Pan-RAS inhibitor compound

Abstract

Provided are a compound represented by formula (I), a pharmaceutical composition comprising the compound, and use of the compound represented by formula (A) in the prevention and / or treatment of cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Description

A pan-RAS inhibitor compound TECHNICAL FIELD

[0001] The present application relates to a compound, in particular to a highly active pan-RAS inhibitor and its use. BACKGROUND

[0002] RAS is one of the most frequently mutated genes in human tumors, with mutations occurring in about 30% of tumor patients, of which KRAS accounts for about 85% of RAS mutations. Mutations of KRAS exist in 88% of pancreatic cancer, 50% of colorectal adenocarcinoma, and 32% of lung adenocarcinoma, and the development of KRAS targeting inhibitors has great clinical significance and value.

[0003] KRAS is a membrane-bound protein with GTPase activity, which cycles between the GDP-bound inactive conformation and the GTP-bound active conformation through nucleotide exchange, performing the function of a "molecular switch". KRAS in the GTP-bound state can activate multiple signaling pathways including RAF-MEK-ERK, PI3K-AKT, and regulate cell growth, proliferation, differentiation, and apoptosis, and other life processes.

[0004] KRAS mutations (such as G12C, G12D, G12V, G13D, etc.) affect GTPase activating proteins (GAPs) mediated GTP hydrolysis, increase KRAS in the GTP-bound active state, and over-activate downstream signaling pathways, ultimately leading to tumor occurrence and development. However, due to the lack of a corresponding hydrophobic pocket suitable for drug binding in the KRAS protein, and its affinity to GTP and GDP is at the picomolar level (~ 20 pM), it is very difficult to develop inhibitors that compete for KRAS, and in the past few decades, KRAS has been considered an undruggable target.

[0005] In May 2021, AMG510 was approved by FDA for marketing, used for the treatment of locally advanced or metastatic non-small cell lung cancer carrying KRAS G12C G12C mutation, breaking the history of KRAS "undruggable". However, G12C mutation only accounts for a small part of KRAS mutations, and there is currently a lack of satisfactory and effective inhibitor compounds for KRAS mutations at other sites and other RAS types (NRAS, HRAS), and a large number of clinical needs have not been met, therefore, the development of effective pan-RAS inhibitor compounds is needed in the prior art. SUMMARY

[0006] The present application provides a high-activity pan-RAS inhibitor. Such structure is different from the existing KRAS inhibitors which act by covalent binding, but acts by mediating the formation of a ternary complex of a ubiquitous chaperone protein (such as Cyclophilin A) and RAS protein in cells. The formation of the ternary complex can block the binding of RAS to its downstream effector molecules (such as RAF) by steric hindrance, inhibit the activation of MAPK and PI3K-AKT signaling pathways, and thus inhibit the occurrence and development of tumors, and play a role in treating tumors and other diseases. G12C The present application provides a high-activity pan-RAS inhibitor. Such structure is different from the existing KRAS inhibitors which act by covalent binding, but acts by mediating the formation of a ternary complex of a ubiquitous chaperone protein (such as Cyclophilin A) and RAS protein in cells. The formation of the ternary complex can block the binding of RAS to its downstream effector molecules (such as RAF) by steric hindrance, inhibit the activation of MAPK and PI3K-AKT signaling pathways, and thus inhibit the occurrence and development of tumors, and play a role in treating tumors and other diseases.

[0007] In one aspect, the present application provides a compound having the structure of formula (A), or an isotopic derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0008] wherein:

[0009] Cya represents or which is optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3 alkyl;

[0010] A represents optionally substituted 4- to 8-membered heterocycloalkylene, optionally substituted phenylene, or optionally substituted 5- to 6-membered heteroarylene;

[0011] B represents a single bond, optionally substituted 4- to 12-membered heterocycloalkylene, optionally substituted 5- to 6-membered heteroarylene, or optionally substituted phenylene;

[0012] X represents O, NR6, or CR7R7’;

[0013] W represents halogen, optionally substituted amino, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, or optionally substituted phenyl;

[0014] L represents a single bond or -(C1-C6)alkylene-, any methylene of which can be replaced with carbonyl, NR a , O, or S; each methylene of the -(C1-C6)alkylene- is independently substituted with 0, 1, 2, 3, or 4 C1-C3 alkyl, and two substituents of the same C atom can form a 3- to 8-membered ring with the C atom;

[0015] R2 represents a C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), which may optionally be substituted with 0, 1, or 2 substituents selected from the following: -OR a -SR a Or -NR a R a ';

[0016] R4 represents hydrogen, -(C0-C6 alkylene) OR a -(C0-C6 alkylene)SR a Or -(C0-C6 alkylene)NR a R a ', 3-8 membered cycloalkyl or 4-12 membered heterocycloalkyl, wherein each of the C0-C6 alkylene, 3-8 membered cycloalkyl or 4-12 membered heterocycloalkyl can be independently selected from 0, 1, 2, 3 or 4 alkyl groups selected from halogen, oxo, -OR a -SR a -NR a R a Substitution with ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-C3-C8 cycloalkyl or -(C0-C3 alkylene)-4-8 heterocyclic alkyl groups;

[0017] R5 represents -OR a -NR a R a 'Or -Cy1-(R8)' m ;

[0018] Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocyclic alkyl, wherein the ring can be spirocyclic, bridged ring, or fused ring;

[0019] R6 represents -OR a -NR a R a ';

[0020] R7 and R7' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 membered heterocyclic alkyl); R7 and R7' can form a 4-8 membered ring with the C atom they are connected to, and the 4-8 membered ring optionally contains 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0021] R8 represents hydrogen, halogen, oxometalate, and =NR independently. a -OR a -SR a, -NR a R a , cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R a , C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl groups can be independently substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl;

[0022] Cy0represents a 5-12 membered aromatic or heteroaromatic ring;

[0023] R A each independently is selected from the group consisting of H, halogen, CN, C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C0-C6alkylene)-ORa, -(C0-C6alkylene)-SRa, or -(C0-C6alkylene)-NRaRa’, and optionally, two adjacent or non-adjacent R A on Cy0together with the ring atoms of Cy0may form a 6-10 membered ring, which can be further substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C1-C3alkyl, -ORa, -SRa, or -NRaRa’;

[0024] L0is selected from the group consisting of a single bond, -(C1-C6)alkylene, -(C2-C6)alkenylene, any methylene of said -(C1-C6)alkylene or -(C2-C6)alkenylene can be replaced with a carbonyl, NRa, O, or S, and said -(C1-C6)alkylene or -(C2-C6)alkenylene is optionally substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, C1-C3alkyl;

[0025] R CH, halogen, C1-C6alkyl, -(C0-C6alkylene)-ORa, -(C0-C6alkylene)-SRa, or -(C0-C6alkylene)-NRaRa';

[0026] R D H, C1-C6alkyl, -(C1-C6alkylene)-ORa, -(C1-C6alkylene)-SRa, or -(C1-C6alkylene)-NRaRa';

[0027] R E , R F each independently H, C1-C6alkyl, halogen, -(C0-C6alkylene)-ORa, -(C0-C6alkylene)-SRa, or -(C0-C6alkylene)-NRaRa'; and optionally, R E , R F may form, with the C atom to which they are attached, a 3-6 membered ring which can additionally contain 0, 1, or 2 heteroatoms selected from N, O, S;

[0028] Z represents N or CR3, Z' represents N or CR3', wherein R3, R3' each independently represents hydrogen, halogen, C1-C6alkyl, -(C0-C6alkylene)(C3-C8)cycloalkyl, or -(C0-C6alkylene)CN;

[0029] wherein m, q each independently represents 0, 1, 2, or 3;

[0030] R a , R a each independently represents hydrogen, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; when R a , R a are attached to the same N atom, said R a and R a together with the N atom to which they are attached can form a 4-8 membered ring which optionally can contain 1, 2, or 3 heteroatoms selected from N, O, or S;

[0031] each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0032] In some embodiments, the compound has the structure according to formula (A'):

[0033] wherein A, X, W, B, L, R A , R C , R D , RE R F Z, Z', R2, R4, R5, Cya, Cy0, L0, q are defined as in formula (A).

[0034] In some embodiments, R C R D is H.

[0035] In some embodiments, Z represents CR3and Z' represents CR3'.

[0036] In some embodiments, L0is ethenylene, -(Ci-C3)alkylene, or a single bond; more preferably, L0is a single bond.

[0037] In some embodiments, R E R F are each independently selected from H, Ci-C6alkyl, and optionally, R E R F may form, together with the C atom to which they are attached, a 3-6 membered ring, which can additionally contain 0, 1, or 2 heteroatoms selected from N, O, S; more preferably, R E R F are each independently selected from Ci-C3alkyl.

[0038] In some embodiments, the compound has the structure of formula (B):

[0039] wherein:

[0040] represents a single or double bond;

[0041] X1, X2each independently represents C or N;

[0042] Y1, Y2, Y3each independently represents no bond, a single bond, CR A , N, NR1', O, S, wherein R1'represents Ci-C6alkyl, -(Co-C6alkylene)-(C3-C8cycloalkyl), -(Co-C6alkylene)-(4-8 membered heterocycloalkyl), -(Ci-C6alkylene)-ORa, -(Ci-C6alkylene)-SRa, or -(Ci-C6alkylene)-NRaRa'; wherein when Y3is CR A , optionally R1may form, together with the R A substituent of Y3and the N, X1and C atoms to which they are attached, a 6-10 membered ring, which can be further substituted by 0, 1, 2, 3, or 4 substituents selected from halogen, Ci-C3alkyl, -ORa, -SRa, or -NRaRa';

[0043] R1represents C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-ORa, -(C1-C6alkylene)-SRa, or -(C1-C6alkylene)-NRaRa’;

[0044] t is selected from 0, 1, 2, or 3;

[0045] A, X, W, B, L, R C , R D , R E , R F , Z, Z’, R2, R4, R5, Cya, t are as defined in any preceding claim.

[0046] In some embodiments, the compound has the structure of formula (B’):

[0047] wherein, A, X, W, B, L, R C , R D , R E , R F , Z, Z’, R2, R4, R5, Cya, t are as defined in formula (B).

[0048] In some embodiments, is selected from wherein Q represents CR A or N, T represents NR1’, O or S, and optionally, when Y3is CR A R1may be taken together with the R A substituent on Y3together with the ring atoms on Cy0to form a 6-10 membered ring, which can be further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, C1-C3alkyl, -ORa, -SRa, or -NRaRa’.

[0049] In some embodiments, represents and optionally, R1may be taken together with the R A substituent on Y3together with the N, X1and C atoms to which it is attached to form a 6-10 membered ring, which can be further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, C1-C3alkyl, -OH.

[0050] In some embodiments, represents

[0051] In some embodiments, R A each independently selected from H, halogen, CN, C1-C3 alkyl; more preferably, R A each independently represents H or F.

[0052] In one aspect, the present application provides a compound having the structure of Formula (I), or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof:

[0053] wherein:

[0054] Cya represents or optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3 alkyl; A represents optionally substituted 4- to 6-membered heterocycloalkylene, optionally substituted phenylene, or optionally substituted 5- to 6-membered heteroarylene;

[0055] B represents a single bond, optionally substituted 4- to 12-membered heterocycloalkylene, optionally substituted 5- to 6-membered heteroarylene, or optionally substituted phenylene;

[0056] X represents O, NR6, or CR7R7’;

[0057] W represents halogen, optionally substituted amino, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkyl, optionally substituted 4- to 12-membered heterocycloalkyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, or optionally substituted phenyl;

[0058] L represents a single bond or -(C1-C6)alkylene-, any methylene of which can be replaced with carbonyl, NR a , O, or S; each methylene of said -(C1-C6)alkylene is independently substituted with 0, 1, 2, 3, or 4 C1-C3 alkyl, and two substituents of the same C atom can form a 3- to 8-membered ring with said C atom;

[0059] R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4- to 8-membered heterocycloalkyl), -(C1-C6 alkylene)-OR a , -(C1-C6 alkylene)-SR aor -(C1-C6alkylene)-NR a R a ’;

[0060] R2represents C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), or -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), which is optionally substituted with 0, 1, or 2 substituents selected from -OR a , -SR a , or -NR a R a ’;

[0061] R3, R3’ each independently represents hydrogen, halogen, C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), or -(C0-C6alkylene)-CN;

[0062] R4represents hydrogen, -OR a , -SR a , or -NR a R a ’;

[0063] R5represents -OR a , -NR a R a ’ or -Cy1-(R8) m ;

[0064] Cy1represents C3-C 12 cycloalkyl or 4-12 membered heterocycloalkyl, which ring can be spiro, bridged, fused;

[0065] R6represents -OR a , -NR a R a ’;

[0066] R7, R7’ each independently represents hydrogen, halogen, C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl); said R7and R7’together with the common attached C atom can form a 4-8 membered ring, which 4-8 membered ring optionally contains 0, 1, 2, or 3 heteroatoms selected from N, O, or S;

[0067] R8each independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a ’, cyano, -C(O)OR a , -C(O)Ra -C(O)NR a R a -S(O)2R a -S(O)R a -S(O)(NR a )R a C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl can be independently substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -OR a -SR a -NR a R a cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl;

[0068] wherein m represents 0, 1, 2, or 3;

[0069] R a R a each independently represents hydrogen, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; when R a R a are attached to the same N atom, said R a and R a together with the N atom to which they are attached can form a 4-8 membered ring, said 4-8 membered ring optionally can contain 1, 2, or 3 heteroatoms selected from N, O, or S;

[0070] each of the alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0071] In some embodiments of the present application, the compound has the structure of formula (I’):

[0072] wherein R1, R2, R3, R3’, R4, R5, Cya, A, B, L, X, W are defined as in formula (I).

[0073] In some embodiments of the present application, Cya represents or optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl.

[0074] In some embodiments of the present application, Cya represents which is optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3 alkyl; preferably, Cya represents In some embodiments of the application, Cya represents or which is optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3 alkyl; preferably, Cya represents

[0075] In some embodiments of the application, A represents an optionally substituted 4- to 6-membered heterocycloalkylene group or an optionally substituted 5- to 6-membered heteroarylene group; preferably, A represents an optionally substituted thiazolylene group; more preferably, A represents an unsubstituted thiazolylene group.

[0076] In some embodiments of the application, B represents a single bond, phenylene, or an optionally substituted 5- to 6-membered heteroarylene group; preferably, B represents an optionally substituted or more preferably, B represents or

[0077] In some embodiments of the application, X represents O or CH2.

[0078] In some embodiments of the application, W represents halogen, optionally substituted C1-C4 alkyl, optionally substituted 4- to 8-membered heterocycloalkyl, or optionally substituted C3-C8 cycloalkyl.

[0079] In some embodiments of the application, L represents a single bond or -(C1-C6)alkylene-, any methylene of which can be replaced with a carbonyl, NR a , O, or S; preferably, L represents a single bond, -C(O)-, -CH2-, or -O-.

[0080] In some embodiments of the application, R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl); preferably, R1 represents C1-C6 alkyl or C1-C6 haloalkyl; more preferably, R1 represents ethyl or -CH2CF3.

[0081] In some embodiments of the application, R2represents C1-C6alkyl, which can be substituted with 0 or 1 -ORa; preferably, R2represents 1-methoxyethyl; more preferably, R2represents wherein * indicates the point of attachment of R2to the rest of the general formula.

[0082] In some embodiments of the application, R3, R3' each independently represents hydrogen, halogen, C1-C6alkyl; preferably, R3, R3' are H.

[0083] In some embodiments of the application, R4represents H.

[0084] In some embodiments of the application, R5represents -Cy1-(R8) m ;

[0085] In some embodiments of the application, Cy1represents 4-12 membered heterocycloalkyl, which can be spirocyclic, bridged cyclic, annelated; preferably, Cy1represents 4-8 membered heterocycloalkyl, which can be spirocyclic, bridged cyclic, annelated.

[0086] In some embodiments of the application, R7, R7' each independently represents hydrogen, halogen, C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl; preferably, R7, R7' each independently represents hydrogen, halogen, C1-C3alkyl, C3-C6cycloalkyl; said R7and R7' and the common C atom to which they are attached can form a 4-6 membered ring, which optionally can contain 0 or 1 heteroatom selected from N, O or S.

[0087] In some embodiments of the application, R8each independently represents hydrogen, oxo, =NRa, -S(O)2Ra, -C(O)Ra, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; each of the aforementioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl can be independently substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -ORa, -SRa, -NRaRb, cyano, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; preferably, R8each independently represents hydrogen, oxo, =NRa, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; each of the aforementioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl can be independently substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -ORa, -SRa, -NRaRb, cyano, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl. a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; preferably, R8each independently represents hydrogen, oxo, =NR a , C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; each of the aforementioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl can be independently substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NRa R a ; preferably each R8independently represents hydrogen, oxo, =NR a ; each said C1-C6alkyl group can be independently substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -OR a ; -SR a ; -NR a R a ; and each R9independently represents hydrogen, halogen, oxo, -OR a ; -SR a ; -NR a ; and each R10independently represents hydrogen or C1-C6alkyl; more preferably each R a ; and each R10independently represents hydrogen or C1-C3alkyl.

[0088] In some embodiments of the application, m represents 0, 1, or 2.

[0089] In some embodiments of the application, each R a ; and each R a ; independently represents hydrogen, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; preferably each R a ; and each R a ; independently represents hydrogen or C1-C6alkyl; more preferably each R a ; and each R a ; independently represents hydrogen or C1-C3alkyl.

[0090] In one aspect, the application provides a compound having the structure of Formula (II), or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof:

[0091] wherein:

[0092] Cya represents ; or ; optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl;

[0093] X represents O, NR6, or CR7R7’;

[0094] W represents halogen, optionally substituted amino, optionally substituted C1-C4aminoalkyl, optionally substituted C1-C4hydroxyalkyl, optionally substituted C1-C4alkyl, optionally substituted 4 to 12 membered heterocycloalkyl, optionally substituted C3-C 12 C8cycloalkyl, optionally substituted 5 to 6 membered heteroaryl, or optionally substituted phenyl;

[0095] L represents a single bond or -(C1-C6)alkylene-, any methylene of said -(C1-C6)alkylene- being optionally replaced with a carbonyl, NR a , O, or S;

[0096] R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ’;

[0097] R5represents -OR a , -NR a R a ’ or -Cy1-(R8) m ;

[0098] Cy1represents C3-C 12 cycloalkyl or 4-12 membered heterocycloalkyl, which ring can be spiro, bridged, fused;

[0099] R6represents -OR a , -NR a R a ’;

[0100] R7, R7’ each independently represents hydrogen, halogen, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; said R7and R7’ together with the common attached C atom can form a 4-8 membered ring, which 4-8 membered ring optionally can contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0101] R8each independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a ’, cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R a ’, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; said C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl each independently of the other can be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a Ra Substitution with ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-C3-C8 cycloalkyl or -(C0-C3 alkylene)-4-8 heterocyclic alkyl groups;

[0102] Where m represents 0, 1, 2 or 3;

[0103] R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a 'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S;

[0104] The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0105] In some embodiments of the present invention, the compound has the structure of formula (II'):

[0106] The definitions of R1, R5, Cya, L, X, and W are as described in equation (II).

[0107] In some embodiments of the present invention, Cya represents It may optionally be substituted with 0, 1, 2, or 3 substituents selected from halogens or C1-C3 alkyl groups; preferably, Cya represents

[0108] In some embodiments of the present invention, Cya represents or It may optionally be substituted with 0, 1, 2, or 3 substituents selected from halogens or C1-C3 alkyl groups; preferably, Cya represents

[0109] In one aspect, the present invention provides a compound having the structure of formula (III), or an isotopic derivative thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0110] in:

[0111] Cya said or

[0112] X represents O, NR6or CR7R7';

[0113] W represents halogen, C1-C4alkyl, 4- to 8-membered heterocycloalkyl or C3-C8cycloalkyl, each independently of the other(s) optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R b substituents;

[0114] L represents a single bond, -C(O)-, -CH2- or -O-;

[0115] R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4- to 8-membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a or -(C1-C6alkylene)-NR a R a ;

[0116] Cy1represents 4- to 8-membered heterocycloalkyl, which ring can be spiro, bridged, annelated;

[0117] R6represents -OR a , -NR a R a ;

[0118] R7, R7' each independently represent hydrogen, halogen, C1-C3alkyl, C3-C6cycloalkyl; said R7and R7' with the common attached C atom can form a 4- to 6-membered ring, which 4- to 6-membered ring optionally can contain 0 or 1 heteroatom selected from N, O or S;

[0119] R8each independently represents hydrogen, oxo, =NRa, C1-C6alkyl; each independently of the other(s) optionally substituted by 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a ;

[0120] wherein m represents 0, 1 or 2;

[0121] R a , R a ' each independently represent hydrogen, C1-C6alkyl, C3-C8cycloalkyl or 4- to 8-membered heterocycloalkyl;

[0122] Rb each independently represents hydrogen, halogen, C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl, C2-C6alkenyl, or C2-C6alkynyl;

[0123] each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0124] In some embodiments of the application, the compound has the structure according to formula (III’):

[0125] wherein R1, R8, Cy1, Cya, L, X, W, m are defined as in formula (III)

[0126] In some embodiments of the application, Cya represents

[0127] In some embodiments of the application, Cya represents

[0128] In one aspect, the present application provides a compound having the structure according to formula (IV), or an isotopologue derivative, stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0129] wherein:

[0130] Cya represents or optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl;

[0131] Cy2represents optionally substituted 4-12 membered heterocycloalkylene, optionally substituted 5-6 membered heteroarylene, or optionally substituted phenylene;

[0132] X represents O, NR6, or CR7R7’;

[0133] W represents halogen, optionally substituted amino, optionally substituted C1-C4aminoalkyl, optionally substituted C1-C4hydroxyalkyl, optionally substituted C1-C4alkyl, optionally substituted 4-12 membered heterocycloalkyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted phenyl;

[0134] L represents a single bond or -(C1-C6)alkylene-, any methylene of said -(C1-C6)alkylene- being optionally replaced with a carbonyl, NR a , O, or S;

[0135] R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ’;

[0136] R5represents -OR a , -NR a R a ’ or -Cy1-(R8) m ;

[0137] Cy1represents C3-C 12 cycloalkyl or 4-12 membered heterocycloalkyl, which ring can be spiro, bridged, fused;

[0138] R6represents -OR a , -NR a R a ’;

[0139] R7, R7’ each independently represents hydrogen, halogen, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; said R7and R7’ together with the common attached C atom can form a 4-8 membered ring, which 4-8 membered ring optionally can contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0140] R8each independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a ’, cyano, -COOR a , -COR a , -C(O)NR a R a ’, -S(O)2R a , -S(O)R a , -S(O)(NR a )R a ’, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; said C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl each independently can be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R aC3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl, wherein said alkyl, alkylene, cycloalkyl, heterocycloalkyl are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of halogen, cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl;

[0141] wherein m represents 0, 1, 2, or 3;

[0142] R a , R a each independently represent hydrogen, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; when R a , R a are attached to the same N atom, said R a and R a together with the N atom to which they are attached can form a 4-8 membered ring, said 4-8 membered ring optionally can contain 1, 2, or 3 heteroatoms selected from N, O, or S;

[0143] said alkyl, alkylene, cycloalkyl, heterocycloalkyl, each independently can be substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0144] In some embodiments of the present application, the compound has the structure of formula (IV’):

[0145] wherein R1, X, W, Cya, R5, Cy2, L are defined as in formula (IV).

[0146] In some embodiments of the present application, Cya represents which optionally can be substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl; preferably, Cya represents

[0147] In some embodiments of the present application, Cya represents or which optionally can be substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl; preferably, Cya represents

[0148] In some embodiments of the present application, Cya represents

[0149] wherein:

[0150] Cya represents or

[0151] Cy2represents or

[0152] X represents O, NR6or CR7R7';

[0153] W represents halogen, C1-C4alkyl, 4- to 8-membered heterocycloalkyl or C3-C8cycloalkyl, each independently of the other(s) optionally substituted with 0, 1, 2, 3, 4, 5 or 6 R b substituents;

[0154] L represents a single bond, -C(O)-, -CH2- or -O-;

[0155] R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4- to 8-membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a or -(C1-C6alkylene)-NR a R a ;

[0156] Cy1represents 4- to 8-membered heterocycloalkyl, which ring can be spiro, bridged, annelated;

[0157] R6represents -OR a , -NR a R a ;

[0158] R7, R7' each independently represent hydrogen, halogen, C1-C3alkyl, C3-C6cycloalkyl; said R7and R7' with the common attached C atom can form a 4- to 6-membered ring, which 4- to 6-membered ring optionally can contain 0 or 1 heteroatom selected from N, O or S;

[0159] R8each independently represents hydrogen, oxo, =NRa, -S(O)2R a , -COR a , C1-C6alkyl, C3-C8cycloalkyl or 4- to 8-membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4- to 8-membered heterocycloalkyl can be independently of the others substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl or 4- to 8-membered heterocycloalkyl;

[0160] wherein m represents 0, 1 or 2;

[0161] R a , R a each independently represents hydrogen, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl;

[0162] R b each independently represents hydrogen, halogen, C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl, C2-C6alkenyl or C2-C6alkynyl;

[0163] each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be independently substituted with 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

[0164] In some embodiments of the application, the compound has the structure of formula (V’):

[0165] wherein R1, X, W, Cya, Cy2, L, Cy1, R8, m are defined as in formula (V).

[0166] In some embodiments of the application, Cya represents

[0167] In some embodiments of the application, Cya represents

[0168] In some embodiments of the application, each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be independently substituted with 0, 1, 2, 3 or 4 substituents selected from F, Cl, Br; preferably, with 0, 1, 2, 3 or 4 substituents selected from F, Cl; more preferably, with 0, 1, 2, 3 or 4 F.

[0169] In one aspect, the present application also provides a compound having the structure of:

[0170] In yet another aspect, the present application provides a pharmaceutical composition comprising the aforementioned compound, or an isotopic derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0171] In another aspect, the present application provides use of the aforementioned compound, or an isotopic derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease.

[0172] In yet another aspect, the present application provides a method for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of the aforementioned compound, or an isotopic derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof and / or a pharmaceutical composition.

[0173] In some embodiments, the cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease is a RAS protein related disease. Preferably, the RAS protein is one or more of KRAS protein, NRAS protein, or HRAS protein.

[0174] In some embodiments, the cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease comprises a RAS mutation. Preferably, the RAS mutation comprises one or more of KRAS mutation, NRAS mutation, or HRAS mutation. Preferably, the RAS mutation is at position 12, 13, and / or 61. More preferably, the RAS mutation comprises one or more of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G13D, NRAS Q61L, KRAS G12A, KRAS G12S, or NRAS Q61K.

[0175] It is specifically noted that herein, when referring to a "compound" of the structure of formula (x), it is meant to generically encompass also stereoisomers, diastereoisomers, enantiomers, racemic mixtures, and isotopic derivatives thereof.

[0176] It is well known to the person skilled in the art that a salt, a solvate, a hydrate of a compound are alternative forms of existence of the compound, which can be converted into the compound under certain conditions, and therefore it is specifically noted that herein, when referring to a compound of the structure of formula (x), it is meant to generically encompass also a pharmaceutically acceptable salt thereof, and further a solvate and a hydrate thereof.

[0177] Similarly, when referring to a compound in this article, its prodrug, metabolites, and nitrogen oxides are generally also included.

[0178] The pharmaceutically acceptable salts described in this invention can be formed using, for example, inorganic or organic acids: “Pharmaceutically acceptable salt” means a salt that, within a reasonable medical judgment, is suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and has a reasonable benefit / risk ratio. The salts can be prepared in situ during the final separation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent, as outlined below. For example, the free base function can react with a suitable acid. Examples of pharmaceutically acceptable inorganic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed using other methods in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-enolate, glyceryl phosphate, gluconate, hernisulfate, heptaate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pyrate, pectinate, persulfate, 3-phenylpropionate, phosphate, bitter salts, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically usable salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed by counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0179] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example by dissolving the compounds of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol, and acetonitrile), adding an excess of an aqueous solution of an organic or inorganic acid to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid, and then separating the precipitated salt.

