40(d,J=2.9Hz,1H),7.56(d,J=8.6Hz,1H),7.32–7.23(m,3H ),5.63(t,J=9.3Hz,1H),5.44(d,J=10.2Hz,1H),4.61–4.54(m,1H),4.35–4.19(m,3H),4.03(d,J =11.9Hz,1H),3.94(d,J=11.0Hz,1H),3.83(d,J=11.0Hz,1H),3.67-3.61(m,1H),3.48-3.44(m,1H),3 .38(d,J=14.9Hz,1H),3.31-3.25(m,4H),3.15(d,J=14.3Hz,1H),3.05(dd,J=14.9,8.7Hz,1H),2.83-2 .78(m,1H),2.70-2.64(m,1H),2.60(t,J=5.3Hz,3H),2.36(s,3H),2.21-2.03(m,3H),1.97–1.90(m,1H ),1.82–1.70(m,1H),1.63-1.54(m,3H),1.51(d,J=6.6Hz,3H),1.46(s,9H),0.93(s,3H),0.74(s,3H).

[0390] Step 8: Synthesis of Compound 1-7

[0391] Compound 1-6A (55.00 mg) was added to DCM (2.00 mL). HCl / dioxane (0.83 mL, 4 M) was then slowly added under N2 protection in an ice-water bath. The mixture was allowed to warm to room temperature and allowed to react for 3 h. After completion of the reaction, the reaction mixture was concentrated to obtain a crude product. 10 mL of toluene was added to the crude product and the mixture was concentrated to obtain the target compound 1-7 (48.00 mg, 99.30% yield). ESI-MS m / z: 728.0 [M+H] + .

[0392] Step 9: Synthesis of Compound 1

[0393] To the reaction flask, (1S,2S)-2-methylcyclopropanecarboxylic acid (17.20 mg), HATU (50.20 mg), DIEA (50 μL), and ACN (5.00 mL) were added sequentially. After stirring at 0°C for 15 min, starting material 1-7 (48.00 mg) was added, and the mixture was then transferred to room temperature for 1 h. After completion of the reaction, the solvent was evaporated under reduced pressure, and the concentrate was purified by preparative chromatography to obtain the title compound 1 (39.8 mg, 74.54% yield). ESI-MS m / z: 809.61 [M+H]+ . 1 H NMR (500MHz, CDCl3) δ8.58(d,J=1.7Hz,1H),8.42(d,J=2.9Hz,1H),7.57(dd,J=8 .6,1.6Hz,1H),7.31(d,J=8.6Hz,1H),7.27(s,1H),7.09(d,J=3.0Hz,1H),6.42(d ,J=9.7Hz,1H),5.89(t,J=9.0Hz,1H),4.60(d,J=13.0Hz,1H),4.35(td,J=12.1, 3.3Hz,1H),4.24-4.16(m,2H),4.04–3.96(m,2H),3.86–3.74(m,3H),3.45(d,J=1 4.9Hz,1H),3.32-3.26(m,5H),3.23–3.16(m,1H),3.11(dd,J=14.9,8.6Hz,1H), 2.69-2.60(m,5H),2.42(d,J=14.4Hz,1H),2.38(s,3H),2.32-2.21(m,1H),2.01- 1.94(m,2H),1.85-1.80(m,1H),1.51(d,J=6.5Hz,3H),1.30–1.19(m,4H),1.10( d,J=6.0Hz,3H),0.96(s,3H),0.91–0.86(m,1H),0.66-6.60(m,1H),0.40(s,3H).

[0394] Example 2: Synthesis of compound (1S,2S)-N-((63S,4S,Z)-10,10-dimethyl-12-(4-methylpiperazin-1-yl)-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6)-pyridazinonecycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide

[0395] Step 1: Synthesis of compound 2-1

[0396] To a 500 mL three-necked flask, 3-bromo-5-fluoroacrylonitrile (13.60 g, 67.66 mmol), THF / tetrahydrofuran (180.00 mL), DIEA (16.77 mL, 101.49 mmol), and piperazine (6.41 g, 74.43 mmol) were added sequentially and stirred at room temperature. After completion of the reaction as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, separated, and the organic phase was concentrated to obtain a crude product of compound 2-1 (18.1 g), which was used directly in the next reaction. ESI-MS m / z: 264.10, 269.09 [M+H] + .

[0397] Step 2: Synthesis of compound 2-2

[0398] To a 500 mL three-necked flask, compound 2-1 (18.00 g, 67.38 mmol), EtOH (200.00 mL), H2O (40.00 mL), and NaOH (13.48 g, 336.92 mmol) were added in sequence. The mixture was heated in an oil bath and maintained at 80-90°C. After completion of the reaction as monitored by LC-MS, the reaction solution was concentrated to dryness, and 200 mL of water and 100 mL of THF were added again. The anhydrous ethanol was removed by concentration to obtain a mixture containing compound 2-2, which was used directly in the next reaction. ESI-MS m / z: 286.08, 288.05, [M+H] + .

[0399] Step 3: Synthesis of compound 2-3

[0400] To the post-treatment mixture containing compound 2-2 (19.28 g, 67.38 mmol), THF (200.00 mL) and H₂O (150.00 mL) were added. The mixture was transferred to a 500 mL three-necked flask, followed by the addition of NaOH (8.09 g, 202.15 mmol). The mixture was stirred at room temperature, and then CbzCl (18.97 mL, 134.77 mmol) was added dropwise. After completion of the dropwise addition, the reaction was stirred continuously. After completion of the reaction, the pH was adjusted to approximately 3-4 by LC-MS monitoring. The mixture was extracted three times with ethyl acetate, and the organic phases were combined and washed sequentially with water and brine. The organic phases were separated and concentrated to obtain the crude product. The product was then purified by silica gel column chromatography (DCM to DCM / MeOH = 95 / 5) to obtain the target compound 2-3 (19.1 g). ESI-MS m / z: 420.24, 422.26 [M+H] + .

[0401] Step 4: Synthesis of compound 2-4

[0402] To a 500 mL single-necked flask, compound 2-3 (19.10 g, 45.45 mmol), THF (200.00 mL), and CDI (11.05 g, 68.17 mmol) were added sequentially. The mixture was heated in an oil bath and refluxed. After cooling to room temperature overnight (approximately 15 hours), the mixture was cooled to room temperature and then MeOH / methanol (200.00 mL) was added. The reaction was continued with stirring. After completion of the reaction, as monitored by LC-MS, the mixture was added to saturated aqueous ammonium chloride along with another batch of the reaction mixture (2-3: 7.4 g) and quenched. The mixture was extracted with ethyl acetate, washed with brine, separated, and the organic phase concentrated to yield the crude product. The crude product was then purified by silica gel column chromatography (PE-PE / EA = 50 / 50) to afford the target compound 2-4 (20.5 g). ESI-MS m / z: 434.23, 436.24, [M+H] + .

[0403] Step 5: Synthesis of Compound 2-5

[0404] To a 500 mL three-necked flask, compound 2-4 (7500.00 mg, 17.27 mmol), THF (150.00 mL), and MeOH (30.00 mL) were added sequentially. The mixture was cooled in a water bath and NaBH4 (3266.58 mg, 86.35 mmol) was added portionwise. After addition, the reaction mixture was stirred continuously. After completion of the reaction, as monitored by LC-MS, the reaction mixture was quenched by adding saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, washed with brine, separated, and the organic phase was concentrated to obtain the crude product. The product was then separated and purified by silica gel column chromatography (PE / EA = 95 / 5 to 50 / 50) to obtain the target compound 2-5 (5.43 g). ESI-MS m / z: 406.29, 408.29, [M+H] + .

[0405] Step 6: Synthesis of Compound 2-6

[0406] To a 50 mL single-necked flask, compound 2-5 (630.00 mg, 1.55 mmol), compound 1-1 (1068.56 mg, 3.10 mmol), DMSO (6.00 mL), and THF (1.20 mL) were added sequentially. Sodium tert-butoxide (372.56 mg, 3.88 mmol) was added and the reaction was stirred at room temperature. After completion of the reaction as monitored by TLC, the reaction mixture was quenched by adding saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, washed with brine, separated, and the organic phase was concentrated to obtain the crude product. The crude product was then separated and purified by silica gel column chromatography (PE-PE / EA = 50 / 50) to obtain the target compound 2-6 (528 mg).

[0407] Step 7: Synthesis of Compound 2-7

[0408] Compound 2-6 (528.00 mg, 0.91 mmol) and TBAF (5.00 mL, 1 M THF solution) were added to a 50 mL single-necked flask and stirred at room temperature overnight. After completion of the reaction, the reaction solution was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine, followed by separation. The organic phase was concentrated to obtain a crude product, which was then purified by silica gel column chromatography (PE-PE / EA = 50 / 50) to obtain the target compound 2-7 (308 mg). ESI-MS m / z: 464.27, 466.28, [M+H] + .

[0409] Step 8: Synthesis of compound 2-8

[0410] To a 50 mL single-necked flask, compound 2-7 (308.00 mg, 0.66 mmol), DCM (10.00 mL), DIEA (0.27 mL, 1.66 mmol), and DMAP (8.10 mg, 0.07 mmol) were added in sequence. TosCl (189.69 mg, 0.99 mmol) was then added in batches. After addition, the reaction was stirred at room temperature. After completion of the reaction, the reaction solution was monitored by LC-MS. Silica gel was added to the reaction solution for sample mixing and sand preparation. The solution was then separated and purified by silica gel column chromatography (PE / EA = 90 / 10 to 50 / 50) to obtain compound 2-8 (251 mg). ESI-MS m / z: 618.36, 620.37, [M+H] + .

[0411] Step 9: Synthesis of compound 2-9

[0412] To a 10 mL single-necked flask, compound 2-8 (196.14 mg, 0.32 mmol), M2 (200.00 mg, 0.29 mmol), K2CO3 (99.62 mg, 0.72 mmol), [PdCl2(dppf)]CH2Cl2 (23.52 mg, 0.03 mmol), toluene (3.00 mL), dioxane (1.00 mL), and water (1.00 mL) were added in sequence. The atmosphere was replaced with nitrogen and protected with oil bath heating, and the temperature was kept at 60-65°C. After completion of the reaction as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed with water and brine in sequence, separated, and the aqueous phase was extracted with DCM. The organic phases were combined and concentrated to give a crude product, which was separated and purified by Prep-TLC (DCM / MeOH = 20 / 1) to give compound 2-9 (220 mg), which was used directly in the next reaction.

[0413] Step 10: Synthesis of compound 2-10

[0414] To a 10 mL single-necked flask, compound 2-9 (220.00 mg, 0.20 mmol), DMF (2.00 mL), and Cs2CO3 (129.68 mg, 0.40 mmol) were added sequentially. The mixture was heated in an oil bath at 60-65°C under nitrogen protection. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the organic phase was concentrated to obtain crude compound 2-10. This was then separated and purified by silica gel column chromatography (DCM to DCM / MeOH = 20 / 1) to obtain the target compound 2-10 (59 mg). ESI-MS m / z: 933.53, [M+H] + .

[0415] 1 H NMR (500MHz, CDCl3) δ8.60(d,J=1.6Hz,1H),8.37(d,J=2.9Hz,1H),7.59(dd,J=8.5,1 .7Hz,1H),7.30(d,J=9.9Hz,2H),7.08(d,J=2.9Hz,1H),5.58(t,J=9.4Hz,1H),5.43( d,J=10.3Hz,1H),4.88(d,J=12.6Hz,1H),4.59(d,J=13.2Hz,1H),4.34(td,J=12.1,3 .3Hz,1H),4.23(d,J=12.6Hz,1H),4.14–4.05(m,2H),4.02(d,J=12.2Hz,1H),3.87–3. 75(m,3H),3.41(d,J=14.8Hz,1H),3.38–3.31(m,1H),3.30(t,J=5.1Hz,4H),3.20(d, J=14.4Hz,1H),3.05(dd,J=14.9,8.8Hz,1H),2.68(td,J=12.9,3.0Hz,1H),2.64–2.5 6(m,4H),2.39(s,1H),2.36(s,3H),2.35–2.19(m,2H),2.02-1.95(m,5H),1.93–1.87 (m,1H),1.85-1.76(m,1H),1.62-1.56(m,1H),1.47(s,9H),0.96(s,3H),0.45(s,3H).

[0416] Step 11: Synthesis of compound 2-11

[0417] To a 10 mL single-necked flask, compound 2-10 (59.00 mg, 0.06 mmol), MeOH (3.00 mL), and Pd(OH)2 / C (71.00 mg, 0.51 mmol, 10% Pd) were added sequentially. The atmosphere was replaced with hydrogen, and the reaction was stirred at room temperature. After completion of the reaction as monitored by LC-MS, the reaction was filtered, the catalyst was removed, and the filtrate was concentrated to obtain crude compound 2-11 (42 mg), which was used directly in the next reaction. ESI-MS m / z: 799.53, [M+H] + .

[0418] Step 12: Synthesis of Compound 2-12

[0419] To a 10 mL single-necked flask, compound 2-11 (42.00 mg, 0.05 mmol), MeOH (2.00 mL), 37% aqueous formaldehyde solution (2.00 mL), and HOAc (0.10 mL) were added sequentially and stirred at room temperature for 20 minutes. NaBH3CN (16.53 mg, 0.26 mmol) was added and the reaction was stirred at room temperature. After completion of the reaction, ethylenediamine was added to quench the excess formaldehyde, followed by addition to saturated aqueous sodium bicarbonate solution and quenching. The mixture was then extracted with DCM and separated. The organic phase was concentrated to obtain the crude product (45 mg, white foamy solid), which was then separated and purified by Prep-HPLC alkaline method. The eluate was lyophilized to obtain the target compound 2-12 (22 mg). ESI-MS m / z: 813.50, [M+H] + .

[0420] Step 13: Synthesis of Compound 2-13

[0421] To a 10 mL single-necked flask, compound 2-12 (22.00 mg, 0.03 mmol), DCM (2.00 mL), and HCl (4M in dioxane) (1.00 mL) were added in sequence and stirred at room temperature. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated to dryness, DCM was added, and the mixture was concentrated again to dryness. The crude product of compound 2-13 (19.1 mg, hydrochloride) was obtained and used directly in the next reaction. ESI-MS m / z: 713.54, [M+H] + .

[0422] Step 14: Synthesis of Compound 2

[0423] To a 10 mL single-necked flask, (1S,2S)-2-methylcyclopropane-1-carboxylic acid (8.02 mg, 0.08 mmol), HATU (45.70 mg, 0.12 mmol), and DIEA (0.04 mL) were added sequentially and stirred at room temperature for 30 minutes. The mixture was cooled in an ice-water bath, followed by the addition of a solution of compound 2-13 (19.00 mg, 0.03 mmol) in acetonitrile. After completion of the reaction, as monitored by LC-MS, the reaction solution was directly purified by acidic Prep-HPLC, and the eluate was lyophilized to yield the target compound 2 (11.9 mg).

[0424] ESI-MS m / z:795.59, [M+H] + . 1 H NMR(500MHz,DMSO)δ9.82(s,1H),8.53(d,J=9.0Hz,1H),8.49(d,J=1.7Hz,1H),8.44 (d,J=2.8Hz,1H),7.81(s,1H),7.72(dd,J=8.6,1.7Hz,1H),7.50(d,J=8.6Hz,1H),7. 38(d,J=2.9Hz,1H),5.53(t,J=9.2Hz,1H),5.08(d,J=12.2Hz,1H),4.71(d,J=12.6Hz ,1H),4.28–4.11(m,4H),4.03(t,J=13.4Hz,2H),3.95-3.91(m,1H),3.69(d,J=11.0H z,1H),3.68–3.57(m,2H),3.53(d,J=11.9Hz,2H),3.33(d,J=14.5Hz,1H),3.27-3.0 3(m,6H),3.00(d,J=14.4Hz,1H),2.79-2.72(m,1H),2.36(d,J=14.3Hz,1H),2.31–2. 21(m,1H),2.10(d,J=12.1Hz,1H),1.83–1.78(m,3H),1.53–1.47(m,2H),1.08-1.04( m,4H),1.06(s,3H),0.95(s,3H),0.89-0.85(m,1H),0.57-0.53(m,1H),0.36(s,3H).

[0425] Example 4 Synthesis of Compound (1S,2S)-2-methyl-N-((19S,63S,4S,Z)-19,10,10-trimethyl-12-(4-methylpiperazin-1-yl)-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazino[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinocycloundecane-4-yl)cyclopropane-1-carboxamide

[0426] Step 1: Synthesis of compound 4-1

[0427] To a 50 mL single-necked flask, compound 2-5 (1.00 g, 2.46 mmol), M3 (1.32 g, 3.69 mmol), DMSO (10.00 mL), and THF (2 mL) were added sequentially. Sodium tert-butoxide (0.59 g, 6.15 mmol) was added and the reaction was stirred at room temperature. After completion of the reaction as monitored by TLC, the reaction mixture was added to saturated aqueous ammonium chloride solution for quenching. The mixture was extracted with ethyl acetate, washed with brine, separated, and the organic phase was concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain the target compound 4-1 (0.5 g). ESI-MS m / z: 592.41, [M+H] + .

[0428] Step 2: Synthesis of compound 4-2

[0429] Compound 4-1 (0.5 g, 0.84 mmol) and TBAF (5 mL, 1 M THF solution) were added to a 50 mL single-necked flask and stirred at room temperature overnight. After completion of the reaction, the reaction solution was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine, followed by separation. The organic phase was concentrated to obtain a crude product, which was then purified by silica gel column chromatography to obtain the target compound 4-2 (0.43 g). ESI-MS m / z: 478.33, [M+H] + .

[0430] Step 3: Synthesis of compound 4-3

[0431] To a 50 mL single-necked flask, compound 4-2 (0.43 g, 0.9 mmol), DCM (5.00 mL), DIEA (0.37 mL, 2.25 mmol), and DMAP (10 mg, 0.09 mmol) were added in sequence, followed by the addition of TosCl (0.26 g, 1.35 mmol) in batches. After addition, the mixture was stirred at room temperature. After completion of the reaction, the reaction solution was monitored by LC-MS. Silica gel was added to the reaction solution for sample mixing and sand preparation. The mixture was then separated and purified by silica gel column chromatography to obtain compound 4-3 (185 mg). ESI-MS m / z: 632.34, [M+H] + .

[0432] Step 4: Synthesis of compound 4-4

[0433] To a 10 mL single-necked flask, compound 4-3 (164 mg, 0.26 mmol), M2 (150 mg, 0.22 mmol), K2CO3 (75 mg, 0.54 mmol), [PdCl2(dppf)] (16 mg, 0.02 mmol), toluene (3.00 mL), dioxane (1.00 mL), and water (1.00 mL) were added sequentially. The atmosphere was replaced with nitrogen and protected with oil bath heating, maintaining the temperature at 60-65°C. After completion of the reaction as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, separated, and the aqueous phase was extracted with DCM. The organic phases were combined and concentrated to give a crude product, which was separated and purified by Prep-TLC to give compound 4-4 (276 mg). ESI-MS m / z: 1119.66, [M+H] + .

[0434] Step 5: Synthesis of compound 4-5

[0435] To a 10 mL single-necked flask, compound 4-4 (226 mg, 0.20 mmol), DMF (25.00 mL), and Cs2CO3 (197 mg, 0.61 mmol) were added sequentially. The mixture was heated in an oil bath at 60-65°C under nitrogen protection. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the organic phase was concentrated to obtain crude compound 4-5. This was then separated and purified by silica gel column chromatography to obtain the target compound 4-5 (15 mg). ESI-MS m / z: 947.64, [M+H] + .

[0436] 1H NMR (500MHz, CDCl3) δ8.56(d,J=1.7Hz,1H),8.32(d,J=2.8Hz,1H),7.58(dd,J=8.6,1.7 Hz,1H),7.37(d,J=4.4Hz,4H),7.37–7.29(m,2H),7.28(s,1H),7.07(d,J=2.8Hz,1H),5. 56(dd,J=10.2,8.5Hz,1H),5.43-5.39(m,1H),5.16(s,2H),4.89(d,J=15.9Hz,1H),4.82 -4.76(m,1H),4.58(d,J=13.0Hz,1H),4.52(d,J=16.0Hz,1H),4.33(td,J=12.1,3.3Hz,1 H),4.03–3.94(m,2H),3.91–3.80(m,2H),3.76(d,J=11.2Hz,1H),3.72-3.69(m,4H),3. 40(d,J=14.9Hz,1H),3.22(s,4H),3.13(d,J=14.4Hz,1H),3.04(dd,J=15.0,8.7Hz,1H), 2.69-2.63(m,1H),2.26–2.16(m,2H),2.09–1.98(m,1H),1.97-1.93(m,1H),1.87-1.79( m,2H),1.60-1.54(m,1H),1.47(s,9H),1.06(d,J=6.7Hz,3H),0.92(s,3H),0.50(s,3H).

[0437] Step 6: Synthesis of Compound 4-6

[0438] To a 10 mL single-necked flask, compound 4-5 (15 mg, 0.02 mmol), MeOH (2.00 mL), and Pd(OH)2 / C (18 mg, 0.13 mmol, 10% Pd) were added sequentially. The atmosphere was replaced with hydrogen, and the reaction was stirred at room temperature. After completion of the reaction as monitored by LC-MS, the reaction was filtered, the catalyst was removed, and the filtrate was concentrated to obtain crude compound 4-6 (15 mg), which was used directly in the next reaction. ESI-MS m / z: 813.60, [M+H] + .

[0439] Step 7: Synthesis of Compound 4-7

[0440] To a 10 mL single-necked flask, compound 4-6 (15 mg, 0.02 mmol), MeOH (2.00 mL), 37% formaldehyde solution (15 mg), and HOAc (0.10 mL) were added in sequence and stirred at room temperature for 20 minutes. NaBH3CN (2.3 mg, 0.04 mmol) was added and the reaction was stirred at room temperature. After the reaction was completed as monitored by LC-MS, ethylenediamine was added to quench the excess formaldehyde in the reaction solution, which was then added to a saturated sodium bicarbonate aqueous solution and quenched. The solution was then extracted with DCM and separated; the organic phase was concentrated to obtain a crude product of compound 4-7 (15 mg, white foamy solid). ESI-MS m / z: 827.62, [M+H] + .

[0441] Step 8: Synthesis of Compound 4-8

[0442] To a 10 mL single-necked flask, compound 4-7 (15 mg, 0.02 mmol), DCM (1.00 mL), and HCl (4 M in dioxane) (1.00 mL) were added in sequence and the reaction was stirred at room temperature. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated to dryness, DCM was added, and the reaction solution was concentrated to dryness again. The crude product of compound 4-8 (slightly yellow solid powder, 15 mg, hydrochloride) was obtained and used directly in the next reaction. ESI-MS m / z: 727.57, [M+H] + .

[0443] Step 9: Synthesis of compound 4

[0444] To a 10 mL single-necked flask, (1S,2S)-2-methylcyclopropanecarboxylic acid (2.5 mg, 0.025 mmol), HATU (16 mg, 0.041 mmol), and DIEA (0.02 mL, 0.124 mmol) were added in sequence and stirred at room temperature for 30 minutes. The mixture was cooled in an ice-water bath, and then a solution of compound 4-8 (15.00 mg, 0.021 mmol) in acetonitrile was added. After completion of the reaction monitored by LC-MS, the reaction solution was directly separated and purified by Prep-HPLC acidic method, and the eluate was lyophilized to obtain the target compound 4 (7.9 mg). ESI-MS m / z: 809.61, [M+H] + .

[0445] 1H NMR(500MHz,DMSO)δ9.72(s,1H),8.52(d,J=9.0Hz,1H),8.44–8.34(m,2H),7.78(s,1H ),7.70(d,J=7.5Hz,1H),7.54(d,J=8.9Hz,1H),7.33(d,J=2.5Hz,1H),5.51(t,J=9.2H z,1H),5.06(d,J=12.1Hz,1H),5.00–4.92(m,1H),4.78(d,J=16.2Hz,1H),4.45(d,J=1 6.1Hz,2H),4.21(dd,J=30.6,11.9Hz,3H),4.01–3.83(m,4H),3.76(d,J=12.8Hz,2H),3 .56(d,J=5.1Hz,2H),3.31(d,J=14.3Hz,1H),3.14(dd,J=14.7,9.4Hz,2H),3.07–2.99 (m,2H),2.95(d,J=14.3Hz,1H),2.86(s,3H),2.76(s,1H),2.19(d,J=14.4Hz,1H),2.0 9(d,J=10.4Hz,1H),1.91–1.72(m,4H),1.51(d,J=3.8Hz,2H),1.24(s,1H),1.07(s,3H ),0.98(d,J=6.6Hz,3H),0.91(s,3H),0.88(s,1H),0.55(d,J=7.4Hz,1H),0.42(s,3H).

[0446] Example 5 Synthesis of Compound (1S,2S)-2-methyl-N-((15S,19S,63S,4S,Z)-15,19,10,10-tetramethyl-12-(4-methylpiperazin-1-yl)-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)cyclopropane-1-carboxamide

[0447] Step 1: Synthesis of compound 5-1

[0448] To a 50 mL single-necked flask, M4-3 (1.00 g, 2.38 mmol), (R)-3-((tert-butyldimethylsilyl)oxy)butyl 4-methylbenzenesulfonate (2.13 g, 5.95 mmol), DMSO (10.00 mL), THF (2 mL) were added in sequence, followed by sodium tert-butoxide (0.57 g, 5.95 mmol), and the reaction was stirred at room temperature. After completion of the reaction as monitored by TLC, the reaction mixture was added to saturated aqueous ammonium chloride solution and quenched; the mixture was extracted with ethyl acetate, washed with brine, separated, and the organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain the target compound 5-1 (0.77 g). ESI-MS m / z: 606.43, [M+H] + .