[0180] The precursors or metabolites described in this invention can be precursors or metabolites known in the art, as long as they are metabolized and transformed in vivo to form compounds. For example, "prodrug" refers to those prodrugs of the compounds of this invention that, within a reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism, or through N-demethylation of the compounds of this invention.

[0181] The term "solvate" as used in this invention refers to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0182] The "stereoisomerism" described in this invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism and optical isomerism. Conformational isomerism refers to the phenomenon where organic molecules with a certain configuration undergo different spatial arrangements of atoms or groups of atoms due to the rotation or twisting of carbon or carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair conformation and boat conformation in the cyclohexane structure. "Stereoisomers" refer to compounds of this invention containing one or more asymmetric centers, thus allowing them to exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. The compounds of this invention have asymmetric centers, each of which produces two optical isomers. The scope of this invention includes all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds. The compounds of this invention can exist as tautomers, which have different hydrogen bonding sites through one or more double bond shifts. For example, ketones and their enol forms are ketone-enol tautomers. All tautomers and mixtures thereof are included in the compounds of this invention. All enantiomers, diastereomers, racemates, mesomates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof of compounds of formulas (I) to (V) are included within the scope of this invention.

[0183] An "isotopically-labeled" compound of the application is defined as a compound of the application having one or more atoms replaced by an isotope of the atom naturally occurring in the molecule. Isotopically-labeled compounds of this application are useful in metabolic studies, as diagnostic tools, as probes in assays, and the like. In particular, an isotopically-labeled compound of the application can serve as an active depot for purposes of delivery of the drug into tissues in the body. An isotopically-labeled compound of the application can also exhibit differences in metabolic stability or clearance compared to a non-labeled compound. 2 H and 3 H; carbon isotopes: 11 C, 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotopically-labeled compounds are useful in metabolic studies, as diagnostic tools, as probes in assays, and the like. In particular, an isotopically-labeled compound of the application can serve as an active depot for purposes of delivery of the drug into tissues in the body. An isotopically-labeled compound of the application can also exhibit differences in metabolic stability or clearance compared to a non-labeled compound. 3 H and carbon 13 C are preferred for their ease of preparation and detection. Substitution with heavier isotopes such as deuterium ( 2 H) affords certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0184] The present application also provides the use of a compound of the present application for the manufacture of a medicament for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease.

[0185] In addition, the present application provides a pharmaceutical composition for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, a neurodegenerative disease, an attention-related disease, or an immune-mediated disease, which comprises a compound of the present application as an active ingredient. The pharmaceutical composition can optionally comprise a pharmaceutically acceptable carrier.

[0186] In addition, the present application provides a method for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, a neurodegenerative disease, an attention-related disease, or an immune-mediated disease, which comprises administering a compound of the present application to a mammal in need thereof.

[0187] Representative examples of inflammatory diseases, autoimmune diseases, and immune-mediated diseases can include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritides, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung diseases, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic lung inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (hives), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic rhinosinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0188] Representative examples of cancers or tumors can include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis cancer, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, larynx cancer, hypopharynx cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urological cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratocarcinoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, or plasmacytoma.

[0189] When the compound of the present application or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for the treatment of cancer or tumor, the compound of the present application or a pharmaceutically acceptable salt thereof can provide an enhanced anticancer effect.

[0190] Representative examples of the anticancer agent for the treatment of cancer or tumor can include, but are not limited to, cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, goserelin analogs, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, sirolimus lipidate, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crotetuzumab, dabrafenib, dacotuzumab, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, seribantumab, sorafenib, sunitinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, velpatasarin, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab ozogamicin, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, and anti-CTLA-4 antibodies, or any combination thereof.

[0191] When the compound of the present application or a pharmaceutically acceptable salt thereof is administered in combination with another therapeutic agent for the treatment of inflammatory diseases, autoimmune diseases and immune-mediated diseases, the compound of the present application or a pharmaceutically acceptable salt thereof can provide an enhanced therapeutic effect.

[0192] Representative examples of therapeutic agents for the treatment of inflammatory diseases, autoimmune diseases and immune-mediated diseases can include, but are not limited to, steroidal drugs (e.g., prednisone, prednisolone, methylprednisolone, cortisone, hydrocortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFa agents (e.g., etanercept, infliximab, adalimumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one or more therapeutic agents selected therefrom can be included in the pharmaceutical composition of the present application.

[0193] Other features of the present application will become apparent in the course of the detailed description of exemplary embodiments which are given for the purpose of illustration and not of limitation, the following examples were prepared, isolated and characterized using the methods disclosed herein.

[0194] The compounds of the present application can be prepared in a number of ways known to one skilled in the art of organic synthesis, either by adapting the methods described below or by using synthetic methods or by variations of synthetic methods known to those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in solvents appropriate to the reagents and materials employed and appropriate to the solvent used for the synthesis. One skilled in the art of organic synthesis will recognize that the order of synthetic steps can be varied for reasons of practicality or to optimize yield. DETAILED DESCRIPTION

[0195] The terms used in the present application, including the specification and claims, are defined as follows, if not otherwise indicated. The conventional methods of mass spectrometry, nuclear magnetic, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used, if not otherwise indicated. In the present application, "or" or "and" means "and / or", if not otherwise indicated.

[0196] In the specification and claims, given chemical formulae or names shall encompass all stereoisomers and optical isomers and racemates thereof in which the above-mentioned isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the application. Multiple geometric isomers can also exist for C=C double bonds, C=N double bonds, ring systems, etc., in the described compounds, and all such stable isomers are contemplated in the present application. The present application describes the cis- and trans- (or E- and Z-) geometric isomers of the compounds of the application and they can be isolated in their mixtures or in separate isomer form. The compounds of the application can be isolated in optically active or racemic forms. All methods used in the preparation of the compounds of the application and intermediates made therein are considered to be part of the present application. When preparing enantiomeric or diastereomeric products, they can be separated by conventional methods, e.g., by chromatography or fractional crystallization. The end products of the application are obtained in free (neutral) or salt form, depending on the method conditions. Both the free forms and the salts of these end products are within the scope of the application. If desired, one form of a compound can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into the free compound or another salt; a mixture of isomeric compounds of the application can be separated into the individual isomers. The compounds of the application, their free forms and salts can exist in various tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged thereby. It is understood that all tautomeric forms which can exist are included within the present application.

[0197] In the present application, when a listed linking group does not indicate its direction of attachment, its direction of attachment is arbitrary, e.g. where L is -C(O)NH-, which can be attached to the phenyl and cyclohexyl groups in the order of reading from left to right to form or in the order of reading from left to right in reverse to form The combination of the linking group and the attached groups is only allowed if this results in a stable compound. In some preferred embodiments of the present application, the order of reading is from left to right.

[0198] Unless otherwise defined, the definitions of substituents of the present application are independent of each other, e.g. (by way of illustration and not limitation), in one aspect, for R a (or R a ') in one substituent, it is independent of its definition in a different substituent. Specifically, when R a (or R a ') is selected in one substituent for one definition, it does not mean that R a (or R a) have the same definition. More specifically, for example (and without limitation) for NR a R a ) in R a (when R a ) is defined as hydrogen, it does not mean that R a R a ) in R a (when R a ) is necessarily hydrogen. In another aspect, when there is more than one R a (when R a ) in a substituent, the R a (when R a ) are also each independent. For example, in the substituent -(CR a R a’ ) m -O-(CR a R a’ ) n -, where m+n is greater than or equal to 2, the m+n R a (when R a ) are each independent and can have the same or different meanings.

[0199] The term "optionally substituted X" or "or "optionally substituted X" is intended to be equivalent to "X, wherein X is optionally substituted" (e.g., "alkyl, wherein the alkyl is optionally substituted"). It is not intended to mean that the feature "X" (e.g., alkyl) is itself optional. As described herein, certain compounds of interest can contain one or more "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced, as appropriate, with a suitable substituent group, such as any of the substituents or groups described herein. Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be the same or different at each position. For example, in the term "optionally substituted C1-C6 alkyl-C2-C9 heteroaryl," either the alkyl moiety, the heteroaryl moiety, or both can be optionally substituted. Combinations of substituents and variables envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are not substantially altered when subjected to conditions that would not cause substantial alteration of a compound's fundamental chemical structure.

[0200] Suitable monovalent substituents on the optionally substitutable carbon atoms of an "optionally substituted" or "optionally substituted" group can be independently: deuterium; halogen; -(CH2) 0-4 Ro; -(CH2) 0-4 ORo; -O(CH2) 0-4 Ro; -O-(CH2) 0- 4C(O)ORo; -(CH2) 0-4 CH(ORo)2; -(CH2) 0-4 SRo; -(CH2) 0-4 Ph, which group can be substituted with Ro; -(CH2) 0-4 O(CH2) 0-1 Ph, which group can be substituted with Ro; -CH=CHPh, which group can be substituted with Ro; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which group can be substituted with Ro; 4-11 membered saturated or unsaturated heterocycloalkyl (e.g., 4-8 membered saturated or unsaturated heterocycloalkyl (e.g., pyridyl)), which group can be additionally optionally substituted (e.g., with methyl); 3-8 membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; -(CH2) 0-4 N(Ro)2; -(CH2) 0-4 N(Ro)C(O)Ro; -N(Ro)C(S)Ro; -(CH2) 0- 4N(Ro)C(O)NRo2; -N(Ro)C(S)NRo2; -(CH2) 0-4 N(Ro)C(O)ORo; -N(Ro)N(Ro)C(O)Ro; -N(Ro)N(Ro)C(O)NRo2; -N(Ro)N(Ro)C(O)ORo; -(CH2) 0-4 C(O)Ro; -C(S)Ro; -(CH2) 0- 4C(O)ORo; -(CH2) 0-4 -C(O)-N(Ro)2; -(CH2) 0-4 -C(O)-N(Ro)-Ro2-Ro; -C(NCN)NRo2; -(CH2) 0-4 C(O)SRo; -(CH2) 0-4 C(O)OSiRo3; -(CH2) 0-4 OC(O)Ro; -OC(O)(CH2) 0-4 SRo; -SC(S)SRo; -(CH2) 0-4 SC(O)Ro; -(CH2) 0-4C(O)NRo2; -C(S)NRo2; -C(S)SRo; -(CH2) 0- 4OC(O)NRo2; -C(O)N(ORo)Ro; -C(O)C(O)Ro; -C(O)CH2C(O)Ro; -C(NORo)Ro; -(CH2) 0-4 SSRo; -(CH2) 0-4 Ro2Ro; -(CH2) 0-4 Ro2ORo; -(CH2) 0-4 ORo2Ro; -Ro2NRo2; -(CH2) 0-4 S(O)Ro; -N(Ro)Ro2NRo2; -N(Ro)Ro2Ro; -N(ORo)Ro; -C(NORo)NRo2; -C(NH)NRo2; -P(O)2Ro; -P(O)Ro2; -P(O)(ORo)2; -OP(O)Ro2; -OP(O)(ORo)2; -OP(O)(ORo)Ro; -SiRo; -(C 1-4 straight, branched or cyclic alkylene)O-N(Ro)2; or -(C 1-4 straight, branched or cyclic alkylene)C(O)O-N(Ro)2, wherein each Ro can be substituted as defined below and independently is hydrogen, -C 1-6 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH-(5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of Ro, together with their intervening atom(s), form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring system having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0201] Suitable monovalent substituents on R° (or a ring formed by taking two independent R°'s together with their intervening atom(s)) are independently halogen, -(CH2) 0-2 R●, -(haloR●), -(CH2) 0-2 OH, -(CH2) 0-2 OR●, -(CH2) 0- 2CH(OR●)2, -O(haloR●), -CN, -N3, -(CH2) 0-2 C(O)R●, -(CH2) 0-2 C(O)OH, -(CH2) 0- 2C(O)OR●, -(CH2) 0-2 SR●, -(CH2) 0-2 SH, -(CH2) 0-2NH2, -(CH2) 0-2 NHR., -(CH2) 0- 2NR.2, -NO2, -SiR.3, -OSiR.3, -C(O)SR., -(C 1-4 linear or branched alkylene)C(O)OR. or -SSR., wherein each R. is unsubstituted or, if preceded by "halo," substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable bivalent substituents on saturated carbon atoms of Ro include =O and =S.

[0202] Suitable bivalent substituents on saturated carbon atoms of an "optionally substituted" group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHRo2R*, =NR*, =NOR*, -O(C(R*2)) 2-3 O-, or -S(C(R*2)) 2-3 S-, wherein R* is selected, at each occurrence independently, from hydrogen; C 1- 6aliphatic, which can be substituted as defined below; or unsubstituted 5-6 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable bivalent substituents on adjacent substitutable carbons bound to an "optionally substituted" group include: -O(CR*2) 2-3 O-, wherein R* is selected, at each occurrence independently, from hydrogen; C 1-6 aliphatic, which can be substituted as defined below; or unsubstituted 5-6 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0203] Suitable substituents on the aliphatic group of R* include halogen, -R., -(haloR.), -OH, -OR., -O(haloR.), -CN, -C(O)OH, -C(O)OR., -NH2, -NHR., -NR.2, or -NO2, wherein each R. is unsubstituted or, if preceded by "halo," substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0204] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R +, -NR + 2, -C(O)R + , -C(O)OR + , -C(O)C(O)R + , -C(O)CH2C(O)R + , -Ro2R + , -Ro2NR + 2, -C(S)NR + 2, -C(NH)NR + 2 or -N(R + )Ro2R + ; wherein R + each independently is hydrogen; C 1-6 aliphatic, which aliphatic can be substituted as defined below; unsubstituted -OPh; or unsubstituted 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or notwithstanding the definition above, two independent occurrences of R + , together with their intervening atom, form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring, having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0205] R + Suitable substituents on the aliphatic group of R 1-4 each independently is halogen, -R●, -(haloR●), -OH, -OR●, -O(haloR●), -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2, or -NO2, wherein each R● is unsubstituted or, when preceded by "halo", substituted only with one or more halogens, and is independently C 0-1 aliphatic, -CH2Ph, -O(CH2) + Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R

[0206] Unless otherwise defined, the term "single bond" or "bond" or "direct bond" as used herein means that two atoms are connected by a saturated covalent bond. For example, when L represents a single bond, "A-L-B" means that A and B are connected by a saturated covalent bond, i.e., "A-B"; for another example, when L represents a single bond, "-CH2-L-NH-" means that -CH2- and -NH- are connected by a saturated covalent bond, i.e., "-CH2-NH-".

[0207] The term "alkyl" as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "Ci-C6alkyl" denotes alkyl having from 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i-butyl, t-butyl), and pentyl (e.g., n-pentyl, i-pentyl, neopentyl). The alkyl group can be unsubstituted or substituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In the present context, alkyl is preferably an alkyl group having 1 to 6, more preferably having 1 to 4 carbon atoms.

[0208] The term "alkylene" as used herein is intended to include both branched and straight-chain, saturated aliphatic hydrocarbon groups, including or not including cyclic alkyl groups, having the specified number of carbon atoms, which is a residue derived from removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. For example, "C0-C6alkylene" denotes alkylene having 0 (i.e., a bond), 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (e.g., -(CH2)3-, -(CHCH3)CH2-, -CH(CH2CH3)-), and the like. In the present context, alkylene is preferably an alkylene group having 0-6, 0-4, 0-3, 1-6, 1-4, 1-3 carbon atoms. In the present context, alkylene is preferably an alkylene group not including cyclic alkyl groups.

[0209] The term "cycloalkyl" refers to monocyclic, polycyclic, or branched cyclic alkyl groups. For example, C3-C 12 cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". In the present context, cycloalkyl can be saturated or partially unsaturated carbocyclic rings, for example, a 6-membered cycloalkyl group can include 0-2 double bonds, and a 12-membered cycloalkyl group can include 0-5 double or triple bonds. Polycyclic cycloalkyl groups such as bicyclic and tricyclic cycloalkyl groups include bridged, spiro, or fused ring cycloalkyl groups. Cycloalkyl groups can be unsubstituted or substituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In the present invention, cycloalkyl is preferably C3-C 12 cycloalkyl, more preferably C3-C8cycloalkyl.

[0210] Similarly, the term "heterocycloalkyl" refers to a monocyclic ring structure in which at least one carbon atom in the ring structure is replaced with a heteroatom selected from N, O, S, and P. In the present context, a heterocycloalkyl group can be a saturated or partially unsaturated heterocycle, for example, a 6-membered heterocycloalkyl group can include 0-2 double bonds, and a 12-membered heterocycloalkyl group can include 0-5 double or triple bonds. The N atoms can optionally be quaternized, and the N and S atoms can optionally be oxidized (i.e., NO, SO, and SO2). It includes monocyclic, bicyclic, and tricyclic ring systems, including spiro, fused, and bridged ring systems. A heterocycloalkyl group can be unsubstituted or substituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In the present invention, a heterocycloalkyl group is preferably a 4-12 membered heterocycloalkyl group, more preferably a 4-8 membered heterocycloalkyl group.

[0211] In the present invention, the term "fused" refers to a polycyclic group formed by two or more ring structures sharing two adjacent atoms with each other.

[0212] In the present invention, the term "bridged" refers to a polycyclic group in which two rings in the system share more than two ring atoms.

[0213] In the present invention, the term "spiro" refers to a polycyclic group in which a single ring shares one carbon atom (referred to as a spiro atom) with another ring.

[0214] The term "alkenyl" denotes a straight or branched chain hydrocarbon group containing one or more double bonds and typically having a length of from 2 to 20 carbon atoms. For example, "C2-C6alkenyl" contains from two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. In the present context, an alkenyl group is preferably a C2-C6alkenyl group.

[0215] The term "cycloalkenyl" refers to a monocyclic or bicyclic ring alkenyl group. Monocyclic ring alkenyl groups refer to C3-C8cycloalkenyl groups, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic ring alkenyl groups include bridged, spiro, or fused ring alkenyl groups.

[0216] The term "alkynyl" denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and typically having a length of from 2 to 20 carbon atoms. For example, "C2-C6alkynyl" contains from two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like. In the present context, an alkynyl group is preferably a C2-C6alkynyl group.

[0217] The term "alkoxy" or "alkyloxy" means -O-alkyl. "C1-C6alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, C6alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy (e.g., n- propyloxy and isopropyloxy), and t-butyloxy. In the present context, alkoxy is preferably an alkoxy group having from 1 to 6, more preferably having from 1 to 4 carbon atoms. Similarly, "alkylthio" or "thioalkoxy" denotes an alkyl group as defined above attached through a sulfur bridge; for example, methyl-S- and ethyl-S-. The alkoxy group can be unsubstituted or substituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0218] The term "carbonyl" refers to an organic functional group (C=0) connected by a double bond between a carbon and an oxygen atom.

[0219] The term "aryl", alone or in combination with other terms, means a monocyclic, bicyclic or tricyclic ring system having from 5 to 12 ring members, wherein at least one ring is aromatic and wherein each ring in the system contains from 3 to 7 ring members. In certain embodiments of the application, "aryl" means an aromatic ring system, which includes, but is not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" means an alkyl residue attached to an aryl ring, non-limiting examples of which include benzyl, phenethyl, and the like. A fused aryl group can be attached to another group at a suitable position on either the cycloalkyl or aromatic ring. The dashed line drawn from the ring system indicates that the bond can be attached to any suitable ring atom. The aryl group can be unsubstituted or substituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0220] The term "heterocycle" when used, means fully saturated, partially saturated, and fully unsaturated ring structures containing heteroatoms, including heteroaromatic rings.

[0221] The term "heteroaryl" means a stable 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered polyaromatic heterocyclic ring that contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; it includes structures in which a cycloalkane or heterocycloalkane is fused to an aromatic ring such as a benzene ring or a heteroaromatic ring such as a pyridine ring, the point of attachment of the substituent being at the cycloalkane, heterocycloalkane, aromatic, or heteroaromatic ring. Nitrogen and sulfur heteroatoms can optionally be oxidized. The nitrogen atoms are substituted or unsubstituted (i.e., N or NR, where R is H or, if defined, another substituent). The heterocyclic rings can be attached to their side groups at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein can be substituted on carbon or nitrogen atoms if the resulting compound is stable. The nitrogen in the heterocyclic ring can optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocyclic ring exceeds 1, then these heteroatoms are not adjacent to one another. Preferably, the total number of S and O atoms in the heterocyclic ring is not more than 1. The heteroaryl group can be unsubstituted or substituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.Examples of aryl hetero groups include, but are not limited to, azetidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, imidazopyridinyl, indoleninyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, oxindolyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-l,2,5-thiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienopyridyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, lH-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, 1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.The term "heteroaryl" can also include biaryl structures formed from the above defined "aryl" groups with monocyclic "heteroaryl" groups, such as, but not limited to, "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", "-pyrimidylbiphenyl-"; wherein the present application also includes fused ring and spiro compounds containing, for example, the above heterocycles.

[0222] The term "substituted" as used herein means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that a stable compound results. Ring double bonds as used herein are double bonds between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0223] In the present disclosure, the one or more halogens can each be independently selected from fluorine, chlorine, bromine, and iodine.

[0224] "Halo" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" / "haloalkylene" is intended to include branched and straight-chain saturated aliphatic alkyl / alkylene groups having the specified number of carbon atoms substituted by one or more halogens. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptafluoropropyl. Examples of haloalkyl groups also include "fluoroalkyl" intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted by one or more fluorine atoms. "Halo cycloalkyl" / "halo heterocycloalkyl" is intended to include cycloalkyl / heterocycloalkyl groups having the specified number of carbon atoms substituted by one or more halogens. In the present application, the halogen atoms are preferably fluorine or chlorine, more preferably fluorine. In the present text, groups are considered to be halogenated unless it is specifically indicated that a certain alkyl, cycloalkyl, heterocycloalkyl, or alkylene group cannot be substituted by halogen, or it can be inferred from the context that the group does not include halogenated, or it is common general knowledge in the art that the group is not suitable for halogenation.

[0225] "Haloalkoxy" or "haloalkyloxy" denotes an oxygen-bridged haloalkyl group as defined above having the specified number of carbon atoms. For example, "halo C1-C6alkoxy" is intended to include C1, C2, C3, C4, C5, C6haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" denotes a sulfur-bridged haloalkyl group as defined above having the specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0226] In the present disclosure, "xxyl" or "xyI" means a divalent xx substituent, for example, "methylene" means a divalent methyl group, which can also be represented as "-CH2-"; for another example, "phenylene" means a divalent phenyl group, which can also be represented as "-C6H4-". The two bonds of the above divalent substituent can be on different atoms, or on the same atom, either on carbon atom or on other heteroatom, for example, "piperidinylene" can represent or

[0227] In the present disclosure, the expression C x1 -C x2 indicates that the number of carbon atoms in the substituent group can be from x1 to x2. For example, C0-C8 indicates that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C1-C8 indicates that the group contains 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C2-C8 indicates that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C3-C8 indicates that the group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C4-C8 indicates that the group contains 4, 5, 6, 7 or 8 carbon atoms, C0-C6 indicates that the group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C1-C6 indicates that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C2-C6 indicates that the group contains 2, 3, 4, 5 or 6 carbon atoms, C3-C6 indicates that the group contains 3, 4, 5 or 6 carbon atoms.

[0228] In the present disclosure, the expression "x1-x2-membered ring" is used when referring to cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), which means that the number of ring atoms of the group can be from x1 to x2. For example, a 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, which can have from 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; a 3-6 membered ring means that the cyclic group can be a 3, 4, 5, or 6 membered ring, which can have from 3, 4, 5, or 6 ring atoms; a 3-8 membered ring means that the cyclic group can be a 3, 4, 5, 6, 7, or 8 membered ring, which can have from 3, 4, 5, 6, 7, or 8 ring atoms; a 3-9 membered ring means that the cyclic group can be a 3, 4, 5, 6, 7, 8, or 9 membered ring, which can have from 3, 4, 5, 6, 7, 8, or 9 ring atoms; a 4-7 membered ring means that the cyclic group can be a 4, 5, 6, or 7 membered ring, which can have from 4, 5, 6, or 7 ring atoms; a 5-8 membered ring means that the cyclic group can be a 5, 6, 7, or 8 membered ring, which can have from 5, 6, 7, or 8 ring atoms; a 5-12 membered ring means that the cyclic group can be a 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, which can have from 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; a 6-12 membered ring means that the cyclic group can be a 6, 7, 8, 9, 10, 11, or 12 membered ring, which can have from 6, 7, 8, 9, 10, 11, or 12 ring atoms. The ring atoms can be carbon atoms or heteroatoms, e.g., heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more ring heteroatoms, e.g., heteroatoms selected from N, O, and S.

[0229] In cases wherein there are nitrogen atoms on the compounds of the present application (e.g., amines), these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxides) to obtain other compounds of the present application. Thus, a shown and claimed nitrogen atom is considered to cover both the shown nitrogen and the N-oxide thereof to obtain derivatives of the present application.

[0230] When any variable occurs more than one time in any constituent or formula for a compound, its definition is independent each time it occurs. Thus, for example, if a group is shown to be substituted with 0-3 R, the group can optionally be substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0231] The term "patient" as used herein refers to an organism to be treated by the methods of the present application. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, monkeys, equines, bovines, porcines, canines, felines, etc.) and most preferably refers to humans.

[0232] The term "effective amount" as used herein means that amount of a drug or pharmaceutical agent (i.e., a compound of the present application), which will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means that amount which results in improved treatment, healing, prevention, or lessening of disease, disorder, or side effects, or decrease in the rate of advancement of a disease or disorder, compared to that which would occur in the absence of the administration of the above amount to the relevant subject. An effective amount can be given in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope an effective amount for enhancing normal physiological function.

[0233] The term "treatment" as used herein includes any effect that relieves, reduces, modulates, ameliorates, or eliminates a condition, disease, disorder, etc., or a symptom thereof.

[0234] The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, and / or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0235] The phrase "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate or zinc stearate, or steric acid), or solvent / capsule, involved in

[0236] The term "pharmaceutical composition" means a composition comprising a compound of the present application in combination with at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" means a medium generally accepted in the art for the delivery of a biologically active agent to an animal, particularly a mammal, and includes, i.e., an adjuvant, excipient, or vehicle, such as diluents, preserving agents, fillers, flow regulators, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, and dispersing agents, depending on the nature of the dosage form and mode of delivery.

[0237] Specific Pharmaceutical and Medical Terms

[0238] The term "acceptable," as used herein, means that a prescribed component or active ingredient has no excessively deleterious effects on the health of the general treatment objectives.

[0239] The term "cancer," as used herein, refers to an uncontrolled abnormal growth of cells and, under certain conditions, is capable of metastasizing (spreading). This type of cancer includes, but is not limited to, solid tumors (e.g., bladder, bowel, brain, breast, uterine, cardiac, kidney, lung, lymphatic tissue (lymphoma), ovarian, pancreatic or other endocrine organ (e.g., thyroid), prostate, skin (melanoma), or blood tumors (e.g., non-leukemic leukemia).

[0240] The term "co-administration" or its grammatical equivalents, as used herein, means that several selected therapeutic agents are administered to a patient, either in the same or different administration modalities, at the same or different times.

[0241] The term "enhance" or "enhancing," as used herein, means that the intended result is increased or prolonged in either potency or duration. Thus, in the context of enhancing the therapeutic effect of a drug, the term "enhancing" means that the drug has the ability to increase or prolong the potency or duration of action in the system. As used herein, "enhancing value" means the ability to maximize the enhancement of another therapeutic agent in the desired system.

[0242] The term "immune disease" refers to a disease or condition resulting from an adverse or deleterious reaction to an endogenous or exogenous antigen. The result is usually a dysfunction of cells, or destruction and dysfunction as a result, or destruction of organs or tissues that can produce the immune condition.

[0243] The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and the like; experimental animals including rodents such as rats, mice and guinea pigs, and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred aspect, the selected mammal is a human.

[0244] The terms "treatment," "treatment regime," or "therapy," as used herein, include alleviating, inhibiting or ameliorating a disease symptom or condition; inhibiting the onset of a complication; ameliorating or preventing a potential metabolic syndrome; inhibiting the development of a disease or condition, such as controlling the progression of a disease or condition; relieving a disease or condition; causing regression of a disease or condition; relieving a complication caused by a disease or condition, or preventing and / or treating a symptom caused by a disease or condition.

[0245] As used herein, a compound or pharmaceutical composition is administered in an amount effective to achieve an improvement in a disease, condition, or disorder, particularly an improvement in the severity thereof, delay of onset, slowing of progression, or reduction in the duration thereof. The improvement can be attributed to or associated with administration, whether fixed or intermittent, continuous or discontinuous.

[0246] Examples

[0247] General procedures

[0248] When a preparation route is not included, the starting materials and reagents used in the present application are known products, which can be synthesized according to the methods known in the art, or can be obtained by purchasing commercially available products. The commercially available reagents used are not further purified. Room temperature refers to 20-30°C.

[0249] Unless otherwise specified in the reaction examples, the reactions are carried out under a nitrogen atmosphere. The nitrogen atmosphere refers to that the reaction flask is connected to a nitrogen balloon of about 1 L.

[0250] The hydrogenation reaction is usually carried out by vacuuming and filling hydrogen repeatedly for 3 times. The hydrogen atmosphere refers to that the reaction flask is connected to a hydrogen balloon of about 1 L.

[0251] Microwave reaction uses Initiator + microwave reactor.

[0252] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by a (Bruker Ascend TM 500 type) nuclear magnetic instrument, and the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broad singlet, d = doublet, t = triplet, m = multiplet. The coupling constant is listed as J value, measured in Hz.

[0253] Preparative reverse phase chromatography uses Thermo (UltiMate 3000) preparative reverse phase chromatograph. Flash column chromatography uses Agilent (FS-9200T) automatic column machine, and silica gel pre-packed column uses Sanso (S-1000) pre-packed column. The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specification of the product separated and purified by thin layer chromatography is 0.4 mm-0.5 mm.

[0254] The LC-MS analysis method is as follows:

[0255] ​1) Mass Spectrometry Method: Thermo Fisher MSQ PLUS mass spectrometer, ESI source, positive ion mode. Ion source parameter settings: drying gas temperature 350℃; drying gas flow rate 10 L / min; MS Range: 120-1000.

[0256] 2) Liquid chromatography conditions: Column: Waters XBridge (3.5 μm, 50 mm x 4.6 mm); mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile solution, linear gradient elution according to the following Table 1; flow rate: 2 mL / min; column temperature: 30℃; ultraviolet detection wavelength: 214 nm, 254 nm, 280 nm; sample injection volume 2 μL.

[0257] Table 1. Gradient elution conditions

[0258] The HPLC analysis method is as follows:

[0259] Column: Waters XBridge phenyl (3.5 μm, 150 mm x 4.6 mm); mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile solution, linear gradient elution according to the following Table 2; flow rate: 1 mL / min; column temperature: 30℃; ultraviolet detection wavelength: 214 nm, 254 nm, 280 nm; sample injection volume 2 μL.

[0260] Table 2. Gradient elution conditions

[0261] The synthesis method of some intermediates in the invention is as follows:

[0262] Intermediate 1

[0263] Intermediate 1 is prepared from the following steps:

[0264] First step: dissolve methyl 2,2-dimethyl-3-hydroxypropanoate INT-1a (100 g, 756.67 mmol) in N,N-dimethylformamide (1 L), add imidazole (128.8 g, 1.89 mol), stir to dissolve, and drop tert-butyldiphenylsilyl chloride (228.8 g, 832.34 mmol) at 20℃, continue to stir for 4 hours after dropping is completed. After the reaction is complete, pour the reaction liquid into 3 L of ice water, and extract the suspension with ethyl acetate (1 L*2), wash the organic phase with water 3 times, and concentrate under reduced pressure to obtain colorless oil INT-1b, which is used directly in the next step without purification. ESI-MS (m / z): 371.2 [M+H] + ;

[0265] Second step: The residue INT-1b from the previous step was added to methanol (2 L), and 360 g of 33% sodium hydroxide aqueous solution was added. The mixture was stirred at 20 °C for 17 hours. After the reaction was completed, water (1 L) was added, and methanol was removed under reduced pressure. The residue was extracted with petroleum ether (1 L*5), and the water phase was adjusted to pH 4-5 with hydrochloric acid. A large amount of white solid was precipitated, and stirring was continued for 30 minutes. Filtration and drying gave white solid INT-1c (269 g, yield 90%). ESI-MS (m / z): 357.8 [M+H] + ;

[0266] Third step: INT-1c (130 g, 364.63 mmol) was dissolved in dichloromethane (500 mL), and dichlorosulfoxide (130.1 g, 1.09 mol, 79.35 mL) was added at room temperature. N,N-dimethylformamide (0.05 ml) was added dropwise, and stirring was continued at 60 °C for 3 hours. After the reaction was completed, dichloromethane and the remaining dichlorosulfoxide were removed under reduced pressure. The residue was added to petroleum ether (300 mL) and distilled until no distillate was obtained. This was repeated 2-3 times, and finally a light yellow oil INT-1d was obtained. Dichloromethane (200 mL) was added and used as is.

[0267] Fourth step: 5-bromoindole INT-1e (64.8 g, 331 mmol) was dissolved in dichloromethane (400 mL), and diethylaluminum chloride solution (198 mL, 396 mmol, 2M in hexanes) was added at 0 °C. After the addition was completed, stirring was continued for 30 minutes, and the dichloromethane solution of INT-1d obtained above was added dropwise to the reaction bottle. After the addition was completed, stirring was continued for 2 hours. After the reaction was completed, the reaction solution was slowly poured into 1 L of an ice-cold aqueous solution of potassium sodium tartrate (3 eq), and stirring was continued for 5 hours. After the system was stabilized, dichloromethane was removed under reduced pressure, and the residue was extracted with ethyl acetate (1 L*2) and washed with water. The organic phase was concentrated by rotary evaporation to give a brown oil. The oil was added to a mixture of petroleum ether / ethyl acetate = 10 / 1 (2 L), and a solid was precipitated by stirring at 20 °C. Filtration gave yellow solid INT-1f (139 g, yield 78%). ESI-MS (m / z): 534.8 [M+H] + ;

[0268] Fifth step: INT-1f (100 g, 187.07 mmol) was dissolved in tetrahydrofuran (500 mL), and lithium borohydride (12.23 g, 561.21 mmol) was added under ice bath conditions. After the addition was completed, the system was stirred for 20 minutes, and then warmed to 60°C and stirred overnight. After the raw material disappeared, the reaction solution was slowly added to ice water (200 mL) for quenching, extracted with ethyl acetate (500 mL*3), and the organic phase was washed with water, dried, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (500 mL), 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid diethyl ester (28.43 g, 112.24 mmol) and p-toluenesulfonic acid (21.35 g, 112.24 mmol) were added, and stirred at room temperature for 3 hours. After the reaction was completed, the dichloromethane was removed by reduced pressure concentration, and the residue was dissolved in methanol (500 mL). A previously prepared 14% aqueous lithium hydroxide solution (100 mL) was added, and stirred at room temperature for 3 hours. The filtrate was dried at room temperature to obtain yellow solid INT-1g (84 g, yield 86.26%). ESI-MS (m / z): 520.2 [M+H] + ;

[0269] Sixth step: INT-1g (50 g, 96 mmol) was dissolved in tetrahydrofuran (250 mL), and tetrabutylammonium fluoride (197 mL, 1M in THF) was added. The mixture was stirred at 60°C overnight. After the reaction was completed, the reaction solution was added to water (300 mL), extracted with ethyl acetate (200 mL*3), washed with water, and concentrated under reduced pressure to obtain a brown oil. The residue was dissolved in methanol (40 mL), and water (20 mL) was added. The mixture was washed with petroleum ether (40 mL*5), and concentrated under reduced pressure to remove methanol. The residue was extracted with ethyl acetate (50 mL*2), and the organic phase was washed with water and dried to obtain yellowish oil INT-1h (25 g, yield 90.40%). ESI-MS (m / z): 282.8 [M+H] + ;

[0270] Seventh step: Compound INT-1h (25 g, 88.7 mmol) was dissolved in dioxane (250 mL), potassium acetate (21.7 g, 221.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (3.24 g, 4.4 mmol), neopentyl glycol diborate (24.1 g, 106.4 mmol) were added, and the mixture was stirred at 90 °C under nitrogen protection for 4 h. LCMS was used to monitor the reaction. When the reaction was completed, the mixture was filtered through celite, and the filtrate was concentrated. Dichloromethane (200 mL) was added to the concentrated solution, and 15% sodium hydroxide aqueous solution (17.7 g, 3548 mmol) was added. The mixture was concentrated under reduced pressure until the aqueous phase was clear. The aqueous phase was extracted with dichloromethane once, and the pH of the aqueous phase was adjusted to 3-4 with hydrochloric acid under ice bath conditions. A large amount of yellow solid was precipitated. The mixture was stirred for another 30 min, and the yellow solid was collected by filtration to obtain compound INT-1i (17.96 g, yield 82.1%). ESI-MS (m / z): 248.4 [M+H] + ;

[0271] Eighth step: Compound INT-1i (35 g, 142 mmol) and compound INT-1k (51.8 g, 142 mmol) were dissolved in dioxane (350 mL) and water (17.5 mL), and potassium carbonate (39.2 g, 284 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (5.2 g, 7.1 mmol) were added. The mixture was stirred at 90 °C under nitrogen protection for 17 h. LCMS was used to monitor the reaction. When the reaction was completed, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water, and dried to obtain brown oil compound INT-1j. The compound was used directly in the next step without further purification. ESI-MS (m / z): 488.4 [M+H] + ;

[0272] Ninth step: Compound INT-1j (62.3 g, 142 mmol) was dissolved in dichloromethane (700 mL). 4-Dimethylaminopyridine (866 mg, 7.1 mmol) and triethylamine (43.0 g, 426 mmol) were added, and acetic anhydride (14.5 g, 142 mmol) was added dropwise at 0 °C. After the addition was completed, the ice bath was removed, and the mixture was allowed to warm to room temperature. The mixture was stirred for 1-2 h. After the reaction was completed, the mixture was washed with water, dried, and concentrated to obtain brown oil. The brown oil was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain yellow oil compound INT-1l (62.3 g, yield 83.2%). ESI-MS (m / z): 530.5 [M+H] + ;

[0273] Step 10: Compound INT-11 (62.3 g, 117.9 mmol) was dissolved in N,N- dimethylformamide (620 mL), N-iodosuccinimide (26.5 g, 117.9 mmol) was added, and the reaction was stirred at 10 °C overnight. LCMS monitoring showed that the starting material was completely consumed. The reaction solution was slowly poured into ice water (3000 mL). A solid was precipitated upon stirring. Filtration, washing with water, and air-drying gave yellow solid compound INT-1m (64.2 g, yield 87%). ESI-MS (m / z): 656.3 [M+H] + ;

[0274] Step 11: Compound INT-1m (64 g, 99.1 mmol) was dissolved in tetrahydrofuran (640 mL) and water (128 mL). Lithium hydroxide monohydrate (11.86 g, 282.4 mmol) was added, and the reaction was stirred at 70 °C for 1 h. LCMS monitoring showed that the starting material was completely consumed. Water (300 mL) was added to the reaction solution, which was then concentrated under reduced pressure. Methyltetrahydrofuran (200 mL) was added, and the pH was adjusted to 4-5 with 4 M hydrochloric acid. The organic phase was extracted with methyltetrahydrofuran (200 mL*3), washed with brine 3 times, and thoroughly rotary-evaporated to give yellow solid compound INT-1n (56.5 g, yield 95%). ESI-MS (m / z): 600.5 [M+H] + ;

[0275] Step 12: Compound INT-1n (57 g, 95.0 mmol), 1-methylimidazole (38.9 g, 475 mmol), and (S)-methyl hexahydro pyridazine-3-carboxylate trifluoroacetate (52.7 g, 142.5 mmol) were dissolved in acetonitrile (800 mL). A solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (40.0 g, 142.5 mmol) in acetonitrile (400 mL) was added dropwise at 0 °C. After the addition was complete, the reaction was stirred for 1 h. LCMS monitoring showed that the starting material was completely consumed. Water (1000 mL) was added to the reaction solution, which was extracted with dichloromethane (1000 mL*3). Rotary-evaporation gave yellow solid compound INT-1o (56.5 g, yield 95%). ESI-MS (m / z): 726.3 [M+H] + ;

[0276] Thirteenth step: Compound INT-1o (56.5 g, 77.8 mmol) was dissolved in tetrahydrofuran (560 mL) and water (112 mL), lithium hydroxide (4.66 g, 194.7 mmol) was added, and the reaction was carried out at 10 °C for 2 hours. LCMS monitoring showed that the reaction was complete. Water (300 mL) was added, and the pH was adjusted to 5-6 with 4M hydrochloric acid. After extraction with methyl tetrahydrofuran and washing with brine, the layers were separated. The solvent was completely removed by rotary evaporation to obtain yellow solid compound INT-1p (55.4 g, yield 88.16%). ESI-MS (m / z): 712.6 [M+H] + ;

[0277] Fourteenth step: N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (59.1 g, 210.8 mmol) and 1-methylimidazole (26.5 g, 323.2 mmol) were added to acetonitrile (2000 mL), and the solution was stirred clear. A THF solution of compound INT-1p (100 g / 1000 mL, 140.5 mmol) was added dropwise at 10-20 °C. After the dropwise addition was completed, the reaction was stirred for 1-2 hours. LCMS monitoring showed that the reaction was complete. The solvent was removed by rotary evaporation, and water (1000 mL) was added to the residue. The residue was extracted with dichloromethane (1000 mL*3), and the pH was adjusted to 3-4 with hydrochloric acid. The organic phase was rotary evaporated to obtain a yellow solid. Recrystallization with isopropanol yielded compound INT-1q (59 g, yield 60%). ESI-MS (m / z): 694.6 [M+H] + ;

[0278] Fifteenth step: Compound INT-1q (37 g, 53.35 mmol), 2-dicyclohexylphosphino-2',6'-dimethyl-biphenyl (6.6 g, 16.0 mmol), tris(dibenzylideneacetone)dipalladium (5.86 g, 6.40 mmol), and potassium acetate (18.3 g, 186.7 mmol) were dissolved in toluene (370 mL), and pinacolborane (34.1 g, 266.7 mmol, 38.7 mL) was added under nitrogen protection. After the dropwise addition was completed, the reaction was carried out at 50 °C for 3 hours under nitrogen protection. LCMS monitoring showed that the reaction was complete. The reaction solution was filtered, and the filtrate was purified by silica gel column chromatography to obtain yellow solid compound INT-1 (31 g, yield 82%). ESI-MS (m / z): 694.8 [M+H] + .

[0279] Intermediate 2

[0280] Intermediate 2 was prepared by the following steps:

[0281] Step 1: Compound INT-2a (43 g, 199 mmol), bis(pinacolato)diboron (55.6 g, 219 mmol), methoxy(cyclooctadiene)iridium dimer (1.30 g, 1.99 mmol) and 4,4-di-tert-butyl-2,2'-bipyridyl (2.67 g, 9.95 mmol) were added to tetrahydrofuran (500 mL) and the reaction was stirred at 75 °C under nitrogen for 16 hours. LCMS monitoring showed that the starting material was completely converted. The excess tetrahydrofuran was removed by rotary evaporation to obtain a brown residue INT-2b, which was used directly in the next step without purification. ESI-MS (m / z): 358.3 [M+H] + .

[0282] Step 2: The residue INT-2b from the previous step was added to methanol (200 mL), and concentrated hydrochloric acid (100 mL) was added. The reaction was refluxed for 3 hours. LCMS monitoring showed that the starting material was consumed. The methanol was removed by rotary evaporation. Water (200 mL) was added to the residue, and the pH was adjusted to 13 with a 30% sodium hydroxide solution. The mixture was extracted with dichloromethane to remove impurities. The aqueous phase was cooled to 0-5 °C, and the pH was adjusted to 6-7 with hydrochloric acid. The solid was washed out by further stirring. The solid was filtered and air-dried to obtain white solid compound INT-2c (41.3 g, yield 80%). ESI-MS (m / z): 276.3 [M+H] + .

[0283] Step 3: Compound INT-2c (41.3 g, 159 mmol) was added to acetonitrile (400 mL), and N-iodosuccinimide (35.8 g, 239 mmol) was added. The reaction was stirred at 80 °C overnight. LCMS monitoring showed that the starting material was consumed. The acetonitrile was removed by rotary evaporation. The residue was added to ethyl acetate (300 mL), washed with water, dried, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain white solid compound INT-2 (45.6 g, yield 85%). ESI-MS (m / z): 358.1 [M+H] + .

[0284] Intermediate 3

[0285] Intermediate 3 was prepared by the following steps:

[0286] Step 1: Dissolve (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine INT-2 (20 g, 58.5 mmol) in tetrahydrofuran (200 mL), and add cuprous iodide (1.11 g, 5.85 mmol), dichlorobis(triphenylphosphine)palladium (4.1 g, 5.85 mmol), triethylamine (11.8 g, 117 mmol) and 4-propyn-1-morpholine INT-3a (8.78 g, 70.2 mmol) successively. Stir the reaction mixture at room temperature for 3 hours under nitrogen protection. After the reaction is completed, concentrate the reaction solution under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / ethyl acetate = 1 / 1) to obtain compound INT-3 (18 g, yield 90.7%) in light yellow oil. ESI-MS (m / z): 339.4 [M+H] + .

[0287] Intermediate 4

[0288] Intermediate 4 is prepared by the following steps:

[0289] Step 1: Dissolve compound INT-1 (18.4 g, 26.5 mmol) in a mixed solution of 1,4-dioxane (200 mL) and water (40 mL), and add INT-1 (9 g, 26.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.94 g, 2.65 mmol) and potassium phosphate (16.9 g, 79.6 mmol) successively. Stir the reaction mixture at 70°C for 16 hours under nitrogen protection. After the reaction is completed, add water (200 mL) to the reaction system, extract with ethyl acetate (200 mL*2), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate, and purify the residue by silica gel column chromatography (ethyl acetate) to obtain compound INT-4a (18.6 g, yield 85%) in light yellow solid. ESI-MS (m / z): 826.7 [M+H] + .

[0290] Second step: Compound INT-4a (18 g, 21.8 mmol) was dissolved in N,N- dimethylformamide (180 mL), and cesium carbonate (28.4 g, 87.2 mmol) and iodoethane (10.2 g, 65.4 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (1000 mL) was added to the reaction system, extracted with ethyl acetate (500 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative liquid chromatography to obtain compound INT-4b (6.5 g, yield 35%, LC-MS retention time RT=1.95 min) as a light yellow solid and its atropisomer compound INT-4b' (9.8 g, yield 52.5%, LC-MS retention time RT=1.92 min) as a light yellow solid. ESI-MS (m / z): 854.7 [M+H] + .

[0291] Third step: Compound INT-4b (6.5 g, 7.6 mmol) was dissolved in dichloromethane (35 mL), and trifluoroacetic acid (35 mL) was added under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust PH=8, extracted with dichloromethane (100 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-4 (5.4 g, yield 95%) as a light yellow solid. ESI-MS (m / z): 754.7 [M+H] + .

[0292] Intermediate 5

[0293] Intermediate 5 was prepared by the following steps:

[0294] First step: Compound INT-5a (1 g, 8.8 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride monoethyl ester (1.21 g, 8.8 mmol) and N,N- diisopropylethylamine (983 mg, 9.72 mmol) were added under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction liquid was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain compound INT-5b (1.35 g, yield 71.7%) as a colorless oil. ESI-MS (m / z): 214.2 [M+H] + .

[0295] Second Step: Dissolve compound INT-5b (660 mg, 3.1 mmol) in tetrahydrofuran (5 mL) and water (5 mL), add lithium hydroxide (89 mg, 3.7 mmol) under ice bath. Stir the reaction mixture at room temperature for 2 hours. After the reaction is complete, lyophilize the reaction solution to obtain white solid compound INT-5 (573 mg, yield 100%). ESI-MS (m / z): 186.2 [M+H] + .

[0296] Intermediate 6

[0297] Replace INT-5a in the synthesis step of intermediate INT-5 with cyclopropylmethylamine, compound INT-6 can be obtained by similar methods and reaction steps. ESI-MS (m / z): 144.2 [M+H] + .

[0298] Intermediate 7

[0299] Replace INT-5a in the synthesis step of intermediate INT-5 with piperidine, compound INT-7 can be obtained by similar methods and reaction steps. ESI-MS (m / z): 158.2 [M+H] + .

[0300] Intermediate 8

[0301] Replace INT-5a in the synthesis step of intermediate INT-5 with aniline, compound INT-8 can be obtained by similar methods and reaction steps. ESI-MS (m / z): 166.2 [M+H] + .

[0302] Intermediate 9

[0303] Replace INT-5a in the synthesis step of intermediate INT-5 with benzylamine, compound INT-9 can be obtained by similar methods and reaction steps. ESI-MS (m / z): 180.2 [M+H] + .

[0304] Intermediate 10

[0305] Replace INT-5a in the synthesis step of intermediate INT-5 with N-methylpiperazine, compound INT-10 can be obtained by similar methods and reaction steps. ESI-MS (m / z): 173.2 [M+H] + .

[0306] Intermediate 11

[0307] Intermediate 11 was prepared from the following steps:

[0308] Step 1: Compound INT-11a (3.54 g, 16.1 mmol) was dissolved in toluene (50 mL), and INT-2 (5 g, 14.6 mmol), palladium acetate (328 mg, 1.46 mmol), 1,1'-binaphthalene-2,2'-diphenylphosphine (1.82 g, 2.92 mmol) and cesium carbonate (11.9 g, 36.6 mmol) were added successively. The reaction mixture was stirred at 100 °C for 16 h under nitrogen protection. After the reaction was completed, diatomite was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound INT-11b (4.5 g, yield 70.9%) as a light yellow solid. ESI-MS (m / z): 434.2 [M+H] + .

[0309] Step 2: Compound INT-11b (420 mg, 0.97 mmol) was dissolved in a mixed solution of 1,4-dioxane (10 mL) and water (2 mL), and INT-1 (670 mg, 0.97 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (71 mg, 0.097 mmol) and potassium phosphate (615 mg, 2.9 mmol) were added successively. The reaction mixture was stirred at 70 °C for 16 h under nitrogen protection. After the reaction was completed, water (20 mL) was added to the reaction system, extracted with ethyl acetate (20 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative thin layer chromatography (ethyl acetate) to obtain compound INT-11c (820 mg, yield 92.2%) as a light yellow solid. ESI-MS (m / z): 921.7 [M+H] + .

[0310] Step 3: Compound INT-11c (820 mg, 0.89 mmol) was dissolved in N,N- dimethylformamide (10 mL), to which cesium carbonate (870 mg, 2.67 mmol) and iodoethane (278 mg, 1.78 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (50 mL) was added to the reaction system, which was extracted with ethyl acetate (50 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain white solid compound INT-11d (150 mg, yield 17.8%, LC-MS retention time RT = 2.06 min) and its atropisomer yellowish solid compound INT-11d' (300 mg, yield 35.6%, LC-MS retention time RT = 2.05 min). ESI-MS (m / z): 949.7 [M+H] + .

[0311] Step 4: Compound INT-11d (150 mg, 0.16 mmol) was dissolved in methanol (5 mL), to which palladium hydroxide (30 mg) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. After the reaction was completed, it was filtered with diatomite, and the filtrate was concentrated to obtain white solid compound INT-11 (117 mg, yield 90%). ESI-MS (m / z): 815.7 [M+H] + .

[0312] Intermediate 12

[0313] Intermediate 12 was prepared by the following steps:

[0314] Step 1: Compound INT-11 (270 mg, 0.33 mmol) was dissolved in acetonitrile (5 mL), to which 2-bromoethyl methyl ether (55 mg, 0.40 mmol), potassium carbonate (46 mg, 0.33 mmol) and potassium iodide (55 mg, 0.33 mmol) were added in sequence. The reaction mixture was stirred at 60°C for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction system, which was extracted with ethyl acetate (20 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain white solid compound INT-12a (230 mg, yield 79.5%). ESI-MS (m / z): 873.7 [M+H] + .

[0315] Second Step: Compound INT-12a (230 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added into the solution under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added into the reaction system under ice bath to adjust pH = 8, extracted with dichloromethane (30 mL*2), the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-12 (190 mg, yield 93.3%) as a light yellow solid. ESI-MS (m / z): 773.8 [M+H] + .

[0316] Intermediate 13

[0317] Intermediate 13 was prepared by the following steps:

[0318] First Step: Compound INT-11 (300 mg, 0.37 mmol) was dissolved in methanol (10 mL), formaldehyde aqueous solution (0.1 mL) was added into the reaction solution dropwise at room temperature, and the reaction solution was stirred at room temperature for 10 minutes. Then sodium cyanoborohydride (46 mg, 0.74 mmol) was slowly added into the reaction solution, and the reaction solution was continuously stirred at room temperature for 3 hours. LCMS detection showed that the reaction was complete. Saturated ammonium chloride aqueous solution was added into the reaction system to quench the reaction, extracted with dichloromethane, and the organic phase was combined and concentrated to obtain compound INT-13a (250 mg, yield 81.9%) as a white solid. ESI-MS (m / z): 829.8 [M+H] + .

[0319] Second Step: Compound INT-13a (250 mg, 0.3 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added into the solution under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added into the reaction system under ice bath to adjust pH = 8, extracted with dichloromethane (30 mL*2), the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-13 (190 mg, yield 86.4%) as a light yellow solid. ESI-MS (m / z): 729.8 [M+H] + .

[0320] Intermediate 14

[0321] Compound INT-14 can be obtained by replacing INT-5a in the synthesis step of intermediate INT-5 with morpholine, using similar methods and reaction steps. ESI-MS (m / z): 160.2 [M+H] + .

[0322] Intermediate 15

[0323] Intermediate 15 was prepared from the following steps:

[0324] Step 1: Compound INT-2 (300 mg, 0.88 mmol) was dissolved in ethanol (5 mL) and water (2 mL), and cuprous iodide (17 mg, 0.088 mmol), sodium ascorbate (8.7 mg, 0.044 mmol), N,N'-dimethylethylenediamine (12 mg, 0.13 mmol) and sodium azide (68 mg, 1.05 mmol) were added successively. The reaction mixture was stirred at 50 °C for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction system, extracted with ethyl acetate (20 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain white solid compound INT-15a (164 mg, yield 72.7%). ESI-MS (m / z): 257.2 [M+H] + .

[0325] Step 2: Compound INT-15a (164 mg, 0.64 mmol) was dissolved in tert-butyl alcohol (2 mL) and water (2 mL), and 4-propyn-1-morpholine (240 mg, 1.91 mmol), sodium ascorbate (632 mg, 3.19 mmol), and copper sulfate (509 mg, 3.19 mmol) were added successively. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction system, extracted with ethyl acetate (20 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound INT-15 (164 mg, yield 67.3%) in light yellow oil. ESI-MS (m / z): 382.3 [M+H] + .

[0326] Intermediate 16

[0327] Intermediate 16 was prepared from the following steps

[0328] Step 1: Compound INT-16a (1.0 g, 7.93 mmol) was dissolved in ethanol (10 mL) and water (5 mL), hydroxylamine hydrochloride (2.2 g, 31.7 mmol) and sodium carbonate (2.52 g, 23.8 mmol) were added successively. The reaction was stirred at 90 °C overnight. LCMS was used to monitor the reaction. The reaction was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-16b (901 mg, yield 71.4%) as a white solid. ESI-MS (m / z): 160.2 [M+H] + .