[0449] Step 2: Synthesis of compound 5-2

[0450] Compound 5-1 (0.77 g, 1.26 mmol) and TBAF (7 mL, 1 M THF solution) were added to a 50 mL single-necked flask and stirred at room temperature overnight. After completion of the reaction, the reaction solution was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine, followed by separation. The organic phase was concentrated to obtain a crude product, which was then purified by silica gel column chromatography (PE-PE / EA = 50 / 50) to obtain the target compound 5-2 (0.55 g). ESI-MS m / z: 492.34, [M+H] + .

[0451] Step 3: Synthesis of compound 5-3

[0452] To a 50 mL single-necked flask, compound 5-2 (0.36 g, 0.731 mmol), DCM (5.00 mL), DIEA (0.36 mL, 2.19 mmol), and DMAP (0.179 g, 1.462 mmol) were added in sequence, followed by the addition of TosCl (0.279 g, 1.46 mmol) in batches. After addition, the reaction was stirred at room temperature. After completion of the reaction, the reaction solution was monitored by LC-MS. Silica gel was added to the reaction solution for sample mixing and sand preparation. The product was then separated and purified by silica gel column chromatography to obtain compound 5-3 (0.23 g). ESI-MS m / z: 646.34, [M+H] + .

[0453] Step 4: Synthesis of compound 5-4

[0454] To a 10 mL single-necked flask, compound 5-3 (224 mg, 0.35 mmol), M2 (200 mg, 0.29 mmol), K2CO3 (100 mg, 0.72 mmol), [PdCl2(dppf)] (21 mg, 0.03 mmol), toluene (3.00 mL), dioxane (1.00 mL), and water (1.00 mL) were added sequentially. The atmosphere was replaced with nitrogen and protected with oil bath heating at 60-65°C. After completion of the reaction as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, separated, and the aqueous phase was extracted with DCM. The organic phases were combined and concentrated to give a crude product, which was separated and purified by Prep-TLC to give compound 5-4 (246 mg). ESI-MS m / z: 1133.68, [M+H] + .

[0455] Step 5: Synthesis of compound 5-5

[0456] To a 10 mL single-necked flask, compound 5-4 (200 mg, 0.20 mmol), DMF (20.00 mL), and Cs2CO3 (291 mg, 0.89 mmol) were added sequentially. The mixture was heated in an oil bath at 60-65°C under nitrogen protection. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the organic phase was concentrated to obtain crude compound 5-5. This was then separated and purified by silica gel column chromatography to obtain the target compound 5-5 (12 mg). ESI-MS m / z: 961.64, [M+H] + .

[0457] Step 6: Synthesis of compound 5-6

[0458] To a 10 mL single-necked flask, compound 5-5 (12 mg, 0.02 mmol), MeOH (2.00 mL), and Pd(OH)2 / C (18 mg, 0.13 mmol, 10% Pd) were added sequentially. The atmosphere was replaced with hydrogen, and the reaction was stirred at room temperature. After completion of the reaction as monitored by LC-MS, the reaction was filtered, the catalyst was removed, and the filtrate was concentrated to obtain crude compound 5-6 (12 mg), which was used directly in the next reaction. ESI-MS m / z: 817.62, [M+H] + .

[0459] Step 7: Synthesis of compound 5-7

[0460] To a 10 mL single-necked flask, compound 5-6 (12 mg, 0.02 mmol), MeOH (2.00 mL), 37% formaldehyde solution (12 mg), and HOAc (0.10 mL) were added in sequence and stirred at room temperature for 20 minutes. NaBH3CN (2 mg, 0.03 mmol) was added and the reaction was stirred at room temperature. After the reaction was completed as monitored by LC-MS, ethylenediamine was added to quench the excess formaldehyde in the reaction solution, which was then added to a saturated sodium bicarbonate aqueous solution and quenched. The solution was then extracted with DCM and separated; the organic phase was concentrated to obtain a crude product of compound 5-7 (12 mg, white foamy solid). ESI-MS m / z: 841.64, [M+H] + .

[0461] Step 8: Synthesis of Compound 5-8

[0462] To a 10 mL single-necked flask, compound 5-7 (12 mg, 0.02 mmol), DCM (1.00 mL), and HCl (4 M in dioxane) (1.00 mL) were added in sequence and the reaction was stirred at room temperature. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated to dryness, DCM was added, and the reaction solution was concentrated to dryness again. The crude product of compound 5-8 (slightly yellow solid powder, 13 mg, hydrochloride) was obtained and used directly in the next reaction. ESI-MS m / z: 727.57, [M+H] + .

[0463] Step 9: Synthesis of compound 5

[0464] To a 10 mL single-necked flask, (1S,2S)-2-methylcyclopropanecarboxylic acid (2 mg, 0.025 mmol), HATU (12 mg, 0.032 mmol), and DIEA (0.016 mL, 0.097 mmol) were added in sequence and stirred at room temperature for 30 minutes. The mixture was cooled in an ice-water bath, and then a solution of compound 5-8 (13 mg, 0.021 mmol) in acetonitrile was added. After completion of the reaction monitored by LC-MS, the reaction solution was directly separated and purified by Prep-HPLC acidic method, and the eluate was lyophilized to obtain the target compound 5 (2.1 mg). ESI-MS m / z: 823.63, [M+H] + .

[0465] Example 21: Synthesis of compound (1S,2S)-N-((15S,63S,4S,Z)-12-(4-ethylpiperazin-1-yl)-15,10,10-trimethyl-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazinyl[5,6-a]indole-2)-thiazole-6(1,3)-pyridazinylcycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide

[0466] Step 1: Synthesis of compound 21

[0467] To a 10 mL single-necked flask, (1S,2S)-2-methylcyclopropanecarboxylic acid (8.8 mg, 0.09 mmol), HATU (38.5 mg, 0.10 mmol), and DIEA (0.04 mL, 0.27 mmol) were added in sequence and stirred at room temperature for 10 minutes. The mixture was cooled in an ice-water bath, and then a solution of compound 84-2 (50.00 mg, 0.07 mmol) in acetonitrile was added. After completion of the reaction monitored by LC-MS, the reaction solution was directly separated and purified by Prep-HPLC acidic method, and the eluate was lyophilized to obtain the target compound 21 (10.0 mg). ESI-MS m / z: 823.63, [M+H] + .

[0468] 1H NMR (500MHz, CDCl3) δ8.59 (s, 1H), 8.43 (s, 1H), 7.58 (d, J = 8.1Hz, 1H), 7.36 –7.27(m,2H),7.09(s,1H),6.46(d,J=9.0Hz,1H),5.89(t,J=11.0Hz,1H),4 .61(d,J=12.1Hz,1H),4.36(t,J=11.4Hz,1H),4.28–4.17(m,2H),4.06–3.9 6(m,2H),3.86–3.75(m,3H),3.45(d,J=14.7Hz,1H),3.40–3.28(m,5H),3.19 (d,J=14.0Hz,1H),3.15–3.08(m,1H),2.80–2.71(m,4H),2.60(d,J=6.4Hz, 2H),2.41(d,J=14.4Hz,1H),2.37–2.20(m,3H),2.01–1.92(m,2H),1.87–1. 77(m,1H),1.65–1.57(m,1H),1.55–1.46(m,3H),1.38–1.32(m,1H),1.29–1 .23(m,2H),1.22–1.15(m,4H),1.13–1.07(m,3H),0.96(s,3H),0.40(s,3H).

[0469] Example 22: Synthesis of Compound (1S,2S)-N-((15S,63S,4S,Z)-12-(4-(2-methoxyethyl)piperazin-1-yl)-15,10,10-trimethyl-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxo-1(13,15)-pyrido[3',2':7,8][1,5]oxazolo[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazin-4-yl)-2-methylcyclopropane-1-carboxamide

[0470] Compound (1S,2S)-2-methylcyclopropanecarboxylic acid (5.85 mg, 0.06 mmol) was dissolved in acetonitrile (2.00 mL). DIEA (0.06 mL, 0.39 mmol) and HATU (22.21 mg, 0.06 mmol) were added sequentially in an ice-water bath. After reacting for 10 min in an ice-water bath, a solution of compound 101-2 (30.00 mg, 0.04 mmol) in acetonitrile (2.00 mL) and DIEA (0.06 mL, 0.39 mmol) was added and the mixture was reacted at room temperature for 1 h. The product was concentrated to dryness and used for preparative isolation to obtain compound 22 (19.00 mg, 56.87%). ESI-MS m / z: 853.79, [M+H] + .

[0471] 1 H NMR(500MHz,DMSO)δ8.56(d,J=9.0Hz,1H),8.49(s,1H),8.40(d,J=2.7Hz,1H),7.81 (s,1H),7.75–7.68(m,1H),7.49(d,J=8.6Hz,1H),7.21(d,J=2.7Hz,1H),5.52(t,J= 9.3Hz, 1H), 5.08 (d, J = 12.2Hz, 1H), 4.23 (dd, J = 11.9, 9.4Hz, 2H), 4.15 (q, J = 6.2Hz, 1H),4.08–3.97(m,2H),3.67(d,J=11.0Hz,1H),3.60(t,J=13.7Hz,2H),3.46(t,J=5 .7Hz,2H),3.24(s,7H),3.15(dt,J=14.6,9.8Hz,2H),3.00(d,J=14.4Hz,1H),2.75( dd,J=16.2,12.0Hz,1H),2.56(s,3H),2.41(d,J=14.4Hz,1H),2.30(s,1H),2.11(d, J=10.3Hz,1H),1.80(s,3H),1.56–1.45(m,3H),1.37(d,J=6.3Hz,4H),1.07(s,5H), 0.95(s,3H),0.86(dd,J=7.6,4.1Hz,3H),0.56(dd,J=7.4,5.6Hz,1H),0.32(s,3H).

[0472] Example 37 Synthesis of Compound N-((15S,63S,4S,Z)-12-(4-ethylpiperazin-1-yl)-15,10,10-trimethyl-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)-3-methylbicyclo[1.1.1]pentane-1-carboxamide

[0473] Step 1: Synthesis of compound 37

[0474] To a 10 mL single-necked flask, 1-methylbicyclo[1.1.1]pentane-3-carboxylic acid (11.76 mg, 0.09 mmol) and N,N-dimethylformamide (1.00 mL) were added sequentially. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (35.44 mg, 0.09 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.62 mmol) were added at 0°C and stirred for 10 minutes. Finally, compound 84-2 (46.00 mg, 0.06 mmol) was added and stirred at 0°C for 10 minutes. The reaction was monitored for completion by LC-MS, and the reaction solution was directly purified by pre-HPLC to obtain the target compound 37 (16.70 mg). ESI-MS m / z: 849.8 [M+H] + .

[0475] 1H NMR (500MHz, Methanol-d4) δ8.56(d,J=1.5Hz,1H),8.38(d,J=2.9Hz,1H),7.68(dd,J=8.6,1.6Hz,1H),7.54(s,1H),7.44(d,J=8.6Hz,1H),7.31(d,J=3. 0Hz,1H),5.69–5.63(m,1H),4.60(s,2H),4.42(d,J=12.8Hz,1H),4.33–4.2 6(m,2H),4.15(dd,J=12.4,5.7Hz,1H),4.06(dd,J=14.5,5.0Hz,1H),3.82–3 .68(m,3H),3.43–3.39(m,5H),3.29–3.25(m,1H),3.20(d,J=14.5Hz,1H),2 .87–2.74(m,5H),2.72–2.63(m,2H),2.49(d,J=14.8Hz,1H),2.38(t,J=13.6 Hz,1H),2.27–2.20(m,1H),1.98(s,6H),1.83(d,J=12.9Hz,1H),1.62-1.57 (m,1H),1.47(d,J=6.5Hz,3H),1.24–1.17(m,6H),1.00(s,3H),0.41(s,3H).

[0476] Example 38: Synthesis of Compound N-((15S,63S,4S,Z)-12-(4-(2-methoxyethyl)piperazin-1-yl)-15,10,10-trimethyl-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxo-1(13,15)-pyrido[3',2':7,8][1,5]oxazolo[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinecycloundecane-4-yl)-3-methylbicyclo[1.1.1]pentane-1-carboxamide

[0477] Compound 3-methylbicyclo[1.1.1]pentane-1-carboxamide (5.89 mg, 0.05 mmol) was dissolved in acetonitrile (2.00 mL). DIEA (0.06 mL, 0.39 mmol) and HATU (22.21 mg, 0.06 mmol) were added sequentially in an ice-water bath. After reacting for 10 min in an ice-water bath, a solution of compound 101-2 (30.00 mg, 0.04 mmol) in acetonitrile (2.00 mL) and DIEA (0.06 mL, 0.39 mmol) was added and the mixture was reacted at room temperature for 1 h. The product was concentrated to dryness and used for preparative isolation to obtain compound 38 (9.00 mg, 25.22%). ESI-MS m / z: 879.91, [M+H] + .

[0478] Example 39 Synthesis of Compound 3-methyl-N-((15S,63S,4S,Z)-15,10,10-trimethyl-5,7-dioxo-12-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazino[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinocycloundecane-4-yl)bicyclo[1.1.1]pentane-1-carboxamide

[0479] Step 1: Synthesis of compound 39-1

[0480] Compound M4 (90.00 mg, 0.11 mmol), DIPEA (0.19 mL, 1.11 mmol), and 2,2,2-trifluoroethyl p-toluenesulfonate (56.29 mg, 0.22 mmol) were dissolved in DMF (2.00 mL) and reacted at 80°C for 3 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the layers were separated. The organic phase was concentrated to obtain a crude product, which was then separated and purified by silica gel column chromatography to obtain the target compound 39-1 (75 mg). ESI-MS m / z: 894.41, 895.42 [M+H] + .

[0481] Step 2: Synthesis of compound 39-2

[0482] Compound 39-1 (65.00 mg, 0.07 mmol) was dissolved in DCM (1.00 mL), and then HCl (4 M in dioxane) (1.50 mL) was added. The mixture was allowed to react at room temperature for 30 min. The reaction solution was concentrated to give crude compound 39-2 (95 mg), which was used directly in the next reaction. ESI-MS m / z: 794.35, 795.34 [M+H] + .

[0483] Step 3: Synthesis of compound 39

[0484] Compound 1-methylbicyclo[1.1.1]pentane-3-carboxylic acid (20.23 mg, 0.16 mmol) was dissolved in DMF (1.00 mL) and cooled to 0°C. DIPEA (0.19 mL, 1.07 mmol) and HATU (81.29 mg, 0.21 mmol) were then added and reacted at 0°C for 5 min. Compound 39-2 (85.00 mg, 0.11 mmol) was then added and reacted at 0°C for 5 min. After completion of the reaction, the reaction was monitored by LC-MS and separated by preparative chromatography (acetonitrile:water (containing 0.05% diethylamine) = 5:1) to yield the title compound 39 (51 mg). ESI-MS m / z: 902.41, 903.42 [M+H] + .

[0485] 1H NMR (500MHz, CDCl3) δ8.59(d,J=1.7Hz,1H),8.42(d,J=2.9Hz,1H),7.58(dd,J=8.6,1.6 Hz,1H),7.31(d,J=8.6Hz,1H),7.28(s,1H),7.08(d,J=3.0Hz,1H),6.36(d,J=9.7Hz,1H) ,5.87–5.78(m,1H),4.58(d,J=12.8Hz,1H),4.34(td,J=12.1,3.3Hz,1H),4.22(dq,J=17 .7,6.1Hz,2H),4.05–3.96(m,2H),3.86–3.74(m,3H),3.46(d,J=14.9Hz,1H),3.35–3.27 (m,5H),3.19(d,J=14.4Hz,1H),3.15–3.02(m,3H),2.87(q,J=4.2Hz,4H),2.72–2.63(m,1H),2.41(d,J=14.3Hz,1H),2.32(t,J=14.0Hz,1H),2. 28–2.19(m,1H),1.97(s,6H),1.88–1.76(m,1H),1.71–1.60(m,6H),1.5 1(d,J=6.4Hz,3H),1.25(s,1H),1.22(s,3H),0.96(s,3H),0.40(s,3H).

[0486] Example 40 Synthesis of Compound N-((15S,63S,4S,Z)-12-(4-cyclopropylpiperazin-1-yl)-15,10,10-trimethyl-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)-3-methylbicyclo[1.1.1]pentane-1-carboxamide

[0487] Step 1: Synthesis of compound 40

[0488] Compound 1-methylbicyclo[1.1.1]pentane-3-carboxylic acid (34.19 mg, 0.27 mmol) was dissolved in acetonitrile (4.00 mL). DIEA (0.37 mL, 2.26 mmol) and HATU (128.78 mg, 0.34 mmol) were added sequentially under an ice-water bath. After reacting for 10 min under an ice-water bath, a solution of compound 85-9 (170.00 mg, 0.23 mmol) in acetonitrile (4.00 mL) and DIEA (0.37 mL, 2.26 mmol) was added and the mixture was reacted at room temperature for 1 h. The mixture was concentrated to dryness to obtain compound 40 (67.00 mg, 33.84%). ESI-MS m / z: 861.48 [M+H] + .

[0489] 1 H NMR (500MHz, DMSO) δ8.51(d,J=1.0Hz,1H),8.40(d,J=2.8Hz,1H),8.00(d,J=9.0Hz,1H),7.79( s,1H),7.70(dd,J=8.6,1.4Hz,1H),7.48(d,J=8.6Hz,1H),7.21(d,J=2.8Hz,1H),5.48(t,J=9. 4Hz,1H),5.09(d,J=12.2Hz,1H),4.29–4.19(m,2H),4.15(q,J=6.3Hz,1H),4.03(dd,J=12.6,4 .9Hz,2H),3.69(d,J=11.0Hz,1H),3.64–3.55(m,2H),3.38(dd,J=14.6,9.3Hz,1H),3.29(d,J= 14.3Hz,1H),3.24–3.13(m,5H),3.01(d,J=14.4Hz,1H),2.75(td,J=12.6,5.0Hz,1H),2.69(d, J=17.2Hz,4H),2.41(d,J=14.3Hz,1H),2.29(t,J=10.3Hz,1H),2.11(d,J=10.0Hz,1H),1.93–1 .85(m,6H),1.80(s,3H),1.65(ddd,J=10.1,6.6,3.6Hz,1H),1.52(dt,J=18.1,12.5Hz,1H),1. 37(d,J=6.4Hz,3H),1.19(s,3H),0.95(s,3H),0.50–0.40(m,2H),0.33(dd,J=7.3,4.8Hz,5H).

[0490] Example 80: Synthesis of Compound 3-Methyl-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-(4-methylpiperazin-1-yl)-5,7-dioxo-18,19,61,62,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyridin[3':7,8][1,5]oxazinyl[5,6-a]indole-2)-thiazole-6(1,3)-pyridazinone-undecane-4-yl)bicyclo[1.1.1]pentane-1-carboxamide

[0491] Step 1: Synthesis of compound 80-1

[0492] M5-2 (2.00 g), triethylamine (4.66 mL), and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium (II) chloride (0.21 g) were added to DCM (10.00 mL). Formic acid (1.27 mL) was then slowly added in portions under N2 protection in an ice-water bath. The mixture was allowed to warm to room temperature and allowed to react for 72 h. After completion of the reaction, 100 mL of water was added to quench the reaction mixture. The mixture was then extracted four times with EA (60 mL). The organic phases were combined, washed with saturated sodium chloride, and concentrated to obtain a crude product. The crude product was then separated by column chromatography to obtain the target compound 80-1 (1.80 g, 89.40% yield). ESI-MS m / z: 300.2, 302.2 [M+H] + .

[0493] Step 2: Synthesis of compound 80-2

[0494] Compound 80-1 (1.00 g) and compound 1-1 (2.30 g) were added to DMSO (15.00 mL) and THF (2.00 mL). Under N2 protection, a solution of sodium tert-butoxide (0.80 g) in THF (2.00 mL) was slowly added at room temperature. The mixture was reacted at 40°C for 5 h. After the reaction, 30 mL of water was added to quench the reaction mixture. The mixture was then extracted three times with 30 mL of EA. The organic phases were combined, washed with saturated sodium chloride, and concentrated to obtain a crude product. The crude product was separated by column chromatography to obtain the target compound 80-2 (1.00 g, 63.53% yield). ESI-MS m / z: 472.5, 474.5 [M+H] + .

[0495] Step 3: Synthesis of compound 80-3

[0496] Compound 80-2 (1.00 g) and TBAF (4.23 mL, 1.00 mol / L) were added to THF (2.00 mL) and reacted at 50°C under N2 protection for 1 h. After the reaction, 30 mL of water was added to the reaction solution to quench the reaction. The mixture was then extracted five times with 30 mL of DCM. The organic phases were combined, washed with saturated sodium chloride, and concentrated to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 97:3 to 90:10) to obtain the target compound 80-3 (0.78 g, 100% yield). ESI-MS m / z: 358.3, 360.3 [M+H] + .

[0497] Step 4: Synthesis of compound 80-4

[0498] Compound 80-3 (780.00 mg), triethylamine (0.76 mL), and DMAP (26.60 mg) were sequentially added to a DCM (10.00 mL) solution. Under N2 protection, the temperature was lowered to 0°C, and TsCl (830.12 mg) was slowly added. The mixture was then allowed to warm to room temperature and allowed to react for 12 hours. After completion of the reaction, 100 mL of water was added to quench the reaction mixture. The mixture was then extracted three times with 50 mL of DCM and washed twice with 50 mL of saturated sodium chloride. The combined organic phases were concentrated to obtain a crude product, which was then separated by column chromatography to yield the target compound 80-4 (1300.00 mg, 100% yield). ESI-MS m / z: 512.4, 514.4 [M+H] + .

[0499] Step 5: Synthesis of compound 80-5

[0500] Compound 80-4 (265.97 mg), intermediate M2 (300.00 mg), PdCl2(dppf) (31.61 mg), and K2CO3 (149.43 mg) were added to toluene (4.50 mL), 1,4-dioxane (1.50 mL), and water (1.00 mL). The mixture was then reacted at 65°C under N2 protection for 2 h. After completion of the reaction, 30 mL of water was added to quench the reaction mixture. The mixture was then extracted three times with 30 mL of DCM and washed twice with 30 mL of saturated sodium chloride. The combined organic phases were concentrated to obtain the crude product, which was then separated by column chromatography to yield the target compound 80-5 (280.00 mg, 64.79% yield). ESI-MS m / z: 1000.2 [M+H] + .

[0501] Step 6: Synthesis of compound 80-6

[0502] Compound 80-5 (280.00 mg) and Cs2CO3 (183.00 mg) were added to DMF (3.00 mL) and reacted at 90°C under N2 protection for 0.5 h. After completion of the reaction, 50 mL of water was added to the reaction solution to quench the reaction. The solution was then extracted three times with 40 mL of DCM and washed four times with 30 mL of saturated sodium chloride. The combined organic phases were concentrated to obtain a crude product, which was then separated by column chromatography to afford compound 80-6 (170.00 mg, 75.52% yield). ESI-MS m / z: 828.1 [M+H] + .

[0503] 1 H NMR (500MHz, CDCl3) δ8.60(d,J=1.6Hz,1H),8.42(d,J=3.0Hz,1H),7.58(dd,J =8.5,1.7Hz,1H),7.32-7.27(m,2H),7.09(d,J=2.9Hz,1H),5.58(t,J=9.4Hz,1 H),5.48(d,J=10.4Hz,1H),4.61-4.56(m,1H),4.38-4.32(m,1H),4.26-4.17( m,2H),4.09–3.95(m,2H),3.87–3.73(m,3H),3.41(d,J=14.8Hz,1H),3.35-3.3 1(m,5H),3.20(d,J=14.4Hz,1H),3.05(dd,J=14.9,8.8Hz,1H),2.68(td,J=12 .9,3.0Hz,1H),2.62-3.58(m,4H),2.43(d,J=14.4Hz,1H),2.36(s,3H),2.32–2 .29(m,1H),2.22–2.18(m,1H),1.99-1.92(m,2H),1.84-1.76(m,1H),1.62-1. 56(m,1H),1.51(d,J=6.5Hz,3H),1.51–1.41(m,9H),0.97(s,3H),0.41(s,3H).

[0504] Step 7: Synthesis of compound 80-7

[0505] Compound 80-6 (175.00 mg) was added to DCM (3.00 mL). HCl / dioxane (2 mL, 4 M) was then slowly added under N2 protection in an ice-water bath. The mixture was allowed to warm to room temperature and allowed to react for 3 h. After completion of the reaction, the reaction mixture was concentrated to obtain a crude product. 10 mL of toluene was added to the crude product and the resulting product was concentrated to afford the target compound 80-7 (133.00 mg, 86.47% yield). ESI-MS m / z: 728.0 [M+H]+ .

[0506] Step 8: Synthesis of compound 80

[0507] To a 10 mL single-necked flask, 1-methylbicyclo[1.1.1]pentane-3-carboxylic acid (19.78 mg, 0.16 mmol), HATU (91.41 mg, 0.24 mmol), acetonitrile (3.00 mL), and DIEA (0.14 mL, 0.84 mmol) were added sequentially and stirred at room temperature for 1 hour. The mixture was cooled in an ice-water bath, and a solution of compound 80-7 (76.00 mg, 0.10 mmol) in acetonitrile was added dropwise, and the reaction was continued with stirring. After completion of the reaction as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, washed with brine, and concentrated to obtain the crude product. The product was then separated and purified by preparative liquid phase acidic separation. The eluate was adjusted to pH 8 with saturated aqueous sodium bicarbonate, extracted with DCM, and concentrated to remove the DCM. The resulting compound was dissolved in acetonitrile, added with purified water, and lyophilized to obtain the target compound 80 (48.4 mg). ESI-MS m / z: 835.78 [M+H]. + .