[0329] Step 2: Compound INT-2 (20 g, 58.5 mmol) and vinylboronic acid pinacol ester (10.8 g, 70.2 mmol) were dissolved in 1,4-dioxane (120 mL) and water (12 mL), potassium carbonate (16.2 g, 117.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (2.12 g, 2.92 mmol) were added. The reaction was stirred at 60 °C overnight under N2 protection. LCMS was used to monitor the reaction. The excess solvent was removed by distillation under reduced pressure. The residue was added to water (100 mL) and extracted with ethyl acetate (100 mL*3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound INT-16c (13 g, yield 92.0%) as a white solid. ESI-MS (m / z): 242.2 [M+H] + .

[0330] Step 3: Compound INT-16c (13 g, 53.69 mmol) was dissolved in tetrahydrofuran (300 mL), water (100 mL) was added and stirred, sodium periodate (28.7 g, 134.2 mmol) and potassium osmate (157.50 mg, 536.9 umol) were added. The reaction was stirred at 40 °C for 3 hours. LCMS was used to monitor the reaction. The reaction was separated into water and organic phases. The organic phase was extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-16d (11.2 g, yield 85.5%) as a white solid. ESI-MS (m / z): 244.5 [M+H] + .

[0331] Fourth step: Compound INT-16d (500 mg, 2.05 mmol) was dissolved in formic acid (2 mL), hydrogen peroxide (697 mg, 20.5 mmol) was added under ice bath, the reaction was continued to stir for 6 hours under ice bath, LCMS was used to monitor the reaction of the raw material until complete. Water was added to the system, extracted with dichloromethane, dried organic phase, dried with anhydrous sodium sulfate, filtered and concentrated to obtain white solid compound INT-16e (500 mg, yield 93.9%). ESI-MS (m / z): 260.4 [M+H] + .

[0332] Fifth step: Compound INT-16e (220 mg, 0.85 mmol) was dissolved in N,N- dimethylformamide (4 mL), INT-16b (202 mg, 1.27 mmol), 2-(7-azobenzo triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (482 mg, 1.27 mmol) and N,N- diisopropyl ethylamine (328 mg, 2.54 mmol) were added in turn, the reaction was stirred at 60°C for 16 hours, LCMS was used to monitor the reaction of the raw material until complete, water was added to the system, extracted with dichloromethane, dried organic phase, dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-16 (38 mg, yield 11.7%) in light yellow oil. ESI-MS (m / z): 383.4 [M+H] + .

[0333] Intermediate 17

[0334] Intermediate 17 was prepared by the following steps:

[0335] First step: Compound INT-17a (38 mg, 0.19 mmol) was dissolved in toluene (2 mL), INT-2 (50 mg, 0.15 mmol), palladium acetate (3 mg, 0.015 mmol), 1,1'- binaphthalene-2,2'-bis diphenylphosphine (18 mg, 0.03 mmol) and cesium carbonate (119 mg, 0.37 mmol) were added in turn. The reaction mixture was stirred at 100°C under nitrogen protection for 16 hours. After the reaction was completed, diatomite was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound INT-17 (30 mg, yield 49.5%) in light yellow solid. ESI-MS (m / z): 404.2 [M+H] + .

[0336] Intermediate 18

[0337] Using (cyclopropylmethyl)methylamine to replace INT-5a in the synthesis of intermediate INT-5, compound INT-18 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 158.2 [M+H] + .

[0338] Intermediate 19

[0339] Using tetrahydropyrrole to replace INT-5a in the synthesis of intermediate INT-5, compound INT-19 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 144.2 [M+H] + .

[0340] Intermediate 20

[0341] Using cyclopropylamine to replace INT-5a in the synthesis of intermediate INT-5, compound INT-20 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 130.2 [M+H] + .

[0342] Intermediate 21

[0343] Using cyclohexylamine to replace INT-5a in the synthesis of intermediate INT-5, compound INT-21 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 172.2 [M+H] +

[0344] Intermediate 22

[0345] Using azetidine to replace INT-5a in the synthesis of intermediate INT-5, compound INT-22 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 130.2 [M+H] +

[0346] Intermediate 23

[0347] Intermediate 23 is prepared from the following steps:

[0348] Step 1 : Compound INT-23a (42 mg, 0.48 mmol) was dissolved in N,N- dimethylformamide (2 mL), followed by the addition of INT-2 (150 mg, 0.44 mmol), cuprous iodide (4 mg, 0.022 mmol), N,N'-dimethylethylenediamine (4 mg, 0.044 mmol) and potassium phosphate (186 mg, 0.88 mmol). The reaction mixture was subjected to microwave reaction at 120 °C for 2 hours under nitrogen protection. After the reaction was completed, diatomite was used for filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 4) to obtain compound INT-23 (120 mg, yield 90.9%) in light yellow solid. ESI-MS (m / z): 301.2 [M+H] + .

[0349] Intermediate 24

[0350] Compound INT-24 was obtained by replacing INT-17a in the synthesis step of intermediate INT-17 with 1-methylpiperazin-2-one, using similar methods and reaction steps. ESI-MS (m / z): 328.2 [M+H] + .

[0351] Intermediate 25

[0352] Intermediate 25 was prepared by the following steps:

[0353] Step 1 : Compound INT-25a (500 mg, 5 mmol) was dissolved in toluene (5 mL), followed by the addition of benzyl alcohol (810 mg, 7.5 mmol), diphenyl phosphorazide (1.65 g, 6 mmol) and N,N-diisopropylethylamine (968 mg, 7.5 mmol). The reaction mixture was subjected to reaction at 110 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain compound INT-25b (750 mg, yield 73.2%) in colorless oil. ESI-MS (m / z): 206.2 [M+H] + .

[0354] Second Step: Compound INT-25b (150 mg, 0.73 mmol) was dissolved in methanol (5 mL), to which palladium hydroxide (30 mg) and hydrochloric acid dioxane (0.37 mL, 1.46 mmol, 4M) were added. The reaction mixture was stirred at room temperature for 16 hours under hydrogen atmosphere. After the reaction was completed, it was filtered with diatomite, and the filtrate was concentrated to obtain white solid compound INT-25c (78 mg, yield 99.2%). ESI-MS (m / z): 72.2 [M+H] + .

[0355] Using INT-25c to replace INT-5a in the synthesis steps of intermediate INT-5, compound INT-25 can be obtained by similar methods and reaction steps. ESI-MS (m / z): 144.2 [M+H] + .

[0356] Intermediate 26

[0357] Intermediate 26 was prepared by the following steps:

[0358] First Step: Compound INT-26a (200 mg, 1.37 mmol) was dissolved in dichloromethane (6 mL), and acetone (88 mg, 1.51 mmol), acetic acid (25 mg, 0.41 mmol), magnesium sulfate (99 mg, 0.82 mmol) and sodium triacetoxyborohydride (871 mg, 4.11 mmol) were added in turn. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, saturated sodium bicarbonate solution (20 mL) was added, extracted with ethyl acetate (20 mL*2), the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain colorless oil compound INT-26b (257 mg, yield 100%). ESI-MS (m / z): 189.3 [M+H] + .

[0359] Using INT-26b to replace INT-5a in the synthesis steps of intermediate INT-5, compound INT-26 can be obtained by similar methods and reaction steps. ESI-MS (m / z): 261.2 [M+H] + .

[0360] Intermediate 27

[0361] Compound INT-27 was obtained by replacing INT-17a in the synthesis of intermediate INT-17 with (S)-octahydro-pyrazino[2,1-c][1,4]oxazinedihydrochloride, using similar procedures and reaction steps. ESI-MS (m / z): 372.3 [M+H] + .

[0362] Intermediate 28

[0363] Intermediate 28 was prepared by the following steps:

[0364] First step: Compound INT-28a (500 mg, 2.65 mmol) was dissolved in dichloromethane (5 mL), N,N-diisopropylethylamine (513 mg, 3.97 mmol) and methanesulfonic anhydride (553 mg, 3.17 mmol) were added successively under ice bath. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, water (20 mL) was added to the reaction system, extracted with dichloromethane (20 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give brown solid compound INT-28b (687 mg, yield 97.2%). ESI-MS (m / z): 267.2 [M+H] + .

[0365] Second step: Compound INT-28b (687 mg, 2.57 mmol) was dissolved in morpholine (5 mL), N,N-diisopropylethylamine (997 mg, 7.72 mmol) was added under ice bath. The reaction mixture was stirred at room temperature for 8 hours. After the reaction was completed, water (20 mL) was added to the reaction system, extracted with dichloromethane (20 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give brown solid compound INT-28c (600 mg, yield 90.4%). ESI-MS (m / z): 258.2 [M+H] + .

[0366] Third step: Compound INT-28c (300 mg, 1.16 mmol) was dissolved in 1,4-dioxane (5 mL), pinacol diboronic acid (325 mg, 1.28 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (85 mg, 0.12 mmol) and potassium acetate (342 mg, 3.49 mmol) were added successively. The reaction mixture was stirred at 100°C under N2 protection overnight, LCMS monitoring showed that the raw material was completely reacted, filtered with diatomite, the filtrate was concentrated to give black solid crude compound INT-28d, which was used directly in the next step reaction without purification. ESI-MS (m / z): 306.3 [M+H]+ .

[0367] Fourth Step: The crude compound INT-28d obtained above was dissolved in 1,4-dioxane (5 mL) and water (0.5 mL), and INT-2 (320 mg, 0.91 mmol), potassium carbonate (376 mg, 2.72 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (66 mg, 0.12 mmol) were added successively. The reaction was stirred at 50 °C under N2 protection overnight. LCMS monitoring showed that the reaction was complete. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound INT-28 (332 mg, yield 93.1%) as a light yellow solid. ESI-MS (m / z): 393.3 [M+H] + .

[0368] Intermediate 29

[0369] Intermediate 29 was prepared by the following steps:

[0370] First Step: Compound INT-29a (400 mg, 4.08 mmol) was dissolved in water (8 mL), and sodium hydroxide (326 mg, 8.15 mmol) and potassium permanganate (1.16 g, 7.34 mmol) were added successively in batches under ice bath. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, it was filtered, and the filter residue was washed with water. The water phase was adjusted to PH ≈ 2 with hydrochloric acid, extracted with dichloromethane (20 mL*2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound INT-29 (209 mg, yield 40%) as a colorless oil. ESI-MS (m / z): 129.2 [M+H] + .

[0371] Intermediate 30

[0372] Intermediate 30 was prepared by the following steps:

[0373] Step 1: Dissolve oxalyl diethyl ester (2 g, 13.7 mmol) in tetrahydrofuran (20 mL), drop INT-30a (12.3 mL, 1 mol / L in THF) solution in tetrahydrofuran at -78 °C. After the drop is completed, the reaction mixture is stirred at this temperature for 2 hours. After the reaction is complete, add saturated ammonium chloride solution to quench the reaction. Extract with ethyl acetate (50 mL*2), combine the organic phase, and wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound INT-30 (1.2 g, yield 51.5%) as colorless oil. ESI-MS (m / z): 171.2 [M+H] + .

[0374] Step 2: Dissolve compound INT-30b (300 mg, 1.76 mmol) in tetrahydrofuran (3 mL) and water (3 mL), add lithium hydroxide monohydrate (148 mg, 3.53 mol). The reaction mixture is stirred at room temperature for 2 hours. After the reaction is complete, the reaction is lyophilized to obtain white solid compound INT-30 (250 mg, yield 95.8%). ESI-MS (m / z): 143.2 [M+H] + .

[0375] Intermediate 31

[0376] Intermediate 31 is prepared by the following steps:

[0377] Step 1: Dissolve compound INT-2 (5 g, 14.6 mmol) in N,N-dimethylformamide (50 mL), add zinc cyanide (1.03 g, 8.8 mmol) and tetrakis(triphenylphosphine)palladium (1.69 g, 1.46 mmol) in turn. Stir overnight under nitrogen protection at 100 °C, monitor the complete reaction of the raw material by LCMS, add ammonia water (5 mL) to quench the reaction, extract with ethyl acetate (200 mL*2), combine the organic phase, and wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain white solid compound INT-31a (2.1 g, yield 59.6%). ESI-MS (m / z): 241.2 [M+H] + .

[0378] Second Step: Compound INT-31a (150 mg, 0.62 mmol) was dissolved in ethanol (6 mL), hydroxylamine hydrochloride (86 mg, 1.24 mmol) and triethylamine (126 mg, 1.24 mmol) were added successively. The reaction was stirred at 80 °C for 3 h. LCMS was used to monitor the reaction. The reaction was completed. The reaction was concentrated to give the crude compound INT-31b as colorless oil. The crude compound was used directly in the next step without purification. ESI-MS (m / z): 274.2 [M+H] + .

[0379] Third Step: The crude compound INT-31b obtained above was dissolved in toluene (5 mL), chloroacetic anhydride (213 mg, 1.24 mmol) was added. The reaction was stirred at 110 °C for 16 h. LCMS was used to monitor the reaction. The reaction was completed. Water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL*2). The organic phase was combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the compound INT-31c (110 mg, yield 53.2%) as colorless oil. ESI-MS (m / z): 332.2 [M+H] + .

[0380] Fourth Step: Compound INT-31c (60 mg, 0.18 mmol) was dissolved in ethanol (6 mL), sodium iodide (27 mg, 0.18 mmol) and morpholine (16 mg, 0.18 mmol) were added. The reaction was stirred at 80 °C for 3 h. LCMS was used to monitor the reaction. The reaction was completed. The reaction was concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 20 / 1) to give the compound INT-31 (44 mg, yield 63.6%) as colorless oil. ESI-MS (m / z): 383.2 [M+H] + .

[0381] Intermediate 32

[0382] Intermediate 32 was prepared by the following steps:

[0383] First Step: Compound INT-16e (770 mg, 2.96 mmol) was dissolved in methanol (10 mL), thionyl chloride (1.06 g, 8.9 mmol) was added. The reaction was stirred at 70 °C for 3 h. LCMS was used to monitor the reaction. The reaction was completed. The reaction was concentrated to give the compound INT-32a (800 mg, yield 98.6%) as yellowish oil. ESI-MS (m / z): 274.1 [M+H] + .

[0384] Second Step: Compound INT-32a (600 mg, 2.19 mmol) was dissolved in ethanol (6 mL), hydrazine hydrate (329 mg, 6.57 mmol) was added. The reaction was stirred at 90 °C for 16 hours, LCMS was used to monitor the reaction. The reaction was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-32b (550 mg, yield 91.7%) as colorless oil. ESI-MS (m / z): 274.2 [M+H] + .

[0385] Third Step: Compound INT-32b (300 mg, 1.09 mmol) was dissolved in N,N- dimethylformamide (3 mL), morpholine acetic acid (238 mg, 1.64 mmol), 1- hydroxybenzotriazole (222 mg, 1.64 mmol), N,N-diisopropylethylamine (328 mg, 2.54 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (315 mg, 1.64 mmol) were added successively. The reaction was stirred at room temperature for 16 hours, LCMS was used to monitor the reaction. Water was added to the system, dichloromethane was used to extract, the organic phase was dried, anhydrous sodium sulfate was used to dry, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound INT-32c (350 mg, yield 79.7%) as yellow oil. ESI-MS (m / z): 401.3 [M+H] + .

[0386] Fourth Step: Compound INT-32c (350 mg, 0.87 mmol) was dissolved in tetrahydrofuran (2 mL), borogage reagent (208 mg, 0.87 mmol) was added. The reaction was stirred at 80 °C for 16 hours, LCMS was used to monitor the reaction. The reaction was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-32 (300 mg, yield 89.7%) as colorless oil. ESI-MS (m / z): 383.2 [M+H] + .

[0387] Intermediate 33

[0388] Compound INT-33 can be obtained by using N-methylcyclopropylamine hydrochloride to replace INT-5a in the synthesis of intermediate INT-5, using similar methods and reaction steps. ESI-MS (m / z): 144.2 [M+H] + .

[0389] Intermediate 34

[0390] Intermediate 34 is prepared by the following steps:

[0391] Step 1: Compound INT-34a (100 mg, 0.56 mmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and lithium hydroxide monohydrate (47 mg, 1.12 mol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was lyophilized to give a white compound INT-34 (84 mg, 100% yield). ESI-MS (m / z): 152.2 [M+H] + .

[0392] Intermediate 35

[0393] By replacing intermediate INT-5a in the synthesis step of INT-5 with N-ethylmethylamine, and using a similar method and reaction steps, compound INT-35 can be obtained. ESI-MS (m / z): 132.2 [M+H] + .

[0394] Intermediate 36

[0395] Intermediate 36 is prepared by the following steps:

[0396] Step 1: Compound INT-28a (300 mg, 1.59 mmol) was dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (513 mg, 3.97 mmol) and tert-butyldimethylchlorosilane (263 mg, 1.75 mmol) were added sequentially under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a colorless oily compound INT-36a (480 mg, 99.7% yield). ESI-MS (m / z): 303.2 [M+H] + .

[0397] Step 2: Compound INT-36a (233 mg, 0.77 mmol) was dissolved in 1,4-dioxane (3 mL) and water (3 mL), INT-2c (200 mg, 0.77 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (56 mg, 0.08 mmol) and sodium carbonate (245 mg, 2.31 mmol) were added successively. The reaction was stirred at 60 °C under nitrogen overnight. LCMS was used to monitor the reaction. When the starting material was consumed completely, the reaction was filtered through celite, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 30 / 1) to give compound INT-36 (80 mg, yield 23.7%) as a white solid. ESI-MS (m / z): 438.3 [M+H] + .

[0398] Intermediate 37

[0399] Compound INT-37 was obtained by replacing INT-34a in the synthesis of intermediate INT-34 with 2-(N-methoxy-N-methylamino)-2-oxoacetic acid ethyl ester, using similar methods and reaction procedures. ESI-MS (m / z): 134.2 [M+H] + .

[0400] Intermediate 38

[0401] Compound INT-38 was obtained by replacing INT-5a in the synthesis of intermediate INT-5 with 2-oxa-6-aza-spiro[3,3]heptane, using similar methods and reaction procedures. ESI-MS (m / z): 170.1 [M-H] - .

[0402] Intermediate 39

[0403] Intermediate 39 was prepared by the following steps:

[0404] Step 1 : Sodium hydride (134 mg, 3.35 mmol, 60% purity) was dissolved in tetrahydrofuran (5 mL) under nitrogen. INT-39b (264 mg, 2.58 mmol) was added and the reaction was stirred for 30 minutes in an ice bath. Then INT-39a (500 mg, 2.58 mmol) was added and the reaction was stirred for 2 hours in an ice bath. After the reaction was completed by LCMS, saturated ammonium chloride aqueous solution (20 mL) was added to the reaction system, extracted with ethyl acetate (20 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane) to obtain compound INT-39c (288 mg, yield 43.0%) as a brown solid. ESI-MS (m / z): 259.3 [M+H] + .

[0405] Step 2: Compound INT-39c (200 mg, 0.77 mmol) was dissolved in 1,4-dioxane (3 mL), and pinacol diborane (196 mg, 0.77 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (56 mg, 0.08 mmol) and potassium acetate (227 mg, 2.32 mmol) were added successively. The reaction system was replaced with nitrogen and heated to 100°C and stirred for 12 hours. After the raw material was completely reacted by LCMS, the reaction was cooled to room temperature, and the reaction was filtered with diatomite. The filtrate was concentrated to obtain compound INT-39d (236 mg, yield 99.9%) as a crude product. ESI-MS (m / z): 307.6 [M+H] + .

[0406] Step 3: Compound INT-39d (236 mg, 0.77 mmol) and compound INT-2 (220 mg, 0.64 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (47 mg, 0.06 mmol) and potassium carbonate (266 mg, 1.93 mmol) were added successively. The reaction system was replaced with nitrogen and heated to 50°C and stirred for 12 hours. After the raw material was completely reacted by LCMS, the reaction was cooled to room temperature, and the reaction was filtered with diatomite. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain INT-39 (182 mg, yield 71.9%) as a yellow oily liquid. ESI-MS (m / z): 394.4 [M+H] + .

[0407] Intermediate 40

[0408] Intermediate 40 was prepared by the following steps:

[0409] Step 1: Compound INT-16d (1.0 g, 4.10 mmol) was dissolved in ethanol (10 mL) and water (5 mL), then hydroxylamine hydrochloride (313.2 mg, 4.51 mmol) and sodium acetate (613.3 mg, 4.51 mmol) were added, stirred at room temperature for 1 hour, LCMS monitoring showed that the raw material was completely reacted, and light yellow solid compound INT-40a (1.06 g, yield 94.2%) was obtained by suction filtration. ESI-MS (m / z): 259.4 [M+H] + .

[0410] Step 2: Compound INT-40a (1.06 g, 3.86 mmol) was dissolved in tetrahydrofuran (15 mL), N-chlorosuccinimide (1.20 g, 9.01 mmol) was added, stirred at room temperature for 3 hours, LCMS monitoring showed that the raw material was completely reacted, added water (30 mL), extracted with ethyl acetate (20 mL*3), and the organic phase was concentrated to obtain light yellow solid compound INT-40b (1.1 g, yield 85.8%). ESI-MS (m / z): 293.0 [M+H] + .

[0411] Step 3: Intermediate INT-40b (739 mg, 3.75 mmol) and intermediate INT-40c (550 mg, 1.87 mmol) were dissolved in a mixed solvent of dichloromethane (7 mL) and water (7 mL), and sodium bicarbonate (472.2 mg, 5.62 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. LCMS detection showed that the reaction was completed. Saturated brine was added to the reaction system, dichloromethane was extracted, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain white solid compound INT-40 (625 mg, yield 73.4%). ESI-MS (m / z): 454.3 [M+H] + .

[0412] Intermediate 41

[0413] Intermediate 41 was prepared by the following steps:

[0414] Step 1: Compound INT-1 (500 mg, 0.72 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2.5 mL) was added to the solution under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust pH = 8, and ethyl acetate was added for extraction. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-41a (400 mg, yield 93.5%) as a light yellow solid. ESI-MS (m / z): 594.7

[0415] [M+H] + .

[0416] Step 2: Compound INT-41a (400 mg, 0.54 mmol) was dissolved in N,N-dimethylformamide (4 mL), 2-cyclopropyl-2-oxoacetic acid (114 mg, 1.08 mmol), N,N-diisopropyl ethylamine (139 mg, 1.08 mmol) and 2-(7-azobenzo triazole)-N,N,N',N'-tetramethyl urea hexafluorophosphate (307 mg, 0.81 mmol) were added to the solution in sequence. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added to the reaction system, and ethyl acetate was added for extraction. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to obtain compound INT-41 (350 mg, yield 94.1%) as a light yellow solid. ESI-MS (m / z): 690.6 [M+H] + .

[0417] Intermediate 42

[0418] Intermediate 42 was prepared by the following steps:

[0419] Step 1 : Compound INT-42a (200 mg, 2.04 mmol) was added dropwise to a solution of 1,4-diacetylpiperazine-2,5-dione (403.8 mg, 2.04 mmol) in tetrahydrofuran (4 mL) under nitrogen atmosphere, followed by dropwise addition of a solution of potassium tert-butoxide (228.7 mg, 2.04 mmol) in tert-butanol (4 mL) and stirred at room temperature for 3 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give a white solid. The solid was added to hydrochloric acid aqueous solution (6 N, 6 mL) and the reaction was stirred at 100 °C for 8 hours. LCMS monitoring showed the starting material was consumed completely, after cooling to room temperature, the reaction was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 9 / 1) to give compound INT-42 (20 mg, yield 6.3%) as a brown oily liquid. ESI-MS (m / z): 155.4 [M-H] - .

[0420] Intermediate 43

[0421] Intermediate 43 was prepared by the following steps:

[0422] Step 1 : Sodium hydride (127 mg, 3.18 mmol, 60% purity) was dissolved in tetrahydrofuran (5 mL) under nitrogen atmosphere. INT-43a (300 mg, 1.59 mmol) was added at 0 °C and the reaction was stirred at 0 °C for 30 minutes. Then iodomethane (450 mg, 3.17 mmol) was added and the reaction was stirred at 0 °C for 2 hours. After LCMS monitoring showed the reaction was complete, saturated aqueous ammonium chloride solution (20 mL) was added to the reaction, extracted with ethyl acetate (20 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 ) to give compound INT-43b (116 mg, yield 36.0%). ESI-MS (m / z): 203.4 [M+H] + .

[0423] Second Step: Compound INT-43b (116 mg, 0.57 mmol) was dissolved in 1,4-dioxane (3 mL), and then Pd(dppf)Cl2(42 mg, 0.06 mmol), potassium acetate (168 mg, 1.71 mmol) and bis(pinacolato)diboron (160 mg, 0.63 mmol) were added successively. After the reaction system was replaced by nitrogen, it was heated to 100 °C and stirred for 12 h. LCMS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, it was filtered with celite, and the filtrate was concentrated to obtain compound INT-43c (142 mg, yield 99.9%) as a crude product. ESI-MS (m / z): 251.4 [M+H] + .

[0424] Third Step: Compound INT-43c (142 mg, 0.57 mmol) and compound INT-2 (162 mg, 0.47 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), and then Pd(dppf)Cl2(35 mg, 0.05 mmol) and potassium carbonate (196 mg, 1.42 mmol) were added successively. After the reaction system was replaced by nitrogen, it was heated to 50 °C and stirred for 12 h. LCMS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, it was filtered with celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain liquid INT-43 (147 mg, yield 91.9%) as a yellow oil. ESI-MS (m / z): 338.4 [M+H] + .

[0425] Intermediate 44

[0426] Compound INT-44 can be obtained by replacing INT-5a in the synthesis step of intermediate INT-5 with N-methylpropargylamine, using similar methods and reaction steps. ESI-MS (m / z): 140.1 [M-H] - .

[0427] Intermediate 45

[0428] Compound INT-45 can be obtained by replacing INT-5a in the synthesis step of intermediate INT-5 with 3-methoxy-azetidine hydrochloride, using similar methods and reaction steps. ESI-MS (m / z): 158.3 [M-H] - .

[0429] Intermediate 46

[0430] Intermediate 46 was prepared by the following steps:

[0431] First Step: Compound INT-46a (800 mg, 3.69 mmol) and compound INT-2c (958 mg, 3.69 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL), and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (270 mg, 0.37 mmol) and potassium carbonate (1.53 g, 11.06 mmol) were added in turn. After the reaction system was replaced with nitrogen, it was heated to 50 °C and stirred for 12 hours. LCMS monitoring showed that the raw material was completely reacted. After the reaction liquid was cooled to room temperature, it was filtered with diatomite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain brown solid INT-46b (300 mg, yield 23.1%). ESI-MS (m / z): 352.4 [M+H] + .

[0432] Second Step: Compound INT-46b (80 mg, 0.23 mmol) was dissolved in tetrahydrofuran (3 mL), and the reaction liquid was replaced with nitrogen. Lithium aluminum hydride (18 mg, 0.45 mmol) was slowly added at 0 °C. The reaction continued to be stirred at 0 °C for 1 hour. LCMS monitoring showed that the raw material was completely reacted. Water (2 mL) was added to the reaction mixture to quench the reaction, followed by the addition of sodium hydroxide aqueous solution (2 mL), and ethyl acetate (5 mL*2) was extracted. The combined organic phase was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 8) to obtain yellow liquid INT-46c (35 mg, yield 47.5%). ESI-MS (m / z): 324.2 [M+H] + .

[0433] Third Step: Compound INT-46c (20 mg, 0.06 mmol) was dissolved in dichloromethane (3 mL), and methyl sulfonic anhydride (22 mg, 0.12 mmol) and N,N-diisopropyl ethylamine (32 mg, 0.25 mmol) were added in turn. The reaction mixture was stirred at room temperature for 3 hours. LCMS monitoring showed that the raw material was completely reacted. Water (10 mL) was added to the reaction mixture to quench the reaction, and ethyl acetate (10 mL*2) was extracted. The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude compound INT-46d (24 mg, yield 99%). ESI-MS (m / z): 402.3 [M+H] + .