[0508] 1 H NMR (500MHz, CDCl3) δ8.58(d,J=1.6Hz,1H),8.42(d,J=3.0Hz,1H),7.57(dd,J=8.6,1.7Hz,1H),7.31(d,J=8.6Hz,1H),7.28(s,1H),7.09(d,J=3.0Hz,1H ),6.37(d,J=9.7Hz,1H),5.85-5.81(m,1H),4.57(d,J=12.7Hz,1H),4.36-4 .30(m,1H),4.25-4.18(m,2H),4.05–3.96(m,2H),3.85–3.74(m,3H),3.46(d ,J=14.9Hz,1H),3.31-3.27(m,5H),3.19(d,J=14.4Hz,1H),3.11(dd,J=15. 0,8.5Hz,1H),2.70-2.64(m,1H),2.64-2.61(m,4H),2.42(d,J=14.5Hz,1H), 2.38(s,3H),2.36–2.21(m,2H),2.00–1.93(m,8H),1.82-1.79(m,1H),1.64 -1.57(m,1H),1.51(d,J=6.4Hz,3H),1.22(s,3H),0.97(s,3H),0.41(s,3H).

[0509] Example 81: Synthesis of (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-(4-methylpiperazin-1-yl)-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazinyl[5,a]indole-2-(4,2)-thiazole)-pyridazinylcycloundecane-4-yl)cyclopropane-1-carboxamide

[0510] To a 10 mL single-necked flask, (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (21.34 mg, 0.16 mmol), acetonitrile (3.00 mL), HATU (99.35 mg, 0.26 mmol), and DIEA (0.14 mL, 0.84 mmol) were added sequentially and stirred at room temperature for 1 hour. The mixture was cooled in an ice-water bath, and a solution of compound 80-7 (76.00 mg, 0.10 mmol) in acetonitrile was added, and the reaction was continued with stirring. After completion of the reaction as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, washed with brine, and concentrated to obtain the crude product. The crude product was then separated and purified by preparative liquid phase acidic separation. The eluate was adjusted to pH approximately 8 with saturated aqueous sodium bicarbonate, extracted with DCM, concentrated to remove the DCM, and the resulting compound was dissolved in acetonitrile, added with purified water, and lyophilized to obtain the target compound 81 (48.9 mg). ESI-MS m / z: 845.64 [M+H] + .

[0511] 1H NMR (500MHz, CDCl3) δ8.58(d,J=1.6Hz,1H),8.42(d,J=2.9Hz,1H),7.57(dd,J=8.5,1. 7Hz,1H),7.31(d,J=8.5Hz,1H),7.28(s,1H),7.09(d,J=2.9Hz,1H),6.68(d,J=9.5Hz,1 H),5.96–5.71(m,2H),4.60(d,J=13.1Hz,1H),4.35(td,J=12.2,3.4Hz,1H),4.24-4.18 (m,2H),4.06–3.96(m,2H),3.82(s,2H),3.83–3.74(m,1H),3.47(d,J=14.9Hz,1H),3.3 3-3.28(m,5H),3.19(d,J=14.4Hz,1H),3.14(dd,J=15.0,8.5Hz,1H),2.69(td,J=12.9 ,3.0Hz,1H),2.64-2.61(m,4H),2.42(d,J=14.4Hz,1H),2.38(s,3H),2.33-2.23(m,2H) ,1.98-1.87(m,2H),1.85-1.81(m,1H),1.75–1.66(m,2H),1.67–1.55(m,1H),1.51(d,J =6.5Hz,3H),1.32(dt,J=9.1,4.3Hz,1H),1.19–1.11(m,1H),0.97(s,3H),0.41(s,3H).

[0512] Example 83 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-morpholinyl-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazino[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinocycloundecane-4-yl)cyclopropane-1-carboxamide

[0513] Step 1: Synthesis of compound 83-1

[0514] Compound 3-bromo-5-fluoro-pyridine-2-carbonitrile (3.00 g, 14.93 mmol) was dissolved in 30 mL of DMF and cooled to 0°C. Morpholine (1.43 g, 16.42 mmol) and triethylamine (4.15 mL, 29.85 mmol) were then added sequentially and stirred at room temperature for 1 hour. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, separated, concentrated, and then slurried with DCM / PE (1:10) and filtered to obtain the target compound 83-1 (4.17 g). ESI-MS m / z: 267.00, 268.12 [M+H] + .

[0515] Step 2: Synthesis of compound 83-2

[0516] Compound 83-1 (4.00 g, 14.92 mmol) was dissolved in 40.00 mL of tetrahydrofuran and cooled to -20°C. MeMgBr (4.45 g, 37.30 mmol) was then added and the mixture was allowed to warm to room temperature for 4 h. After completion of the reaction, as monitored by LC-MS, 6 M HCl was added dropwise to quench the reaction. Saturated sodium bicarbonate was then added to adjust the pH to 7-8. The reaction solution was diluted with ethyl acetate and washed sequentially with water and brine. The organic phase was separated and concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain the target compound 83-2 (2.75 g). ESI-MS m / z: 284.02, 285.11 [M+H] + .

[0517] Step 3: Synthesis of compound 83-3

[0518] Dissolve triethylamine (29.25 mL, 210.43 mmol) in a 50 mL three-necked flask under nitrogen and cool to 0°C. Then, slowly add formic acid (2.02 g, 43.84 mmol) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (0.28 g, 0.44 mmol). The reaction was allowed to proceed at 40°C for 15 min. The mixture was then cooled to room temperature and compound 83-2 (2.50 g, 8.77 mmol) was added. The reaction was continued at room temperature for 12 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with DCM, washed sequentially with water and brine, and the organic phase was concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain the target compound 83-3 (2.37 g). ESI-MS m / z: 286.03, 287.07 [M+H]. + .

[0519] Step 4: Synthesis of compound 83-4

[0520] Compound 83-3 (2.27 g, 7.91 mmol) and 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate) (9.53 g, 27.67 mmol) were dissolved in DMSO (20.00 mL) and THF (4.00 mL) under nitrogen. The temperature was lowered to 10°C, and sodium tert-butoxide (1.90 g, 19.76 mmol) was added. The mixture was allowed to react at 10°C for 1 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the organic phase was concentrated to obtain the crude product, which was then separated and purified by silica gel column chromatography to obtain the target compound 83-4 (2.72 g). ESI-MS m / z: 458.16, 458.18 [M+H]. + .

[0521] Step 5: Synthesis of compound 83-5

[0522] Compound 83-4 (2.60 g, 5.66 mmol) was dissolved in THF (20.00 mL), and TBAF (11.32 mL, 1.00 M, 11.32 mmol) was added. The mixture was allowed to react at 50°C for 1 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the layers were separated. The organic phase was concentrated to obtain a crude product, which was then separated and purified by silica gel column chromatography to obtain the target compound 83-5 (1.93 g). ESI-MS m / z: 344.07, 344.11 [M+H] + .

[0523] Step 6: Synthesis of compound 83-6

[0524] Compound 83-5 (2.10 g, 6.08 mmol), TEA (2.54 mL, 18.25 mmol), and DMAP (0.37 g, 3.04 mmol) were dissolved in DCM (20.00 mL) under nitrogen atmosphere. The temperature was lowered to 0°C, and TosCl (2.32 g, 12.17 mmol) was added. The reaction was allowed to react at room temperature for 12 h. After completion of the reaction, as monitored by LC-MS, saturated ammonium chloride was added to quench the reaction. The reaction solution was diluted with DCM and washed sequentially with water and brine. The organic phase was separated and concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain the target compound 83-6 (2.24 g). ESI-MS m / z: 498.08, 399.09 [M+H] +。

[0525] Step 7: Synthesis of compound 83-7

[0526] Compound 83-6 (158.62 mg, 0.32 mmol), compound M2 (150.00 mg, 0.26 mmol), [PdCl2(dppf)]CH2Cl2 (21.64 mg, 0.03 mmol), and K2CO3 (109.75 mg, 0.79 mmol) were dissolved in toluene (3.00 mL), dioxane (1.00 mL), and water (1.00 mL) under nitrogen atmosphere at 65°C for 2 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the organic phase was concentrated to obtain the crude product, which was then separated and purified by silica gel column chromatography to obtain the target compound 83-7 (180 mg). ESI-MS m / z: 985.41, 986.42 [M+H] +。

[0527] Step 8: Synthesis of compound 83-8

[0528] Compound 83-7 (160.00 mg, 0.16 mmol) was dissolved in DMF (2.00 mL), and Cs2CO3 (158.54 mg, 0.49 mmol) was added. The mixture was allowed to react at 65°C for 1 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the layers were separated. The organic phase was concentrated to obtain a crude product, which was then separated and purified by silica gel column chromatography to obtain the target compound 83-8 (114 mg). ESI-MS m / z: 813.39, 814.40 [M+H] +。

[0529] Step 9: Synthesis of compound 83-9

[0530] Compound 83-8 (100.00 mg, 0.12 mmol) was dissolved in DCM (1.00 mL), and HCl (4 M in dioxane) (1.50 mL) was added. The mixture was allowed to react at room temperature for 30 min. The reaction mixture was concentrated to give crude compound 83-9 (120 mg), which was used directly in the next reaction. ESI-MS m / z: 713.39, 714.40 [M+H] + .

[0531] Step 10: Synthesis of compound 83

[0532] Compound (1S,2S)-2-(Difluoromethyl)cyclopropanecarboxylic acid (94.79 mg, 0.70 mmol) was dissolved in DMF (1.00 mL) and cooled to 0°C. DIPEA (0.81 mL, 4.64 mmol) and HATU (353.08 mg, 0.93 mmol) were then added and the mixture was allowed to react at 0°C for 5 min. Compound 83-9 (60 mg, 0.08 mmol) was then added and the mixture was allowed to react at 0°C for 5 min. After completion of the reaction, the reaction was monitored by LC-MS and separated by preparative chromatography (acetonitrile:water (containing 0.05% diethylamine) = 5:1) to yield the target compound 83 (25.9 mg). ESI-MS m / z: 832.49 [M+H] + .

[0533] 1 H NMR (500MHz, CDCl3) δ8.58(d,J=1.6Hz,1H),8.42(d,J=2.9Hz,1H),7.58(dd, J=8.5,1.7Hz,1H),7.34–7.27(m,2H),7.08(d,J=3.0Hz,1H),6.67(d,J=9.5H z,1H),5.96–5.68(m,2H),4.59(d,J=13.0Hz,1H),4.36(td,J=12.1,3.3Hz,1 H),4.26-4.18(m,2H),4.05–3.96(m,2H),3.93–3.86(m,4H),3.83(s,2H),3. 82–3.73(m,1H),3.47(d,J=14.9Hz,1H),3.35-3.29(m,1H),3.24(t,J=4.9Hz ,4H),3.22–3.10(m,2H),2.70-3.64(m,1H),2.42(d,J=14.4Hz,1H),2.34-3. 23(m,2H),2.0-1.96(m,1H),1.85-1.81(m,1H),1.64-1.57(m,4H),1.52(d,J =6.5Hz,3H),1.33-1.29(m,1H),1.17-1.13(m,1H),0.98(s,3H),0.41(s,3H).

[0534] Single crystal growth of compound 83

[0535] 10 mg of compound 83 was added to a 3 ml sample vial, and 1 ml of a mixed solvent of ethanol / water (19 / 1, v / v) was added to prepare a solution at room temperature. The solution was filtered through a 0.22 μm PTFE filter membrane, sealed with a sealing film, and then placed in a 20 ml sample vial filled with purified water. Slow gas-liquid diffusion crystallization was carried out at room temperature in a water atmosphere to obtain a single crystal sample.

[0536] Single crystal X-ray diffraction data of compound 83 were collected using a Bruker D8 VENTURE single crystal diffraction instrument. The crystal structure was analyzed using the direct method (Shelxs97), which showed that the crystal belongs to the monoclinic system, the space group is P2(1), and the crystal parameters are: a=9.3519(4), b=25.2142(12), α=90,β=111.4680(10),γ=90°,unit cell volume The least squares method was used to correct structural parameters and identify atomic species. Geometric calculation and the difference Fourier method were used to obtain the positions of all hydrogen atoms. After refinement, R1 = 0.0873, wR2 = 0.1319 (all data), and S = 1.023. The refined Flack x (μ) was 0.01 (10). The absolute molecular configuration of compound 83 in the crystal is shown in Figure 2, the molecular structure ellipsoid is shown in Figure 3, and the unit cell stacking projection along the c-axis is shown in Figure 4.

[0537] Example 84 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-12-(4-ethylpiperazin-1-yl)-15,10,10-trimethyl-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)cyclopropane-1-carboxamide

[0538] Step 1: Synthesis of compound 84-1

[0539] To a 25 mL single-necked flask, M4 (200.0 mg, 0.25 mmol), dichloromethane (5.00 mL), N,N-diisopropylethylamine (0.12 mL, 0.74 mmol), and iodoethane (39 μL, 0.49 mmol) were added in sequence. The reaction was stirred at room temperature. After completion of the reaction as monitored by LC-MS, water was added to quench the reaction, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, and concentrated to give crude compound 84-1 (white solid, 200.0 mg). ESI-MS m / z: 841.52 [M+H] + .

[0540] Step 2: Synthesis of compound 84-2

[0541] To a 10 mL thumb flask, compound 84-1 (200.0 mg, 0.24 mmol), DCM (4.00 mL), and HCl (4 M in dioxane) (2.00 mL) were added sequentially and the reaction was stirred at room temperature. After completion of the reaction, as monitored by LC-MS, the reaction solution was neutralized with saturated sodium bicarbonate solution, extracted with DCM, washed with saturated brine, and concentrated to give crude compound 84-2 (yellow solid, 200.0 mg). ESI-MS m / z: 740.98 [M+H] + .

[0542] Step 3: Synthesis of compound 84

[0543] To a 10 mL single-necked flask, (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (37 μL, 0.36 mmol), HATU (140.0 mg, 0.36 mmol), and DIEA (0.16 mL, 0.95 mmol) were added sequentially and stirred at room temperature for 10 minutes. The mixture was cooled in an ice-water bath, followed by the addition of a solution of 84-2 (200.0 mg, 0.26 mmol) in acetonitrile. Following completion of the reaction, as monitored by LC-MS, the reaction solution was directly purified by alkaline Prep-HPLC, and the eluate was lyophilized to yield the target compound 84 (98.8 mg).

[0544] ESI-MS m / z: 859.48, [M+H]+. 1H NMR (500MHz, CDCl3) δ8.58(d,J=1.6Hz,1H),8.43(d,J=2.9Hz,1H),7.57(dd,J=8.6,1.7Hz,1H),7.34-7.27(m,2H),7.09(d,J=2.9Hz,1H),6.63( d,J=9.6Hz,1H),5.97-5.71(m,2H),4.60(d,J=12.7Hz,1H),4.38-4.32( m,1H),4.24-4.18(m,2H),4.05-3.96(m,2H),3.84-3.75(m,3H),3.51-3. 44(m,1H),3.36-3.28(m,4H),3.19(d,J=14.4Hz,1H),3.14(dd,J=15.0, 8.5Hz,1H),2.72-3.62(m,5H),2.65(s,4H),2.51(d,J=11.7Hz,2H),2.42 (d,J=14.4Hz,1H),2.33-2.19(m,2H),1.84-1.80(m,1H),1.51(d,J=6.5 Hz,3H),1.36-1.23(m,3H),1.16-1.12(m,4H),0.97(s,3H),0.40(s,3H).

[0545] Example 85 Synthesis of Compound (1S,2S)-N-((15S,63S,4S,Z)-12-(4-cyclopropylpiperazin-1-yl)-15,10,10-trimethyl-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazino[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinocycloundecane-4-yl)-2-(difluoromethyl)cyclopropane-1-carboxamide

[0546] Step 1: Synthesis of compound 85-1

[0547] Under ice-water conditions, 3-bromo-5-fluoro-pyridine-2-carbonitrile (2.00 g, 9.95 mmol), triethylamine (4.15 mL, 29.85 mmol), and 1-cyclopropylpiperazine (1.26 g, 9.95 mmol) were added sequentially to DMF (20.00 mL) and allowed to react at room temperature for 1 h. Water (50 mL) was added to the reaction solution, which was then extracted with 40 mL*2 of EA, washed with 40 mL*2 of saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to afford crude compound 85-1 (3.00 g, 98.85%), which was used directly in the next reaction. ESI-MS m / z: 307.12 [M+H] + .

[0548] Step 2: Synthesis of compound 85-2

[0549] Compound 85-1 (3.00 g, 9.17 mmol) was dissolved in tetrahydrofuran (60.00 mL), the atmosphere was replaced with nitrogen, and methylmagnesium bromide (9.11 mL, 3.00 mol / L, 27.34 mmol) was added dropwise at -20°C. The temperature was raised to room temperature and the reaction was allowed to react for 2 h. The reaction solution was added dropwise to 40 mL of icy saturated aqueous ammonium chloride solution. The pH was adjusted to 3 with 1N aqueous hydrochloric acid. After stirring for 10 min, the pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution. The solution was extracted with 40 mL of EA, washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:EA = 75%:25%) to obtain compound 85-2 (2.24 g, 70.75%). ESI-MS m / z: 324.10, [M+H] + .

[0550] Step 3: Synthesis of compound 85-3

[0551] Compound 85-2 (2.24 g, 6.91 mmol), (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (0.22 g, 0.35 mmol), and TEA (4.80 mL, 34.55 mmol) were added to DCM (10.00 mL). Formic acid (1.33 g, 34.55 mmol) was added under an ice-water bath and allowed to react at room temperature for 72 h. Water (50 mL) was added to the reaction solution, which was then extracted with DCM (40 mL x 2), washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, and separated by column chromatography to yield compound 85-3 (1.90 g, 84.30%). ESI-MS m / z: 326.17 [M+H] + .

[0552] Step 4: Synthesis of compound 85-4

[0553] Compound 85-3 (1.90 g, 5.82 mmol) and 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate) (4.01 g, 11.65 mmol) were added to DMSO (30.00 mL), followed by a solution of sodium tert-butoxide (1.40 g, 14.56 mmol) in tetrahydrofuran (6.00 mL). The mixture was reacted at 40°C for 2 h. Water (50 mL) was added to the reaction solution, which was then extracted with 40 mL*2 of EA, washed with 40 mL*2 of saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:EA = 80%:20%) to obtain compound 85-4 (1.44 g, 49.59%). ESI-MS m / z: 498.24, [M+H] + .

[0554] Step 5: Synthesis of compound 85-5

[0555] Compound 85-4 (1.44 g, 2.89 mmol) and tetrabutylammonium fluoride (4.33 mL, 1.00 mol / L, 4.33 mmol) were added to tetrahydrofuran (15.00 mL) and reacted at 50°C for 1 h. The mixture was concentrated to dryness and separated by column chromatography to obtain compound 85-5 (0.97 g, 87.39%). ESI-MS m / z: 384.10, [M+H] + .

[0556] Step 6: Synthesis of compound 85-6

[0557] Compound 85-5 (0.97 g, 2.52 mmol), DMAP (0.03 g, 0.25 mmol), and TEA (0.88 mL, 6.31 mmol) were added to DCM (10.00 mL). p-Toluenesulfonyl chloride (0.96 g, 5.05 mmol) was added portionwise in an ice-water bath and allowed to react at room temperature for 2 h. 50 mL of water was added to the reaction solution, which was then extracted with 40 mL of DCM twice, washed with 40 mL of saturated brine twice, dried over anhydrous sodium sulfate, and separated by column chromatography to yield compound 85-6 (1.00 g, 73.57%). ESI-MS m / z: 538.18, [M+H] + .

[0558] Step 7: Synthesis of compound 85-7

[0559] Compound 85-6 (326.06 mg, 0.61 mmol), compound M2 (350.00 mg, 0.50 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (41.24 mg, 0.05 mmol), potassium carbonate (174.35 mg, 1.26 mmol), water (0.50 mL), and 1,4-dioxane (2.00 mL) were added to toluene (6.00 mL) and reacted at 65°C under a nitrogen atmosphere for 2 h. The mixture was concentrated and separated by column chromatography (DCM:EA = 70%:30%) to give compound 85-7 (400 mg, 77.32%). ESI-MS m / z: 485.47, [M+H] + .

[0560] Step 8: Synthesis of compound 85-8

[0561] Compound 85-7 (350.00 mg, 0.34 mmol) and cesium carbonate (222.47 mg, 0.68 mmol) were added to DMF (8.00 mL) and reacted at 80°C for 1 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with 40 mL*2 of EA. The mixture was washed with 40 mL*2 of saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:EA = 70%:30%) to obtain compound 85-8 (290 mg, 99.57%). ESI-MS m / z: 853.69, [M+H] + .

[0562] Step 9: Synthesis of compound 85-9

[0563] Compound 85-8 (290.00 mg, 0.34 mmol) was dissolved in DCM (1.00 mL), and hydrochloric acid (4 M in dioxane) (2.00 mL) was added. The mixture was allowed to react at room temperature for 1 h. The reaction solution was concentrated to dryness, diluted with 5 mL of toluene, and concentrated again to dryness to obtain crude compound 85-9 (250 mg), which was used directly in the next reaction. ESI-MS m / z: 753.02, [M+H] + .

[0564] Step 10: Synthesis of compound 85

[0565] Compound (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (36.88 mg, 0.27 mmol) was dissolved in acetonitrile (4.00 mL). DIEA (0.37 mL, 2.26 mmol) and HATU (128.78 mg, 0.34 mmol) were added sequentially under ice-water bath. After reacting under ice-water bath for 10 min, a solution of compound 85-9 (170.00 mg, 0.23 mmol) in acetonitrile (4.00 mL) and DIEA (0.37 mL, 2.26 mmol) was added and the mixture was reacted at room temperature for 1 h. The mixture was concentrated to dryness to obtain compound 85 (66.00 mg, 33.36%). ESI-MS m / z: 871.42, [M+H] + .

[0566] 1 H NMR (500MHz, DMSO) δ8.89(d,J=9.0Hz,1H),8.50(d,J=1.1Hz,1H),8.40(d,J= 2.8Hz,1H),7.81(s,1H),7.71(dd,J=8.6,1.5Hz,1H),7.49(d,J=8.6Hz,1H),7 .20(d,J=2.8Hz,1H),5.95(td,J=56.7,5.1Hz,1H),5.56(t,J=9.4Hz,1H),5. 11(d,J=12.2Hz,1H),4.28–4.19(m,2H),4.15(q,J=6.3Hz,1H),4.03(dd,J=12 .5,4.4Hz,2H),3.68(d,J=10.9Hz,1H),3.60(dd,J=14.9,9.7Hz,2H),3.38(d ,J=14.5Hz,1H),3.24–3.11(m,6H),3.01(d,J=14.4Hz,1H),2.76(td,J=12.7, 8.2Hz,1H),2.70–2.63(m,4H),2.41(d,J=14.3Hz,1H),2.29(t,J=10.4Hz,1H ),2.10(dt,J=9.1,5.5Hz,2H),1.81(s,3H),1.69–1.61(m,2H),1.58–1.47(m, 1H),1.37(d,J=6.4Hz,3H),1.10–0.99(m,2H),0.95(s,3H),0.48–0.40(m,2H),0.37–0.28(m,5H).

[0567] Example 86 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-12-(4-isopropylpiperazin-1-yl)-15,10,10-trimethyl-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)cyclopropane-1-carboxamide

[0568] Step 1: Synthesis of compound 86-1

[0569] Under nitrogen, acetone (7 μL) and ZnCl2 (100 μL, 1 M in THF) were added sequentially to a solution of M4 (50.0 mg) in MeOH (2.0 mL). The mixture was then stirred in a 40°C oil bath for 1 hour. Sodium cyanoborohydride (19.3 mg) was then added, and the reaction was stirred in a 40°C oil bath for 2 hours. Acetone (7 μL) and ZnCl2 (100 μL, 1 M in THF) were then added, and the mixture was stirred in a 40°C oil bath for 1 hour. Sodium cyanoborohydride (19.3 mg) was added again, and the reaction was stirred in a 40°C oil bath for 2 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM. The aqueous phase was extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (0-5% MeOH / DCM) to obtain compound 86-1 (40 mg). ESI-MS m / z: 855.5, [M+H] + .

[0570] Step 2: Synthesis of compound 86-2

[0571] To a solution of compound 86-1 (40 mg) in DCM (2.0 mL) was added HCl (4 M in dioxane) (2.0 mL), and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, as monitored by LC-MS, the reaction solution was concentrated to dryness. The crude product of compound 86-2 (slightly yellow solid powder, 40 mg, hydrochloride) was obtained and used directly in the next reaction. ESI-MS m / z: 755.5, [M+H] + .

[0572] Step 3: Synthesis of compound 86

[0573] To a solution of (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (14.4 mg) in acetonitrile (1.0 mL) was added HATU (40.3 mg) and DIEA (44 μL) at room temperature. The solution was stirred at room temperature for 10 minutes. A solution of 86-2 and DIEA (44 μL) in acetonitrile (1.0 mL) was then added, and the system was stirred at room temperature for another 30 minutes. After the reaction, the system was concentrated, and the concentrate was separated by preparative chromatography (acetonitrile:water (containing 0.1% formic acid) = 1:1) to yield the target compound 86 (19.2 mg, 41% yield). ESI-MS m / z: 873.9 [M+H] + .

[0574] 1 H NMR (500MHz, DMSO) δ8.89(d,J=9.0Hz,1H),8.50(d,J=1.2Hz,1H),8.40(d,J=2.8Hz,1H),7.81(s,1H),7.71(dd,J=8.6,1.5Hz,1H) ,7.49(d,J=8.6Hz,1H),7.20(d,J=2.9Hz,1H),5.95(td,J=56.7,5.1Hz,1H),5.56(t,J=9.4Hz,1H),5.11(d,J=12.2Hz,1H),4.28– 4.19(m,2H),4.14(q,J=6.2Hz,1H),4.07–3.99(m,2H),3.70–3.56(m,3H),3.38(d,J=14.6Hz,1H),3 .25(s,4H),3.20–3.10(m,2H),3.01(d,J=14.3Hz,1H),2.76(t,J=14.1Hz,1H),2.68(dt,J=13.0,6.5 Hz,1H),2.62–2.54(m,4H),2.41(d,J=14.3Hz,1H),2.29(s,1H),2.13–2.06(m,2H),1.87–1.75(m,3 H),1.65(dd,J=9.5,4.6Hz,1H),1.37(d,J=6.4Hz,3H),1.08–0.97(m,8H),0.95(s,3H),0.32(s,3H).

[0575] Example 87 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-12-((2-(dimethylamino)ethyl)(methyl)amino)-15,10,10-trimethyl-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinylcycloundecane-4-yl)cyclopropane-1-carboxamide

[0576] Step 1: Synthesis of compound 87-1

[0577] To a 100 mL single-necked flask, 3-bromo-5-fluoro-pyridine-2-carbonitrile (3.00 g, 14.93 mmol), N,N-dimethylformamide (30.00 mL), and N,N,N'-trimethylethylenediamine (2.13 mL, 16.42 mmol) were added sequentially and stirred at room temperature. After completion of the reaction, as monitored by LC-MS, the DMF was removed by concentration to afford crude compound 87-1 (white solid powder, 4.50 g), which was used directly in the next reaction. ESI-MS m / z: 283.15 [M+H] + .

[0578] Step 2: Synthesis of compound 87-2

[0579] Compound 87-1 (4.20 g, 14.83 mmol) and THF / tetrahydrofuran (50.00 mL) were added sequentially to a 100 mL three-necked flask. Under a nitrogen atmosphere and in an ice bath, methylmagnesium bromide (14.83 mL, 3 mol / Lin THF, 44.49 mmol) was slowly added dropwise. The mixture was slowly returned to room temperature and stirred for reaction. After the reaction was completed as monitored by LC-MS, a saturated ammonium chloride solution was added to the reaction solution in an ice bath to quench the reaction. The mixture was extracted twice with dichloromethane, the organic phases were combined, washed with saturated brine, and concentrated to obtain a crude product. Compound 87-2 was purified by silica gel column chromatography (white solid powder, 3.30 g). ESI-MS m / z: 300.20 [M+H] + .

[0580] Step 3: Synthesis of compound 87-3

[0581] To a 50 mL three-necked flask, compound 87-2 (1.00 g, 3.33 mmol), dichloromethane (10.00 mL), s,s-Noyori catalyst (0.11 g, 0.17 mmol), and triethylamine (2.32 mL, 16.66 mmol) were added sequentially. Under a nitrogen atmosphere and in an ice bath, formic acid (0.63 mL, 16.66 mmol) was slowly added dropwise, and the mixture was slowly returned to room temperature and stirred for reaction. After completion of the reaction as monitored by LC-MS, compound 87-3 was purified by silica gel column chromatography to obtain a yellow oil, 0.80 g. ESI-MS m / z: 302.32 [M+H] + .

[0582] Step 4: Synthesis of compound 87-4

[0583] To a 50 mL single-necked flask, compound 87-3 (0.70 g, 2.32 mmol), dimethyl sulfoxide (10.00 mL), tetrahydrofuran (2.00 mL), and 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate (3.59 g, 10.42 mmol) were added in sequence. Under a nitrogen atmosphere and an ice bath, sodium tert-butoxide (0.56 g, 5.79 mmol) was slowly added, and the mixture was slowly returned to room temperature and stirred for reaction. After the reaction was completed as monitored by LC-MS, a saturated ammonium chloride solution was added to the reaction solution under an ice bath to quench the reaction. The mixture was extracted twice with ethyl acetate and twice with dichloromethane. The organic phases were combined, washed with saturated brine, and concentrated to obtain a crude product. Compound 87-4 (yellow oil, 0.85 g) was purified by silica gel column chromatography. ESI-MS m / z: 474.56 [M+H] + .

[0584] Step 5: Synthesis of compound 87-5

[0585] To a 25 mL single-necked flask, compound 87-4 (0.85 g, 1.79 mmol), THF / tetrahydrofuran (2.00 mL), and tetrabutylammonium fluoride (3.58 mL, 1 mol / L / THF, 3.58 mmol) were added sequentially. The reaction was stirred at 50°C. After completion of the reaction as monitored by LC-MS, water was added to the reaction solution under an ice bath to quench the reaction. The mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, and concentrated to obtain the crude product. Compound 87-5 was purified by silica gel column chromatography to obtain a yellow oil, 0.66 g. ESI-MS m / z: 360.12 [M+H] + .

[0586] Step 6: Synthesis of compound 87-6

[0587] To a 25 mL single-necked flask, compound 87-5 (0.60 g, 1.67 mmol), dichloromethane (10.00 mL), 4-dimethylaminopyridine (0.51 g, 4.16 mmol), and p-toluenesulfonyl chloride (0.64 g, 3.33 mmol) were added in sequence. The reaction was stirred at room temperature. After completion of the reaction, monitored by LC-MS, the product was purified by silica gel column chromatography to yield compound 87-6 (yellow solid, 0.44 g). ESI-MS m / z: 514.36 [M+H] + .

[0588] Step 7: Synthesis of compound 87-7

[0589] To a 5 mL microwave tube, compound 87-6 (89.0 mg, 0.17 mmol), M2 (89.0 mg, 0.12 mmol), potassium carbonate (40.0 mg, 0.29 mmol), toluene (1.50 mL), 1,4-dioxane (0.50 mL), water (0.50 mL), and PdCl2(dppf) (8.4 mg, 0.01 mmol) were added in sequence. After nitrogen substitution, the reaction was stirred at 65°C. After completion of the reaction, monitored by LC-MS, compound 87-7 was purified by silica gel column chromatography to obtain compound 87-7 (yellow solid, 60.0 mg). ESI-MS m / z: 987.51 [M+H] + .

[0590] Step 8: Synthesis of compound 87-8

[0591] To a 10 mL thumb flask, compound 87-7 (60.0 mg, 0.06 mmol), cesium carbonate (39.0 mg, 0.12 mmol), and N,N-dimethylformamide (30.00 mL) were added sequentially and stirred at 80°C. After completion of the reaction, as monitored by LC-MS, the mixture was concentrated to remove DMF, dissolved in DCM, filtered, and the filtrate concentrated to afford crude product 87-8 (yellow solid, 35.0 mg). ESI-MS m / z: 829.37 [M+H] + .

[0592] Step 9: Synthesis of compound 87-9

[0593] To a 10 mL thumb flask, compound 87-8 (35.0 mg, 0.04 mmol), DCM (2.00 mL), and HCl (4 M in dioxane) (1.00 mL) were added sequentially and the reaction was stirred at room temperature. After completion of the reaction as monitored by LC-MS, the reaction solution was neutralized with saturated sodium bicarbonate solution, extracted with DCM, washed with saturated brine, and concentrated to give crude compound 87-9 (yellow solid, 30.0 mg). ESI-MS m / z: 729.35 [M+H] + .

[0594] Step 10: Synthesis of Compound 87

[0595] To a 10 mL single-necked flask, (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (6 μL, 0.06 mmol), HATU (47 mg, 0.12 mmol), and DIEA (27 μL, 0.16 mmol) were added in sequence and stirred at room temperature for 10 minutes. The mixture was cooled in an ice-water bath, and then a solution of compound 87-9 (30.0 mg, 0.04 mmol) in acetonitrile was added. After completion of the reaction as monitored by LC-MS, the reaction solution was directly separated and purified by a Prep-HPLC alkaline method, and the eluate was lyophilized to obtain the target compound 87 (1.6 mg). ESI-MS m / z: 847.48, [M+H] + .

[0596] 1 H NMR (500MHz, CDCl3) δ8.52(d,J=1.5Hz,1H),8.16(d,J=2.9Hz,1H),7.50(dd,J=8.6,1.5Hz 1H),7.24(t,J=10.3Hz,2H),6.80(d,J=2.9Hz,1H),6.60(d,J=9.7Hz,1H),5.89–5.64(m,2H),5.29–5 .26(m,6H),4.56–4.49(m,1H),4.34–4.24(m,1H),4.18–4.02(m,4H),3.97–3.89(m,3H),3.76(s,3H), 3.44–3.38(m,2H),3.29–3.21(m,1H),3.17–3.02(m,3H),2.73–2.58(m,3H),2.42–2.35(m,3H),2.31 –2.23(m,3H),2.17–2.12(m,7H),1.79–1.72(m,3H),1.44(d,J=6.8Hz,7H),0.91(s,4H),0.33(s,3H).

[0597] Example 89 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-(4-methyl-1,4-diazepin-1-yl)-5,7-dioxo-18,19,61,62,63,64,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepin[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)cyclopropane-1-carboxamide

[0598] Step 1: Synthesis of compound 89-1

[0599] Under ice-water conditions, 3-bromo-5-fluoro-pyridine-2-carbonitrile (2.00 g, 9.95 mmol), triethylamine (4.15 mL, 29.85 mmol), and N-methylhomopiperazine (1.25 g, 10.95 mmol) were added sequentially to DMF (20.00 mL) and allowed to react at room temperature for 1 h. Water (50 mL) was added to the reaction solution, which was then extracted with 40 mL of EA (2 x 40 mL), washed with saturated brine (2 x 40 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to afford crude compound 89-1 (2.90 g, 98.74%), which was used directly in the next reaction. ESI-MS m / z: 295.07 [M+H] + .

[0600] Step 2: Synthesis of compound 89-2

[0601] Compound 89-1 (2.90 g, 9.82 mmol) was dissolved in tetrahydrofuran (60.00 mL), the atmosphere was replaced with nitrogen, and methylmagnesium bromide (9.17 mL, 3.00 mol / L, 27.51 mmol) was added dropwise at -20°C. The temperature was raised to room temperature and the reaction was allowed to react for 2 h. The reaction solution was added dropwise to 40 mL of icy saturated aqueous ammonium chloride solution. The pH was adjusted to 3 with 1N aqueous hydrochloric acid. After stirring for 10 min, the pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution. The solution was extracted with 40 mL of EA, washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound 89-2 (1.17 g, 38.14%). ESI-MS m / z: 312.07, [M+H] + .

[0602] Step 3: Synthesis of compound 89-3

[0603] Compound 89-2 (1.17 g, 3.75 mmol), (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium(II) chloride (0.12 g, 0.19 mmol), and TEA (2.60 mL, 18.74 mmol) were added to DCM (10.00 mL). Formic acid (0.72 g, 18.74 mmol) was added under an ice-water bath and allowed to react at room temperature for 72 h. Water (50 mL) was added to the reaction solution, which was then extracted with DCM (40 mL x 2), washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, and separated by column chromatography to yield compound 89-3 (0.61 g, 51.80%). ESI-MS m / z: 314.22 [M+H] + .

[0604] Step 4: Synthesis of compound 89-4

[0605] Compound 89-3 (610.00 mg, 1.94 mmol) and 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate (2006.58 mg, 5.82 mmol) were added to DMSO (10.00 mL), followed by a solution of sodium tert-butoxide (466.40 mg, 4.85 mmol) in tetrahydrofuran (2.00 mL). The mixture was reacted at 40°C for 1 h. 50 mL of water was added to the reaction solution, and the mixture was extracted with 40 mL*2 of EA, washed with 40 mL*2 of saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound 89-4 (690.00 mg, 73.05%). ESI-MS m / z: 486.28, [M+H] + .

[0606] Step 5: Synthesis of compound 89-5

[0607] Compound 89-4 (680.00 mg, 1.40 mmol) and tetrabutylammonium fluoride (2.10 mL, 1.00 mol / L, 2.10 mmol) were added to tetrahydrofuran (7.00 mL) and reacted at 50°C for 1 h. The mixture was concentrated to dryness and separated by column chromatography to obtain compound 89-5 (500.00 mg, 96.09%). ESI-MS m / z: 372.13, [M+H] + .

[0608] Step 6: Synthesis of compound 89-6

[0609] Compound 89-5 (500.00 mg, 1.34 mmol), DMAP (328.15 mg, 2.69 mmol), and TEA (1.12 mL, 8.06 mmol) were added to DCM (10.00 mL). p-Toluenesulfonyl chloride (1280.19 mg, 6.71 mmol) was added portionwise in an ice-water bath and allowed to react at room temperature for 2 h. 50 mL of water was added to the reaction solution, and the mixture was extracted with DCM (40 mL x 2), washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound 89-6 (700.00 mg, 99.00%). ESI-MS m / z: 526.22, [M+H] + .

[0610] Step 7: Synthesis of compound 89-7

[0611] Compound 89-6 (303.57 mg, 0.58 mmol), compound M2 (200.00 mg, 0.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (23.52 mg, 0.03 mmol), potassium carbonate (99.62 mg, 0.72 mmol), water (0.50 mL), and 1,4-dioxane (2.00 mL) were added to toluene (6.00 mL) and reacted at 65°C under a nitrogen atmosphere for 2 h. The mixture was concentrated and separated by column chromatography to obtain compound 89-7 (200 mg, 68.46%). ESI-MS m / z: 479.42, [M+H] + .

[0612] Step 8: Synthesis of compound 89-8

[0613] Compound 89-7 (200.00 mg, 0.20 mmol) and cesium carbonate (128.63 mg, 0.39 mmol) were added to DMF (5.00 mL) and reacted at 85°C for 1 h. 50 mL of water was added to the reaction solution, and the mixture was extracted with 40 mL*2 of EA. The mixture was washed with 40 mL*2 of saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound 89-8 (130 mg, 78.30%). ESI-MS m / z: 841.66, [M+H] + .

[0614] Step 9: Synthesis of compound 89-9

[0615] Compound 89-8 (130.00 mg, 0.15 mmol) was dissolved in DCM (1.00 mL), and hydrochloric acid (4 M in dioxane) (2.00 mL) was added. The mixture was allowed to react at room temperature for 1 h. The reaction solution was concentrated to dryness, diluted with 5 mL of toluene, and concentrated again to dryness to obtain crude compound 89-9 (90 mg, 78.57%), which was used directly in the next reaction. ESI-MS m / z: 741.66, [M+H] + .

[0616] Step 10: Synthesis of Compound 89

[0617] Compound (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (11.02 mg, 0.08 mmol) was dissolved in acetonitrile (3.00 mL). DIEA (0.11 mL, 0.68 mmol) and HATU (38.35 mg, 0.10 mmol) were added sequentially in an ice-water bath. After reacting for 10 min in an ice-water bath, a solution of compound 89-9 (50.00 mg, 0.07 mmol) in acetonitrile (3.00 mL) and DIEA (0.11 mL, 0.68 mmol) was added and the mixture was reacted at room temperature for 1 h. The mixture was concentrated to dryness to obtain compound 89 (7 mg, 11.49%). ESI-MS m / z: 859.49, [M+H] + .

[0618] Example 91 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-(4-(methyl-d3)piperazin-1-yl)-5,7-dioxo-18,19,61,62,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)cyclopropane-1-carboxamide

[0619] Step 1: Synthesis of compound 91-1

[0620] To a 10 mL single-necked flask, M4 (50.00 mg, 0.06 mmol), DMF (1.00 mL), and DIEA (0.03 mL, 0.15 mmol) were added sequentially. CD3I (8.91 mg, 0.06 mmol) in N,N-dimethylformamide (1.00 mL) was then added dropwise, and the mixture was stirred at room temperature. After completion of the reaction, as monitored by LC-MS, the reaction solution was added to a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phases were combined, washed with brine, separated, and concentrated to give the crude product. Perp-TLC separation and purification yielded the target compound 91-1 (35 mg, beige foamy solid). ESI-MS m / z: 830.65 [M+H] + .

[0621] Step 2: Synthesis of compound 91-2

[0622] To a 10 mL single-necked flask, compound 91-1 (62.00 mg, 0.07 mmol), DCM (2.00 mL), and HCl (4 M in dioxane) (1.50 mL) were added sequentially and stirred at room temperature. After completion of the reaction as monitored by LC-MS, the reaction solution was concentrated to dryness, acetonitrile was added, and concentrated again to dryness (3 mL x 2). The hydrochloride salt of the target compound 91-2 (54.5 mg, light yellow powder) was obtained and used directly in the next reaction. ESI-MS m / z: 730.25, [M+H] + .

[0623] Step 3: Synthesis of compound 91

[0624] To a 10 mL single-necked flask, (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (20.33 mg, 0.15 mmol), ACN (3.00 mL), HATU (85.21 mg, 0.22 mmol), and DIEA (0.10 mL, 0.60 mmol) were added sequentially and stirred at room temperature for 30 minutes. After cooling in an ice-water bath, a solution of compound 91-2 (hydrochloride salt: 54.50 mg, 0.07 mmol) in acetonitrile was added dropwise. After adding 1 mL of acetonitrile, several drops of DIEA were added until completely dissolved. After completion of the reaction, the reaction mixture was diluted with ethyl acetate overnight, washed sequentially with water and then brine, separated, and the organic phase was concentrated to obtain the crude product. This was then purified by Perp-HPLC, and the eluate was lyophilized to yield the target compound 91 (22.5 mg). ESI-MS m / z: 848.63, [M+H] + .

[0625] 1H NMR (500MHz, CDCl3) δ8.51(d,J=1.7Hz,1H),8.36(d,J=2.9Hz,1H),7.51(dd,J=8. 6,1.6Hz,1H),7.27–7.20(m,2H),7.02(d,J=3.0Hz,1H),6.68(d,J=9.5Hz,1H),5. 90–5.64(m,2H),4.53(d,J=13.0Hz,1H),4.29(td,J=12.1,3.3Hz,1H),4.16(dq,J =18.1,6.2Hz,2H),3.99–3.89(m,2H),3.75(s,2H),3.75–3.65(m,1H),3.40(d,J= 14.8Hz,1H),3.34(s,4H),3.25(td,J=12.4,3.2Hz,1H),3.16–3.04(m,2H),2.75( s,4H),2.62(td,J=12.9,3.0Hz,1H),2.34(d,J=14.4Hz,1H),2.25-2.13(m,2H),1 .88–1.70(m,2H),1.63–1.48(m,2H),1.44(d,J=6.5Hz,3H),1.41–1.28(m,1H),1. 25-1.21(m,1H),1.12–0.98(m,1H),0.82–0.77(m,1H),0.91(s,3H),0.34(s,3H).

[0626] Example 94 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-12-(3-(dimethylamino)azetidin-1-yl)-15,10,10-trimethyl-5,7-dioxo-18,19,61,62,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazeno[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)cyclopropane-1-carboxamide

[0627] Step 1: Synthesis of compound 94-1

[0628] 3-Bromo-5-fluoro-pyridine-2-carbonitrile (3.0 g) was added to a 50 mL single-necked flask, followed by anhydrous DMF (30 mL). TEA (9 mL) and 3-(dimethylamino)azetidine dihydrochloride (2.9 g) were weighed in and reacted at room temperature for 0.5 h. After the reaction, saturated brine (25 mL) was added, and the mixture was extracted with EA. The organic phase was concentrated to dryness to obtain the target compound 94-1 (3.5 g, 83.5% yield). ESI-MS m / z: 281.2 [M+H] + .

[0629] Step 2: Synthesis of compound 94-2

[0630] Compound 94-1 (3.5 g) and anhydrous THF (70 mL) were added to a 250 mL three-necked flask. The temperature was lowered to 0°C under N2 protection, and MeMgBr (3 M in THF, 12 mL) was slowly added dropwise. The mixture was allowed to warm to room temperature and allowed to react for 2 h. After the reaction, HCl (1N, 30 mL) was added to the reaction solution, followed by extraction with EA. The organic phase was collected, and the aqueous phase was extracted twice with EA (30 mL). The organic phases were collected and combined, dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography to yield the target compound 94-2 (3.34 g, 90% yield). ESI-MS m / z: 298.4 [M+H] + .

[0631] Step 3: Synthesis of compound 94-3

[0632] Compound 94-2 (3.34 g) was added to a 25 mL single-necked flask, followed by TEA (20 mL) and s,s-Noyori catalyst (0.356 g). The temperature was lowered to 0°C under N2 protection, and formic acid (2 mL) was slowly added dropwise. The reaction was allowed to react at room temperature for 12 h. After the reaction, ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution for extraction. The organic phase was collected, and the aqueous phase was extracted twice with ethyl acetate (25 mL). The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain the target axially chiral compound 94-3 (4.3 g, crude product). ESI-MS m / z: 300.3 [M+H] + .

[0633] Step 4: Synthesis of compound 94-4

[0634] Compound 94-3 (1.05 g), 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate (2.25 g), and DMSO / ACN (12 mL / 3 mL) were weighed into a reaction flask. The temperature was lowered to 10°C under N2 protection. Sodium tert-butoxide (1.0 g) was added and the reaction was allowed to proceed at room temperature for 1.0 h. Upon completion of the reaction, the temperature was lowered to 0°C, diluted with tap water (50 mL), and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography to afford 94-4 (1.99 g, crude product). ESI-MS m / z: 472.6 [M+H] + .

[0635] Step 5: Synthesis of Compound 94-5

[0636] Compound 94-4 (1.99 g) was added to a 50 mL single-necked flask, followed by anhydrous TBAF (1N in THF, 7 mL). The mixture was allowed to react at room temperature for 1.0 h. After the reaction, calcium carbonate (5 g), DOWEX(R) 50WX8 resin (8 g), and methanol (20 mL) were added, and the reaction was continued at room temperature for 1.0 h. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the target compound 94-5 (2.37 g, crude product). ESI-MS m / z: 358.3 [M+H] + .

[0637] Step 6: Synthesis of Compound 94-6

[0638] Compound 94-5 (2.37 g) was added to a 50 mL single-necked flask, followed by anhydrous DCM (20 mL). TEA (3 mL) and DMAP (0.9 g) were weighed in. The temperature was lowered to 0°C under N2 protection, and TsCl (2.53 g) was added. The reaction was allowed to react at room temperature for 1.0 h. After the reaction, saturated brine (25 mL) was added, and the mixture was extracted with DCM. The organic phase was concentrated to dryness, and the concentrate was purified by column chromatography to obtain the target compound 94-6 (1.10 g, 30% yield). ESI-MS m / z: 512.6 [M+H] + .

[0639] Step 7: Synthesis of compound 94-7

[0640] Compound 94-6 (202 mg), M2 (110 mg), Pd(dppf)Cl2 in DCM (30 mg), and potassium carbonate (63 mg) were weighed into separate 100 mL single-necked vials. Toluene (6 mL), 1,4-dioxane (2 mL), and 2 mL of water were added. The atmosphere was replaced with nitrogen three times and the temperature was raised to 65°C for 5 h. After the reaction, 20 mL each of EA and water were added to the reaction mixture for extraction. The aqueous phase was extracted twice more with EA. The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to yield the target compound 94-7 (200 mg, 88% yield). ESI-MS m / z: 999.4 [M+H] + .

[0641] Step 8: Synthesis of compound 94-8

[0642] Compound 94-7 (200 mg) was added to a 25 mL single-necked vial, followed by the addition of Cs2CO3 (250 mg) and anhydrous DMF (12 mL). The mixture was reacted at 80°C under nitrogen for 1 h. After completion of the reaction, the mixture was diluted with tap water (50 mL) and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography to yield the target compound 94-8 (125 mg, 75.5% yield). ESI-MS m / z: 827.2 [M+H] + .

[0643] Step 9: Synthesis of compound 94-9

[0644] Compound 94-8 (125 mg) was added to a 25 mL single-necked vial, and 15 mL of hydrochloric acid (4 M in dioxane) was added. The mixture was allowed to react at room temperature for 1 h. After the reaction, the mixture was concentrated under reduced pressure to obtain the hydrochloride salt of the target compound 94-9 (140 mg, crude product). ESI-MS m / z: 727.1 [M+H] + .

[0645] Step 10: Synthesis of compound 94

[0646] Compound (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (70 mg) was added to a 25 mL single-necked vial. HATU (131 mg), N,N-diisopropylethylamine (0.28 mL), and anhydrous acetonitrile (10 mL) were weighed in and allowed to react at room temperature for 10 minutes. A solution of previously isolated compound 94-9 (140 mg) in acetonitrile (5 mL) was then added dropwise at room temperature and allowed to react for 15 minutes. After the reaction, the mixture was concentrated and the concentrate was purified using preparative purification (60% acetonitrile / water) to yield the target compound 94 (19.7 mg, 13.44% yield). ESI-MS m / z: 845.3 [M+H] + .

[0647] 1 H NMR (500MHz, CDCl3) δ8.57(s,1H),7.60(d,J=8.6Hz,1H),7.31(d,J=10.8Hz,1H),6.96(s,1H),6.73(d,J=9.2Hz,1H),5.97–5.81(m,2 H).,4.60(d,J=11.8Hz,1H),4.36(td,J=12.1,3.2Hz,1H),4.27–4.17(m,2H),4.10(dd,J=23.7,9.7Hz,1H),4.00(dd,J=14.5,4.4Hz, 1H),3.85–3.75(m,5H),3.50–3.43(m,1H),3.32(td,J=12.3,2.8Hz,1H),3.22–3.12(m,2H), 2.85(td,J=14.0,2.1Hz,2H),2.70(td,J=12.9,2.6Hz,1H),2.47–2.39(m,1H),2.36(d,J=13. 4Hz,7H),2.31–2.22(m,2H),2.03–1.94(m,4H),1.91–1.79(m,3H),1.74–1.56(m,3H),1.52(d ,J=6.4Hz,3H),1.28(ddd,J=14.3,8.1,4.9Hz,2H),1.14(dt,J=8.6,5.4Hz,1H),0.97(s,3H).