[0434] Fourth step: compound INT-46d (24 mg, 0.06 mmol) and morpholine (16 mg, 0.18 mmol) were dissolved in dichloromethane (3 mL), N,N-diisopropylethylamine (32 mg, 0.25 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. LCMS monitoring showed that the raw material was completely reacted. Water (10 mL) was added to the reaction mixture to quench the reaction, extracted with ethyl acetate (10 mL*2), the combined organic phase was concentrated under reduced pressure, the residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1 / 9) to obtain compound INT-46 (13 mg, yield 53.6%). ESI-MS (m / z): 393.4 [M+H] + .

[0435] Intermediate 47

[0436] Compound INT-47 can be obtained by replacing INT-5a in the synthesis step of intermediate INT-5 with azetidin-3-ol, using similar methods and reaction steps. ESI-MS (m / z): 144.1 [M-H] - .

[0437] Intermediate 48

[0438] Compound INT-48 can be obtained by replacing INT-5a in the synthesis step of intermediate INT-5 with 3,3-difluoroazetidine hydrochloride, using similar methods and reaction steps. ESI-MS (m / z): 164.2 [M-H] - .

[0439] Intermediate 49

[0440] Compound INT-49 can be obtained by replacing INT-5a in the synthesis step of intermediate INT-5 with N-isopropylmethylamine, using similar methods and reaction steps. ESI-MS (m / z): 144.2 [M-H] - .

[0441] Intermediate 50

[0442] Compound INT-50 can be obtained by replacing INT-5a in the synthesis step of intermediate INT-5 with 1,1,2-trimethylhydrazine dihydrochloride, using similar methods and reaction steps. ESI-MS (m / z): 145.2 [M-H] - .

[0443] Intermediate 51

[0444] Compound INT-51 can be obtained by replacing INT-5a in the synthesis of intermediate INT-5 with 3,3-dimethylazetidine hydrochloride, using similar methods and reaction procedures. ESI-MS (m / z): 156.6 [M-H] - .

[0445] Intermediate 52

[0446] Compound INT-52 can be obtained by replacing INT-5a in the synthesis of intermediate INT-5 with 3-methylazetidine hydrochloride, using similar methods and reaction procedures. ESI-MS (m / z): 142.2 [M-H] - .

[0447] Intermediate 53

[0448] Compound INT-53 can be obtained by replacing INT-5a in the synthesis of intermediate INT-5 with cyclopropylamine hydrochloride, using similar methods and reaction procedures. ESI-MS (m / z): 168.2 [M-H] - .

[0449] Intermediate 54

[0450] Compound INT-54 can be obtained by replacing INT-3a in the synthesis of intermediate INT-3 with 2-(2-propargyloxy)tetrahydropyran, using similar methods and reaction procedures. ESI-MS (m / z): 354.3 [M+H] + .

[0451] Intermediate 55

[0452] Intermediate 55 was prepared by the following steps:

[0453] Step 1: Compound INT-1 (1.57 g, 2.26 mmol) was dissolved in a mixture of 1,4-dioxane (15 mL) and water (1.5 mL), followed by the addition of INT-54 (800 mg, 2.26 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (165 mg, 0.226 mmol) and potassium phosphate (1.44 g, 6.78 mmol). The reaction mixture was stirred at 70 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered with celite, and the residue was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain light yellow oil solid INT-55a (1.50 g, yield 78.9%). ESI-MS (m / z): 841.6 [M+H]+ .

[0454] Second Step: Compound INT-55a (1.2 g, 1.43 mmol) was dissolved in N,N- dimethylformamide (10 mL), to which cesium carbonate (1.39 g, 4.28 mmol) and iodoethane (556 mg, 3.57 mmol) were added. The reaction mixture was stirred at room temperature for 8 hours. After the reaction was completed, water (100 mL) was added to the reaction system, extracted with ethyl acetate (60 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by preparative liquid chromatography to obtain compound INT-55b (280 mg, yield 22.6%, LC-MS retention time RT=2.21 min) and its axial chiral isomer compound INT-55b' (540 mg, yield 43.6%, LC-MS retention time RT=2.16 min) as yellowish solid. ESI-MS (m / z): 869.8 [M+H] + .

[0455] Third Step: Compound INT-55b (200 mg, 0.23 mmol) was dissolved in methanol (3 mL), to which p-toluenesulfonic acid monohydrate (175 mg, 0.92 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, water (30 mL) was added to the reaction system, extracted with ethyl acetate (30 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-55c (160 mg, yield 89%) as yellow oil. ESI-MS (m / z): 785.6 [M+H] + .

[0456] Fourth Step: Compound INT-55c (140 mg, 0.18 mmol) was dissolved in tetrahydrofuran (3 mL) and diethyl ether (3 mL), to which p-toluenesulfonyl chloride (68 mg, 0.36 mmol) and potassium hydroxide (20 mg, 0.36 mmol) were added. The reaction mixture was stirred at 0°C for 2 hours. After the reaction was completed, dichloromethane (30 mL) was added to the reaction system, washed with water (15 mL*2) and saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane / methanol=20 / 1) to obtain INT-55 (110 mg, yield 66%). ESI-MS (m / z): 939.9 [M+H] + .

[0457] Intermediate 56

[0458] INT-56 was obtained by replacing INT-3a in the synthesis of intermediate INT-3 with 4-propargylthiomorpholine-1,1-dioxide using similar methods and procedures. ESI-MS (m / z): 387.2 [M+H] + .

[0459] Intermediate 57

[0460] INT-57 was obtained by replacing INT-5a in the synthesis of intermediate INT-5 with 3,3-difluoropyrrolidine hydrochloride using similar methods and procedures. ESI-MS (m / z): 178.2 [M-H] - .

[0461] Intermediate 58

[0462] INT-58 was obtained by replacing INT-5a in the synthesis of intermediate INT-5 with 3-methoxyazetidine hydrochloride using similar methods and procedures. ESI-MS (m / z): 158.3 [M-H] - .

[0463] Intermediate 59

[0464] INT-59 was obtained by replacing INT-5a in the synthesis of intermediate INT-5 with tert-butyl azetidin-3-yl(methyl)carbamate hydrochloride using similar methods and procedures. ESI-MS (m / z): 259.6 [M+H] + .

[0465] Intermediate 60

[0466] INT-60 was obtained by replacing INT-5a in the synthesis of intermediate INT-5 with 4-azaspiro[2.4]heptane hydrochloride using similar methods and procedures. ESI-MS (m / z): 168.3 [M-H] - .

[0467] Intermediate 61

[0468] INT-61 was obtained by replacing INT-5a in the synthesis of intermediate INT-5 with (S)-2-methylazetidine hydrochloride using similar methods and procedures. ESI-MS (m / z): 142.4 [M-H] - .

[0469] Intermediate 62

[0470] Using (4-(prop-2-yn-1-yl)piperazine-1-carboxylic acid tert-butyl ester instead of INT-3a in the synthesis of intermediate INT-3, compound INT-62 can be obtained using similar methods and procedures. ESI-MS (m / z): 439.4 [M+H] + .

[0471] Intermediate 63

[0472] Using (R)-2-methylazetidine instead of INT-5a in the synthesis of intermediate INT-5, compound INT-63 can be obtained using similar methods and procedures. ESI-MS (m / z): 142.3 [M-H] - .

[0473] Intermediate 64

[0474] Using 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine instead of INT-17a in the synthesis of intermediate INT-17, compound INT-64 can be obtained using similar methods and procedures. ESI-MS (m / z): 337.3 [M+H] + .

[0475] Intermediate 65

[0476] Using (S)-3-pyrrolidinol instead of INT-5a in the synthesis of intermediate INT-5, compound INT-65 can be obtained using similar methods and procedures. ESI-MS (m / z): 158.3 [M-H] - .

[0477] Intermediate 66

[0478] Using 3-azabicyclo[3.1.0]hexane hydrochloride instead of INT-5a in the synthesis of intermediate INT-5, compound INT-66 can be obtained using similar methods and procedures. ESI-MS (m / z): 154.4 [M-H] - .

[0479] Intermediate 67

[0480] Using 3,3-dimethylpyrrole hydrochloride instead of INT-5a in the synthesis of intermediate INT-5, compound INT-67 can be obtained using similar methods and procedures. ESI-MS (m / z): 170.1 [M-H]- .

[0481] Intermediate 68

[0482] INT-17a in the synthesis step of intermediate INT-17 with 5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-A]pyrazine, compound INT-68 can be obtained in a similar manner and by using similar reaction steps. ESI-MS (m / z): 338.3 [M+H] + .

[0483] Intermediate 69

[0484] INT-5a in the synthesis step of intermediate INT-5 with 2,2-dimethylazetidine hydrochloride, compound INT-69 can be obtained in a similar manner and by using similar reaction steps. ESI-MS (m / z): 156.4 [M-H] - .

[0485] Intermediate 70

[0486] INT-5a in the synthesis step of intermediate INT-5 with (R)-2-methylpyrrolidine, compound INT-70 can be obtained in a similar manner and by using similar reaction steps. ESI-MS (m / z): 156.2 [M-H] - .

[0487] Intermediate 71

[0488] Intermediate 71 was prepared by the following steps:

[0489] Step 1: Compound INT-71a (156 mg, 0.71 mmol) was dissolved in a mixture of 1,4- dioxane (5 mL) and water (0.5 mL), and INT-2 (220 mg, 0.64 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (47.1 mg, 0.064 mmol) and potassium carbonate (266.7 mg, 1.92 mmol) were added successively. The reaction mixture was stirred at 55 °C for 16 hours under nitrogen protection. After the reaction was completed, water (20 mL) was added to the reaction system, extracted with ethyl acetate (30 mL*2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound INT-71 (200 mg, yield 79.5%) as a light yellow solid. ESI-MS (m / z): 391.2 [M+H] + .

[0490] Intermediate 72

[0491] Intermediate 72 was prepared by the following steps:

[0492] Step 1: INT-72a (411 mg, 2.89 mmol) was dissolved in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL), and INT-2c (500 mg, 1.92 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (141 mg, 0.192 mmol) and sodium carbonate (612 mg, 5.77 mmol) were added successively. The reaction mixture was stirred at 50 °C for 16 h under nitrogen protection. After the reaction was completed, water (20 mL) was added to the reaction system, and the organic phase was extracted with ethyl acetate (30 mL*2), combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain compound INT-72b (180 mg, yield 29.0%) as a white solid. ESI-MS (m / z): 322.2 [M+H] + .

[0493] Step 2: INT-72b (100 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL), and morpholine (54 mg, 0.62 mmol) and glacial acetic acid (2 mg, 0.031 mmol) were added. After stirring at room temperature for 30 min, sodium triacetoxyborohydride (132 mg, 0.62 mmol) was added. The reaction solution was continuously stirred at room temperature for 16 h, and LCMS was used to monitor the completion of the reaction. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, and dichloromethane was used to extract. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-72 (100 mg, yield 81.9%) as a light yellow solid. ESI-MS (m / z): 393.4 [M+H] + .

[0494] Intermediate 73

[0495] Compound INT-73 can be obtained by replacing INT-5a in the synthesis steps of intermediate INT-5 with diisopropylamine, using similar methods and reaction steps. ESI-MS (m / z): 174.3 [M+H] + .

[0496] Intermediate 74

[0497] INT-74 was obtained by replacing INT-5a in the synthesis of intermediate INT-5 with diisopropylamine hydrochloride, using similar methods and reaction procedures. ESI-MS (m / z): 146.5 [M+H] + .

[0498] Intermediate 75

[0499] INT-75 was obtained by replacing INT-5a in the synthesis of intermediate INT-5 with dicyclobutylamine hydrochloride, using similar methods and reaction procedures. ESI-MS (m / z): 198.8 [M+H] + .

[0500] Intermediate 76

[0501] INT-76 was obtained by replacing INT-5a in the synthesis of intermediate INT-5 with 2,2-dimethyltetrahydropyrrole hydrochloride, using similar methods and reaction procedures. ESI-MS (m / z): 170.1 [M-H] - .

[0502] Intermediate 77

[0503] INT-77 was obtained by replacing INT-3a in the synthesis of intermediate INT-3 with 1-propargylpiperidine, using similar methods and reaction procedures. ESI-MS (m / z): 337.4 [M+H] + .

[0504] Intermediate 78

[0505] INT-78 was obtained by replacing INT-71a in the synthesis of intermediate INT-71 with tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate, using similar methods and reaction procedures. ESI-MS (m / z): 465.4 [M+H] + .

[0506] Intermediate 79

[0507] Intermediate 79 was prepared by the following steps:

[0508] Step 1: Intermediate INT-40b (150 mg, 0.51 mmol) and intermediate INT-3a (95 mg, 0.77 mmol) were dissolved in a mixture solvent of dichloromethane (2 mL) and water (2 mL), and sodium bicarbonate (129 mg, 1.53 mmol) was added. The reaction was stirred at room temperature for 4 hours. LCMS was used to detect the end of the reaction. Saturated brine was added to the reaction system, dichloromethane was extracted, the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain colorless oily liquid INT-79 (160 mg, yield 81%). ESI-MS (m / z): 382.7 [M+H] + .

[0509] Intermediate 80

[0510] Intermediate 80 was synthesized by replacing INT-5a in the synthesis step of intermediate INT-5 with (S)-2-methylpyrrolidine, using similar methods and reaction steps. ESI-MS (m / z): 158.2 [M+H] + .

[0511] Intermediate 81

[0512] Intermediate 5 was prepared by the following steps:

[0513] Step 1: Compound INT-81a (3 g, 20.5 mmol) was dissolved in ethyl acetate (30 mL), and paraformaldehyde (924 mg, 30.8 mmol) and diethylamine (1.65 g, 30.8 mmol) were added under ice bath. The reaction mixture was stirred at 80°C for 3 hours. After the reaction was complete, it was cooled to room temperature, diluted with water (50 mL), adjusted to PH = 1 with 4N hydrochloric acid, concentrated, extracted with ethyl acetate (50 mL*2), the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain colorless oily compound INT-81 (1.5 g, yield 64.0%). ESI-MS (m / z): 115.2 [M+H] + .

[0514] Intermediate 82

[0515] Intermediate 82 was synthesized by replacing INT-81a in the synthesis step of intermediate INT-81 with cyclopentylmalonic acid, using similar methods and reaction steps. ESI-MS (m / z): 141.2 [M+H] + .

[0516] Intermediate 83

[0517] Intermediate 83 was prepared by the following steps:

[0518] Step 1: Compound INT-83a (3 g, 26.28 mmol) was dissolved in carbon tetrachloride (30 mL), and bromine (4.2 g, 26.28 mmol) was added dropwise. The reaction was allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction was concentrated and dissolved in dichloromethane (40 mL), and triethylamine (2.85 g, 28.12 mmol) was added dropwise at 0 °C. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was extracted with dichloromethane (40 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound INT-83b (4.6 g, 90.7%) as a brown oil. ESI-MS (m / z): 193.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 3.74 (s, 3H), 2.08 (s, 3H), 2.01 (s, 3H).

[0519] Step 2: INT-83b (300 mg, 1.55 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and water (3 mL), and lithium hydroxide monohydrate (84.77 mg, 2.02 mmol) was added. The reaction was allowed to react at room temperature for 3 hours. After the reaction was completed, the reaction was lyophilized to obtain compound INT-83 (278.2 mg, 100%) as a white solid. ESI-MS (m / z): 179.2 [M+H] + .

[0520] Intermediate 84

[0521] Intermediate 84 was prepared by the following steps:

[0522] Step 1: Compound INT-84a (2.0 g, 28.5 mmol) was dissolved in ethanol (30 mL), and diethyl malonate (4.6 g, 28.5 mmol), acetic acid (34 mg, 0.57 mmol), and piperidine (49 mg, 0.57 mmol) were sequentially added at room temperature. The reaction was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound INT-84b (4.3 g, yield 71.0%) as a colorless oily liquid. ESI-MS (m / z): 213.2 [M+H] +.

[0523] Step 2: To a suspension of cuprous iodide (2.96 g, 15.6 mmol) in tetrahydrofuran (30 mL) was added cyclopropyl magnesium bromide (28.3 mL, 28.3 mmol) slowly at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 30 min, then a solution of INT-84b (3.0 g, 14.2 mmol) in tetrahydrofuran (10 mL) was added slowly at -78 °C. After the addition was completed, the reaction was allowed to warm to room temperature and stirred for 16 h. After the reaction was completed, the reaction was quenched with an aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give compound INT-84c (1.9 g, 52.9%) as colorless oil. ESI-MS (m / z): 255.3 [M+H] + .

[0524] Step 3: Compound INT-84c (800 mg, 3.2 mmol) was dissolved in methanol (3 mL) and water (3 mL), and potassium hydroxide (353 mg, 6.4 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was concentrated, and the residue was dissolved in water (30 mL) and adjusted to pH = 3 with 4 M hydrochloric acid. The reaction was extracted with ethyl acetate (20 mL*3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound INT-84d (600 mg, yield 96.3%) as yellow oil. ESI-MS (m / z): 199.3 [M+H] + .

[0525] Step 4: Compound INT-84d (300 mg, 1.5 mmol) was dissolved in ethyl acetate (10 mL), and paraformaldehyde (68 mg, 2.3 mmol) and diethylamine (122 mg, 1.7 mmol) were added at 0 °C. The reaction mixture was stirred at 80 °C for 3 h. After the reaction was completed, the reaction was cooled to room temperature, diluted with water (20 mL) and adjusted to pH = 1 with 4 N hydrochloric acid. The reaction was extracted with ethyl acetate (20 mL*2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give compound INT-84 (200 mg, yield 79.5%) as colorless oil. ESI-MS (m / z): 167.3 [M+H] + .

[0526] Intermediate 85

[0527] Intermediate 85 was prepared by the following steps:

[0528] First Step: Dissolve INT-85a (6.15 g, 25.83 mmol) in tetrahydrofuran (30 mL), add sodium hydride (1.03 g, 25.83 mmol) at 0 °C. The reaction solution is reacted at 0 °C for half an hour, then add acetone (1.50 g, 25.83 mmol), continue to react at 65 °C for 3 hours. After the reaction is completed, add an aqueous solution of ammonium chloride to the reaction solution, extract with ethyl acetate (30 mL*2), dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound INT-85b (2 g, yield 54.5%) in colorless oil. ESI-MS (m / z): 143.3 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 4.13-4.09 (m, 2H), 1.96-1.91 (m, 3H), 1.81-1.76 (m, 6H), 1.22 (t, J = 7.0 Hz, 3H).

[0529] Second Step: Dissolve INT-85b (415 mg, 2.92 mmol) in a mixture of ethanol (5 mL) and water (5 mL), add potassium hydroxide (180.1 mg, 3.21 mmol), and stir the reaction at 85 °C for 12 hours. After the reaction is completed, freeze-dry the reaction solution to obtain white solid compound INT-85 (333 mg, yield 100%). ESI-MS (m / z): 115.3 [M+H] + .

[0530] Intermediate 86

[0531] Intermediate 86 is prepared by the following steps:

[0532] First Step: Under nitrogen atmosphere at 0 °C, add TiCl4 (1.51 mL, 13.74 mmol) dropwise to a solution of compound INT-86a (2 g, 12.49 mmol) in toluene (20 mL), stir for ten minutes, then slowly add pyridine (2.01 mL, 24.97 mmol) dropwise to the above solution. After the addition is complete, react at room temperature overnight. After the reaction is completed, add saturated ammonium chloride solution (30 mL) to quench the reaction, extract with ethyl acetate (30 mL*3), dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product is purified by silica gel column chromatography (petroleum ether / dichloromethane = 1 / 3) to obtain compound INT-86b (1.6 g, yield 60.4%) in colorless oil. ESI-MS (m / z): 213.4 [M+H] + .

[0533] Second step: Compound INT-86b (1.6 g, 7.54 mmol) was dissolved in ethanol (20 mL), palladium-carbon (10% wt, 160 mg) was added, and the reaction was stirred under a hydrogen atmosphere overnight. After the reaction was complete, the palladium-carbon was removed by filtration, and the filtrate was rotary evaporated to give INT-86c (1.5 g, 92.9% yield) as a colorless oily liquid. ESI-MS (m / z): 215.3 [M+H] + .

[0534] Third step: Compound INT-86c (1.5 g, 7.0 mmol) was dissolved in methanol (10 mL) and water (2 mL), sodium hydroxide (1.12 g, 28 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was complete, it was concentrated, the residual solid was dissolved in water (30 mL), 4M hydrochloric acid was added to adjust the pH to 3, and ethyl acetate (20 mL*3) was added to extract the organic phase, which was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound INT-86d (800 mg, 72.3% yield) as a yellow oily liquid. ESI-MS (m / z): 159.3 [M+H] + .

[0535] Fourth step: Compound INT-86d (800 mg, 5.06 mmol) was dissolved in ethyl acetate (10 mL), and paraformaldehyde (228 mg, 7.6 mmol) and diethylamine (407 mg, 7.6 mmol) were added at 0°C. The reaction mixture was stirred at 80°C for 3 hours. After the reaction was complete, it was cooled to room temperature, diluted with water (20 mL), adjusted to pH 1 with 4N hydrochloric acid, concentrated, extracted with ethyl acetate (20 mL*2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound INT-86 (200 mg, 31.3% yield) as a colorless oily liquid. ESI-MS (m / z): 127.3 [M+H] + .

[0536] Intermediate 87

[0537] Intermediate 87 was prepared by the following steps:

[0538] Step 1 : Compound INT-1i (760 mg, 3.07 mmol), INT-87a (960 mg, 2.67 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium dichloride (196 mg, 0.27 mmol) and potassium phosphate (1.7 g, 8.02 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (1 mL), and the reaction solution was stirred at 70 °C under nitrogen atmosphere overnight. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 4) to obtain compound INT-87b (1.05 g, yield 81%) as brown oil. ESI-MS (m / z): 482.3 [M+H] + .

[0539] Step 2: INT-87b (800 mg, 1.66 mmol), acetic anhydride (847 mg, 8.31 mmol), triethylamine (504 mg, 4.98 mmol) were dissolved in 1,2-dichloroethane (30 mL), and the reaction solution was stirred at 65 °C overnight. After the reaction was completed, water (30 mL) was added to the reaction solution, and extraction was performed with dichloromethane. The combined organic phase was dried and concentrated to obtain a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-87c (810 mg, yield 91%) as yellow oil. ESI-MS (m / z): 524.2 [M+H] + .

[0540] Step 3: INT-87c (525 mg, 1.01 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N-iodosuccinimide (328 mg, 1.46 mmol) was added at room temperature. The reaction solution was stirred at 50 °C for 1 hour. After the reaction was completed, water (30 mL) and saturated sodium thiosulfate solution (10 mL) were added to the reaction solution, extraction was performed with ethyl acetate, and the combined organic phase was dried and concentrated to obtain compound INT-87d (575 mg, yield 88%). ESI-MS (m / z): 650.5 [M+H] + .

[0541] Step 4: INT-87d (575 mg, 0.88 mmol) was dissolved in tetrahydrofuran (10 mL) and water (5 mL), and then lithium hydroxide (184 mg, 4.4 mmol) was added. The reaction solution was stirred at 55 °C for 1 hour. After the reaction was completed, water (10 mL) was added to the reaction solution, and then the reaction solution was adjusted to pH = 5 with 1N hydrochloric acid solution. Extraction was performed with ethyl acetate, and the combined organic phase was dried and concentrated to obtain compound INT-87e (427 mg, yield 82%). ESI-MS (m / z): 594.3 [M+H] + .

[0542] Step 5: Dissolve INT-87e (366 mg, 0.56 mmol) and N-methylimidazole (230 mg, 2.81 mmol) in acetonitrile (5 mL), and stir the reaction mixture at 0 °C for 1 h, then add (S)-methyl hexahydropyridazine-3-carboxylate trifluoroacetate (311 mg, 1.76 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (236 mg, 0.84 mmol), and continue to stir the reaction mixture at 0 °C for 0.5 h. After the reaction is completed, add saturated ammonium chloride solution (10 mL) to the reaction mixture, extract with ethyl acetate, dry and concentrate the combined organic phase to obtain a crude product, which is purified by silica gel column chromatography (ethyl acetate) to obtain compound INT-87f (289 mg, yield 71%) as yellow oil. ESI-MS (m / z): 720.5 [M+H] + .

[0543] Step 6: Dissolve INT-87f (434 mg, 0.61 mmol) in tetrahydrofuran (6 mL) and water (3 mL), then add lithium hydroxide (56 mg, 1.22 mmol), and stir the reaction mixture at 0 °C for 1 h. After the reaction is completed, add water (5 mL) to the reaction mixture, then adjust the reaction mixture to pH = 5 with 1 N hydrochloric acid solution, extract with ethyl acetate, dry and concentrate the combined organic phase to obtain compound INT-87g (391 mg, yield 92%). ESI-MS (m / z): 706.7 [M+H] + .

[0544] Step 7: Dissolve N-methylimidazole (63 mg, 0.76 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (357 mg, 1.27 mmol) in acetonitrile (7 mL), and stir the reaction mixture at 0 °C for 1 h, then slowly add a tetrahydrofuran (7 mL) solution of compound INT-87g (360 mg, 0.51 mmol), and stir the reaction mixture at 0 °C for 0.5 h. After the reaction is completed, add saturated ammonium chloride solution (10 mL) to the reaction mixture, extract with ethyl acetate, dry and concentrate the combined organic phase to obtain a crude product. Purify the crude product by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound INT-87h (185 mg, yield 53%) as brown solid. ESI-MS (m / z): 688.7 [M+H] + .

[0545] Step 8: 2-Dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (18 mg, 44 umol), INT-87h (100 mg, 2.67 mmol), tris(dibenzylideneacetone)dipalladium (16 mg, 17 umol), potassium acetate (50 mg, 0.51 mmol), and pinacolborane (93 mg, 0.73 mmol) were dissolved in toluene (4 mL) and the reaction was stirred at 60 °C for 3 hours under nitrogen atmosphere. After the reaction was completed, the reaction was filtered and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-87 (80 mg, 79% yield) as a brown solid. ESI-MS (m / z): 688.6 [M+H] + .

[0546] Intermediate 88

[0547] Intermediate 88 was prepared by the following steps:

[0548] Step 1: INT-88a (1.0 g, 5.64 mmol), iron powder (3.2 g, 56.37 mmol), and acetone (491 mg, 8.45 mmol) were dissolved in tetrahydrofuran (30 mL) and the reaction was stirred at 65 °C for 12 hours. After the reaction was completed, the reaction was filtered and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound INT-88b (650 mg, 77.6%) as a colorless oil. ESI-MS (m / z): 149.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) d 3.74 (s, 3H), 2.13 (s, 3H), 2.00 (s, 3H).

[0549] Step 2: INT-88b (120 mg, 0.81 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and water (3 mL), and lithium hydroxide monohydrate (101.66 mg, 2.42 mmol) was added. The reaction was stirred at room temperature for 4 hours. After the reaction was completed, the reaction was lyophilized to give compound INT-88 (108 mg, 99.4%) as a white solid. ESI-MS (m / z): 135.2 [M+H] + .

[0550] Intermediate 89

[0551] Compound INT-89 can be obtained by replacing cyclopropylmagnesium bromide in the synthesis of intermediate INT-84 with methylmagnesium bromide, using similar methods and procedures. ESI-MS (m / z): 141.2 [M+H] + .

[0552] Intermediate 90

[0553] Compound INT-90 can be obtained by replacing INT-87a in the synthesis of intermediate INT-87 with (S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid methyl ester, using similar methods and procedures. ESI-MS (m / z): 687.7 [M+H] + .

[0554] Intermediate 91

[0555] Compound INT-91 can be obtained by replacing cyclopropylmagnesium bromide in the synthesis of intermediate INT-84 with ethylmagnesium bromide, using similar methods and procedures. ESI-MS (m / z): 155.2 [M+H] + .