[0648] Example 95 Synthesis of Compound (1S,2S)-2-methyl-N-((19R,63S,4S,Z)-19,10,10-trimethyl-12-(4-methylpiperazin-1-yl)-5,7-dioxo-18,19,61,62,63,64,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazino[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinocycloundecane-4-yl)cyclopropane-1-carboxamide

[0649] Step 1: Synthesis of compound 95-1

[0650] To a 50 mL single-necked flask, compound 2-5 (1.50 g, 3.69 mmol), (S)-3-((tert-butyldimethylsilyl)oxy)butyl 4-methylbenzenesulfonate (3.97 g, 11.08 mmol), DMSO (15 mL), and THF (3 mL) were added sequentially. Sodium tert-butoxide (0.89 g, 9.23 mmol) was added and the reaction was stirred at room temperature. After completion of the reaction, as monitored by TLC, the reaction mixture was quenched by adding saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, washed with brine, and the layers were separated. The organic phase was concentrated to obtain the crude product, which was then separated and purified by silica gel column chromatography (PE-PE / EA = 50 / 50) to obtain the target compound 95-1 (1.59 g). ESI-MS m / z: 592.41, [M+H] + .

[0651] Step 2: Synthesis of compound 95-2

[0652] To a 50 mL single-necked flask, compound 95-1 (1.59 g, 0.84 mmol) and TBAF (15 mL, 1 M THF solution) were added and stirred at room temperature overnight. After completion of the reaction, as monitored by TLC, the reaction solution was diluted with ethyl acetate and washed sequentially with saturated aqueous ammonium chloride and brine. The organic phase was concentrated to obtain a crude product, which was then purified by silica gel column chromatography (PE-PE / EA = 50 / 50) to obtain the target compound 95-2 (1.28 g). ESI-MS m / z: 478.33, [M+H] + .

[0653] Step 3: Synthesis of compound 95-3

[0654] To a 50 mL single-necked flask, compound 95-2 (1.28 g, 2.676 mmol), DCM (13.00 mL), DIEA (1.33 mL, 8.03 mmol), and DMAP (0.98 g, 8.03 mmol) were added in sequence. TosCl (1.02 g, 5.35 mmol) was then added in portions. After addition, the reaction was stirred at room temperature. After completion of the reaction, monitored by LC-MS, silica gel was added to the reaction solution for sample mixing and sand preparation. The mixture was then separated and purified by silica gel column chromatography (PE / EA = 90 / 10 to 50 / 50) to obtain compound 95-3 (1.2 g). ESI-MS m / z: 632.34, [M+H] + .

[0655] Step 4: Synthesis of compound 95-4

[0656] To a 10 mL single-necked flask, compound 95-3 (274 mg, 0.43 mmol), M2 (250 mg, 0.36 mmol), K2CO3 (125 mg, 0.90 mmol), [PdCl2(dppf)] (26 mg, 0.04 mmol), toluene (3.00 mL), dioxane (1.00 mL), and water (1.00 mL) were added sequentially. The atmosphere was replaced with nitrogen and protected with oil bath heating at 60-65°C. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, separated, and the aqueous phase was extracted with DCM. The organic phases were combined and concentrated to give the crude product, which was separated and purified by Prep-TLC to give compound 95-4 (230 mg). ESI-MS m / z: 1119.66, [M+H] + .

[0657] Step 5: Synthesis of compound 95-5

[0658] To a 10 mL single-necked flask, compound 95-4 (210 mg, 0.19 mmol), DMF (20.00 mL), and Cs2CO3 (183 mg, 0.56 mmol) were added sequentially. The mixture was heated in an oil bath at 60-65°C under nitrogen protection. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the organic phase was concentrated to obtain crude compound 5. This was then separated and purified by silica gel column chromatography to obtain the target compound 95-5 (17 mg). ESI-MS m / z: 947.64, [M+H] + .

[0659] Step 6: Synthesis of compound 95-6

[0660] To a 10 mL single-necked flask, compound 95-5 (17 mg, 0.02 mmol), MeOH (2.00 mL), and Pd(OH)2 / C (20 mg, 0.14 mmol, 10% Pd) were added sequentially. The atmosphere was replaced with hydrogen, and the reaction was stirred at room temperature. After completion of the reaction as monitored by LC-MS, the reaction was filtered, the catalyst removed, and the filtrate concentrated to afford crude compound 95-6 (17 mg), which was used directly in the next reaction. ESI-MS m / z: 813.60, [M+H] + .

[0661] Step 7: Synthesis of compound 95-7

[0662] To a 10 mL single-necked flask, compound 95-6 (15 mg, 0.02 mmol), MeOH (2.00 mL), 37% formaldehyde solution (17 mg), and HOAc (0.10 mL) were added sequentially and stirred at room temperature for 20 minutes. NaBH3CN (2.6 mg, 0.04 mmol) was added and the reaction was stirred at room temperature. After completion of the reaction, as monitored by LC-MS, ethylenediamine was added to quench the excess formaldehyde in the reaction solution. The solution was then added to a saturated aqueous sodium bicarbonate solution and quenched, and extracted with DCM. The layers were separated and the organic phase was concentrated to obtain crude compound 95-7 (17 mg). ESI-MS m / z: 827.62, [M+H] + .

[0663] Step 8: Synthesis of compound 95-8

[0664] To a 10 mL single-necked flask, compound 95-7 (17 mg, 0.02 mmol), DCM (1.00 mL), and HCl (4 M in dioxane) (1.00 mL) were added sequentially and the reaction was stirred at room temperature. After completion of the reaction as monitored by LC-MS, the reaction solution was concentrated to dryness, DCM was added, and the mixture was concentrated again to dryness. The crude product of compound 95-8 (slightly yellow solid powder, 15 mg, hydrochloride) was obtained and used directly in the next reaction. ESI-MS m / z: 727.57, [M+H] + .

[0665] Step 9: Synthesis of compound 95

[0666] To a 10 mL single-necked flask, (1S,2S)-2-methylcyclopropanecarboxylic acid (2.5 mg, 0.025 mmol), HATU (16 mg, 0.041 mmol), and DIEA (0.02 mL, 0.124 mmol) were added sequentially and stirred at room temperature for 30 minutes. The mixture was cooled in an ice-water bath, followed by the addition of a solution of compound 8 (15.00 mg, 0.021 mmol) in acetonitrile. Following completion of the reaction, as monitored by LC-MS, the reaction solution was directly purified by acidic Prep-HPLC, and the eluate was lyophilized to yield the target compound 95 (2.8 mg). ESI-MS m / z: 809.61, [M+H]+.

[0667] Example 96 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-(4-(4-methylpiperazin-1-yl)phenyl)-5,7-dioxo-18,19,61,62,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)cyclopropane-1-carboxamide

[0668] Step 1: Synthesis of compound 96-1

[0669] Compound 5-bromo-3-chloroacrylonitrile (2.0 g, 9.2 mmol) was added to anhydrous THF (20.00 mL) under nitrogen protection. Methylmagnesium bromide (8.58 ml, 25.75 mmol) was added dropwise at -5°C. The mixture was allowed to react for 2 h at -5°C, then poured into a saturated ammonium chloride solution. The pH was adjusted to 2 with 1N HCl. The mixture was stirred at room temperature for 5 min, and then the pH was adjusted to 8 with sodium carbonate. The mixture was extracted with EA, washed with brine, dried, and separated by column chromatography to obtain compound 96-1 (2.0 g, 92.74%). ESI-MS m / z: 235.28, [M+H] + .

[0670] Step 2: Synthesis of compound 96-2

[0671] Triethylamine (14.23 mL, 102.36 mmol) was added to a 50 mL three-necked flask under nitrogen protection. Formic acid (1.96 g, 42.65 mmol) was added dropwise at 0°C. After completion of the addition, Noyori catalyst (ss) (0.27 g, 0.43 mmol) was added at 0°C. The mixture was stirred for 10 min, and compound 96-1 (2.00 g, 8.53 mmol) was added. The mixture was allowed to warm to room temperature and allowed to react for 24 h. EA was added for dilution, the mixture was washed with brine, dried over anhydrous sodium sulfate, and separated by column chromatography (PE:EA = 4:1) to obtain compound 96-2 (1.80 g, 89.23%). ESI-MS m / z: 237.26, [M+H] + .

[0672] Step 3: Synthesis of compound 96-3

[0673] Compound 96-2 (1.00 g, 4.23 mmol), S1 (1.41 g, 4.65 mmol), PdCl2(dppf) (0.31 g, 0.42 mmol), potassium carbonate (1.75 g, 12.69 mmol), 1,4-dioxane (15.00 mL), and water (3.00 mL) were added to a 20 ml microwave tube, bubbling with nitrogen, and reacted at 70°C for 3 h. Water was added, extracted with EA, washed with brine, dried and spin-dried, and separated by column chromatography to obtain compound 96-3 (1.32 g, 94.07%). ESI-MS m / z: 332.41, [M+H] + .

[0674] Step 4: Synthesis of compound 96-4

[0675] Compound 96-3 (1.50 g, 4.52 mmol) and 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate) (4.67 g, 13.56 mmol) were added to DMSO (15.00 mL), followed by a solution of sodium tert-butoxide (1.09 g, 11.30 mmol) in tetrahydrofuran (3.00 mL). The mixture was reacted at 40°C for 1 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with 40 mL*2 of EA, washed with 40 mL*2 of saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound 96-4 (1.20 g, 52.65%). ESI-MS m / z: 504.28, [M+H] + .

[0676] Step 5: Synthesis of Compound 96-5

[0677] Compound 96-4 (1.2 g, 2.38 mmol) and tetrabutylammonium fluoride (3.57 mL, 1.00 mol / L, 3.57 mmol) were added to tetrahydrofuran (10.00 mL) and reacted at 50°C for 1 h. The mixture was concentrated to dryness and separated by column chromatography to afford compound 96-5 (0.52 mg, 56.03%). ESI-MS m / z: 390.35, [M+H] + .

[0678] Step 6: Synthesis of compound 96-6

[0679] Compound 96-5 (0.50 g, 1.28 mmol), DMAP (0.16 g, 1.28 mmol), and TEA (0.36 mL, 2.56 mmol) were added to DCM (10.00 mL). p-Toluenesulfonyl chloride (0.37 g, 1.92 mmol) was added portionwise in an ice-water bath and allowed to react at room temperature for 2 h. Water (50 mL) was added to the reaction solution, which was then extracted with DCM (40 mL x 2), washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, and separated by column chromatography to yield compound 96-6 (0.52 g, 74.53%). ESI-MS m / z: 544.26, [M+H] + .

[0680] Step 7: Synthesis of compound 96-7

[0681] Compound 96-6 (258.88 mg, 0.48 mmol), compound M2 (300.00 mg, 0.43 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (31.53 mg, 0.04 mmol), potassium phosphate (183.61 mg, 0.86 mmol), water (0.50 mL), and 1,4-dioxane (2.00 mL) were added to toluene (6.00 mL) and reacted at 70°C under a nitrogen atmosphere for 3 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with 40 mL*2 of EA, washed with 40 mL*2 of saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound 96-7 (270.00 mg, 58.05%). ESI-MS m / z: 538.62, [M+H] + .

[0682] Step 8: Synthesis of compound 96-8

[0683] Compound 96-7 (270.00 mg, 0.25 mmol) and cesium carbonate (163.63 mg, 0.50 mmol) were added to DMF (15.00 mL) and reacted at 70°C for 2 h. 50 mL of water was added to the reaction solution, and the mixture was extracted with 40 mL*2 of EA. The mixture was washed with 40 mL*2 of saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound 96-8 (170 mg, 74.96%). ESI-MS m / z: 903.63, [M+H] + .

[0684] Step 9: Synthesis of compound 96-9

[0685] Compound 96-8 (170.00 mg, 0.19 mmol) was dissolved in DCM (1.00 mL), and hydrochloric acid (4 M in dioxane) (2.00 mL) was added. The mixture was allowed to react at room temperature for 1 h. The reaction solution was concentrated to dryness, diluted with 5 mL of toluene, and concentrated again to dryness to obtain crude compound 96-9 (150 mg, 99.25%), which was used directly in the next reaction. ESI-MS m / z: 803.57, [M+H] + .

[0686] Step 10: Synthesis of Compound 96

[0687] Compound (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (16.26 mg, 0.12 mmol) was dissolved in acetonitrile (3.00 mL). DIEA (0.16 mL, 1.00 mmol) and HATU (58.81 mg, 0.15 mmol) were added sequentially in an ice-water bath. After reacting for 10 min in an ice-water bath, a solution of compound 96-9 (80.00 mg, 0.10 mmol) in acetonitrile (3.00 mL) and DIEA (0.16 mL, 1.00 mmol) was added and the mixture was reacted at room temperature for 1 h. The mixture was concentrated to dryness to obtain compound 96 (23.00 mg, 24.59%). ESI-MS m / z: 921.57, [M+H] + .

[0688] 1H NMR(500MHz,DMSO)δ9.97(s,1H),9.02(d,J=2.2Hz,1H),8.92(d,J=9.0Hz,1H ),8.53(s,1H),7.99(d,J=2.2Hz,1H),7.84(s,1H),7.75(dd,J=15.3,5.1Hz,3 H),7.54(d,J=8.6Hz,1H),7.14(d,J=8.9Hz,2H),5.95(td,J=56.7,5.1Hz,1H ),5.56(t,J=9.4Hz,1H),5.14(d,J=12.2Hz,1H),4.31(t,J=6.3Hz,1H),4.23( dd,J=15.9,7.4Hz,2H),4.14–4.03(m,2H),3.97(s,2H),3.71(d,J=10.9Hz,1 H),3.62(dd,J=25.9,11.6Hz,2H),3.53(d,J=11.8Hz,2H),3.38(d,J=14.4Hz, 1H),3.26(t,J=11.5Hz,1H),3.14(dd,J=14.7,8.9Hz,3H),3.03(t,J=12.9Hz ,3H),2.87(d,J=3.7Hz,3H),2.76(d,J=6.6Hz,1H),2.38(dd,J=23.8,13.4Hz, 2H),2.13–2.07(m,2H),1.81(s,3H),1.70–1.61(m,1H),1.57–1.48(m,1 H),1.44(d,J=6.3Hz,3H),1.09–0.98(m,2H),0.92(s,3H),0.34(s,3H).

[0689] Example 97 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-((1-methylpiperidin-4-yl)oxy)-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinylcycloundecane-4-yl)cyclopropane-1-carboxamide

[0690] Step 1: Synthesis of Compound 97-1

[0691] To a 25 mL single-necked flask, 1-methylpiperidin-4-ol (0.77 g, 6.72 mmol) and N,N-dimethylformamide (10.00 mL) were added sequentially. Sodium hydride (0.40 g, 60%, 9.95 mmol) was added portionwise at 0°C and stirred at 0°C for 10 minutes. Finally, 3-bromo-5-fluoro-pyridine-2-carbonitrile (1.00 g, 4.98 mmol) was added. Stir at room temperature for 1 hour. LC-MS monitored the reaction completion. The reaction solution was poured into water, and the precipitated solid was filtered and the filter cake rinsed with water. The filter cake was dried to yield the target compound 97-1 (1.14 g). ESI-MS m / z: 296.0 [M+H] + .

[0692] Step 2: Synthesis of Compound 97-2

[0693] To a 50 mL three-necked flask, compound 97-1 (1.14 g, 3.85 mmol) and tetrahydrofuran (10.00 mL) were added sequentially. The temperature was lowered to -20°C under nitrogen atmosphere, and methylmagnesium iodide (3.85 mL, 3.00 mol / L, 11.55 mmol) was then added dropwise. Stir at 0°C for 1 hour. LC-MS monitored the reaction completion, quenched with saturated NH4Cl solution, and adjusted to pH 4 with dilute hydrochloric acid. Stirred for 30 minutes. The pH was then adjusted to pH 8 with saturated NaHCO3 solution. Extraction was performed twice with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure and purification by column chromatography afforded the target compound 97-2 (0.39 g). ESI-MS m / z: 313.0 [M+H] + .

[0694] Step 3: Synthesis of Compound 97-3

[0695] To a 25 mL three-necked flask, triethylamine (4.34 mL, 31.21 mmol) was added. Under nitrogen, the temperature was lowered to 0°C, and formic acid (0.24 mL, 6.24 mmol) was added dropwise. (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (15.78 mg, 0.03 mmol) was then added. The reaction mixture was heated to 40°C and stirred for 15 minutes. The mixture was cooled to room temperature and finally compound 97-2 (391.00 mg, 1.25 mmol) and dichloromethane (1.00 mL) were added. The mixture was stirred at room temperature for 24 hours. LC-MS monitored the reaction completion. The mixture was extracted twice with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by column chromatography to yield the target compound 97-3 (279.00 mg). ESI-MS m / z: 315.1 [M+H] + .

[0696] Step 4: Synthesis of compound 97-4

[0697] To a 25 mL single-necked flask, compound 97-3 (259.00 mg, 0.82 mmol), dimethyl sulfoxide (4.00 mL), tetrahydrofuran (1.00 mL), and 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate (990.90 mg, 2.88 mmol) were added sequentially. Sodium tert-butoxide (197.42 mg, 2.05 mmol) was added portionwise at 10°C and stirred at room temperature for 1 hour. LC-MS monitored the completion of the reaction, and the reaction mixture was quenched by adding saturated aqueous ammonium chloride. The mixture was extracted twice with ethyl acetate, washed three times with saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound 97-4 (293.00 mg). ESI-MS m / z: 487.2 [M+H] + .

[0698] Step 5: Synthesis of Compound 97-5

[0699] To a 25 mL single-necked flask, compound 97-4 (293.00 mg, 0.60 mmol) and tetrahydrofuran (5.00 mL) were added sequentially. Tetrabutylammonium fluoride (0.90 mL, 1.00 mol / L, 0.90 mmol) was added dropwise at 0°C, and the reaction mixture was heated to 50°C and stirred for 1 hour. LC-MS monitored the reaction completion, and the mixture was concentrated under reduced pressure and purified by column chromatography to yield the target compound 97-5 (183.00 mg). ESI-MS m / z: 373.1 [M+H] + .

[0700] Step 6: Synthesis of Compound 97-6

[0701] To a 25 mL single-necked flask, compound 97-5 (173.00 mg, 0.46 mmol), dichloromethane (3.00 mL), and 4-dimethylaminopyridine (5.67 mg, 0.05 mmol) were added sequentially. Then, p-toluenesulfonyl chloride (176.73 mg, 0.93 mmol) and triethylamine (0.16 mL, 1.16 mmol) were added portionwise and stirred at room temperature for 4 hours. LC-MS monitored the reaction completion, and the mixture was concentrated under reduced pressure and purified by column chromatography to yield the target compound 97-6 (254.00 mg). ESI-MS m / z: 527.1 [M+H] + .

[0702] Step 7: Synthesis of compound 97-7

[0703] To a 10 mL single-necked flask, compound 97-6 (78.86 mg, 0.15 mmol), M2 (80.00 mg, 0.12 mmol), toluene (1.50 mL), 1,4-dioxane (0.50 mL), water (0.50 mL), potassium carbonate (39.74 mg, 0.29 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (9.39 mg, 0.01 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the temperature was raised to 65°C under nitrogen protection, with stirring for 3 hours. LC-MS monitored the reaction completion, and the product was extracted twice with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography to yield the target compound 97-7 (42.00 mg). ESI-MS m / z: 507.7 1 / 2 [M+2H] + .

[0704] Step 8: Synthesis of Compound 97-8

[0705] To a 10 mL single-necked flask, compound 97-7 (42.00 mg, 0.04 mmol), N,N-dimethylformamide (1.50 mL), and cesium carbonate (40.47 mg, 0.12 mmol) were added sequentially. The temperature was raised to 80°C and stirred for 1 hour. LC-MS monitored the reaction completion. The reaction solution was diluted with ethyl acetate, washed three times with water and then brine, concentrated under reduced pressure, and purified by column chromatography to yield the target compound 97-8 (32.00 mg). ESI-MS m / z: 842.4 [M+H] + .

[0706] Step 9: Synthesis of compound 97-9

[0707] To a 10 mL single-necked flask, compound 97-8 (32.00 mg, 0.04 mmol), dichloromethane (1.00 mL), and hydrochloric acid (4 M in dioxane) (1.00 mL) were added sequentially and stirred at room temperature for 0.5 hours. LC-MS monitored the reaction completion, and the product was concentrated under reduced pressure. The crude product was used directly in the next step to obtain crude compound 97-9 (28.00 mg). ESI-MS m / z: 742.4 [M+H] + .

[0708] Step 10: Synthesis of Compound 97

[0709] To a 10 mL single-necked flask, (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (7.70 mg, 0.06 mmol) and N,N-dimethylformamide (1.00 mL) were added sequentially. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (21.52 mg, 0.06 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.38 mmol) were added at 0°C and stirred for 10 minutes. Finally, 97-9 (28.00 mg, 0.04 mmol) was added and stirred at 0°C for 10 minutes. The reaction was monitored for completion by LC-MS, and the reaction solution was directly purified by pre-HPLC to obtain the target compound 97 (10.70 mg). ESI-MS m / z: 860.4 [M+H] + .

[0710] 1 H NMR (500MHz, Methanol-d4) δ8.56(d,J=1.6Hz,1H),8.43(d,J=2.9Hz,1H),7.70(dd,J=8.7,1.6Hz,1H),7.56(s ,1H),7.48–7.42(m,2H),5.80(dd,J=16.0,4.4Hz,1H),5.71–5.65(m,2H),4.43(d,J=12.0Hz,1H),4.35–4.27( m,2H),4.17(dd,J=12.4,5.8Hz,1H),4.07(dd,J=14.6,5.0Hz,1H),3.81–3.66(m,3H),3.46(d,J=14.9Hz,1H), 3.26–3.19(m,2H),2.77(s,3H),2.49–2.44(m,1H),2.39(t,J=16.7Hz,1H),2.27–2.15(m,3H),2.07(dt,J=9.1, 4.8Hz,3H),1.95(t,J=15.2Hz,2H),1.86–1.71(m,6H),1.61(dt,J=13.1,6.5Hz,1H),1.48( d,J=6.5Hz,3H),1.15(dtt,J=14.7,10.3,4.9Hz,4H),1.01(d,J=11.9Hz,4H),0.40(s,3H).

[0711] Example 98 Synthesis of Compound N-((15S,63S,4S,Z)-12-(4-(2,2-difluoroethyl)piperazin-1-yl)-15,10,10-trimethyl-5,7-dioxo-18,19,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazino[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinocycloundecane-4-yl)-3-methylbicyclo[1.1.1]pentane-1-carboxamide

[0712] Step 1: Synthesis of Compound 98-1

[0713] Compound M4 (100.00 mg, 0.12 mmol), 2,2-difluoroethyl p-toluenesulfonate (28.97 mg, 0.14 mmol), and DIEA (0.06 mL, 0.37 mmol) were added to DMF (3.00 mL) and reacted at 40°C for 2 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with 40 mL*2 of EA. The mixture was washed with 40 mL*2 of saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to afford crude compound 98-1 (90.00 mg, 83.43%). ESI-MS m / z: 877.65 [M+H] + .

[0714] Step 2: Synthesis of compound 98-2

[0715] Compound 98-1 (90.00 mg, 0.10 mmol) was dissolved in DCM (1.00 mL), and hydrochloric acid (4 M in dioxane) (2.00 mL) was added. The mixture was allowed to react at room temperature for 1 h. The reaction solution was concentrated to dryness, diluted with 5 mL of toluene, and concentrated again to dryness to obtain crude compound 98-2 (70 mg, 87.81%), which was used directly in the next reaction. ESI-MS m / z: 777.54, [M+H] + .

[0716] Step 3: Synthesis of Compound 98

[0717] Compound 1-methylbicyclo[1.1.1]pentane-3-carboxylic acid (13.64 mg, 0.11 mmol) was dissolved in acetonitrile (2.00 mL). DIEA (0.15 mL, 0.90 mmol) and HATU (51.41 mg, 0.14 mmol) were added sequentially in an ice-water bath. After reacting for 10 min in an ice-water bath, a solution of compound 98-2 (70.00 mg, 0.09 mmol) in acetonitrile (2.00 mL) and DIEA (0.15 mL, 0.90 mmol) was added and the mixture was reacted at room temperature for 1 h. The mixture was concentrated to dryness to obtain compound 98 (32.00 mg, 39.64%). ESI-MS m / z: 885.43, [M+H] + .

[0718] 1 H NMR(500MHz,DMSO)δ8.50(s,1H),8.41(d,J=2.8Hz,1H),8.00(d,J=9.0Hz,1H),7.80 (s,1H),7.71(dd,J=8.6,1.4Hz,1H),7.49(d,J=8.6Hz,1H),7.23(d,J=2.8Hz,1H),6 .18(tt,J=55.7,4.3Hz,1H),5.48(t,J=9.4Hz,1H),5.09(d,J=12.2Hz,1H),4.28–4. 19(m,2H),4.15(q,J=6.3Hz,1H),4.03(dd,J=12.7,4.9Hz,2H),3.68(d,J=10.9Hz,1H ),3.60(t,J=14.0Hz,2H),3.38(dd,J=14.7,9.3Hz,1H),3.30(s,1H),3.27(s,4H),3 .16(t,J=11.4Hz,1H),3.00(d,J=14.5Hz,1H),2.78(tt,J=22.3,11.1Hz,3H),2.68( s,4H),2.41(d,J=14.2Hz,1H),2.29(s,1H),2.10(d,J=11.1Hz,1H),1.90–1.76(m,9 H),1.56–1.47(m,1H),1.37(d,J=6.3Hz,3H),1.19(s,3H),0.96(s,3H),0.32(s,3H).

[0719] Example 99 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)-5,7-dioxo-18,19,61,16,2,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazeno[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)cyclopropane-1-carboxamide

[0720] Step 1: Synthesis of Compound 99-1

[0721] To a 100 mL single-necked flask, benzyl 3-oxoazetidine-1-carboxylate (5 g, 24.37 mmol), 1,2-dichloroethane (25.00 mL), 1-methylpiperazine (4.07 mL, 36.55 mmol), and glacial acetic acid (2.09 mL, 36.55 mmol) were added sequentially and stirred at 40°C for 3 h. Sodium triacetoxyborohydride (10.33 g, 48.73 mmol) was then added and stirred at 40°C for 2 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with dichloromethane, washed sequentially with water and brine, and the organic phase was concentrated to obtain the crude product, which was then separated and purified by silica gel column chromatography to yield the target compound 99-1 (6.34 g, off-white solid powder). ESI-MS m / z: 290 [M+H] + .