[0556] Intermediate 92

[0557] Intermediate 92 was prepared from the following steps:

[0558] Step 1: INT-32b (2.1 g, 7.66 mmol) and 2-chloroacetimidate hydrochloride (2.0 g, 13.79 mmol) were dissolved in anhydrous ethanol (40 mL), and the reaction was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction was concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound INT-92a (2.1 g, yield 82.4%) as colorless oil. ESI-MS (m / z): 332.4 [M+H] + .

[0559] Second Step: Dissolve INT-92a (100 mg, 0.30 mmol), thiomorpholine-1,1-dioxide (121.9 mg, 0.90 mmol), potassium carbonate (124.7 mg, 0.90 mmol) and potassium iodide (25.0 mg, 0.15 mmol) in acetonitrile (8 mL), the reaction solution was stirred at 70 °C for 3 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (40 mL), the organic phase was dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain compound INT-92 (116 mg, yield 89.5%) as colorless oil. ESI-MS (m / z): 431.2 [M+H] + .

[0560] Intermediate 93

[0561] Intermediate 93 was prepared by the following steps:

[0562] First Step: Dissolve INT-93a (2.0 g, 9.65 mmol) in chloroform (20 mL), add isoamyl nitrite (1.36 g, 11.6 mmol) and acetic acid (116 mg, 1.93 mmol) at room temperature, and stir the reaction solution at 80 °C for 15 minutes. After the reaction was completed, wash with 1N sulfuric acid solution, saturated sodium bicarbonate solution and saturated brine solution respectively. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound INT-93b (1.7 g, yield 80.7%) as bright yellow oil. ESI-MS (m / z): 219.3 [M+H] + .

[0563] Second Step: Add (trifluoromethyl)trimethylsilane (1.56 g, 11.0 mmol) and INT-93b (1.0 g, 4.58 mmol) to a suspension of sodium iodide (1.51 g, 10.1 mmol) in tetrahydrofuran (20 mL), and stir the reaction solution at 60 °C for 5 hours. After the reaction was completed, extract the reaction solution with ethyl acetate (40 mL*2), dry and concentrate the organic phase to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound INT-93c (800 mg, yield 72.7%) as colorless oil. ESI-MS (m / z): 241.2 [M+H] + .

[0564] Step 3: Dissolve INT-93c (150 mg, 0.62 mmol) in dichloromethane (3 mL), add boron tribromide (0.94 mL, 1.87 mmol, 2 mol / L in DCM) under ice bath, stir the reaction solution at 0 °C for 1 hour. After the reaction is completed, quench the reaction with water, extract with ethyl acetate (20 mL*2), dry and concentrate the organic phase to obtain compound INT-93 (70 mg, yield 74.7%) as a colorless oily liquid. ESI-MS (m / z): 151.2 [M+H] + .

[0565] Intermediate 94

[0566] Replace INT-84a in the synthesis steps of intermediate INT-84 with acetaldehyde, replace ethyl magnesium bromide with cyclopropyl magnesium bromide, and use similar methods and reaction steps to obtain compound INT-94. ESI-MS (m / z): 143.2 [M+H] + .

[0567] Intermediate 95

[0568] Intermediate 95 is prepared by the following steps:

[0569] Step 1: Dissolve INT-95a (200 mg, 1.14 mmol), INT-95b (345 mg, 1.71 mmol) and triphenylphosphine (450 mg, 1.71 mmol) in toluene (6 mL), slowly add dibenzyl azodicarboxylate (395 mg, 1.71 mmol) under ice bath, stir the reaction solution at 80 °C for 1 hour. After the reaction is completed, concentrate the reaction solution, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain compound INT-95c (173 mg, yield 42.3%) as a colorless oily liquid. ESI-MS (m / z): 358.3 [M+H] + .

[0570] Second Step: Dissolve INT-95c (113 mg, 0.32 mmol) in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL), add INT-2c (55 mg, 0.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (15.4 mg, 0.021 mmol) and sodium carbonate (67 mg, 0.63 mmol) successively. The reaction mixture was stirred at 60 °C for 16 hours under nitrogen protection. After the reaction was completed, water (20 mL) was added to the reaction system, extracted with ethyl acetate (30 mL*2), the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain white solid compound INT-95 (74 mg, yield 71.3%). ESI-MS (m / z): 493.2 [M+H] + .

[0571] Intermediate 96

[0572] Compound INT-96 can be obtained by replacing INT-86a in the synthesis step of intermediate INT-86 with cyclohexanone, using similar methods and reaction steps. ESI-MS (m / z): 155.2 [M+H] + .

[0573] Intermediate 97

[0574] Intermediate 97 was prepared by the following steps:

[0575] First Step: Dissolve sodium hydride (134 mg, 3.35 mmol, 60% purity) in tetrahydrofuran (5 mL) and replace with nitrogen. Add INT-97b (264 mg, 2.58 mmol) under ice bath and stir for 30 minutes. Then add INT-97a (500 mg, 2.58 mmol) and continue to stir for 2 hours under ice bath. After the reaction is completed by LCMS monitoring, add saturated aqueous ammonium chloride solution (20 mL) to the reaction system, extract with ethyl acetate (20 mL*2), combine the organic phase and wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate, and purify the residue by silica gel column chromatography (dichloromethane) to obtain brown solid compound INT-97c (288 mg, yield 43.0%). ESI-MS (m / z): 358.3 [M+H] + .

[0576] Step 2: Compound INT-97c (200 mg, 0.77 mmol) was dissolved in 1,4-dioxane (3 mL), and then Pd(dppf)Cl2(56 mg, 0.08 mmol), potassium acetate (227 mg, 2.32 mmol) and bis(pinacolato)diboron (196 mg, 0.77 mmol) were added successively. After the reaction system was replaced by nitrogen, it was heated to 100 °C and stirred for 12 h. LCMS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, it was filtered with celite, and the filtrate was concentrated to obtain compound INT-97d (236 mg, yield 99.9%) as a crude product. ESI-MS (m / z): 406.3 [M+H] + .

[0577] Step 3: Compound INT-97d (236 mg, 0.77 mmol) and compound INT-2 (220 mg, 0.64 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), and then Pd(dppf)Cl2(47 mg, 0.06 mmol) and potassium carbonate (266 mg, 1.93 mmol) were added successively. After the reaction system was replaced by nitrogen, it was heated to 50 °C and stirred for 12 h. LCMS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, it was filtered with celite, and the filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound INT-97 (182 mg, yield 71.9%) as a yellow oily liquid. ESI-MS (m / z): 493.4 [M+H] + .

[0578] Intermediate 98

[0579] Compound INT-98 can be obtained by replacing 2-cyclopropyl-2-oxoacetic acid in the synthesis step of intermediate INT-41 with INT-81, using similar methods and reaction procedures. ESI-MS (m / z): 155.2 [M+H] + .

[0580] Intermediate 99

[0581] Compound INT-99 can be obtained by replacing iodoethane in the synthesis step of intermediate INT-55 with 2,2,2-trifluoroethyl trifluoromethanesulfonate, using similar methods and reaction procedures. ESI-MS (m / z): 993.7 [M+H] + .

[0582] Intermediate 100

[0583] Compound INT-100 was obtained by replacing morpholine in the synthesis step of intermediate INT-72 with thiomorpholine-1,1 -dioxide, in a similar manner and procedure. ESI-MS (m / z): 441.3 [M+H] + .

[0584] Intermediate 101

[0585] Compound INT-101 was obtained by replacing thiomorpholine-1,1 -dioxide in the synthesis step of intermediate INT-92 with 1 -tert-butoxycarbonylpiperazine, in a similar manner and procedure. ESI-MS (m / z): 482.2 [M+H] + .

[0586] Intermediate 102

[0587] Compound INT-102 was obtained by replacing morpholine acetic acid in the synthesis step of intermediate INT-32 with 1 -tert-butoxycarbonyl-4-piperidinecarboxylic acid, in a similar manner and procedure. ESI-MS (m / z): 467.2 [M+H] + .

[0588] Intermediate 103

[0589] Intermediate 103 was prepared by the following steps:

[0590] Step 1 : INT-103a (1.0 g, 7.93 mmol) was dissolved in a mixture of ethanol (10 mL) and water (5 mL), hydroxylamine hydrochloride (2.2 g, 31.7 mmol) and sodium carbonate (2.52 g, 23.8 mmol) were added at room temperature, and the reaction solution was stirred at 90 °C for 3 h. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1 ) to obtain white solid compound INT-103b (936 mg, yield 74.2%). ESI-MS (m / z): 160.2 [M+H] + .

[0591] Step 2: INT-103b (200 mg, 1.26 mmol) was dissolved in methanol (5 mL), Raney nickel (40 mg, 20% wt) and acetic acid (151 mg, 2.52 mmol) were added at room temperature, and the reaction solution was stirred under hydrogen atmosphere for 16 h. After the reaction was completed, it was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain yellowish solid compound INT-103c (255 mg, yield 100%). ESI-MS (m / z): 144.2 [M+H]+ .

[0592] Step 3: INT-103c (150 mg, 0.74 mmol) was dissolved in ethanol (5 mL), sodium ethoxide (50 mg, 0.74 mmol) was added at room temperature, and the reaction was stirred at room temperature for 30 minutes. Then INT-32b (101 mg, 0.37 mmol) in ethanol was added, and the reaction was stirred at 85 °C for 16 hours. After the reaction was completed, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound INT-103d (439 mg, yield 70.0%) as a light yellow solid. ESI-MS (m / z): 382.3 [M+H] + .

[0593] Step 4: INT-103d (200 mg, 0.52 mmol) was dissolved in acetonitrile (3 mL), potassium carbonate (217 mg, 1.56 mmol) and iodomethane (111 mg, 0.78 mmol) were added at room temperature, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, water was added, and the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-103 (139 mg, yield 67.0%) as a colorless oil. ESI-MS (m / z): 396.3 [M+H] + .

[0594] Intermediate 104

[0595] Compound INT-104 can be obtained by replacing morpholine acetic acid with 1-tert-butoxycarbonyl-4-piperidine acetic acid in the synthesis steps of intermediate INT-32, using similar methods and reaction steps. ESI-MS (m / z): 481.2 [M+H]

[0596] [M+H] + .

[0597] Intermediate 105

[0598] Compound INT-105 can be obtained by replacing INT-103c with tert-butyl 4- carbamimidoylpiperidine-1-carboxylate in the synthesis steps of intermediate INT-103, using similar methods and reaction steps. ESI-MS (m / z): 480.2 [M+H] + .

[0599] Intermediate 106

[0600] Intermediate 106 was prepared by the following steps:

[0601] Step 1: Dissolve INT-32b (300 mg, 1.09 mmol) in dichloromethane (10 mL), add N,N-diisopropylethylamine (283 mg, 2.18 mmol) and triphosgene (130 mg, 0.44 mmol) under ice-bath, and stir the reaction solution at room temperature for 2 hours. After the reaction is completed, filter the solution and concentrate under reduced pressure. Purify the obtained crude product by silica gel column chromatography (dichloromethane / methanol = 50:1) to obtain compound INT-106a (240 mg, yield 73.1%) as a white solid. ESI-MS (m / z): 300.1 [M+H] + .

[0602] Step 2: Dissolve INT-106a (100 mg, 0.33 mmol) in N,N-dimethylformamide (5 mL), and add N,N-diisopropylethylamine (86 mg, 0.66 mmol), morpholine (58 mg, 0.66 mmol) and Cat's reagent (162 mg, 0.37 mmol) at room temperature. Stir the reaction solution at room temperature for 16 hours. After the reaction is completed, add water (30 mL) and extract with ethyl acetate (20 mL*3). Concentrate the organic phase. Purify the obtained crude product by silica gel column chromatography (dichloromethane / methanol = 50:1) to obtain compound INT-106 (70 mg, yield 56.9%) as a colorless oil. ESI-MS (m / z): 369.2 [M+H] + .

[0603] Intermediate 107

[0604] Replace thiomorpholine-1,1-dioxide with piperidine in the synthesis step of intermediate INT-92, and compound INT-107 can be obtained by using similar methods and reaction steps. ESI-MS (m / z): 381.2 [M+H] + .

[0605] Intermediate 108

[0606] Replace INT-71a with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine-1-carboxylate in the synthesis step of intermediate INT-71, and compound INT-108 can be obtained by using similar methods and reaction steps. ESI-MS (m / z): 480.2 [M+H] + .

[0607] Intermediate 109

[0608] Intermediate 109 is prepared by the following steps:

[0609] Step 1 : Methyl magnesium bromide (4.4 mL, 13.2 mmol) was added dropwise to a solution of compound INT-93c (800 mg, 3.3 mmol) in tetrahydrofuran (10 mL) at 0 °C under nitrogen atmosphere. After the addition was complete, the reaction was allowed to warm to room temperature and stirred overnight. After the reaction was complete, the reaction was quenched by the addition of saturated ammonium chloride solution and extracted with ethyl acetate (20 mL*3). The organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether / dichloromethane = 10: 1) to give compound INT-109a (205 mg, yield 26.5%) as colorless oil. ESI-MS (m / z): 233.4 [M+H] + .

[0610] Step 2: Compound INT-109a (100 mg, 0.43 mmol) was dissolved in methanol (5 mL), and palladium on carbon (10% wt, 10 mg) was added. The reaction was stirred under hydrogen atmosphere for 1 hour. After the reaction was complete, the palladium on carbon was removed by filtration, and the filtrate was concentrated to give INT-109 (40 mg, yield 65.4%) as colorless oil. ESI-MS (m / z): 143.3 [M+H] + .

[0611] Intermediate 110

[0612] Intermediate 110 was prepared by the following steps:

[0613] Step 1 : Compound INT-110a (5.0 g, 59.4 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (18.0 g, 178.2 mmol), 4-dimethylaminopyridine (726 mg, 5.94 mmol) and acetic anhydride (9.1 g, 89.2 mmol) were added under ice bath. The reaction was stirred at 0 °C for 3 hours. After the reaction was complete, the reaction was quenched by the addition of saturated sodium bicarbonate solution (100 mL) and extracted with dichloromethane (100 mL*2). The combined organic phase was washed with saturated brine. The organic phase was concentrated under reduced pressure to give compound INT-110b (2.1 g, yield 28.0%) as yellow oil. ESI-MS (m / z): 127.1 [M+H] + .

[0614] Step 2: Dissolve INT-110b (1.0 g, 7.93 mmol) in tetrahydrofuran (10 mL), add triethylamine (802 mg, 7.93 mmol), cuprous chloride (106.6 mg, 0.79 mmol) and morpholine (828 mg, 9.51 mmol) at room temperature, and stir the reaction mixture at 60 °C for 2 hours under nitrogen atmosphere. After the reaction is completed, add water (30 mL), extract with ethyl acetate (30 mL*3), and concentrate the organic phase to obtain compound INT-110c (970 mg, yield 79.9%) as a brown oil. ESI-MS (m / z): 154.2 [M+H] + .

[0615] Step 3: Dissolve INT-2 (500 mg, 1.46 mmol) in tetrahydrofuran (5 mL), and add cuprous iodide (27.9 mg, 0.146 mmol), dichlorobis(triphenylphosphine)palladium (102.5 mg, 0.146 mmol), triethylamine (444 mg, 4.39 mmol) and INT-110c (269 mg, 1.75 mmol) successively. Stir the reaction mixture at room temperature for 16 hours under nitrogen protection. After the reaction is completed, concentrate the reaction mixture under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-110 (500 mg, yield 93.1%) as a light yellow oil. ESI-MS (m / z): 367.4 [M+H] + .

[0616] Intermediate 111

[0617] Compound INT-111 can be obtained by replacing morpholine with (R)-3-hydroxymethylmorpholine in the synthesis step of intermediate INT-72, using similar methods and reaction steps. ESI-MS (m / z): 423.2 [M+H] + .

[0618] Intermediate 112

[0619] Intermediate 112 is prepared by the following steps:

[0620] Step 1: Compound INT-112a (3.0 g, 26.1 mmol) was dissolved in acetonitrile (30 mL), potassium carbonate (10.8 g, 78.2 mmol), potassium iodide (43 mg, 0.26 mmol) and 2-bromoethyl ether (6.0 g, 26.1 mmol) were added, and the reaction was stirred at 80 °C for 16 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, and dichloromethane (50 mL*2) was used for extraction, and the organic phase was combined and washed with saturated brine. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound INT-112b (3.1 g, yield 64.2%) as a yellow oil. ESI-MS (m / z): 186.2 [M+H] + .

[0621] Step 2: Compound INT-112b (2.0 g, 10.8 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide monohydrate (544 mg, 13.0 mmol) was added under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was freeze-dried to obtain compound INT-112c (1.85 g, yield 100%) as a white solid. ESI-MS (m / z): 172.2 [M+H] + .

[0622] Step 3: Compound INT-32b (150 mg, 0.55 mmol) was dissolved in N,N- dimethylformamide (8 mL), and INT-112c (187 mg, 1.09 mmol), benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate (427 mg, 0.82 mmol) and N,N- diisopropylethylamine (212 mg, 1.64 mmol) were added in turn, and the reaction was stirred at room temperature for 4 hours. LCMS monitoring showed that the raw material was completely reacted, water was added to the system, and dichloromethane was used for extraction, and the organic phase was dried, dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 10:1) to obtain compound INT-112d (200 mg, yield 85.5%) as a yellow oil. ESI-MS (m / z): 427.2 [M+H] + .

[0623] Step 4: Compound INT-112d (200 mg, 0.47 mmol) was dissolved in dichloromethane (5 mL), p-toluenesulfonyl chloride (448 mg, 2.35 mmol) and triethylamine (476 mg, 4.70 mmol) were added successively, the reaction was stirred at room temperature for 4 hours. LCMS monitoring showed that the raw material was completely reacted, water was added to the system, extracted with dichloromethane, the organic phase was dried, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain compound INT-112 (140 mg, yield 73.0%) as a light yellow oil. ESI-MS (m / z): 409.2 [M+H] + .

[0624] Intermediate 113

[0625] Compound INT-113 can be obtained by replacing morpholine in the synthesis step of intermediate INT-106 with thiomorpholine 1,1-dioxide hydrochloride, using similar methods and reaction steps. ESI-MS (m / z): 417.2 [M+H] + .

[0626] Intermediate 114

[0627] Compound INT-114 can be obtained by replacing morpholine in the synthesis step of intermediate INT-106 with thiomorpholine, using similar methods and reaction steps. ESI-MS (m / z): 385.2 [M+H] + .

[0628] Intermediate 115

[0629] Compound INT-115 can be obtained by replacing INT-5a in the synthesis step of intermediate INT-5 with (2S,5S)-2,5-dimethylpyrrolidine, using similar methods and reaction steps. ESI-MS (m / z): 172.2 [M+H] + .

[0630] Intermediate 116

[0631] Compound INT-116 can be obtained by replacing 2-cyclopropyl-2-oxoacetic acid in the synthesis step of intermediate INT-41 with INT-115, using similar methods and reaction steps. ESI-MS (m / z): 747.7 [M+H] + .

[0632] Intermediate 117

[0633] Intermediate 117 was prepared from the following steps:

[0634] Step 1: Compound INT-32b (3.0 g, 10.9 mmol) was dissolved in dichloromethane (30 mL), acetoxyacetyl chloride (1.49 g, 10.9 mmol) and triethylamine (2.21 g, 21.9 mmol) were added successively under ice bath, the reaction solution was stirred at room temperature for 2 hours, LCMS monitoring showed that the starting material was completely reacted, water was added to the system, extracted with dichloromethane, the organic phase was dried, dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain compound INT-117a (3.1 g, yield 75.7%) as colorless oil. ESI-MS (m / z): 374.3 [M+H] + .

[0635] Step 2: Compound INT-117a (3.1 g, 8.3 mmol) was dissolved in dichloromethane (30 mL), p-toluenesulfonyl chloride (1.91 g, 10.0 mmol) and triethylamine (1.26 g, 12.5 mmol) were added successively under ice bath, the reaction solution was stirred at ice bath for 2 hours, LCMS monitoring showed that the starting material was completely reacted, water was added to the system, extracted with dichloromethane, the organic phase was dried, dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound INT-117b (1.49 g, yield 50.6%) as colorless oil. ESI-MS (m / z): 356.3 [M+H] + .

[0636] Step 3: Compound INT-117b (770 mg, 2.16 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), lithium hydroxide monohydrate (181 mg, 4.32 mmol) was added at room temperature, the reaction solution was stirred at room temperature for 1 hour, LCMS monitoring showed that the starting material was completely reacted, water was added to the system, extracted with dichloromethane, the organic phase was dried, dried with anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-117c (540 mg, yield 79.5%) as light yellow solid. ESI-MS (m / z): 314.3 [M+H] + .

[0637] Fourth Step: Compound INT-117c (100 mg, 0.32 mmol) was dissolved in N,N- dimethylformamide (3 mL), and cesium carbonate (207 mg, 0.64 mmol) and iodomethane (68 mg, 0.48 mmol) were added successively at room temperature. The reaction solution was stirred at 40 °C for 16 hours. LCMS monitoring showed that the reaction was complete. Water was added to the system, and extraction was performed with ethyl acetate. The organic phase was dried, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound INT-117 (100 mg, yield 95.7%) as colorless oil. ESI-MS (m / z): 328.3 [M+H] + .

[0638] Intermediate 118

[0639] Compound INT-118 was obtained by replacing morpholine acetic acid with (2R)-1- [(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid in the synthesis step of intermediate INT-32, using similar methods and reaction procedures. ESI-MS (m / z): 453.2 [M+H] + .

[0640] Intermediate 119

[0641] Compound INT-119 was obtained by replacing 2-cyclopropyl-2-oxoacetic acid with INT-30 in the synthesis step of intermediate INT-41, using similar methods and reaction procedures. ESI-MS (m / z): 718.7 [M+H] + .

[0642] Intermediate 120

[0643] Intermediate 120 was prepared by the following steps:

[0644] First Step: Compound INT-120a (100 mg, 0.87 mmol) was dissolved in dichloromethane (3 mL), and triphosgene (129 mg, 0.43 mmol) and potassium carbonate (482 mg, 3.48 mmol) were added successively in an ice bath. The reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, filtration was performed, and the filtrate was concentrated to obtain compound INT-120b (154 mg, yield 100%) as colorless oil. ESI-MS (m / z): 178.2 [M+H] + .

[0645] Second step: dissolve compound INT-120b (154 mg, 0.88 mmol) in dichloromethane (5 mL), add INT-32b (240 mg, 0.88 mmol) and N, N-diisopropyl ethylamine (340 mg, 2.62 mmol) successively under ice bath, stir the reaction solution at 45 °C for 16 hours, monitor the reaction completion by LCMS, add water to the system, extract with dichloromethane, dry the organic phase, dry with anhydrous sodium sulfate, filter and concentrate. Purify the residue by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain compound INT-120c (290 mg, yield 80%) in colorless oil. ESI-MS (m / z): 415.3 [M+H] + .

[0646] Third step: dissolve compound INT-120c (290 mg, 0.70 mmol) in dichloromethane (5 mL), add p-toluenesulfonyl chloride (173 mg, 0.91 mmol) and triethylamine (141 mg, 1.4 mmol) successively under ice bath, stir the reaction solution at room temperature for 2 hours, monitor the reaction completion by LCMS, add water to the system, extract with dichloromethane, dry the organic phase, dry with anhydrous sodium sulfate, filter and concentrate. Purify the residue by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound INT-120 (222 mg, yield 80%) in colorless oil. ESI-MS (m / z): 397.3 [M+H] + .

[0647] Intermediate 121

[0648] Replace morpholine acetic acid with (3S)-1-[(tert-butoxy)carbonyl]piperidine-3-carboxylic acid in the synthesis step of intermediate INT-32, compound INT-121 can be obtained by similar methods and reaction steps. ESI-MS (m / z): 467.2 [M+H] + .

[0649] Intermediate 122

[0650] Replace INT-120a with 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester in the synthesis step of intermediate INT-120, compound INT-122 can be obtained by similar methods and reaction steps. ESI-MS (m / z): 483.2 [M+H] + .

[0651] Intermediate 123

[0652] Intermediate 123 is prepared by the following steps:

[0653] Step 1 : Compound INT-31b (140 mg, 0.51 mmol) was dissolved in N,N- dimethylformamide (3 mL), 1-tert-butoxycarbonyl-4-piperidinecarboxylic acid (117 mg, 0.51 mmol), N,N-diisopropylethylamine (198 mg, 1.53 mmol) and benzotriazol-1- yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (213 mg, 0.56 mmol) were added successively. The reaction was stirred at 100 °C for 16 hours. LCMS was used to monitor the reaction. When the starting material was consumed, water was added to the system. The mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate methanol = 1:2) to give compound INT-123 (66 mg, yield 27.7%) as a light yellow oil. ESI-MS (m / z): 467.3 [M+H] + .

[0654] Intermediate 124

[0655] Compound INT-124 was obtained by replacing morpholine acetic acid in the synthesis step of intermediate INT-32 with (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid using similar methods and reaction procedures. ESI-MS (m / z): 453.2 [M+H] + .

[0656] Intermediate 125

[0657] Compound INT-125 was obtained by replacing morpholine acetic acid in the synthesis step of intermediate INT-32 with (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid using similar methods and reaction procedures. ESI-MS (m / z): 453.2 [M+H] + .

[0658] Intermediate 126

[0659] Compound INT-126 was obtained by replacing INT-16a in the synthesis step of intermediate INT-16 with tert-butyl 4-cyanopiperidine-1-carboxylate using similar methods and reaction procedures. ESI-MS (m / z): 467.2 [M+H] + .

[0660] Intermediate 127

[0661] Intermediate 127 was prepared by the following steps:

[0662] Step 1 : Compound INT-127a (100 mg, 0.86 mmol) was dissolved in water (3 mL), sodium hydroxide (138 mg, 3.44 mmol) and methoxyamine hydrochloride (72 mg, 0.86 mmol) were added successively, the reaction was stirred at room temperature for 16 hours, LCMS monitoring showed that the raw material was completely reacted. Adjusted to PH = 1 with hydrochloric acid, extracted with dichloromethane, dried the organic phase, dried with anhydrous sodium sulfate, filtered and concentrated to give compound INT-127 (50 mg, yield 40.0%) as colorless oil. ESI-MS (m / z): 146.2 [M+H] + .

[0663] Intermediate 128

[0664] Compound INT-128 can be obtained by using 1-benzyloxycarbonyl-4-piperidinecarboxylic acid to replace morpholine acetic acid in the synthesis step of intermediate INT-32, using similar methods and reaction steps. ESI-MS (m / z): 501.2 [M+H] + .

[0665] Intermediate 129

[0666] Compound INT-129 can be obtained by using INT-128 to replace INT-11b in the synthesis step of intermediate INT-11, using similar methods and reaction steps. ESI-MS (m / z): 882.8 [M+H] + .

[0667] Intermediate 130

[0668] Compound INT-130 can be obtained by using INT-130 to replace INT-11 in the synthesis step of intermediate INT-13, using similar methods and reaction steps. ESI-MS (m / z): 796.7 [M+H] + .

[0669] Intermediate 131

[0670] Intermediate 131 was prepared by the following steps:

[0671] First step: Dissolve thiomorpholine INT-131a (4.0 g, 38.8 mmol), benzyl chloroformate (7.94 g, 46.5 mmol), N,N-diisopropylethylamine (15.0 g, 116 mmol) in dichloromethane (40 mL), and stir the reaction solution at room temperature overnight. After the reaction is completed, extract the reaction solution with dichloromethane, dry the organic phase, and concentrate to obtain a crude product. Purify the crude product by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-131b (9.0 g, yield 97.8%) in the form of a light yellow oil. ESI-MS (m / z): 238.3 [M+H] + .

[0672] Second step: Dissolve compound INT-131b (1.0 g, 38.8 mmol) in a mixed solution of methanol (10 mL) and water (5 mL), and add sodium periodate (1.17 g, 5.5 mmol) under ice bath. Stir the reaction solution at room temperature overnight. After the reaction is completed, extract the reaction solution with ethyl acetate, dry the organic phase, and concentrate to obtain a crude product INT-131c (900 mg, yield 84.3%). The crude product is directly used in the next step without purification. ESI-MS (m / z): 254.3 [M+H] + .

[0673] Third step: Dissolve compound INT-131c (850 mg, 3.36 mmol) in 1,2-dichloroethane (15 mL), and add tert-butyl carbamate (1.97 g, 16.8 mmol), rhodium acetate (94 mg, 0.34 mmol), magnesium oxide (541 mg, 13.4 mmol), and iodo-benzenedicarboxylic acid (3.24 g, 10.1 mmol) at room temperature. Stir the reaction solution at 80°C overnight. After the reaction is completed, concentrate the reaction solution. Purify the crude product by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound INT-131d (1.0 g, yield 80.9%) in the form of a light yellow solid. ESI-MS (m / z): 369.3 [M+H] + .

[0674] Fourth step: Dissolve compound INT-131d (850 mg, 2.31 mmol) in methanol (10 mL), and add palladium hydroxide on carbon (85 mg, 10% w / w). Stir the reaction solution at room temperature overnight under a hydrogen atmosphere. After the reaction is completed, filter through diatomaceous earth, and concentrate the filtrate to obtain compound INT-131e (410 mg, yield 75.9%) in the form of a light yellow oil. ESI-MS (m / z): 235.3 [M+H] + .

[0675] Step 5: Compound INT-131e (150 mg, 0.64 mmol) was dissolved in N,N- dimethylformamide (3 mL), cesium carbonate (626 mg, 1.92 mmol) and 3-bromopropyne (114 mg, 0.96 mmol) were added at room temperature. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow solid compound INT-131f (135 mg, yield 77.4%). ESI-MS (m / z): 273.3 [M+H] + .

[0676] Step 6: Compound INT-131f (140 mg, 0.51 mmol) was dissolved in tetrahydrofuran (5 mL), INT-2 (176 mg, 0.51 mmol), cuprous iodide (10 mg, 0.051 mmol), dichlorobis(triphenylphosphine)palladium (36 mg, 0.051 mmol) and triethylamine (104 mg, 1.03 mmol) were added at room temperature. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain a yellow solid compound INT-131 (60 mg, yield 24.0%). ESI-MS (m / z): 486.5 [M+H] + .

[0677] Intermediate 132

[0678] Intermediate 132 was prepared by the following steps:

[0679] Step 1: Compound INT-131 (200 mg, 0.41 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added to the reaction mixture under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust PH = 8, extracted with dichloromethane (30 mL*2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid compound INT-132a (140 mg, yield 88.1%). ESI-MS (m / z): 386.2 [M+H] + .

[0680] Second Step: Compound INT-132a (120 mg, 0.31 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL), sodium hydride (19 mg, 0.47 mmol) was added under ice-bath, the reaction solution was stirred at 0 °C for 30 min, then iodomethane (66 mg, 0.47 mmol) was added, the reaction solution was continued to be stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried and concentrated to obtain a crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 20:1) to obtain yellow solid compound INT-132 (30 mg, yield 24.1%). ESI-MS (m / z): 400.2 [M+H] + .

[0681] Intermediate 133

[0682] Intermediate 133 was prepared by the following steps:

[0683] First Step: Compound INT-102 (300 mg, 0.64 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added under ice-bath. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice-bath to adjust pH = 8, extracted with dichloromethane (30 mL*2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain yellow solid compound INT-133a (230 mg, yield 97.6%). ESI-MS (m / z): 367.2 [M+H] + .

[0684] Second Step: Compound INT-133a (150 mg, 0.41 mmol) was dissolved in methanol (3 mL), 1-ethoxy-1-trimethylsiloxycyclopropane (356 mg, 2.05 mmol) was added at room temperature, the reaction solution was stirred at room temperature for 10 min. Then sodium cyanoborohydride (77 mg, 1.23 mmol) was added, the reaction solution was continued to be stirred at 60 °C for 3 h. LCMS detection showed that the reaction was completed. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with dichloromethane, the organic phase was concentrated after combined. The obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain colorless oil compound INT-133 (95 mg, yield 57.1%). ESI-MS (m / z): 407.3 [M+H] + .

[0685] Intermediate 134

[0686] Using N-(prop-2-yn-1-yl)cyclopropylamine in place of INT-5a in the synthesis of intermediate INT-5, compound INT-134 can be obtained using similar methods and procedures. ESI-MS (m / z): 168.2 [M+H] + .

[0687] Intermediate 135

[0688] Using N-ethylcyclopropylamine in place of INT-5a in the synthesis of intermediate INT-5, compound INT-135 can be obtained using similar methods and procedures. ESI-MS (m / z): 158.2 [M+H] + .

[0689] Intermediate 136

[0690] Using N-(2,2,2-trifluoroethyl)cyclopropylamine hydrochloride in place of INT-5a in the synthesis of intermediate INT-5, compound INT-136 can be obtained using similar methods and procedures. ESI-MS (m / z): 212.2 [M+H] + .

[0691] Intermediate 137

[0692] Using (S)-2-(fluoromethyl)pyrrole hydrochloride in place of INT-5a in the synthesis of intermediate INT-5, compound INT-137 can be obtained using similar methods and procedures. ESI-MS (m / z): 176.2 [M+H] + .

[0693] Intermediate 138

[0694] Using (S)-2-ethylpyrrolidine hydrochloride in place of INT-5a in the synthesis of intermediate INT-5, compound INT-138 can be obtained using similar methods and procedures. ESI-MS (m / z): 172.2 [M+H] + .

[0695] Intermediate 139

[0696] Using dipropargylamine in place of INT-5a in the synthesis of intermediate INT-5, compound INT-139 can be obtained using similar methods and procedures. ESI-MS (m / z): 166.2 [M+H] + .

[0697] Intermediate 140

[0698] Using N-cyclobutyl-N-cyclopropylamine to replace INT-5a in the synthetic procedure of intermediate INT-5, compound INT-140 can be obtained with similar methods and procedures. ESI-MS (m / z): 184.2 [M+H] + .

[0699] Intermediate 141

[0700] Using 8-azabicyclo[3.2.1]octane hydrochloride to replace INT-5a in the synthetic procedure of intermediate INT-5, compound INT-141 can be obtained with similar methods and procedures. ESI-MS (m / z): 184.2 [M+H] + .

[0701] Intermediate 142

[0702] Using (R)-(-)-2-pyrrolidinemethanol to replace INT-5a in the synthetic procedure of intermediate INT-5, compound INT-142 can be obtained with similar methods and procedures. ESI-MS (m / z): 174.2 [M+H] + .

[0703] Intermediate 143

[0704] Using 7-azabicyclo[2,2,1]heptane hydrochloride to replace INT-5a in the synthetic procedure of intermediate INT-5, compound INT-143 can be obtained with similar methods and procedures. ESI-MS (m / z): 170.2 [M+H] + .

[0705] Intermediate 144

[0706] Using (2R)-2-ethynylpyrrolidine to replace INT-5a in the synthetic procedure of intermediate INT-5, compound INT-144 can be obtained with similar methods and procedures. ESI-MS (m / z): 168.2 [M+H] + .

[0707] Intermediate 145

[0708] Using cis-2,5-dimethylpyrrolidine to replace INT-5a in the synthetic procedure of intermediate INT-5, compound INT-145 can be obtained with similar methods and procedures. ESI-MS (m / z): 172.2 [M+H]+ .

[0709] Intermediate 146

[0710] Using (2R,5R)-2,5-dimethylpyrrolidine hydrochloride to replace INT-5a in the synthesis step of intermediate INT-5, compound INT-146 can be obtained by using similar methods and reaction steps. ESI-MS (m / z): 172.2 [M+H] + .

[0711] Intermediate 147

[0712] Using (S)-2-(trifluoromethyl)pyrrolidine to replace INT-5a in the synthesis step of intermediate INT-5, compound INT-146 can be obtained by using similar methods and reaction steps. ESI-MS (m / z): 212.2 [M+H] + .

[0713] Intermediate 148

[0714] Intermediate 148 is prepared by the following steps:

[0715] Step 1: Compound INT-148a (160 mg, 0.76 mmol) was dissolved in dichloromethane (3 mL), and hydrochloric acid dioxane (1 mL, 4 mmol) was added to it under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated to obtain a light yellow solid compound INT-148b (105 mg, yield 94.3%). ESI-MS (m / z): 110.2 [M+H] + .

[0716] Using INT-148b to replace INT-5a in the synthesis step of intermediate INT-5, compound INT-148 can be obtained by using similar methods and reaction steps. ESI-MS (m / z): 182.2 [M+H] + .

[0717] Intermediate 149

[0718] Using 2,6-dimethylpiperidine to replace INT-5a in the synthesis step of intermediate INT-5, compound INT-149 can be obtained by using similar methods and reaction steps. ESI-MS (m / z): 186.2 [M+H] +

[0719] Intermediate 150

[0720] Using 3S,5S-dimethylmorpholine to replace INT-5a in the synthesis of intermediate INT-5, compound INT-150 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 188.2 [M+H] + .

[0721] Intermediate 151

[0722] Using (R)-2-vinylpyrrolidine-1-carboxylic acid tert-butyl ester to replace INT-5a in the synthesis of intermediate INT-5, compound INT-151 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 170.2 [M+H] + .

[0723] Intermediate 152

[0724] Using 3R,5R-dimethylmorpholine to replace INT-5a in the synthesis of intermediate INT-5, compound INT-152 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 188.2 [M+H] + .

[0725] Intermediate 153

[0726] Using (R)-pyrrolidine-2-carboxamide to replace INT-5a in the synthesis of intermediate INT-5, compound INT-153 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 187.2 [M+H] + .

[0727] Intermediate 154

[0728] Using (2R)-2-ethynyl-1-pyrrolidinecarboxylic acid-1,1-dimethylethyl ester to replace INT-148a in the synthesis of intermediate INT-148, compound INT-154 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 168.2 [M+H] + .

[0729] Intermediate 155

[0730] Using 2-(trifluoromethyl)pyrrolidine to replace INT-5a in the synthesis of intermediate INT-5, compound INT-155 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 212.2 [M+H] + .

[0731] Intermediate 156

[0732] Compound INT-156 was obtained by replacing morpholine in the synthesis of intermediate INT-106 with 1-tert-butoxycarbonylpiperazine, using similar methods and procedures. ESI-MS (m / z): 468.2 [M+H] + .

[0733] Intermediate 157

[0734] Compound INT-156 was obtained by replacing morpholine acetic acid in the synthesis of intermediate INT-32 with tetrahydropyran-4-carboxylic acid, using similar methods and procedures. ESI-MS (m / z): 368.2 [M+H] + .

[0735] Intermediate 158

[0736] Compound INT-158 was obtained by replacing thiomorpholine-1,1-dioxide in the synthesis of intermediate INT-92 with tetrahydropyrrole, using similar methods and procedures. ESI-MS (m / z): 367.2 [M+H] + .

[0737] Intermediate 159

[0738] Intermediate 159 was prepared by the following steps:

[0739] Step 1: Compound INT-159a (200 mg, 1.26 mmol) was dissolved in dichloromethane (3 mL), and oxalyl chloride (160 mg, 1.26 mmol) was added. The reaction was stirred at 50 °C for 16 h. After the reaction was completed, the reaction was concentrated to give compound INT-159b (224 mg, yield 100%) as a yellow oil. ESI-MS (m / z): 178.3 [M+H] + .

[0740] Second Step: Compound INT-31b (130 mg, 0.47 mmol) was dissolved in dichloromethane (3 mL), INT-159b (210 mg, 1.18 mmol) and triethylamine (240 mg, 2.37 mmol) were added at room temperature, the reaction was stirred at room temperature for 5 hours. LCMS detection reaction was complete. To the reaction system was added saturated aqueous ammonium chloride solution to quench the reaction, dichloromethane extraction, concentrated organic phase after combined. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain colorless oil compound INT-159 (40 mg, yield 22.8%). ESI-MS (m / z): 369.3 [M+H] + .

[0741] Intermediate 160

[0742] Intermediate 160 was prepared by the following steps:

[0743] First Step: Compound INT-32b (150 mg, 0.55 mmol) was dissolved in 1,4-dioxane (2 mL), zinc chloride (37 mg, 0.27 mmol) was added, the reaction was stirred at room temperature for 10 minutes, the reaction was concentrated. The resulting residue was dissolved in ethanol (3 mL), INT-160a (221 mg, 1.97 mmol) was added, the reaction was stirred at 80°C for 16 hours. After the reaction was complete, the reaction was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain white solid compound INT-160b (150 mg, yield 74.4%). ESI-MS (m / z): 368.3 [M+H] + .

[0744] Second Step: INT-160b (120 mg, 0.33 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (90 mg, 0.66 mmol) and iodomethane (56 mg, 0.39 mmol) were added at room temperature, the reaction was stirred at 70°C for 16 hours, after the reaction was complete, water was added, dichloromethane extraction, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative liquid chromatography to obtain white solid compound INT-160 (35 mg, yield 28.1%). ESI-MS (m / z): 382.3 [M+H] + .

[0745] Intermediate 161

[0746] Compound INT-161 can be obtained by replacing thiomorpholine-1,1-dioxide with thiomorpholine in the synthesis step of intermediate INT-92, in a similar manner and procedure. ESI-MS (m / z): 399.2 [M+H] + .

[0747] Intermediate 162

[0748] Compound INT-162 can be obtained by replacing morpholine with piperidine in the synthesis step of intermediate INT-106, in a similar manner and procedure. ESI-MS (m / z): 367.2 [M+H] + .

[0749] Intermediate 163

[0750] Compound INT-163 can be obtained by replacing morpholine acetate with 3-oxetane acetate in the synthesis step of intermediate INT-32, in a similar manner and procedure. ESI-MS (m / z): 354.2 [M+H] + .

[0751] Intermediate 164

[0752] Compound INT-164 can be obtained by replacing morpholine with cis-2,6-dimethylmorpholine in the synthesis step of intermediate INT-106, in a similar manner and procedure. ESI-MS (m / z): 397.2 [M+H] + .

[0753] Intermediate 165

[0754] Intermediate 165 is prepared by the following steps:

[0755] Step 1: Compound INT-165a (3.68 g, 16.6 mmol) was dissolved in N,N-dimethylformamide (40 mL), potassium carbonate (6.87 g, 49.7 mmol) and morpholine (2.17 g, 24.9 mmol) were added, and the reaction was stirred at 70 °C for 16 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, and dichloromethane (50 mL*2) was used to extract, and the organic phase was combined and washed with saturated brine. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain compound INT-165b (1.78 g, yield 46.8%) as a light yellow oil. ESI-MS (m / z): 230.2 [M+H] + .

[0756] Step 2: Compound INT-165b (1.42 g, 6.19 mmol) was dissolved in dichloromethane (14 mL), hydrochloric acid dioxane (7.75 mL, 31 mmol, 4 M) was added under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated to give compound INT-165c (1.07 g, yield 100%) as a light yellow solid. ESI-MS (m / z): 174.2 [M+H] + .

[0757] Using INT-165c to replace INT-112c in the synthesis of intermediate INT-112, compound INT-165 can be obtained by using similar methods and reaction procedures. ESI-MS (m / z): 411.2 [M+H] + .

[0758] Intermediate 166

[0759] Using (S)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid to replace morpholine acetic acid in the synthesis of intermediate INT-32, compound INT-166 can be obtained by using similar methods and reaction procedures. ESI-MS (m / z): 467.2 [M+H] + .

[0760] Intermediate 167

[0761] Using (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid to replace morpholine acetic acid in the synthesis of intermediate INT-32, compound INT-167 can be obtained by using similar methods and reaction procedures. ESI-MS (m / z): 453.2 [M+H] + .

[0762] Intermediate 168

[0763] Using (R)-1-(tert-butoxycarbonyl)piperidin-3-carboxylic acid to replace morpholine acetic acid in the synthesis of intermediate INT-32, compound INT-168 can be obtained by using similar methods and reaction procedures. ESI-MS (m / z): 467.2 [M+H] + .

[0764] Intermediate 169

[0765] Compound INT-169 was obtained by replacing morpholine acetic acid in the synthesis step of intermediate INT-32 with (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid, in a similar manner and reaction procedure. ESI-MS (m / z): 467.2 [M+H] + .

[0766] Intermediate 170

[0767] Intermediate 170 was prepared by the following steps:

[0768] First Step: INT-170a (477 mg, 1.34 mmol) was dissolved in tetrahydrofuran (5 mL), sodium hydride (59 mg, 1.47 mmol) was added at 0 °C. The reaction was stirred at 0 °C for half an hour, then 2-methylcyclopentanone (120 mg, 1.22 mmol) was added, and the stirring was continued at room temperature for 3 hours. After the reaction was completed, the reaction was extracted with ethyl acetate (30 mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound INT-170b (350 mg, yield 95.9%) as colorless oil.

[0769] Second Step: INT-170b (100 mg, 0.335 mmol) was dissolved in acetonitrile (5 mL), cesium fluoride (102 mg, 0.670 mmol) and acetic acid (101 mg, 1.68 mmol) were added at room temperature. The reaction was stirred at 50 °C for 16 hours. After the reaction was completed, the reaction was extracted with ethyl acetate (30 mL*2), and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound INT-170c (60 mg, yield 97.2%) as colorless oil.

[0770] Third Step: Compound INT-170c (60 mg, 0.33 mmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and lithium hydroxide monohydrate (28 mg, 0.66 mmol) was added under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was lyophilized to obtain compound INT-170 (50 mg, yield 95.6%) as white solid. ESI-MS (m / z): 157.2 [M+H] + .

[0771] Intermediate 171

[0772] Intermediate 171 was prepared by the following steps:

[0773] Step 1: INT-171a (400 mg, 2.79 mmol), 3-bromopropyne (332 mg, 2.79 mmol), potassium carbonate (772 mg, 5.59 mmol) were dissolved in N,N-dimethylformamide (5 mL) and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was extracted with ethyl acetate and the organic phase was dried and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-171b (385 mg, yield 44.5%) as a yellow oil. ESI-MS (m / z): 182.3 [M+H] + .

[0774] Using INT-171b to replace INT-3a in intermediate INT-3, compound INT-171 can be obtained by using similar methods and reaction procedures. ESI-MS (m / z): 395.2 [M+H] + .

[0775] Intermediate 172

[0776] Using 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine to replace INT-171a in intermediate INT-171, compound INT-172 can be obtained by using similar methods and reaction procedures. ESI-MS (m / z): 376.2 [M+H] + .

[0777] Intermediate 173

[0778] Using tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)piperazine-l- carboxylate to replace INT-71a in intermediate INT-71, compound INT-173 can be obtained by using similar methods and reaction procedures. ESI-MS (m / z): 490.2 [M+H] + .

[0779] Intermediate 174

[0780] Intermediate 174 was prepared by the following steps:

[0781] Step 1 : INT-174a (1.0 g, 11.89 mmol) was dissolved in tetrahydrofuran (10 mL) and diisobutylaluminum hydride (8.72 mL, 13.08 mmol) was added under ice bath. After stirring for 30 min, acetone (1.38 g, 23.79 mmol) and boron trifluoride etherate (3.55 g, 24.98 mmol) were added. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was extracted with ethyl acetate. The organic phase was dried and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane = 1 / 1) to give compound INT-174b (170 mg, yield 9.9%) as a yellow oil. ESI-MS (m / z): 145.2 [M+H] + .

[0782] Using INT-174b to replace INT-34a in the synthesis steps of intermediate INT-34, compound INT-174 can be obtained by using similar methods and reaction steps. ESI-MS (m / z): 131.2 [M+H] + .

[0783] Intermediate 175

[0784] Intermediate 175 was prepared by the following steps:

[0785] Step 1 : INT-175a (1.5 g, 14.98 mmol) was dissolved in dioxane (10 mL) and water (2 mL) and triethylenediamine (1.68 g, 14.98 mmol) was added under ice bath. After stirring for 30 min, acetaldehyde (4.5 mL, 22.47 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was extracted with ethyl acetate. The organic phase was dried and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give compound INT-175b (1.45 g, yield 67.1%) as a yellow oil. ESI-MS (m / z): 145.2 [M+H] + .

[0786] Using INT-175b to replace INT-34a in the synthesis steps of intermediate INT-34, compound INT-175 can be obtained by using similar methods and reaction steps. ESI-MS (m / z): 117.2 [M+H] + .

[0787] Intermediate 176

[0788] Intermediate 176 was prepared by the following steps:

[0789] Step 1: INT-176a (5.12 g, 29.72 mmol) was dissolved in methanol (30 mL), and cyclopropyl methyl ketone (2.5 g, 29.72 mmol) was added at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated to obtain white solid compound INT-176b (7 g, yield 98.8%). ESI-MS (m / z): 239.2 [M+H] + .

[0790] Step 2: INT-176b (2.0 g, 8.39 mmol) and N,N,N',N'-tetramethyl ethylenediamine (2.93 g, 25.18 mmol) were dissolved in tetrahydrofuran (30 mL), and n-butyllithium (10.07 mL, 25.18 mmol) was added dropwise at -78°C. After the dropwise addition was completed, the temperature was raised to room temperature and stirred for 3 hours. Then the temperature was lowered to -78°C, and carbon dioxide gas was introduced, and the reaction was stirred for 1 hour. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, and the reaction was extracted with ethyl acetate. The aqueous phase was adjusted to pH = 3, and extracted with dichloromethane (50 mL*3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain yellowish oil compound INT-176 (700 mg, yield 74.4%). ESI-MS (m / z): 113.2 [M+H] + .

[0791] Intermediate 177

[0792] Compound INT-177 was obtained by replacing INT-34a in the synthesis step of intermediate INT-34 with 2-cyclopropylidene ethyl propionate, using similar methods and reaction steps. ESI-MS (m / z): 113.2 [M+H] + .

[0793] Intermediate 178

[0794] Intermediate 178 was prepared by the following steps:

[0795] Step 1 : Compound INT-2 (300 mg, 0.877 mmol) was dissolved in tetrahydrofuran (5 mL), and cuprous iodide (33 mg, 0.175 mmol), dichlorobis(triphenylphosphine)palladium (62 mg, 0.088 mmol), triethylamine (178 mg, 1.75 mmol) and methyl propiolate (89 mg, 1.05 mmol) were added successively. The reaction mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound INT-178a (154 mg, yield 58.9%) as a yellowish oil. ESI-MS (m / z): 298.2 [M+H] + .

[0796] Step 2: Compound INT-178a (154 mg, 0.52 mmol) was dissolved in tetrahydrofuran (1 mL) and water (0.5 mL), and lithium hydroxide (37 mg, 1.56 mmol) was added under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was lyophilized to obtain compound INT-178b (146 mg, yield 99.5%) as a white solid. ESI-MS (m / z): 284.2 [M+H] + .

[0797] Step 3: Compound INT-178b (146 mg, 0.51 mmol) was dissolved in N,N- dimethylformamide (3 mL), and thiomorpholine 1,1-dioxide (83 mg, 0.62 mmol), N,N- diisopropylethylamine (199 mg, 1.54 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (215 mg, 0.57 mmol) were added thereto. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added to the reaction system, and extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain compound INT-178 (156 mg, yield 75.7%) as a yellowish solid. ESI-MS (m / z): 401.2 [M+H] + .

[0798] Intermediate 179

[0799] Compound INT-179 can be obtained by replacing morpholine in the synthesis step of intermediate INT-110 with thiomorpholine 1,1-dioxide hydrochloride, in a similar manner and reaction procedure. ESI-MS (m / z): 415.2 [M+H] + .

[0800] Intermediate 180

[0801] Using tert-butyl 4-ethynylpiperidine-l-carboxylate to replace INT-3a in the synthesis of intermediate INT-3, compound INT-180 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 423.4 [M+H] + .

[0802] Intermediate 181

[0803] Using triethyl 2-fluoro-2-phosphonoacetate to replace INT-85a in the synthesis of intermediate INT-85, compound INT-181 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 119.3 [M+H] + .

[0804] Intermediate 182

[0805] Using methyl 2-cyclopentylacetate to replace INT-83a in the synthesis of intermediate INT-83, compound INT-182 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 205.2 [M+H] + .

[0806] Intermediate 183

[0807] Using methyl 3,3-dicyclopropyl-2-propenoate to replace INT-83a in the synthesis of intermediate INT-83, compound INT-183 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 231.2 [M+H] + .

[0808] Intermediate 184

[0809] Using methyl 3,3-dicyclopropyl-2-propenoate to replace INT-34a in the synthesis of intermediate INT-34, compound INT-184 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 153.2 [M+H] + .

[0810] Intermediate 185

[0811] INT-185 was obtained by replacing methoxyamine hydrochloride in the synthesis step of intermediate INT-127 with hydroxylamine hydrochloride, in a similar manner and reaction procedure. ESI-MS (m / z): 132.2 [M+H] + .

[0812] Intermediate 186

[0813] INT-186 was obtained by replacing INT-72a in the synthesis step of intermediate INT-72b with 2-bromo-5-methoxymidazole, in a similar manner and reaction procedure. ESI-MS (m / z): 324.2 [M+H] + .

[0814] Intermediate 187

[0815] INT-187 was obtained by replacing INT-71a in the synthesis step of intermediate INT-71 with 2-dimethylaminoimidazole-5-boronic acid, in a similar manner and reaction procedure. ESI-MS (m / z): 337.2 [M+H] + .

[0816] Intermediate 188

[0817] INT-188 was obtained by replacing INT-71a in the synthesis step of intermediate INT-71 with 2-methoxymidazole-5-boronic acid, in a similar manner and reaction procedure. ESI-MS (m / z): 324.2 [M+H] + .

[0818] Intermediate 189

[0819] INT-189 was obtained by replacing INT-72a in the synthesis step of intermediate INT-72b with 2-bromo-N,N-dimethyl-5-imidazoleamine, in a similar manner and reaction procedure. ESI-MS (m / z): 337.2 [M+H] + .

[0820] Intermediate 190

[0821] Intermediate 190 was prepared from the following steps

[0822] Step 1 : Dissolve INT-32b (180 mg, 0.66 mmol) in pyridine (2 mL), add thioacetamide (82 mg, 0.98 mmol) at room temperature, stir the reaction mixture at 150 °C for 1 h under microwave condition. After the reaction is completed, concentrate under reduced pressure. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain compound INT-190a (90 mg, yield 45.5%) as a light yellow solid. ESI-MS (m / z): 297.3 [M+H] + .

[0823] Step 2: Dissolve INT-190a (90 mg, 0.30 mmol) in acetonitrile (2 mL), add potassium carbonate (125 mg, 0.90 mmol) and iodomethane (64 mg, 0.45 mmol) at room temperature, stir the reaction mixture at room temperature for 16 h. After the reaction is completed, add water, extract with dichloromethane, dry the organic phase over anhydrous sodium sulfate, filter and concentrate to obtain compound INT-190 (70 mg, yield 74.3%) as a light yellow oil. ESI-MS (m / z): 311.3 [M+H] + .

[0824] Intermediate 191

[0825] Intermediate 191 is prepared by the following steps

[0826] Step 1 : Dissolve compound INT-32b (300 mg, 1.15 mmol) in N,N- dimethylformamide (4 mL), then add N-hydroxyacetamidine (128 mg, 1.73 mmol), N,N- diisopropylethylamine (447 mg, 3.45 mmol), and 2-(7-azobenzotriazol)-N,N,N',N'- tetramethyluronium hexafluorophosphate (658 mg, 1.73 mmol), react the system at 60 °C for 16 h. Monitor the reaction completion by LCMS. Use the reaction mixture directly in the next step without purification. ESI-MS (m / z): 316.3 [M+H] + .

[0827] Step 2: Warm the above reaction mixture to 110 °C and continue to react for 16 h. Monitor the reaction completion by LCMS. Add water to the reaction system, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound INT-191 (60 mg, yield 31.8%) as a light yellow oil. ESI-MS (m / z): 298.3 [M+H] + .