[0722] Step 2: Synthesis of Compound 99-2

[0723] To a 100 mL single-necked flask, compound 99-1 (3 g, 10.37 mmol), palladium on carbon (1.54 g, 10%, 1.45 mmol), methanol (30.00 mL), and acetic acid (10 drops) were added sequentially. After H2 displacement, the mixture was heated in an oil bath at 50°C for 4 h. After completion of the reaction, as monitored by LC-MS, the reaction mixture was filtered through Celite, the filtrate was concentrated to dryness, and purified by silica gel column chromatography to obtain the target compound 99-2 (1.6 g, off-white solid). ESI-MS m / z: 156 [M+H] + .

[0724] Step 3: Synthesis of Compound 99-3

[0725] To a 100 mL single-necked flask, 3-bromo-5-fluoro-pyridine-2-carbonitrile (2 g, 9.95 mmol) and N,N-dimethylformamide (20.00 mL) were added sequentially. 99-2 (1.54 g, 9.95 mmol) and triethylamine (4.15 mL, 29.85 mmol) were then added dropwise at 0°C. The mixture was transferred to room temperature and stirred for 0.5 h. After completion of the reaction, the mixture was extracted three times with water and ethyl acetate. The organic phases were combined, washed sequentially with water and brine, separated, and concentrated to obtain the crude product. The crude product was then separated and purified by silica gel column chromatography to obtain the target compound 99-3 (1.9 g, off-white solid). ESI-MS m / z: 336, 338 [M+H] + .

[0726] Step 4: Synthesis of Compound 99-4

[0727] To a 50 mL three-necked flask, compound 99-3 (1.9 g, 4.16 mmol) and THF (15 mL) were added sequentially. The nitrogen atmosphere was purged three times and the temperature was lowered to -20°C. Methylmagnesium bromide (3.89 mL, 3.00 mol / L, 11.66 mmol) was added dropwise. The mixture was then transferred to 0°C and stirred for 2 h. After completion of the reaction, 1 M dilute hydrochloric acid was added dropwise to adjust the pH to approximately 3-4. The mixture was stirred at room temperature for 15 minutes and then made alkaline with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with brine, and the organic phase was separated and concentrated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain the target compound 99-4 (1.78 g, reddish-brown viscous). ESI-MS m / z: 354, 356 [M+H] + .

[0728] Step 5: Synthesis of Compound 99-5

[0729] To a 100 mL three-necked flask, triethylamine (8.40 mL, 60.47 mmol) was added, followed by formic acid (0.48 mL, 12.60 mmol) at 0°C, and then (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (0.03 g, 0.05 mmol). The mixture was stirred at 40°C for 15 min, cooled to room temperature, and compound 99-4 (1.78 g, 5.04 mmol) was added. The mixture was allowed to react at room temperature (oil temperature 28°C) for 20 h. After completion of the reaction, as monitored by LC-MS, the reaction mixture was added to an aqueous solution, extracted with ethyl acetate, washed with brine, separated, and the organic phase concentrated to obtain the crude product, which was then purified by silica gel column chromatography to yield the target compound 99-5 (1.6 g, reddish-brown viscous). ESI-MS m / z: 356, 358 [M+H] + .

[0730] Step 6: Synthesis of Compound 99-6

[0731] To a 50 mL single-necked flask, compound 99-5 (600.00 mg, 1.69 mmol) and 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate (1163.72 mg, 3.38 mmol) were added sequentially and dissolved in dimethyl sulfoxide (6.00 mL). Sodium tert-butoxide (405.73 mg, 4.22 mmol) in THF / tetrahydrofuran (1.20 mL) was added under ice-cold water and stirred at room temperature for 0.5 h. After completion of the reaction as monitored by LC-MS, the reaction mixture was added to an aqueous solution, extracted with dichloromethane, washed with brine, separated, and the organic phase concentrated to obtain the crude product, which was then separated and purified by silica gel column chromatography to yield the target compound 99-6 (570 mg, reddish-brown viscous). ESI-MS m / z: 527, 529 [M+H] + .

[0732] Step 7: Synthesis of Compound 99-7

[0733] To a 50 mL single-necked flask, compound 99-6 (570 mg, 0.89 mmol), tetrahydrofuran (5.00 mL), and TBAF (1.34 mL, 1 M THF solution) were added and stirred at 50°C for 1 h. After completion of the reaction, as monitored by LC-MS, the sample was added and mixed with silica gel and then purified by silica gel column chromatography to obtain the target compound 99-7 (300 mg, reddish-brown viscous). ESI-MS m / z: 414, 416 [M+H] + .

[0734] Step 8: Synthesis of Compound 99-8

[0735] To a 50 mL single-necked flask, compound 99-7 (200 mg, 0.48 mmol), 4-dimethylaminopyridine (5.91 mg, 0.05 mmol), dichloromethane (3.00 mL), and triethylamine (0.17 mL, 1.21 mmol) were added sequentially. p-Toluenesulfonyl chloride (184.47 mg, 0.97 mmol) was added dropwise under nitrogen at 0°C. The mixture was stirred at room temperature overnight. After completion of the reaction, as monitored by LC-MS, the reaction mixture was added to an aqueous solution, extracted with dichloromethane, washed with brine, and separated. The organic phase was concentrated to obtain the crude product, which was then purified by silica gel column chromatography to yield the target compound 99-8 (270 mg, reddish-brown viscous). ESI-MS m / z: 568, 570 [M+H] + .

[0736] Step 9: Synthesis of compound 99-9

[0737] To a 10 mL single-necked flask, compound 99-8 (100 mg, 0.18 mmol), M2 (122.22 mg, 0.18 mmol), potassium carbonate (60.88 mg, 0.44 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (14.37 mg, 0.02 mmol), toluene (3.00 mL), 1,4-dioxane (1.00 mL), and water (1.00 mL) were added sequentially. The atmosphere was purged with nitrogen three times and stirred at 60-65°C for 1.5 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the organic phases were separated and concentrated to give the crude product. This was then separated and purified by silica gel column chromatography to yield the target compound 99-9 (85 mg, reddish-brown viscous). ESI-MS m / z: 528, [M+2H] 2+ / 2.

[0738] Step 10: Synthesis of Compound 99-10

[0739] To a 10 mL single-necked flask, compound 99-9 (85 mg, 0.08 mmol), DMF (3 mL), and Cs2CO3 (52.52 mg, 0.16 mmol) were added sequentially. The mixture was heated in an oil bath at 60-65°C under nitrogen for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the organic phase was concentrated to afford crude compound 99-10. This was then separated and purified by silica gel column chromatography to yield the target compound 99-10 (71 mg, reddish-brown viscous). ESI-MS m / z: 442, [M+2H] 2+ / 2.

[0740] Step 11: Synthesis of Compound 99-11

[0741] To a 10 mL single-necked flask, compound 99-10 (71 mg, 0.08 mmol), DCM (2.00 mL), and HCl (4 M in dioxane) (1.00 mL) were added sequentially and the reaction was stirred at room temperature for 0.5 h. After completion of the reaction as monitored by LC-MS, the reaction solution was concentrated to dryness, then DCM was added and concentrated again to dryness. The crude product of compound 99-11 (slightly yellow solid powder, 62 mg, hydrochloride) was obtained and used directly in the next reaction. ESI-MS m / z: 783 [M+H] + .

[0742] Step 12: Synthesis of Compound 99

[0743] To a 10 mL single-necked flask, (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (54.85 mg, 0.40 mmol), HATU / N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (229.85 mg, 0.60 mmol), acetonitrile (3.00 mL), and N,N-diisopropylethylamine (0.13 mL, 0.81 mmol) were added sequentially. The mixture was stirred at 0°C for 15 min. A solution of 99-11 (63.00 mg, 0.08 mmol) in acetonitrile (3.00 mL) was then added (DIEA was added dropwise until dissolved). The mixture was stirred at 0°C for 15 min. After completion of the reaction, the reaction mixture was directly purified by acidic Prep-HPLC, and the eluate was lyophilized to obtain the target compound 99 (11.6 mg). ESI-MS m / z: 900 [M+H] + .

[0744] 1 H NMR (500MHz, MeOD) δ8.91(d,J=8.5Hz,1H),8.58(s,1H),7.91(d,J=2.6Hz,1H),7.71(d,J=8.6Hz,1H),7.57(s,1H),7.47(d,J=8.6Hz,1H),7.15(d,J=2 .5Hz,1H),5.93(d,J=3.9Hz,0.2H),5.81(d,J=4.0Hz,0.5H),5.71-5.68(m ,1.3H),4.48–4.25(m,4H),4.21-4.18(m,2H),3.95-3.93(m,2H),3.79-3.7 6(m,2H),3.70-3.64(m,2H),3.60–3.48(m,4H),3.27-3.14(m,4H),2.91(s ,3H),2.81-2.77(m,1H),2.52(d,J=14.6Hz,1H),2.39(s,3H),2.25–2.17(m ,2H),2.10–1.89(m,4H),1.86–1.73(m,2H),1.68–1.56(m,2H),1.51(d,J=6 .6Hz,3H),1.33-1.28(m,3H),1.19-1.11(m,3H),1.03(s,3H),0.44(s,3H).

[0745] Example 100 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-5,7-dioxo-18,19,61,62,63,64,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)cyclopropane-1-carboxamide

[0746] Step 1: Synthesis of compound 100-1

[0747] To a 100 mL single-necked flask, tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (5 g, 22.09 mmol), 37% aqueous formaldehyde solution (17.91 g, 220.93 mmol), and methanol (50.00 mL) were added in sequence. Sodium cyanoborohydride (2.78 g, 44.19 mmol) was added portionwise and stirred at room temperature for 2 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the organic phase was concentrated to obtain the crude product. This was then purified by silica gel column chromatography to yield the target compound 100-1 (5.31 g, off-white solid powder). ESI-MS m / z: 241 [M+H] + .

[0748] Step 2: Synthesis of compound 100-2

[0749] To a 100 mL single-necked flask, compound 100-1 (5.31 g, 22.09 mmol), dichloromethane (20.00 mL), and hydrochloric acid (4 M in dioxane) (40.00 mL) were added sequentially and allowed to react at 25°C for 2 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was concentrated to dryness and stripped twice from dichloromethane to afford the crude target compound 100-2 (3.1 g, off-white solid). This was used directly in the next step without purification. ESI-MS m / z: 141 [M+H] + .

[0750] Step 3: Synthesis of compound 100-3

[0751] To a 100 mL single-necked flask, 3-bromo-5-fluoro-pyridine-2-carbonitrile (2 g, 9.95 mmol) and DMF (20.00 mL) were added sequentially. Compound 100-2 (1.75 g, 9.95 mmol) and triethylamine (4.15 mL, 29.85 mmol) were then added dropwise at 0°C. The mixture was transferred to room temperature and stirred for 0.5 h. After completion of the reaction, the mixture was extracted three times with water and ethyl acetate. The organic phases were combined, washed sequentially with water and brine, separated, and concentrated to obtain the crude product. The crude product was then separated and purified by silica gel column chromatography to obtain the desired product 100-3 (1.34 g, off-white solid). ESI-MS m / z: 322, 324 [M+H] + .

[0752] Step 4: Synthesis of compound 100-4

[0753] To a 50 mL three-necked flask, compound 100-3 (1.34 g, 4.17 mmol) and THF (15 mL) were added sequentially. The nitrogen atmosphere was purged three times and the temperature was lowered to -20°C. Methylmagnesium bromide (3.89 mL, 3.00 mol / L, 11.66 mmol) was added dropwise. The mixture was then transferred to 0°C and stirred for 2 h. After completion of the reaction, 1 M dilute hydrochloric acid was added dropwise to adjust the pH to approximately 3-4. The mixture was stirred at room temperature for 15 minutes and then made alkaline with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with brine, and the organic phase was separated and concentrated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain the target compound 100-4 (1.00 g, reddish-brown viscous). ESI-MS m / z: 339, 341 [M+H] + .

[0754] Step 5: Synthesis of compound 100-5

[0755] To a 500 mL single-necked flask, triethylamine (4.93 mL, 35.48 mmol) was added, followed by formic acid (0.28 mL, 7.39 mmol) at 0°C, and then (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (0.02 g, 0.03 mmol). The mixture was stirred at 40°C for 15 min, cooled to room temperature, and compound 100-4 (1.00 g, 2.96 mmol) was added. The mixture was allowed to react at room temperature (oil temperature 28°C) for 20 h. After completion of the reaction, as monitored by LC-MS, the reaction mixture was added to an aqueous solution, extracted with ethyl acetate, washed with brine, separated, and the organic phase concentrated to obtain the crude product, which was then purified by silica gel column chromatography to yield the target compound 100-5 (0.47 g, reddish-brown viscous). ESI-MS m / z: 341, 343 [M+H] + .

[0756] Step 6: Synthesis of compound 100-6

[0757] To a 50 mL single-necked flask, compound 100-5 (420.00 mg, 1.23 mmol) and 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate (850.61 mg, 2.47 mmol) were added sequentially and dissolved in dimethyl sulfoxide (5.00 mL). Sodium tert-butoxide (296.56 mg, 3.09 mmol) in tetrahydrofuran (1.00 mL) was added under ice-cold water and stirred at room temperature for 0.5 h. After completion of the reaction as monitored by LC-MS, the reaction mixture was added to an aqueous solution, extracted with dichloromethane, washed with brine, separated, and the organic phase concentrated to obtain the crude product, which was then separated and purified by silica gel column chromatography to yield the target compound 100-6 (330 mg, reddish-brown viscous). ESI-MS m / z: 512, 514 [M+H] + .

[0758] Step 7: Synthesis of compound 100-7

[0759] To a 50 mL single-necked flask, compound 100-6 (330 mg, 0.97 mmol), tetrahydrofuran (5.00 mL), and TBAF (0.97 mL, 1 M THF solution) were added and stirred at 50°C for 1 h. After completion of the reaction, the sample was added with silica gel for mixing and then purified by silica gel column chromatography to obtain the target compound 100-7 (280 mg, reddish-brown viscous). ESI-MS m / z: 399, 401 [M+H] + .

[0760] Step 8: Synthesis of Compound 100-8

[0761] To a 50 mL single-necked flask, compound 100-7 (280 mg, 0.7 mmol), 4-dimethylaminopyridine (8.59 mg, 0.07 mmol), dichloromethane (3.00 mL), and triethylamine (0.24 mL, 1.76 mmol) were added sequentially. p-Toluenesulfonyl chloride (268.01 mg, 1.41 mmol) was added dropwise under nitrogen at 0°C. The mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LC-MS, the reaction mixture was added to an aqueous solution, extracted with dichloromethane, washed with brine, separated, and the organic phase concentrated to obtain the crude product. Purification by silica gel column chromatography yielded the target compound 100-8 (320 mg, reddish-brown viscous). ESI-MS m / z: 552, 554 [M+H] + .

[0762] Step 9: Synthesis of compound 100-9

[0763] To a 10 mL single-necked flask were added compound 100-8 (100 mg, 0.18 mmol), M2 (125.55 mg, 0.18 mmol), K2CO3 / potassium carbonate (62.54 mg, 0.45 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (14.78 mg, 0.02 mmol), toluene (3.00 mL), 1,4-dioxane (1.00 mL), and water (1.00 mL). The atmosphere was purged with nitrogen three times and stirred at 60-65°C for 1.5 h. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the organic phases were separated and concentrated to give the crude product. This was then separated and purified by silica gel column chromatography to yield the target compound 100-9 (113 mg, reddish-brown viscous). ESI-MS m / z: 520, [M+2H] 2+ / 2.

[0764] Step 10: Synthesis of compound 100-10

[0765] To a 10 mL single-necked flask, compound 100-9 (113 mg, 0.11 mmol), DMF (3 mL), and Cs2CO3 (70.83 mg, 0.22 mmol) were added sequentially. The mixture was heated in an oil bath at 60-65°C under nitrogen for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed sequentially with water and brine, and the organic phase was concentrated to afford crude compound 1-10. This was then separated and purified by silica gel column chromatography to yield the target compound 100-10 (94 mg, reddish-brown viscous). ESI-MS m / z: 4341 / 2 [M+2] + .

[0766] Step 11: Synthesis of compound 100-11

[0767] To a 10 mL single-necked flask, compound 100-10 (94 mg, 0.08 mmol), DCM (2.00 mL), and HCl (4 M in dioxane) (1.00 mL) were added sequentially and the reaction was stirred at room temperature for 0.5 h. After completion of the reaction as monitored by LC-MS, the reaction solution was concentrated to dryness, then DCM was added and concentrated again to dryness. The crude product of compound 100-11 (slightly yellow solid powder, 83 mg, hydrochloride) was obtained and used directly in the next reaction. ESI-MS m / z: 768 [M+H] + .

[0768] Step 12: Synthesis of Compound 100

[0769] To a 10 mL single-necked flask, (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (84 mg, 0.55 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (312.28 mg, 0.82 mmol), acetonitrile (3.00 mL), and N,N-diisopropylethylamine (0.18 mL, 1.09 mmol) were added sequentially. The mixture was stirred at 0°C for 15 min. Compound 100-11 (84.00 mg, 0.11 mmol) in acetonitrile (3.00 mL) was then added (DIEA was added dropwise until dissolved), and the mixture was stirred at 0°C for 15 min. After completion of the reaction, the reaction solution was directly purified by Prep-HPLC acidic method, and the eluate was lyophilized to obtain the target compound 100 (7.6 mg). ESI-MS m / z: 885 [M+H] + .

[0770] Example 101 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-12-(4-(2-methoxyethyl)piperazin-1-yl)-15,10,10-trimethyl-5,7-dioxo-18,19,61,62,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)cyclopropane-1-carboxamide

[0771] Step 1: Synthesis of compound 101-1

[0772] Compound M4 (100.00 mg, 0.12 mmol), 2-bromoethyl methyl ether (20.52 mg, 0.15 mmol), potassium carbonate (17.00 mg, 0.12 mmol), and potassium iodide (20.42 mg, 0.12 mmol) were added to acetonitrile (2.00 mL) and reacted at 70°C for 8 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with 40 mL*2 of DCM. The mixture was washed with 40 mL*2 of saturated brine, dried over anhydrous sodium sulfate, and isolated by column chromatography to afford crude compound 101-1 (107.00 mg, 99.87%). ESI-MS m / z: 871.71 [M+H] + .

[0773] Step 2: Synthesis of compound 101-2

[0774] Compound 101-1 (107.00 mg, 0.12 mmol) was dissolved in DCM (1.00 mL), and hydrochloric acid (4 M in dioxane) (2.00 mL) was added. The mixture was allowed to react at room temperature for 1 h. The reaction solution was concentrated to dryness, diluted with 5 mL of toluene, and concentrated again to dryness to obtain crude compound 101-2 (90 mg, 95.04%), which was used directly in the next reaction. ESI-MS m / z: 771.49, [M+H] + .

[0775] Step 3: Synthesis of compound 101

[0776] Compound (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (25.41 mg, 0.19 mmol) was dissolved in acetonitrile (5.00 mL). DIEA (0.26 mL, 1.56 mmol) and HATU (88.75 mg, 0.23 mmol) were added sequentially in an ice-water bath. After reacting for 10 min in an ice-water bath, a solution of compound 101-2 (90.00 mg, 0.12 mmol) in acetonitrile (5.00 mL) and DIEA (0.26 mL, 1.56 mmol) was added and the mixture was reacted at room temperature for 1 h. The mixture was concentrated to dryness to obtain compound 101 (73.00 mg, 70.33%). ESI-MS m / z: 889.44, [M+H] + .

[0777] 1H NMR(500MHz,DMSO)δ8.90(d,J=9.0Hz,1H),8.50(s,1H),8.40(d,J=2.8Hz,1H),7.81(s,1H),7.7 1(dd,J=8.6,1.3Hz,1H),7.49(d,J=8.6Hz,1H),7.21(d,J=2.8Hz,1H),5.95(td,J=56.7,5.1Hz, 1H),5.76(s,1H),5.56(t,J=9.4Hz,1H),5.12(d,J=12.2Hz,1H),4.29–4.19(m,2H),4.15(q,J=6 .3Hz,1H),4.03(dd,J=12.4,4.5Hz,2H),3.68(d,J=11.0Hz,1H),3.61(dd,J=21.5,7.5Hz,2H),3 .46(t,J=5.7Hz,2H),3.38(d,J=14.4Hz,1H),3.24(s,7H),3.19–3.11(m,2H),3.01(d,J=14.4Hz ,1H),2.76(dt,J=12.6,8.2Hz,1H),2.58(d,J=13.3Hz,4H),2.52(d,J=5.6Hz,1H),2.42(d,J=14 .3Hz,1H),2.29(t,J=10.2Hz,1H),2.10(dt,J=9.2,5.1Hz,2H),1.81(s,3H),1.66(td,J=9.7,5. 1Hz,1H),1.58–1.48(m,1H),1.37(d,J=6.3Hz,3H),1.09–0.99(m,2H),0.95(s,3H),0.32(s,3H).

[0778] Example 102 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazino[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinocycloundecane-4-yl)cyclopropane-1-carboxamide

[0779] Step 1: Synthesis of compound 102-1

[0780] To a 50 mL single-necked flask, 3-bromo-5-fluoro-pyridine-2-carbonitrile (2.00 g, 9.95 mmol), N,N-dimethylformamide (20.00 mL), and 1-methyl-4-(piperidin-4-yl)piperazine (2.19 g, 11.94 mmol) were added sequentially. Triethylamine (3.46 mL, 24.88 mmol) was added dropwise at 0°C and stirred at room temperature for 1 hour. LC-MS monitored the reaction completion. The reaction solution was poured into water, and the precipitated solid was filtered and the filter cake rinsed with water. The filter cake was dried to yield the target compound 102-1 (3.19 g). ESI-MS m / z: 364.1 [M+H] + .

[0781] Step 2: Synthesis of compound 102-2

[0782] To a 100 mL three-necked flask, compound 102-1 (3.19 g, 8.76 mmol) and tetrahydrofuran (30.00 mL) were added sequentially. The temperature was lowered to -20°C under nitrogen atmosphere, and methylmagnesium bromide (8.76 mL, 3.00 mol / L, 26.27 mmol) was then added dropwise. Stir at room temperature for 1 hour. LC-MS monitored the reaction completion, quenched with saturated NH4Cl solution, and adjusted to pH 4 with dilute hydrochloric acid. Stirred for 10 minutes. The pH was then adjusted to pH 8 with saturated NaHCO3 solution. Extraction was performed twice with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure and purification by column chromatography afforded the target compound 102-2 (2.06 g). ESI-MS m / z: 381.1 [M+H] + .

[0783] Step 3: Synthesis of compound 102-3

[0784] To a 100 mL three-necked flask, triethylamine (15.02 mL, 108.05 mmol) was added. Under nitrogen, the temperature was lowered to 0°C, and formic acid (1.02 mL, 27.01 mmol) was added dropwise. (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (0.07 g, 0.11 mmol) was then added. The reaction was heated to 40°C and stirred for 15 minutes. The mixture was cooled to room temperature and finally 102-2 (2.06 g, 5.40 mmol) and dichloromethane (5.00 mL) were added. The mixture was stirred at room temperature for 24 hours. LC-MS monitored the reaction completion. The mixture was extracted twice with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by column chromatography to yield the target compound 102-3 (1.53 g). ESI-MS m / z: 383.1 [M+H] + .

[0785] Step 4: Synthesis of compound 102-4

[0786] To a 50 mL single-necked flask, compound 102-3 (800.00 mg, 2.09 mmol), dimethyl sulfoxide (10.00 mL), tetrahydrofuran (2.00 mL), and 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate (2.52 g, 7.30 mmol) were added sequentially. Sodium tert-butoxide (501.40 mg, 5.22 mmol) was added portionwise at 10°C and stirred at room temperature for 1 hour. LC-MS monitored the completion of the reaction, and the reaction mixture was quenched by adding saturated aqueous ammonium chloride. The mixture was extracted twice with ethyl acetate, washed three times with saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound 102-4 (972.00 mg). ESI-MS m / z: 555.3 [M+H] + .

[0787] Step 5: Synthesis of compound 102-5

[0788] To a 50 mL single-necked flask, compound 102-4 (970.00 mg, 1.75 mmol) and tetrahydrofuran (10.00 mL) were added sequentially. Tetrabutylammonium fluoride (2.27 mL, 1.00 mol / L, 2.27 mmol) was added dropwise at 0°C, and the mixture was heated to 50°C and stirred for 1 hour. LC-MS monitored the reaction completion, and the mixture was concentrated under reduced pressure and purified by column chromatography to yield the target compound 102-5 (723.00 mg). ESI-MS m / z: 441.2 [M+H] + .

[0789] Step 6: Synthesis of compound 102-6

[0790] To a 50 mL single-necked flask, compound 102-5 (723.00 mg, 1.64 mmol), dichloromethane (10.00 mL), and 4-dimethylaminopyridine (20.04 mg, 0.16 mmol) were added sequentially. Then, p-toluenesulfonyl chloride (624.52 mg, 3.28 mmol) and triethylamine (0.57 mL, 4.09 mmol) were added portionwise. The mixture was stirred at room temperature for 4 hours. LC-MS monitored the reaction completion, and the mixture was concentrated under reduced pressure and purified by column chromatography to obtain the target compound 102-6 (1.14 g). ESI-MS m / z: 595.2 [M+H] + .

[0791] Step 7: Synthesis of compound 102-7

[0792] To a 10 mL single-necked flask, compound 102-6 (154.02 mg, 0.26 mmol), M2 (120.00 mg, 0.17 mmol), toluene (1.50 mL), 1,4-dioxane (0.50 mL), water (0.50 mL), potassium carbonate (59.57 mg, 0.43 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (14.05 mg, 0.02 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the temperature was raised to 65°C under nitrogen protection, with stirring for 3 hours. LC-MS monitored the reaction completion, and the mixture was extracted twice with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography to yield the target compound 102-7 (67.00 mg). ESI-MS m / z: 541.81 / 2 [M+2H] + .

[0793] Step 8: Synthesis of compound 102-8

[0794] To a 10 mL single-necked flask, compound 102-7 (61.00 mg, 0.06 mmol), N,N-dimethylformamide (5.00 mL), and cesium carbonate (55.13 mg, 0.17 mmol) were added sequentially. The temperature was raised to 45°C and stirred for 1 hour. LC-MS monitored the reaction completion. The reaction solution was diluted with ethyl acetate, washed three times with water and then brine, concentrated under reduced pressure, and purified by column chromatography to yield the target compound 102-8 (64.00 mg). ESI-MS m / z: 910.5 [M+H] + .

[0795] Step 9: Synthesis of compound 102-9

[0796] To a 10 mL single-necked flask, compound 102-8 (64.00 mg, 0.07 mmol), dichloromethane (2.00 mL), and hydrochloric acid (4 M in dioxane) (2.00 mL) were added sequentially and stirred at room temperature for 1 hour. LC-MS monitored the reaction completion, and the product was concentrated under reduced pressure. The crude product was used directly in the next step to obtain crude compound 102-9 (57.00 mg). ESI-MS m / z: 810.4 [M+H] + .

[0797] Step 10: Synthesis of Compound 102

[0798] To a 10 mL single-necked flask, (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (14.37 mg, 0.11 mmol) and N,N-dimethylformamide (1.00 mL) were added sequentially. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (40.15 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.70 mmol) were added at 0°C and stirred for 10 minutes. Finally, compound 102-9 (57.00 mg, 0.07 mmol) was added and stirred at 0°C for 10 minutes. The reaction was monitored for completion by LC-MS, and the reaction solution was directly purified by pre-HPLC to obtain the target compound 102 (9.30 mg). ESI-MS m / z: 928.5 [M+H] + .

[0799] 1 H NMR (500MHz, Methanol-d4) δ8.93(d,J=8.5Hz,1H),8.59(d,J=1.6Hz,1H),8.35(d,J=2. 9Hz,1H),7.74–7.70(m,2H),7.58(s,1H),7.48(d,J=8.6Hz,1H),5.87(dd,J=57.3,4.1H z,1H),5.69(td,J=8.1,7.5,2.5Hz,1H),4.41(dd,J=21.2,10.2Hz,2H),4.30(dd,J=12. 1,3.2Hz,1H),4.19–4.02(m,5H),3.80–3.64(m,4H),3.46(d,J=15.1Hz,2H),3.39–3.34 (m,3H),3.28–3.23(m,3H),3.01(d,J=12.0Hz,3H),2.88(s,3H),2.82–2.76(m,1H),2.5 0(d,J=14.5Hz,1H),2.39(d,J=14.7Hz,1H),2.24(d,J=12.7Hz,1H),2.15–2.04(m,4H), 1.97(d,J=12.7Hz,2H),1.84(d,J=13.5Hz,1H),1.81–1.73(m,3H),1.63(tt,J=13.1,6. 4Hz, 2H), 1.53 (d, J = 6.6Hz, 3H), 1.18 (dd, J = 9.3, 4.6Hz, 1H), 1.03 (s, 3H), 0.44 (s, 3H).

[0800] Example 103 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H, 17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinylcycloundec-4-yl)cyclopropane-1-carboxamide

[0801] Step 1: Synthesis of compound 103-1

[0802] Under ice-water conditions, 3-bromo-5-fluoro-pyridine-2-carbonitrile (3.00 g, 14.93 mmol), triethylamine (6.22 mL, 44.78 mmol), and compound 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (4.18 g, 16.42 mmol) were added to DMF (30.00 mL) in sequence and reacted at room temperature for 1 hour. 50 mL of water was added to the reaction solution, and the product precipitated. The product was filtered, and the filter cake was washed with 30 mL of water and dried to obtain the crude product of compound 103-1 (white solid powder, 6.10 g), which was used directly in the next reaction. ESI-MS m / z: 435.11 [M+H] + .

[0803] Step 2: Synthesis of compound 103-2

[0804] Compound 103-1 (6.00 g, 13.78 mmol) was dissolved in tetrahydrofuran (60.00 mL), the atmosphere was replaced with nitrogen, and methylmagnesium bromide (13.78 mL, 3.00 mol / L, 41.35 mmol) was added dropwise at -20°C. The temperature was raised to room temperature and the reaction was allowed to react for 2 h. The reaction solution was added dropwise to 40 mL of icy saturated aqueous ammonium chloride solution. The pH was adjusted to 3 with 1N aqueous hydrochloric acid. After stirring for 10 min, the pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution. The solution was extracted with 40 mL of EA, washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound 103-2 (2.10 g, 33.68%). ESI-MS m / z: 452.18, [M+H] + .

[0805] Step 3: Synthesis of compound 103-3

[0806] Compound 103-2 (2.10 g, 4.64 mmol), (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium(II) chloride (0.15 g, 0.23 mmol), and TEA (6.45 mL, 46.42 mmol) were added to DCM (20.00 mL). Formic acid (1.07 g, 23.21 mmol) was added under an ice-water bath and allowed to react at room temperature for 72 h. Water (50 mL) was added to the reaction solution, which was then extracted with DCM (40 mL x 2), washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, and separated by column chromatography to yield compound 103-3 (1.12 g, 53.10%). ESI-MS m / z: 454.18 [M+H] + .

[0807] Step 4: Synthesis of compound 103-4

[0808] Compound 103-3 (1.12 g, 2.46 mmol) was dissolved in DCM (2.00 mL), and hydrochloric acid (4 M in dioxane) (4.00 mL) was added. The mixture was allowed to react at room temperature for 1 h. The reaction solution was concentrated to dryness, diluted with 40 mL of toluene, and concentrated again to dryness to obtain the crude product of compound 103-4 (0.90 g, reddish-brown solid powder). ESI-MS m / z: 354.13, [M+H] + .

[0809] Step 5: Synthesis of compound 103-5

[0810] Compound 103-4 (0.90 g, 2.54 mmol) was added to methanol (10.00 mL). Acetic acid (0.29 mL, 5.08 mmol) and 37% formaldehyde solution (0.41 g, 37%, 5.08 mmol) were added under an ice-water bath. The mixture was kept warm for 10 minutes. Sodium cyanoborohydride (0.24 g, 3.81 mmol) was then added and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated to dryness, adjusted to alkalinity by adding 7 M methanolic ammonia solution, concentrated to dryness, and separated by column chromatography to obtain compound 103-5 (1.10 g, 117.57%). ESI-MS m / z: 368.16, [M+H] + .

[0811] Step 6: Synthesis of compound 103-6

[0812] Compound 103-5 (1.10 g, 2.99 mmol) and 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate (3.09 g, 8.96 mmol) were added to DMSO (10.00 mL), followed by a solution of sodium tert-butoxide (0.72 g, 7.47 mmol) in tetrahydrofuran (2.00 mL). The mixture was reacted at 40°C for 3 h. 50 mL of water was added to the reaction solution, and the mixture was extracted with 40 mL*2 of EA, washed with 40 mL*2 of saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound 103-6 (0.70 g, 43.48%). ESI-MS m / z: 540.37, [M+H] + .

[0813] Step 7: Synthesis of compound 103-7

[0814] Compound 103-6 (700.00 mg, 1.29 mmol) and tetrabutylammonium fluoride (1.94 mL, 1.00 mol / L, 1.94 mmol) were added to THF / tetrahydrofuran (7.00 mL) and reacted at 50°C for 1 h. The mixture was concentrated to dryness and separated by column chromatography to obtain compound 103-7 (0.52 g, 94.19%). ESI-MS m / z: 426.27, [M+H] + .

[0815] Step 8: Synthesis of compound 103-8

[0816] Compound 103-7 (520.00 mg, 1.22 mmol), DMAP (297.97 mg, 2.44 mmol), and TEA (0.85 mL, 6.10 mmol) were added to DCM (8.00 mL). p-Toluenesulfonyl chloride (813.74 mg, 4.27 mmol) was added portionwise in an ice-water bath and allowed to react at room temperature for 2 h. 50 mL of water was added to the reaction solution, which was then extracted with DCM (40 mL x 2), washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, and separated by column chromatography to afford compound 103-8 (515 mg, 72.74%). ESI-MS m / z: 580.35, [M+H] + .

[0817] Step 9: Synthesis of compound 103-9

[0818] Compound 103-8 (167.44 mg, 0.29 mmol), compound M2 (100.00 mg, 0.14 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (11.76 mg, 0.01 mmol), potassium carbonate (49.82 mg, 0.36 mmol), water (0.50 mL), and 1,4-dioxane (1.00 mL) were added to toluene (3.00 mL) and reacted at 65°C under a nitrogen atmosphere for 2 h. The mixture was concentrated and separated by column chromatography to obtain compound 103-9 (140 mg, 90.96%). ESI-MS m / z: 534.54, [M+H] + .

[0819] Step 10: Synthesis of compound 103-10

[0820] Compound 103-9 (140.00 mg, 0.13 mmol) and cesium carbonate (85.50 mg, 0.26 mmol) were added to DMF (14.00 mL) and reacted at 85°C for 1 h. 50 mL of water was added to the reaction solution, and the mixture was extracted with 40 mL*2 of EA. The mixture was washed with 40 mL*2 of saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound 103-10 (80 mg, 68.12%). ESI-MS m / z: 895.71, [M+H] + .

[0821] Step 11: Synthesis of compound 103-11

[0822] Compound 103-10 (80.00 mg, 0.09 mmol) was dissolved in DCM (1.00 mL), and hydrochloric acid (4 M in dioxane) (2.00 mL) was added. The mixture was allowed to react at room temperature for 1 h. The reaction solution was concentrated to dryness, diluted with 5 mL of toluene, and concentrated again to dryness to obtain crude compound 103-11 (50 mg, 70.35%), which was used directly in the next reaction. ESI-MS m / z: 795.71, [M+H] + .

[0823] Step 12: Synthesis of Compound 103

[0824] Compound (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (10.28 mg, 0.08 mmol) was dissolved in acetonitrile (3.00 mL). DIEA (0.10 mL, 0.63 mmol) and HATU (35.89 mg, 0.09 mmol) were added sequentially in an ice-water bath. After reacting for 10 min in an ice-water bath, a solution of compound 103-11 (50.00 mg, 0.06 mmol) in acetonitrile (3.00 mL) and DIEA (0.10 mL, 0.63 mmol) was added and the mixture was reacted at room temperature for 1 h. The mixture was concentrated to dryness to obtain compound 103 (10 mg, 16.02%). ESI-MS m / z: 913.52, [M+H] + .

[0825] Example 104 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-5,7-dioxo-18,19,61,62,63,64,65-,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazine-cycloundecane-4-yl)cyclopropane-1-carboxamide

[0826] Step 1: Synthesis of Compound 104-1

[0827] To a 50 mL single-necked flask, M4 (200.0 mg, 0.12 mmol), acetic acid (29.5 mg, 0.50 mmol), and methanol (4.00 mL) were added sequentially. Under nitrogen protection, the mixture was cooled in an ice-water bath. N-methyl-4-piperidone (55.7 mg, 0.50 mmol) was slowly added. The mixture was kept warm for 15 min, followed by sodium cyanoborohydride (34.8 mg, 0.36 mmol). The temperature was raised to 50°C and stirred for 3 h. After completion of the reaction, as monitored by LC-MS, saturated sodium bicarbonate was slowly added to the reaction solution to adjust the pH to 8-9. The solution was concentrated to remove methanol and then extracted with EA (20 mL x 3). The combined organic phases were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The concentrated organic phase was concentrated to give crude compound 104-1, which was then purified by silica gel column chromatography to obtain the target product 104-1 (140.0 mg, light yellow solid). ESI-MS m / z:910.21[M+H] + .

[0828] Step 2: Synthesis of compound 104-2

[0829] To a 10 mL single-necked flask, compound 104-1 (140.00 mg, 0.15 mmol), DCM (3.00 mL), and HCl (4 M in dioxane) (1.54 mL) were added sequentially and the reaction was stirred at room temperature. After completion of the reaction as monitored by LC-MS, the reaction solution was concentrated to dryness, DCM was added, and the mixture was concentrated again to dryness. The crude product of compound 104-2 (slightly yellow solid powder, 120.0 mg, hydrochloride) was obtained and used directly in the next reaction. ESI-MS m / z: 810.23, [M+H] + .

[0830] Step 3: Synthesis of compound 104

[0831] To a 10 mL single-necked flask, (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (24.18 mg, 0.18 mmol), HATU (112.62 mg, 0.30 mmol), and DIEA (0.12 mL, 0.74 mmol) were added sequentially and stirred at room temperature for 15 minutes. The mixture was cooled in an ice-water bath, and then a solution of compound 104-2 (120.00 mg, 0.15 mmol) in acetonitrile was added. After completion of the reaction as monitored by LC-MS, the reaction solution was directly separated and purified by a Prep-HPLC alkaline method, and the eluate was lyophilized to obtain the target compound 104 (53.70 mg). ESI-MS m / z: 928.46, [M+H] + .

[0832] 1H NMR (500MHz, DMSO) δ8.88(d,J=9.1Hz,1H),8.49(s,1H),8.39(s,1H),7.80(s,1H),7.71(d,J=8.4Hz,1H),7.49(d,J=8.7Hz,1H),7.19 (s,1H),5.95(s,1H),5.57(d,J=9.0Hz,1H),5.10(d,J=12.2Hz,1H),4.26-4.22(m,2H),4.04-3.99(m,2H),3.67-3.56(m,3H),3.39-3 .36(m,1H),3.25-3.12(m,7H),3.00(d,J=14.4Hz,1H),2.78(d,J=11.7Hz,3H),2.64-2.59(m,4H),2.44-2.38(m,2H),2.31–2.27(m,1 H),2.15-2.08(m,5H),1.99(s,1H),1.85-1.64(m,7H),1.43–1.34(m,6H),1.08–1.03(m,1H),0.95(s,3H),0.85(s,1H),0.32(s,3H).

[0833] Example 105 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-12-(4-(dimethylamino)piperidin-1-yl)-15,10,10-trimethyl-5,7-dioxo-18,19,61,62,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)cyclopropane-1-carboxamide

[0834] Step 1: Synthesis of compound 105-1

[0835] 3-Bromo-5-fluoro-pyridine-2-carbonitrile (3.0 g) was added to a 50 mL single-necked flask, followed by anhydrous DMF (30 mL). TEA (10 mL) and 4-dimethylaminopiperidine (3.5 mL) were weighed in and reacted at room temperature for 0.5 h. After the reaction, saturated brine (25 mL) was added, extracted with EA, and the organic phase was concentrated to dryness to obtain the target compound 105-1 (5.14 g, crude product). ESI-MS m / z: 309.2 [M+H] + .

[0836] Step 2: Synthesis of compound 105-2

[0837] Compound 105-1 (4.8 g) and anhydrous THF (100 mL) were added to a 250 mL three-necked flask. The temperature was lowered to 0°C under N2 protection, and MeMgBr (3 M in THF, 15.6 mL) was slowly added dropwise. The mixture was allowed to warm to room temperature and allowed to react for 2 h. After the reaction, HCl (1N, 30 mL) was added to the reaction solution, and the mixture was extracted with EA. The organic phase was collected, and the aqueous phase was extracted twice with EA (30 mL). The organic phases were collected and combined, dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography to obtain the target compound 105-2 (3.33 g, 65% yield). ESI-MS m / z: 326.4 [M+H] + .

[0838] Step 3: Synthesis of compound 105-3

[0839] Compound 105-2 (3.33 g) was added to a 25 mL single-necked flask, followed by TEA (17 mL) and s,s-Noyori catalyst (0.32 g). The temperature was lowered to 0°C under N2 protection, and formic acid (2 mL) was slowly added dropwise. The reaction was allowed to react at room temperature for 12 h. After the reaction, ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution for extraction. The organic phase was collected and the aqueous phase was extracted twice with ethyl acetate (25 mL). The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain the desired axially chiral compound 105-3 (3.0 g, 90% yield). ESI-MS m / z: 328.3 [M+H] + .

[0840] Step 4: Synthesis of compound 105-4

[0841] 105-3 (1.3 g), 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate (2.23 g), and DMSO / THF (10 mL / 2.5 mL) were weighed into a reaction flask. The temperature was lowered to 10°C under N2 protection. Sodium tert-butoxide (0.80 g) was added and the reaction was allowed to proceed at room temperature for 1.0 h. After the reaction was complete, the temperature was lowered to 0°C and diluted with tap water (50 mL). The reaction was extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography to obtain compound 105-4 (1.69 g, 85% yield). ESI-MS m / z: 500.1 [M+H] + .

[0842] Step 5: Synthesis of compound 105-5

[0843] Compound 105-4 (1.69 g) was added to a 50 mL single-necked flask, followed by anhydrous methanol (20 mL). The temperature was lowered to 0°C under N2 protection, and TMSCl (0.2 mL) was slowly added dropwise. The mixture was allowed to react at room temperature for 1.0 h. After the reaction, the mixture was concentrated to dryness to obtain the target compound 105-5 (1.31 g, 100% yield). ESI-MS m / z: 385.3 [M+H] + .

[0844] Step 6: Synthesis of compound 105-6

[0845] Compound 105-5 (1.31 g) was added to a 50 mL single-necked vial, followed by anhydrous DCM (15 mL). TEA (6 mL) and DMAP (21 mg) were weighed in. The temperature was lowered to 0°C under N2 protection, and TsCl (1.4 g) was added. The reaction was allowed to react at room temperature for 1.0 h. After the reaction, saturated brine (25 mL) was added, and the mixture was extracted with DCM. The organic phase was concentrated to dryness, and the concentrate was purified by column chromatography to obtain the target compound 105-6 (1.80 g, 98% yield). ESI-MS m / z: 540.5 [M+H] + .

[0846] Step 7: Synthesis of compound 105-7

[0847] Compound 105-6 (468 mg), M2 (300 mg), Pd(dppf)Cl2 in DCM (71 mg), and potassium carbonate (180 mg) were weighed into separate 100 mL single-necked vials. Toluene (12 mL), 1,4-dioxane (4 mL), and 4 mL of water were added. The atmosphere was replaced with nitrogen three times and the temperature was raised to 65°C for 5 h. After the reaction, 20 mL each of EA and water were added to the reaction mixture for extraction. The aqueous phase was extracted twice more with EA. The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to yield the target compound 105-7 (310 mg, 70% yield). ESI-MS m / z: 514.6 [M+H] + .

[0848] Step 8: Synthesis of compound 105-8

[0849] Compound 105-7 (310 mg) was added to a 25 mL single-necked vial, followed by the addition of Cs2CO3 (295 mg) and anhydrous DMF (15 mL). The mixture was reacted at 80°C under nitrogen for 1 h. After completion of the reaction, the mixture was diluted with tap water (50 mL) and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography to yield the target compound 105-8 (260 mg, 100% yield). ESI-MS m / z: 854.3 [M+H] + .

[0850] Step 9: Synthesis of compound 105-9

[0851] Compound 105-8 (260 mg) was added to a 25 mL single-necked bottle, and 15 mL of hydrochloric acid (4 M in dioxane) was added. The mixture was allowed to react at room temperature for 1 h. After the reaction, the mixture was concentrated under reduced pressure to obtain the hydrochloride salt of the target compound 105-9 (276 mg, crude product). ESI-MS m / z: 754.2 [M+H] + .

[0852] Step 10: Synthesis of compound 105

[0853] Compound (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (108 mg) was added to a 25 mL single-necked vial. HATU (302 mg), N,N-diisopropylethylamine (0.66 mL), and anhydrous acetonitrile (20 mL) were weighed in and allowed to react at room temperature for 10 min. A solution of previously freed compound 105-9 (260 mg) in acetonitrile (20 mL) was then added dropwise at room temperature and allowed to react for 15 min. After the reaction, the mixture was concentrated and the concentrate was purified using preparative purification (60% acetonitrile / water) to yield the target compound 105 (61.8 mg, 20.5% yield). ESI-MS m / z: 873.4 [M+H] + .

[0854] 1H NMR (500MHz, CDCl3) δ8.59(d,J=1.1Hz,1H),8.44(d,J=2.9Hz,1H),7.57(dd,J=8.6,1.4Hz, 1H),7.31(d,J=8.6Hz,1H),7.28(d,J=3.7Hz,1H),7.10(d,J=2.9Hz,1H),6.98(d,J=9.4Hz,1 H),5.95–5.87(m,1H),5.77(dd,J=57.6,2.9Hz,1H),4.60(d,J=11.8Hz,1H),4.36(td,J=12. 1,3.2Hz,1H),4.27–4.17(m,2H),4.10(dd,J=23.7,9.7Hz,1H),4.00(dd,J=14.5,4.4Hz,1H) ,3.85–3.75(m,5H),3.50–3.43(m,1H),3.32(td,J=12.3,2.8Hz,1H),3.22–3.12(m,2H),2.8 5(td,J=14.0,2.1Hz,2H),2.70(td,J=12.9,2.6Hz,1H),2.47–2.39(m,1H),2.36(d,J=13.4H z,7H),2.31–2.22(m,2H),2.03–1.94(m,4H),1.91–1.79(m,3H),1.74–1.56(m,3H),1.52(d, J=6.4Hz, 3H), 1.28 (ddd, J=14.3, 8.1, 4.9Hz, 2H), 1.14 (dt, J=8.6, 5.4Hz, 1H), 0.97 (s, 3H).

[0855] Example 106 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-(4-morpholinopiperidin-1-yl)-5,7-dioxo-18,19,61,62,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)cyclopropane-1-carboxamide

[0856] Step 1: Synthesis of Compound 106-1

[0857] To a 50 mL single-necked flask, 3-bromo-5-fluoro-pyridine-2-carbonitrile (1.50 g, 7.46 mmol), N,N-dimethylformamide (17.00 mL), and 4-morpholinopiperidine (1.65 g, 9.70 mmol) were added sequentially. Triethylamine (2.59 mL, 18.66 mmol) was added dropwise at 0°C and stirred at room temperature for 1 hour. LC-MS monitored the reaction completion. The reaction solution was poured into water, and the precipitated solid was filtered and the filter cake rinsed with water. The filter cake was dried to yield the target compound 106-1 (2.50 g). ESI-MS m / z: 351.1 [M+H] + .

[0858] Step 2: Synthesis of compound 106-2

[0859] To a 100 mL three-necked flask, 106-1 (2.50 g, 7.12 mmol) and tetrahydrofuran (25.00 mL) were added sequentially. The temperature was lowered to -20°C under nitrogen atmosphere, and methylmagnesium bromide (7.12 mL, 3.00 mol / L, 21.35 mmol) was then added dropwise. The mixture was stirred at room temperature for 2 hours. LC-MS monitored the reaction completion, and the mixture was quenched with saturated NH4Cl solution. Dilute hydrochloric acid was added to adjust the pH to 4 and stirred for 10 minutes. The pH was then adjusted to 8 with saturated NaHCO3 solution. The mixture was extracted twice with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by column chromatography to yield the target compound 106-2 (2.34 g). ESI-MS m / z: 368.1 [M+H] + .

[0860] Step 3: Synthesis of compound 106-3

[0861] To a 100 mL three-necked flask, triethylamine (22.08 mL, 158.85 mmol) was added. Under nitrogen, the temperature was lowered to 0°C, and formic acid (1.20 mL, 31.77 mmol) was added dropwise. (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (0.08 g, 0.13 mmol) was then added. The reaction mixture was heated to 40°C and stirred for 15 minutes. The mixture was cooled to room temperature and finally 106-2 (2.34 g, 6.35 mmol) was added. The mixture was stirred at room temperature for 30 hours. LC-MS monitored the reaction completion. The mixture was extracted twice with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by column chromatography to yield the target compound 106-3 (1.11 g). ESI-MS m / z: 370.1 [M+H] + .

[0862] Step 4: Synthesis of compound 106-4

[0863] To a 50 mL single-necked flask, compound 106-3 (1.11 g, 3.00 mmol), dimethyl sulfoxide (10.00 mL), tetrahydrofuran (2.00 mL), and 3-((tert-butyldimethylsilyl)oxy)propyl-4-methylbenzenesulfonate (3.61 g, 10.49 mmol) were added sequentially. Sodium tert-butoxide (0.72 g, 7.49 mmol) was added portionwise at 10°C and stirred at room temperature for 1 hour. LC-MS monitored the completion of the reaction, and the reaction mixture was quenched by adding saturated aqueous ammonium chloride. The mixture was extracted twice with ethyl acetate, washed three times with saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound 106-4 (1.44 g). ESI-MS m / z: 542.2 [M+H] + .

[0864] Step 5: Synthesis of Compound 106-5

[0865] To a 50 mL single-necked flask, compound 106-4 (1.44 g, 2.65 mmol) and tetrahydrofuran (15.00 mL) were added sequentially. Tetrabutylammonium fluoride (5.31 mL, 1.00 mol / L, 5.31 mmol) was added dropwise at 0°C. The reaction mixture was heated to 50°C and stirred for 1 hour. LC-MS monitored the reaction completion, and the mixture was concentrated under reduced pressure and purified by column chromatography to yield the target compound 106-5 (1.25 g). ESI-MS m / z: 428.1 [M+H] + .

[0866] Step 6: Synthesis of Compound 106-6

[0867] To a 50 mL single-necked flask, compound 106-5 (1.25 g, 2.92 mmol), dichloromethane (13.00 mL), and 4-dimethylaminopyridine (0.71 g, 5.84 mmol) were added in sequence. Then, p-toluenesulfonyl chloride (1.11 g, 5.84 mmol) was added portionwise and stirred at room temperature for 6 hours. After completion of the reaction as monitored by LC-MS, the mixture was concentrated under reduced pressure and purified by column chromatography to yield the target compound 106-6 (0.16 g). ESI-MS m / z: 582.2 [M+H] + .

[0868] Step 7: Synthesis of Compound 106-7

[0869] To a 10 mL single-necked flask, compound 106-6 (100.43 mg, 0.17 mmol), M2 (100.00 mg, 0.14 mmol), toluene (1.50 mL), 1,4-dioxane (0.50 mL), water (0.50 mL), potassium carbonate (49.66 mg, 0.36 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (11.76 mg, 0.01 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the temperature was raised to 65°C under nitrogen protection, followed by stirring for 3 hours. LC-MS monitored the reaction completion, and the mixture was extracted twice with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography to yield the target compound 106-7 (88.00 mg). ESI-MS m / z: 535.31 / 2 [M+2H] + .

[0870] Step 8: Synthesis of Compound 106-8

[0871] To a 10 mL single-necked flask, compound 106-7 (88.00 mg, 0.08 mmol), N,N-dimethylformamide (5.00 mL), and cesium carbonate (80.44 mg, 0.25 mmol) were added sequentially. The temperature was raised to 80°C and stirred for 2 hours. LC-MS monitored the reaction completion. The reaction solution was diluted with ethyl acetate, washed three times with water and then brine, concentrated under reduced pressure, and purified by column chromatography to yield the target compound 106-8 (67.00 mg). ESI-MS m / z: 897.5 [M+H] + .

[0872] Step 9: Synthesis of compound 106-9

[0873] To a 10 mL single-necked flask, compound 106-8 (67.00 mg, 0.07 mmol), dichloromethane (2.00 mL), and hydrochloric acid (4 M in dioxane) (1.50 mL) were added sequentially and stirred at room temperature for 1 hour. LC-MS monitored the reaction completion, and the mixture was concentrated under reduced pressure. The crude product was used directly in the next step to obtain crude compound 106-9 (59.00 mg). ESI-MS m / z: 797.4 [M+H] + .

[0874] Step 10: Synthesis of Compound 106

[0875] To a 10 mL single-necked flask, (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (15.11 mg, 0.11 mmol) and N,N-dimethylformamide (1.00 mL) were added sequentially. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (42.21 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.74 mmol) were added at 0°C and stirred for 10 minutes. Finally, compound 106-9 (59.00 mg, 0.07 mmol) was added and stirred at 0°C for 10 minutes. The reaction was monitored for completion by LC-MS, and the reaction solution was directly purified by pre-HPLC to obtain the target compound 106 (35.20 mg). ESI-MS m / z: 915.4 [M+H] + .

[0876] 1 H NMR(500MHz,Chloroform-d)δ8.58(d,J=1.6Hz,1H),8.42(d,J=2.9Hz,1H),7.58( dd,J=8.6,1.7Hz,1H),7.33–7.28(m,2H),7.09(d,J=3.0Hz,1H),6.72(d,J=9.5Hz ,1H),5.96–5.70(m,2H),4.59(d,J=12.3Hz,1H),4.36(td,J=12.1,3.3Hz,1H),4. 22(dq,J=12.9,6.1Hz,2H),4.07–3.95(m,2H),3.83-3.75(m,8H),3.47(d,J=14.9 Hz,1H),3.31(td,J=12.4,3.2Hz,1H),3.22–3.16(m,1H),3.16–3.06(m,4H),2.88 -2.81(m,2H),2.73–2.66(m,4H),2.42(d,J=14.4Hz,1H),2.36–2.20(m,2H),2.04 –1.99(m,2H),1.85-1.81(m,2H),1.68-1.59(m,1H),1.51(d,J=6.4Hz,2H),1.35( t,J=7.3Hz,6H),1.32–1.29(m,1H),1.17–1.12(m,1H),0.97(s,3H),0.41(s,3H).

[0877] Example 108 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-12-(4-(1-methylazetidin-3-yl)piperazin-1-yl)-5,7-dioxo-18,19,61,62,63,64,65,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazine-cycloundecane-4-yl)cyclopropane-1-carboxamide

[0878] Step 1: Synthesis of compound 108-1

[0879] Under a nitrogen atmosphere, 1-benzyloxycarbonylazetidin-3-one (50.5 mg) and ZnCl2 (0.25 mL, 1 M in THF) were added sequentially to a solution of M4 (100.0 mg) in MeOH (4.0 mL), and the system was stirred in a 40°C oil bath for 1 hour. Sodium cyanoborohydride (38.6 mg) was then added, and the reaction was stirred in a 40°C oil bath for 2 hours. 1-benzyloxycarbonylazetidin-3-one (50.5 mg) and ZnCl2 (0.25 mL, 1 M in THF) were further added, and the system was stirred in a 40°C oil bath for 1 hour. Sodium cyanoborohydride (38.6 mg) was then added, and the reaction was stirred in a 40°C oil bath for 2 hours. After the reaction was completed as monitored by LC-MS, the reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM. The aqueous phase was extracted twice with DCM and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a crude product of compound 108-1 (100 mg). ESI-MS m / z: 502.0, [M+2H] 2+ / 2.

[0880] Step 2: Synthesis of compound 108-2

[0881] To a solution of compound 108-1 (100 mg) in MeOH (4.0 mL) was added Pd(OH)2 / C (50.0 mg, 10% Pd). After multiple hydrogen substitutions, the reaction was stirred at room temperature for 3 hours. After completion of the reaction as monitored by LC-MS, the mixture was filtered, the catalyst removed, and the filtrate concentrated to afford crude compound 108-2 (off-white solid powder, 50 mg), which was used directly in the next reaction. ESI-MS m / z: 435.0, [M+2H] 2+ / 2.

[0882] Step 3: Synthesis of compound 108-3

[0883] To a solution of compound 108-2 (50.0 mg) in MeOH (2.0 mL) was added HOAc (9.9 μL). The system was stirred at room temperature for 10 minutes, followed by the addition of 37% aqueous formaldehyde (11 μL) and sodium cyanoborohydride (4.3 mg). The reaction was stirred at room temperature for 20 minutes. After completion of the reaction as monitored by LC-MS, saturated sodium bicarbonate solution was added to quench the reaction. The fuel was extracted with DCM, and the aqueous phase was extracted twice more with DCM. The combined organic phases were dried over anhydrous sodium sulfate and further concentrated to afford crude 108-3 (40 mg), which was used directly in the next reaction. ESI-MS m / z: 442.0, [M+2H] 2+ / 2.

[0884] Step 4: Synthesis of compound 108-4

[0885] To a solution of compound 108-3 (40 mg) in DCM (2.0 mL) was added trifluoroacetic acid (1.0 mL), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated to dryness. Dichloromethane and saturated carbonic acid solution were then added for extraction and separation, and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate, and further concentrated to give a crude product of compound 108-4 (40 mg, hydrochloride), which was used directly in the next reaction. ESI-MS m / z: 782.5, [M+H] + .

[0886] Step 5: Synthesis of Compound 108

[0887] To a solution of (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (13.9 mg) in acetonitrile (1.0 mL) was added HATU (38.9 mg) and DIEA (42 μL) at room temperature. The solution was stirred at room temperature for 10 minutes. Compound 108-4 and DIEA (42 μL) in acetonitrile (1.0 mL) were then added, and the mixture was stirred at room temperature for another 30 minutes. After the reaction, the mixture was concentrated and the concentrate separated by preparative chromatography (acetonitrile:water (containing 0.05% trifluoroacetic acid) = 3:2). An appropriate amount of sodium bicarbonate solution was added to the resulting solution to neutralize the trifluoroacetic acid. The solution was further concentrated to remove the acetonitrile, and then extracted with dichloromethane. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and further concentrated to yield the target compound 108 (13.0 mg). ESI-MS m / z: 900.5 [M+H] + .

[0888] 1H NMR (500MHz, CDCl3) δ8.58(d,J=1.3Hz,1H),8.42(d,J=2.9Hz,1H),7.58(dd,J=8 .6,1.5Hz,1H),7.31(d,J=8.5Hz,1H),7.29(s,1H),7.08(d,J=2.9Hz,1H),6.64( d,J=9.5Hz,1H),5.90(t,J=8.8Hz,1H),5.86(td,1H),4.60(d,J=11.9Hz,1H),4. 36(td,J=12.1,3.2Hz,1H),4.27–4.16(m,2H),4.00(m,2H),3.82(s,2H),3.81–3 .75(m,1H),3.72–3.63(m,2H),3.47(d,J=14.8Hz,1H),3.35–3.23(m,5H),3.22– 3.02(m,5H),2.73–2.65(m,1H),2.50(d,J=4.3Hz,4H),2.45(s,3H),2.41(d,J=1 4.4Hz,1H),2.37–2.18(m,3H),1.85–1.80(m,2H),1.51(d,J=6.5Hz,3H),1.35–1 .29(m,3H),1.18–1.12(m,1H),0.96(s,3H),0.88(t,J=6.8Hz,1H),0.40(s,3H).

[0889] Example 109 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-15,10,10-trimethyl-5,7-dioxo-12-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-18,19,61,62,63,64,66-octahydro-15H,17H-8-oxa-1(13,15)-pyrido[3',2':7,8][1,5]oxazepa[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinonecycloundecane-4-yl)cyclopropane-1-carboxamide

[0890] Step 1: Synthesis of Compound 109-1

[0891] To a 25 mL single-necked flask, tetrahydropyrone (9 μL, 0.10 mmol), tetrahydrofuran (5.00 mL), and zinc chloride (0.15 mL, 1 mol / L in THF, 0.15 mmol) were added in sequence and stirred at 50°C for 1 h. M4 (80 mg, 0.10 mmol) was added and stirred at 50°C for 1 h. Sodium cyanoborohydride (13.6 mg, 0.22 mmol) was added and the reaction was stirred at 50°C. After completion of the reaction as monitored by LC-MS, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, and concentrated to give crude compound 109-1 (white solid, 52.0 mg). ESI-MS m / z: 897.48 [M+H] + .

[0892] Step 2: Synthesis of compound 109-2

[0893] To a 10 mL thumb flask, compound 109-1 (52.0 mg, 0.06 mmol), DCM (1.00 mL), and HCl (4 M in dioxane) (1.00 mL) were added sequentially and the reaction was stirred at room temperature. After completion of the reaction as monitored by LC-MS, the reaction solution was neutralized with saturated sodium bicarbonate solution, extracted with DCM, washed with saturated brine, and concentrated to give crude compound 109-2 (yellow solid, 50.0 mg). ESI-MS m / z: 796.97 [M+H] + .

[0894] Step 3: Synthesis of compound 109

[0895] To a 10 mL single-necked flask, (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (7 μL, 0.08 mmol), HATU (71.5 mg, 0.19 mmol), and DIEA (42 μL, 0.25 mmol) were added sequentially and stirred at room temperature for 10 minutes. The mixture was cooled in an ice-water bath, followed by the addition of a solution of 109-2 (50.0 mg, 0.06 mmol) in acetonitrile. Following completion of the reaction, as monitored by LC-MS, the reaction solution was directly purified by alkaline Prep-HPLC, and the eluate was lyophilized to yield the target compound 109 (6.6 mg). ESI-MS m / z: 915.10, [M+H]+.

[0896] 1H NMR (500MHz, CDCl3) δ8.58(s,1H),8.40(d,J=1.9Hz,1H),7.57(d,J=8.5Hz,1H),7.34–7.28(m,2H),7.09(d,J=2.1Hz ,1H),6.85(d,J=9.4Hz,1H),5.96–5.67(m,2H),4.59(d,J=12.5Hz,1H),4.41–4.30(m,1H),4.28–4.16(m,2H),4.11–4 .03(m,3H),4.03–3.95(m,1H),3.82(s,3H),3.50–3.28(m,8H),3.23–3.12(m,3H),2.76–2.57(m,2H),2.41(d,J=14. 4Hz,1H),2.36–2.20(m,2H),2.11–1.77(m,10H),1.74–1.57(m,4H),1.51(d,J=6.2Hz,3H),0.97(s,3H),0.40(s,3H).

[0897] Example 110 Synthesis of Compound (1S,2S)-2-(difluoromethyl)-N-((15S,63S,4S,Z)-12-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-15,10,10-trimethyl-5,7-dioxo-18,19,61,6,62,63,64,65,66,66-octahydro-15H,17H-8-oxazine-1(13,15)-pyrido[3',2':7,8][1,5]oxazino[5,6-a]indole-2(4,2)-thiazole-6(1,3)-pyridazinocycloundecane-4-yl)cyclopropane 1-carboxamide

[0898] Step 1: Synthesis of compound 110-1

[0899] The substrate, 3-bromo-5-fluoro-pyridine-2-carbonitrile (1.3 g), was added to a 100 mL single-necked flask. THF (20 mL) was then added, followed by DIEA (2.67 mL) and (S)-octahydropyrazino[2,1-c][1,4]oxazine (0.92 g). The mixture was reacted at room temperature for 0.5 h. After completion of the reaction, saturated NaCl (25 mL) was added, extracted with EA, and purified by column chromatography to yield compound 110-1 (1.58 g). ESI-MS m / z: 323.24 [M+H] + .

[0900] Step 2: Synthesis of compound 110-2

[0901] Compound 110-1 (1.58 g) and anhydrous THF (16 mL) were added to a 100 mL three-necked flask. The temperature was lowered to -20°C under N2 protection, and MeMgBr (3 M in THF, 4.89 mL) was slowly added dropwise. The mixture was allowed to warm to room temperature and allowed to react for 2 h. After the reaction, HCl (1N, 30 mL) was added to the reaction solution, a...

Claims

1. A compound represented by formula (I), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof: in, Indicates whether the bonds in the ring are single or double bonds; Each X1 is the same or different and is independently selected from CR 10 , CR 10 R 10 , N, NR 10 , O, S or S(O) 1-2 ; X2 is selected from O, S, S(O) 1-2 , N or NR 10 ; X3 is selected from N or CR 10 ; X4 Selected from CR 10 or N; X5 Selected from CR 11 or N; X6 from CR 12 or N; X7 from CR 13 or N; X8 from CR 14 or N; X9 from CR 15 or N; X 10 Selected from CR 16 or N; X 11 Selected from C(R 17 )2. O or NR 17 ; L is selected from Ring A is selected from C 5-14 Cycloalkyl, 5-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl; wherein the C 5-14 Cycloalkyl, 5-14 membered heterocyclic group, C 6-18 The aryl or 5-18 membered heteroaryl group is optionally further substituted with one or more R a Substitution; or two R on the same atom a Form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; R1 is selected from H, hydroxyl, C 1-6 Hydroxyalkyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-3 Alkylene-N(R c 2. -C 0-3 Alkylene-C 2-6 Alkenyl, -C 0-3 Alkylene-C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group, -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-5-18 membered heteroaryl; wherein the hydroxyl group, C 1-6 Hydroxyalkyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-3 Alkylene-N(R c 2. -C 0-3 Alkylene-C 2-6 Alkenyl, -C 0-3 Alkylene-C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group, -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-5-18 membered heteroaryl is optionally further substituted with one or more R a Substitution, or two R on the same atom a Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; R2 is selected from H, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R3 is selected from H, halogen, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy or C 1-6 Hydroxyalkyl; Alternatively, R2 and R3 together with the atoms to which they are attached form a carbonyl group, a C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b Substitution; or two R on the same atom b Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; R4 is selected from H, hydroxyl, C 1-6 Hydroxyalkyl, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-N(R c 2. -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group, -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-5-18 membered heteroaryl; wherein the hydroxyl group, C 1-6 Hydroxyalkyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-N(R c 2. -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group, -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-5-18 membered heteroaryl is optionally further substituted with one or more R a Substitution; or two R on the same atom a Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; R 4a Selected from H, halogen, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy or C 1-6 Hydroxyalkyl; wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy or C 1-6 The hydroxyalkyl group is optionally further substituted with one or more R a Substitution; or two R on the same atom a Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; Or, two R 4a Together with the atoms to which they are attached, they form a carbonyl group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; R5 is selected from H, halogen, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy or C 1-6 Hydroxyalkyl; R6 is selected from H, halogen, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 Aryl; wherein the hydroxyl group, C 1-3 Alkoxy, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 The aryl group is optionally further substituted with one or more R a replace; Alternatively, R5 and R6 together with the atoms to which they are attached form a carbonyl group, a C 3-8 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace; R 5a and R 6a are independently H, halogen, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy or C 1-6 Hydroxyalkyl; Or, R 5a and R 6a Together with the atoms to which they are attached, they form a carbonyl group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; R7 is selected from the group consisting of absent, H, halogen, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-14 membered heterocyclyl or 5-10 membered heteroaryl; R8 is selected from the group consisting of absent, H, halogen, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-14 Cycloalkyl-O-, 3-14 membered heterocyclyl-O-, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy or C 1-6 Hydroxyalkyl; Alternatively, R7 and R8 together with the atoms to which they are attached form a C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; Alternatively, two R8 together with the atoms to which they are attached form a C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; M is selected from C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 1-6 heteroalkylene, -C(O)O-CH(R9)-, -C(O)NH-CH(R9)-, or 5-8 membered heteroarylene; R9 is selected from hydrogen or methyl; When M is -C(O)O-CH(R9)- or -C(O)NH-CH(R9)-, CH(R9) therein is bound to -C(R5R6)-; or R6 and R9 together with the atoms to which they are attached form C 3-8 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R b replace; R 10 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group or C 1-6 Haloalkyl; Or, R 10 Together with R8 and the atom to which it is attached, form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; Or, two R 10 Together with the atoms to which they are attached, they form a carbonyl group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 1-6 Haloalkyl; Or, two R 17 Together with the atoms to which they are attached, they form a carbonyl group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; Or, R 13 and R 4a Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; Or, R 16 and R 5a Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; Or, R 17 and R 4a Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more R b replace; Or, R 14 , R 15 , R 16 , R4 and R 4a Any two of them together with the atoms they are connected to form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group is optionally further substituted with one or more R b replace; R a are independently selected from the group consisting of absent, H, hydroxy, oxo, amino, imino, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-3 Alkylene-OR b , -C 0-3 Alkylene-SR b , -C 0-3 Alkylene-N(R b 2. -C 0-3 Alkylene-S(O) 1-2 R b , -C 0-3 Alkylene-S(R b )5, =C(R b 2. C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); wherein the amino, imino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace; Each R b are independently H, halogen, hydroxy, oxo, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 1-6 Haloalkoxy or C 1-6 haloalkyl; wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 1-6 Haloalkoxy or C 1-6 The haloalkyl group is optionally further substituted with one or more H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, amino, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2 substituted; Each R c Each independently selected from H, hydroxyl, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group or C 1-6 Haloalkyl; r is 1-3; preferably 1, 2 or 3; s is 1-3, preferably 1, 2 or 3; t is 0-4, preferably 0, 1, 2, 3 or 4, more preferably 0-3.

2. The compound according to claim 1, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: Formula (I) is selected from formula (I-1): Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a , R 5a , R 6a ,X1,X2,X3,X4,X5,X6,X7,X8,X9,X 10 , X 11 , L, M, ring A, r, s, t are as defined in claim 1.

3. The compound according to claim 1 or 2, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: Formula (I) is selected from formula (II-1) or formula (II-2): Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 10 , R 4a , R 5a , R 6a ,X4,X5,X6,X7,X8,X9,X 10 , X 11 , L, ring A, s, and t are as defined in any one of claims 1-2.

4. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: Formula (I) is selected from formula (II-1a) or formula (II-2a): Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a , R 5a , R 6a ,X4,X5,X6,X7,X8,X9,X 10 , X 11 , L, ring A, s, and t are as defined in any one of claims 1 to 3.

5. The compound according to any one of claims 1 to 4, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: Formula (I) is selected from formula (IIIa-IIIc) or (IIIa'-IIIc'): Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a , R 5a , R 6a ,X4,X5,X6,X7,X8,X9,X 10 , X 11 , Ring A, s, t are as defined in any one of claims 1-4.

6. The compound according to any one of claims 1 to 5, or its tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: The ring A is selected from C 6-18 Aryl or 5-18 membered heteroaryl; wherein the C 6-18 The aryl or 5-18 membered heteroaryl group is optionally further substituted with one or more R a Substitution, the R a Selected from H, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally further substituted with one or more R b Substitution, the R b Selected from H, halogen or C 1-6 alkyl.

7. The compound according to claim 6, or its tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: The C 6-18 The aryl group is selected from a benzene ring.

8. The compound according to claim 6, or its tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: The 5-18 membered heteroaryl group is selected from a thiazole ring or an oxazole ring.

9. The compound according to any one of claims 1 to 8, or its tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: The X4 is selected from N.

10. The compound according to any one of claims 1 to 9, or its tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: The X5 is selected from CH or N.

11. The compound according to any one of claims 1 to 10, or its tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: The X6 is selected from CH or N.

12. The compound according to any one of claims 1 to 11, or its tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: The X7 is selected from CH or N.

13. The compound according to any one of claims 1 to 12, or its tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: The X8 is selected from CH or N.

14. The compound according to any one of claims 1 to 13, or its tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: The X9 is selected from CH or N.

15. The compound according to any one of claims 1 to 14, or its tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: The X 10 Selected from CH.

16. The compound according to any one of claims 1 to 15, or its tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: The X 11 Selected from O.

17. The compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: Formula (I) is selected from Formula (IVa-IVc) or Formula (IVa'-IVc'): Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a , R 5a , R 6a , Ring A, s, t are as defined in any one of claims 1-16.

18. The compound according to claim 17, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: Formula (I) is selected from formula (IVa-1 to IVc-1) or (IVa-1' to IVc-1'): Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a , R 5a , R 6a , ring A, and t are as defined in claim 17.

19. The compound according to any one of claims 1-6, 8-15, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: Formula (I) is selected from Formula (Va-Vc) or Formula (Va'-Vc'): Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a , R 5a , R 6a , s, t as defined in any one of claims 1-6, 8-15.

20. The compound according to claim 19, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: Formula (I) is selected from formula (Va-1 to Vc-1) or formula (Va-1' to Vc-1'): Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 4a , R 5a , R 6a , tAs defined in claim 19.

21. The compound according to claim 1, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, characterized in that: Formula (I) is selected from the structure shown in formula (VI) or formula (VI'): Wherein, R1 and R4 are as defined in claim 1.

22. The compound according to any one of claims 1 to 21, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: The R1 is selected from C 1-6 Alkyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group, -C 0-3 Alkylene-N(R c 2. -C 0-3 Alkylene-C 2-6 Alkenyl or -C 0-3 Alkylene-C 2-6 Alkynyl; wherein the C 1-6 Alkyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group, -C 0-3 Alkylene-N(R c 2. -C 0-3 Alkylene-C 2-6 Alkenyl or -C 0-3 Alkylene-C 2-6 The alkynyl group is optionally further substituted with one or more R a Replace, each R c Each independently selected from H, hydroxyl, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 haloalkyl; said R a Selected from halogen, C 1-6 Alkyl, =C(R b 2. C 1-6 Haloalkyl, C 1-6 Alkoxy or -C 0-3 Alkylene-N(R b ) 2, said R b Selected from H, halogen or C 1-6 Alkyl; or two R on the same atom a Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group.

23. The compound according to any one of claims 1 to 22, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: The R1 is selected from 24. The compound according to any one of claims 1 to 23, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: The R2 is selected from H.

25. The compound according to any one of claims 1 to 24, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: The R3 is selected from H.

26. The compound according to any one of claims 1 to 25, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: The R4 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-3-14 membered heterocyclic group or -C 0-3 Alkylene-N(R c )2; wherein, the C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-3-14 membered heterocyclic group or -C 0-3 Alkylene-N(R c )2 optionally further represented by one or more R a Substitution, the R a are independently selected from the group consisting of absent, H, hydroxy, oxo, amino, imino, cyano, halogen, C 1-6 Alkyl, -C 0-3 Alkylene-N(R b 2. C 1-6 Haloalkyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-3-14 membered heterocyclic group; the amino, imino, C 1-6 Alkyl, -C 0-3 Alkylene-, C 1-6 Haloalkyl, -C 0-3 The alkylene-3-14 membered heterocyclic group is optionally further substituted by one or more R b Replace, each R b are independently selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 Halogenated alkyl.

27. The compound according to any one of claims 1 to 26, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: The R4 is selected from 28. The compound according to any one of claims 1 to 27, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: The R 4a Select from H or C 1-6 alkyl.

29. The compound according to any one of claims 1 to 28, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: R5 is selected from H or C 1-3 alkyl.

30. The compound according to any one of claims 1 to 29, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: R6 is selected from H or C 1-3 alkyl.

31. The compound according to any one of claims 1 to 30, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: The R 5a Select from H or C 1-3 alkyl.

32. The compound according to any one of claims 1 to 31, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: The R 6a Select from H or C 1-3 alkyl.

33. The compound according to any one of claims 1 to 32, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: R7 is selected from H or C 1-3 Alkyl, preferably H.

34. The compound according to any one of claims 1 to 33, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: R8 is selected from H or C 1-3 Alkyl, preferably H.

35. The compound according to any one of claims 1-18, 22-34, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that: The ring A is selected from Wherein, these groups are optionally further substituted by one or more Ra; or two Ra on the same atom form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with one or more Rb.

36. The compound according to any one of claims 1 to 35, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) is selected from the following compounds:

37. A pharmaceutical composition, characterized in that The pharmaceutical composition contains a therapeutically effective amount of the compound according to any one of claims 1 to 36, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof.

38. Use of the compound according to any one of claims 1 to 36, or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 37 in the preparation of a medicament for treating a disease mediated by KRAS.

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