[0828] Intermediate 192

[0829] Compound INT-192 was obtained by replacing morpholine with piperidine in the synthesis of intermediate INT-72, using similar methods and reaction procedures. ESI-MS (m / z): 441.3 [M+H] + .

[0830] Intermediate 193

[0831] Intermediate 193 was prepared from the following steps

[0832] Compound INT-193b was obtained by replacing INT-71a with INT-193a in the synthesis of intermediate INT-71, using similar methods and reaction procedures. ESI-MS (m / z): 320.3 [M+H] + .

[0833] Second step: Compound 193b (184 mg, 0.57 mmol) was dissolved in dichloromethane (3 mL), (S)-5-aminomethylpyrrolidin-2-one (97 mg, 0.86 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (244 mg, 1.15 mmol) was added, and the reaction mixture was continuously stirred at room temperature for 4 hours. LCMS was used to monitor the completion of the reaction. The reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL), and dichloromethane (20 mL*2) was used for extraction. The combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound INT-193c (184 mg, yield 76.5%). ESI-MS (m / z): 418.3 [M+H] + .

[0834] Third step: Compound INT-193c (184 mg, 0.44 mmol) was dissolved in dichloromethane (3 mL), then di-tert-butyl dicarbonate (144 mg, 0.66 mmol) and N,N-diisopropylethylamine (171 mg, 1.32 mmol) were added, and the reaction was stirred at room temperature for 2 hours. LCMS was used to monitor the completion of the reaction. Water was added to the reaction system, and ethyl acetate was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3) to obtain compound INT-193 (216 mg, yield 94.7%) as a colorless oil. ESI-MS (m / z): 518.3 [M+H] + .

[0835] Intermediate 194

[0836] INT-194 was obtained by replacing INT-72a in the synthesis of intermediate INT-72 with 5-chloropyrazine-2-carboxaldehyde, using an analogous method and reaction procedure. ESI-MS (m / z): 393.3 [M+H] + .

[0837] Intermediate 195

[0838] Intermediate 195 was prepared from the following steps

[0839] Step 1: Compound INT-190a (137 mg, 0.46 mmol) was dissolved in dichloromethane (3 mL), then di-tert-butyl dicarbonate (151 mg, 0.69 mmol) and N,N-diisopropylethylamine (179 mg, 1.38 mmol) were added, and the reaction system was reacted at room temperature for 2 hours. LCMS monitoring showed that the raw material was completely reacted. Water was added to the reaction system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound INT-195 (82 mg, yield 44.8%) as a light yellow oil. ESI-MS (m / z): 397.3 [M+H] + .

[0840] Intermediate 196

[0841] INT-196 was obtained by replacing INT-17a in the synthesis of intermediate INT-17 with 4-(4-piperidinyl)morpholine, using an analogous method and reaction procedure. ESI-MS (m / z): 384.2 [M+H] + .

[0842] Intermediate 197

[0843] INT-197 was obtained by replacing morpholine in the synthesis of intermediate INT-72 with 4-piperidinone, using an analogous method and reaction procedure. ESI-MS (m / z): 405.3 [M+H] + .

[0844] Intermediate 198

[0845] INT-198 was obtained by replacing morpholine in the synthesis of intermediate INT-72 with 1-tert-butoxycarbonylpiperazine, using an analogous method and reaction procedure. ESI-MS (m / z): 492.3 [M+H] + .

[0846] Intermediate 199

[0847] Compound INT-199 was obtained by replacing INT-71a in the synthetic steps of Intermediate INT-71 with tert-butyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4- dihydroisoquinoline-2(lH)-carboxylate, in a similar manner and procedure. ESI-MS (m / z): 447.2 [M+H] + .

[0848] Intermediate 200

[0849] Intermediate 200 was prepared from the following steps:

[0850] Compound INT-40b (150 mg, 0.51 mmol) and INT-200a (214 mg, 1.02 mmol) were dissolved in a mixed solvent of dichloromethane (3 mL) and water (3 mL), and sodium bicarbonate (129 mg, 1.53 mmol) was added. The reaction was stirred at room temperature for 1 hour. LCMS detected that the reaction was completed. Saturated brine was added to the reaction system, dichloromethane was extracted, the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain white solid compound INT-200 (161 mg, yield 67.6%). ESI-MS (m / z): 466.2 [M+H] + .

[0851] Intermediate 201

[0852] Compound INT-201 was obtained by replacing INT-71a in the synthetic steps of Intermediate INT-71 with tert-butyl 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4- dihydroisoquinoline-2(lH)-carboxylate, in a similar manner and procedure. ESI-MS (m / z): 447.2 [M+H] + .

[0853] Intermediate 202

[0854] Compound INT-202 was obtained by replacing INT-72a in the synthetic steps of Intermediate INT-72b with tert-butyl 3-bromo-l-methyl-2-oxo-7,8-dihydro-5H-l,6-naphthyridine-6- carboxylate, in a similar manner and procedure. ESI-MS (m / z): 478.2 [M+H]+ .

[0855] Intermediate 203

[0856] Intermediate 203 was prepared from the following steps

[0857] Step 1: Compound INT-31a (1.0 g, 4.15 mmol) was dissolved in ethanol (5 mL), then manganese dioxide (83 mg, 0.95 mmol) and 5% sodium hydroxide aqueous solution (0.2 mL) were added, and the reaction system was reacted at 85 °C for 8 hours. LCMS monitored the complete reaction of the raw material. Filtration, the filtrate was concentrated to white solid compound INT-203a (1.0 g, yield 93.3%). ESI-MS (m / z): 259.2 [M+H] + .

[0858] Step 2: Compound INT-203a (1.0 g, 3.86 mmol) was dissolved in toluene (5 mL), then potassium carbonate (1.33 g, 9.65 mmol) was added, and the reaction system was reacted at 100 °C for 16 hours. LCM S monitored the complete reaction of the raw material. Water was added to the reaction system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound INT-203b (300 mg, yield 24.5%) as a light yellow oil. ESI-MS (m / z): 317.0 [M+H] + .

[0859] Step 3: Compound INT-203b (300 mg, 0.95 mmol) was dissolved in ethyl cyanoformate (2 mL), and the reaction system was reacted at 160 °C for 20 minutes under microwave. The reaction liquid was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-203c (300 mg, yield 85.2%) as a light yellow oil. ESI-MS (m / z): 372.0 [M+H] + .

[0860] Step 4: Compound INT-203c (200 mg, 0.54 mmol) was dissolved in methanol (2 mL), and sodium borohydride (61 mg, 1.61 mmol) was added under ice bath, and the reaction system was reacted at room temperature for 16 hours. LCMS monitored the complete reaction of the raw material. Water was added to the reaction system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-203 (41 mg, yield 23.1%) as a light yellow oil. ESI-MS (m / z): 330.0 [M+H]+ .

[0861] Intermediate 204

[0862] Compound INT-204 can be obtained by replacing INT-17a in the synthesis of intermediate INT-17 with tert-butyl 1,4-diazepane-1-carboxylate, in a similar manner and by using similar reaction steps. ESI-MS (m / z): 414.2 [M+H] + .

[0863] Intermediate 205

[0864] Compound INT-205 can be obtained by replacing INT-17a in the synthesis of intermediate INT-17 with 1,4-oxazepane, in a similar manner and by using similar reaction steps. ESI-MS (m / z): 315.2 [M+H] + .

[0865] Intermediate 206

[0866] Intermediate 206 is prepared by the following steps:

[0867] Step 1: Compound INT-206a (1.0 g, 3.59 mmol) was dissolved in N,N- dimethylformamide (10 mL), and sodium azide (300 mg, 4.67 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (50 mL) was added to the reaction system, and the organic phase was extracted with ethyl acetate (50 mL*2), combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-206b (800 mg, yield 92.6%) as a light yellow oil. ESI-MS (m / z): 241.2 [M+H] + .

[0868] Step 2: Compound INT-2 (1.0 g, 2.92 mmol), trimethylsilyl acetylene (347 mg, 3.51 mmol), cuprous iodide (56 mg, 0.292 mmol), bis(triphenylphosphine)palladium dichloride (205 mg, 0.292 mmol) and triethylamine (592 mg, 5.85 mmol) were dissolved in tetrahydrofuran (10 mL), and the reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated and dried to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound INT-206c (880 mg, yield 96.4%) as a light yellow solid. ESI-MS (m / z): 312.3 [M+H]+ .

[0869] Step 3: INT-206c (800 mg, 2.56 mmol) was dissolved in methanol (10 mL), potassium carbonate (706 mg, 5.12 mmol) was added at room temperature, the reaction was stirred at room temperature for 2 h. After the reaction was completed, water (30 mL) was added, extracted with ethyl acetate (30 mL*2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain compound INT-206d (566 mg, yield 92.3%) as a light yellow solid. ESI-MS (m / z): 240.3 [M+H] + .

[0870] Step 4: Compound INT-206d (300 mg, 1.25 mmol) was dissolved in tert-butyl alcohol (2 mL) and water (2 mL), INT-206b (450 mg, 1.87 mmol), sodium ascorbate (1.24 g, 6.25 mmol), and copper sulfate (997 mg, 6.25 mmol) were added in turn. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, water (20 mL) was added to the reaction system, extracted with ethyl acetate (20 mL*2), the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound INT-206 (460 mg, yield 76.6%) as a light yellow oil. ESI-MS (m / z): 480.3 [M+H] + .

[0871] Intermediate 207

[0872] Compound INT-207 can be obtained by replacing morpholine acetic acid with tetrahydropyran-4-acetic acid in the synthesis steps of intermediate INT-32, using similar methods and reaction steps. ESI-MS (m / z): 382.2 [M+H] + .

[0873] Intermediate 208

[0874] Intermediate 208 was prepared by the following steps:

[0875] Compound INT-208a can be obtained by replacing thiomorpholine-1,1-dioxide with (S)-5-aminomethylpyrrolidin-2-one in the synthesis steps of intermediate INT-92, using similar methods and reaction steps. ESI-MS (m / z): 410.2 [M+H] +.

[0876] Step 2: Compound INT-208a (150 mg, 0.37 mmol) was dissolved in dichloromethane (5 mL), N, N-diisopropylethylamine (142 mg, 1.10 mmol) and di-tert-butyl dicarbonate (160 mg, 0.74 mmol) were added at room temperature, the reaction solution was stirred at room temperature for 2 h. After the reaction was completed, water (30 mL) was added, extracted with ethyl acetate (30 mL*2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain compound INT-208 (120 mg, yield 64.3%) as a colorless oily liquid. ESI-MS (m / z): 510.3 [M+H] + .

[0877] Intermediate 209

[0878] Compound INT-209 was obtained by replacing INT-5a in the synthesis step of intermediate INT-5 with (S)-tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate, using similar methods and reaction steps. ESI-MS (m / z): 299.2 [M+H] + .

[0879] Intermediate 210

[0880] Intermediate 210 was prepared by the following steps

[0881] Step 1: Compound INT-2 (1.0 g, 2.92 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and isopropylmagnesium chloride in tetrahydrofuran (1.5 mL, 3.07 mmol) was slowly added dropwise under an ice-salt bath, and after the addition was completed, it was stirred at this temperature for 20 minutes. Then INT-210a (483 mg, 3.51 mmol) in toluene (1 mL) was slowly added dropwise, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was added, extracted with ethyl acetate (30 mL*2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound INT-210b (697 mg, yield 81.5%) as a colorless oily liquid. ESI-MS (m / z): 292.1 [M+H] + .

[0882] Step 2: To compound INT-210b (332 mg, 1.13 mmol) was added acetamide (201 mg, 3.40 mmol) at room temperature, the reaction was heated to 140 °C and stirred for 2 hours. After the reaction was completed, the reaction mixture was concentrated to get the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to get compound INT-210 (70 mg, yield 20.8%) as a light yellow solid. ESI-MS (m / z): 297.1 [M+H] + .

[0883] Intermediate 211

[0884] Compound INT-211 was obtained by replacing 2-cyclopropyl-2-oxoacetic acid in the synthesis procedure of intermediate INT-41 with INT-19, using similar methods and procedures. ESI-MS (m / z): 719.6 [M+H] + The synthesis of the compounds of the examples of the present application is as follows:

[0885] Example 1

[0886] N 1 -((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-N 2 ,N 2 -dimethyloxalamide

[0887] Example 1 was prepared by the following steps:

[0888] Compound INT-4 (158 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (5 mL), to which N,N-dimethyl oxamate (49 mg, 0.42 mmol), N,N-diisopropylethylamine (81 mg, 0.63 mmol) and (2-oximino-cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholinyl urea hexafluorophosphate (135 mg, 0.31 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added to the reaction system, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative liquid chromatography to obtain compound 1 (105 mg, yield 58.7%) as a white solid. ESI-MS (m / z): 853.8 [M+H] + ; LC-MS retention time RT = 1.64 min. HPLC retention time RT = 11.94 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.18 (d, J = 8.5 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.52 - 8.48 (m, 1H), 7.89 - 7.84 (m, 2H), 7.79 - 7.75 (m, 1H), 7.61 - 7.57 (m, 1H), 5.54 (t, J = 9.0 Hz, 1H), 5.23 - 5.17 (m, 1H), 4.38 - 4.30 (m, 1H), 4.29 - 4.20 (m, 3H), 4.13 - 4.03 (m, 1H), 3.63 - 3.55 (m, 8H), 3.33 - 3.29 (m, 2H), 3.25 (s, 3H), 3.02 (s, 3H), 2.98 - 2.93 (m, 1H), 2.90 (s, 3H), 2.82 - 2.76 (m, 1H), 2.56 - 2.52 (m, 4H), 2.43 - 2.35 (m, 1H), 2.13 - 2.07 (m, 1H), 1.83 - 1.76 (m, 2H), 1.58 - 1.47 (m, 1H), 1.36 (d, J = 6.0 Hz, 3H), 0.92 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.35 (s, 3H).

[0889] Example 2

[0890] N 1 -(cyclohexylmethyl)-N 2 -((6 3 S,4S,Z)-1 1 -ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)oxalamide

[0891] Compound 2 was obtained by replacing N,N-dimethyl oxamic acid with INT-5 in the synthesis of Compound 1, using similar methods and reaction procedures. ESI-MS (m / z): 921.8 [M+H] + ; LC-MS retention time RT = 2.05 min. HPLC retention time RT = 15.41 min. 1 H NMR (500 MHz, DMSO-d6) δ 8.96 (d, J = 9.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.70 (t, J = 6.0 Hz, 1H), 8.51 - 8.49 (m, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.77 - 7.74 (m, 1H), 7.58 (d, J = 9.0 Hz, 1H), 5.53 (t, J = 9.0 Hz, 1H), 5.23 - 5.18 (m, 1H), 4.35-4.31 (m, 1H), 4.28 - 4.19 (m, 3H), 4.12 - 4.03 (m, 1H), 3.66 - 3.59 (m, 6H), 3.58 - 3.54 (m, 3H), 3.32 - 3.30 (m, 1H), 3.25 (s, 3H), 3.09 - 3.04 (m, 1H), 3.00 - 2.93 (m, 2H), 2.82 - 2.73 (m, 1H), 2.56 - 2.52 (m, 4H), 2.42 - 2.36 (m, 1H), 2.13 - 2.07 (m, 1H), 1.85 - 1.77 (m, 2H), 1.70 - 1.57 (m, 6H), 1.56 - 1.48 (m, 2H), 1.36 (d, J = 6.0 Hz, 3H), 1.25 - 1.11 (m, 3H), 0.93 (s, 3H), 0.90 - 0.84 (m, 4H), 0.35 (s, 3H).

[0892] Example 3

[0893] N 1 - (cyclopropylmethyl) -N 2 - ((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)oxalamide

[0894] Compound 3 was obtained by replacing N,N-dimethyl oxamic acid with INT-6 in the synthesis of Compound 1 using similar procedures and reaction steps. ESI-MS (m / z): 879.7 [M+H] + ; LC-MS retention time RT = 1.85 min. HPLC retention time RT = 13.63 min. 1H NMR (500 MHz, DMSO-d6) δ 9.00 (d, J = 9.0 Hz, 1H), 8.84 - 8.79 (m, 2H), 8.51 - 8.49 (m, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.77 - 7.74 (m, 1H), 7.58 (d, J = 9.0 Hz, 1H), 5.53 (t, J = 9.0 Hz, 1H), 5.23 - 4.18 (m, 1H), 4.37 - 4.30 (m, 1H), 4.29 - 4.18 (m, 4H), 4.11 - 4.04 (m, 1H), 3.66 - 3.58 (m, 6H), 3.57 (s, 3H), 3.35 - 3.30 (m, 1H), 3.25 (s, 3H), 3.11 - 3.04 (m, 1H), 3.03 - 2.99 (m, 1H), 2.98 - 2.91 (m, 1H), 2.84 - 2.74 (m, 1H), 2.56 - 2.50 (m, 4H), 2.41 - 2.36 (m, 1H), 2.12 - 2.07 (m, 1H), 1.85 - 1.78 (m, 2H), 1.57 - 1.48 (m, 1H), 1.36 (d, J = 6.0 Hz, 3H), 0.93 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.47 - 0.38 (m, 2H), 0.35 (s, 3H), 0.25 - 0.20 (m, 2H).

[0895] Example 4

[0896] N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-oxo-2-

[0897] (piperidin-1-yl)acetamide

[0898] Compound 4 was obtained by replacing N,N-dimethyl oxamic acid with INT-7 in the synthesis of Compound 1, using similar methods and reaction procedures. ESI-MS (m / z): 893.7 [M+H] + ; LC-MS retention time RT = 1.78 min. 1 H NMR (500 MHz, DMSO) δ 9.19 (d, J = 8.5 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.51 - 8.48 (m, 1H), 7.90 - 7.82 (m, 2H), 7.79 - 7.74 (m, 1H), 7.59 (d, J = 8.5 Hz, 1H), 5.53 (t, J = 9.0 Hz, 1H), 5.23 - 5.18 (m, 1H), 4.37 - 4.18 (m, 4H), 4.12 - 4.02 (m, 1H), 3.65 - 3.52 (m, 8H), 3.47 - 3.35 (m, 4H), 3.30 - 3.27 (m, 2H), 3.25 (s, 3H), 2.98 - 2.91 (m, 1H), 2.82 - 2.75 (m, 1H), 2.57 - 2.50 (m, 4H), 2.42 - 2.35 (m, 1H), 2.13 - 2.07 (m, 1H), 1.85 - 1.75 (m, 2H), 1.69 - 1.60 (m, 2H), 1.60 - 1.46 (m, 5H), 1.35 (d, J = 6.0 Hz, 3H), 0.92 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.35 (s, 3H).

[0899] Example 5

[0900] N 1 -((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-N 2-phenyloxalamide

[0901] Compound 5 was obtained by replacing N,N-dimethyl oxamic acid with INT-8 in the synthesis of Compound 1, using similar procedures and reaction steps. ESI-MS (m / z): 901.7 [M+H] + ; LC-MS retention time RT = 1.97 min. HPLC retention time RT = 14.61 min. 1 H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.19 (d, J = 9.0 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 8.47 - 8.43 (m, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.79 - 7.77 (m, 1H), 7.77 - 7.75 (m, 2H), 7.71 - 7.67 (m, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.33 - 7.27 (m, 2H), 7.12 - 7.06 (m, 1H), 5.54 (t, J = 9.0 Hz, 1H), 5.19 - 5.14 (m, 1H), 4.30 - 4.23 (m, 1H), 4.21 - 4.15 (m, 3H), 4.05 - 3.96 (m, 1H), 3.66 - 3.60 (m, 1H), 3.57 - 3.52 (m, 5H), 3.52 - 3.48 (m, 3H), 3.34 - 3.30 (m, 1H), 3.18 (s, 3H), 2.92 - 2.85 (m, 1H), 2.77 - 2.66 (m, 1H), 2.50 - 2.45 (m, 4H), 2.38 - 2.32 (m, 1H), 2.08 - 2.03 (m, 1H), 1.80 - 1.73 (m, 2H), 1.52 - 1.44 (m, 1H), 1.30 (d, J = 6.0 Hz, 3H), 0.86 (s, 3H), 0.82 (t, J = 7.0 Hz, 3H), 0.30 (s, 3H).

[0902] Example 6

[0903] N 1 -benzyl-N 2 -((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,62 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)oxalamide

[0904] Compound 6 was obtained by replacing N,N-dimethyl oxamic acid with INT-9 in the synthesis of Compound 1, using similar procedures and reaction steps. ESI-MS (m / z): 915.9 [M+H] + ; LC-MS retention time RT = 1.92 min. HPLC retention time RT = 11.11 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.08 (t, J = 6.5 Hz, 1H), 8.81 (d, J = 9.0 Hz, 1H), 8.60 - 8.57 (m, 1H), 8.29 - 8.26 (m, 1H), 7.66 - 7.63 (m, 1H), 7.59 (s, 1H), 7.55 - 7.50 (m, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.15 - 7.09 (m, 2H), 7.09 - 7.01 (m, 3H), 5.32 (t, J = 9.0 Hz, 1H), 5.00 - 4.95 (m, 1H), 4.20 - 4.15 (m, 1H), 4.13 - 4.08 (m, 2H), 4.05 - 3.95 (m, 3H), 3.87 - 3.81 (m, 1H), 3.45 - 3.36 (m, 6H), 3.35 - 3.32 (m, 3H), 3.12 - 3.08 (m, 1H), 3.02 (s, 3H), 2.75 - 2.70 (m, 1H), 2.59 - 2.52 (m, 1H), 2.35 - 2.29 (m, 4H), 2.19 - 2.14 (m, 1H), 1.90 - 1.80 (m, 1H), 1.62 - 1.55 (m, 2H), 1.32 - 1.25 (m, 1H), 1.18 - 1.09 (m, 3H), 0.70 (s, 3H), 0.65 (t, J = 7.0 Hz, 3H), 0.13 (s, 3H).

[0905] Example 7

[0906] N-((6 3 S,4S,Z)-1 1 -ethyl-1 2(2-((S)-1 -methoxyethyl)-5-(3-morpholinoprop-1 -yn-1 -yl)pyridin-3-yl)-10,10- dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-(4- methylpiperazin-1 -yl)-2-oxoacetamide

[0907] Compound 7 was obtained by replacing N,N-dimethyl oxamic acid with INT-10 in the synthesis of Compound 1 using similar procedures and reaction steps. ESI-MS (m / z): 908.9 [M+H] + ; LC-MS retention time RT = 1.64 min.

[0908] Example 8

[0909] N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 (2-((S)-1 -methoxyethyl)-5-(3-morpholinoprop-1 -yn-1 -yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-3-methyl-2-oxobutanamide

[0910] Compound 8 was obtained by using 3-methyl-2-oxobutanoic acid to replace N,N- dimethyloxalamide in the synthesis of compound 1, using similar methods and reaction procedures. ESI-MS (m / z): 852.8 [M+H] + ; LC-MS retention time RT = 1.95 min. 1 H NMR (500 MHz, DMSO) δ 9.04 (d, J = 9.0 Hz, 1H), 8.83 - 8.80 (m, 1H), 8.52 - 8.48 (m, 1H), 7.89 - 7.85 (m, 1H), 7.83 (s, 1H), 7.78 - 7.74 (m, 1H), 7.59 (d, J = 9.0 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.23 - 5.18 (m, 1H), 4.38 - 4.18 (m, 4H), 4.12 - 4.03 (m, 1H), 3.66 - 3.48 (m, 8H), 3.38 - 3.34 (m, 2H), 3.32 - 3.29 (m, 2H), 3.26 (s, 3H), 2.99 - 2.94 (m, 1H), 2.81 - 2.74 (m, 1H), 2.58 - 2.52 (m, 2H), 2.42 - 2.35 (m, 1H), 2.12 - 2.06 (m, 1H), 1.86 - 1.77 (m, 2H), 1.56 - 1.47 (m, 1H), 1.36 (d, J = 6.0 Hz, 3H), 1.28 - 1.21 (m, 1H), 1.12 - 1.02 (m, 6H), 0.92 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.35 (s, 3H).

[0911] Example 9

[0912] N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-oxo-2-phenylacetamide

[0913] Compound 9 was obtained by replacing N,N-dimethyl oxamic acid with benzoyl formic acid in the synthesis of Compound 1, using similar procedures and reaction steps. ESI-MS (m / z): 886.8 [M+H] + ; LC-MS retention time RT = 1.94 min. HPLC retention time RT = 14.39 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.47 (d, J = 8.5 Hz, 1H), 8.84 - 8.80 (m, 1H), 8.48 - 8.42 (m, 1H), 7.99 - 7.91 (m, 3H), 7.83 (s, 1H), 7.75 - 7.67 (m, 2H), 7.58 - 7.52 (m, 3H), 5.63 (t, J = 9.0 Hz, 1H), 5.26 - 5.20 (m, 1H), 4.31 - 4.16 (m, 4H), 4.05 - 3.98 (m, 1H), 3.77 - 3.61 (m, 4H), 3.56 - 3.49 (m, 3H), 3.40 - 3.36 (m, 3H), 3.20 (s, 3H), 2.94 - 2.90 (m, 1H), 2.79 - 2.74 (m, 1H), 2.45 - 2.42 (m, 4H), 2.35 - 2.28 (m, 1H), 2.07 - 2.02 (m, 1H), 1.80 - 1.73 (m, 2H), 1.53 - 1.44 (m, 1H), 1.30 (d, J = 6.0 Hz, 3H), 0.89 - 0.79 (m, 6H), 0.29 (s, 3H).

[0914] Example 10

[0915] N 1 -((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,66 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-N 2 -methyloxalamide

[0916] Compound 10 was synthesized by replacing N,N-dimethyl oxamic acid with 2-(methylamino)-2-oxoacetic acid in the synthesis of Compound 1 with similar procedures and reaction steps. ESI-MS (m / z): 839.9 [M+H] + ; LC-MS retention time RT = 1.72 min. HPLC retention time RT = 12.30 min. 1 H NMR (500 MHz, DMSO-d6) δ 8.91 (d, J = 9.0 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.66 - 8.61 (m, 1H), 8.45 - 8.42 (m, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.74 (s, 1H), 7.71 - 7.66 (m, 1H), 7.54 - 7.49 (m, 1H), 5.46 (t, J = 9.0 Hz, 1H), 5.16 - 5.10 (m, 1H), 4.30 - 4.12 (m, 4H), 4.05 - 3.96 (m, 1H), 3.59 - 3.48 (m, 10H), 3.18 (s, 3H), 2.92 - 2.86 (m, 1H), 2.73 - 2.68 (m, 1H), 2.64 (d, J = 5.0 Hz, 3H), 2.49 - 2.45 (m, 4H), 2.35 - 2.28 (m, 1H), 2.06 - 2.00 (m, 1H), 1.77 - 1.70 (m, 2H), 1.49 - 1.40 (m, 1H), 1.29 (d, J = 6.0 Hz, 3H), 0.86 (s, 3H), 0.81 (t, J = 7.0 Hz, 3H), 0.28 (s, 3H).

[0917] Example 11

[0918] N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-oxopropanamide

[0919] Compound 11 was synthesized by replacing N,N-dimethyl oxamic acid with pyruvic acid in the synthesis of Compound 1 using similar methods and reaction procedures. ESI-MS (m / z): 824.8 [M+H] + ; LC-MS retention time RT = 1.80 min. HPLC retention time RT = 13.21 min. 1 H NMR (500 MHz, DMSO-d6) δ 8.98 - 8.93 (m, 1H), 8.83 - 8.80 (m, 1H), 8.53 - 8.48 (m, 1H), 7.88 - 7.85 (m, 1H), 7.82 (s, 1H), 7.78 - 7.74 (m, 1H), 7.61 - 7.55 (m, 1H), 5.54 (t, J = 9.0 Hz, 1H), 5.24 - 5.15 (m, 1H), 4.38 - 4.17 (m, 4H), 4.11 - 4.02 (m, 1H), 3.65 - 3.53 (m, 8H), 3.31 - 3.29 (m, 1H), 3.25 (s, 3H), 2.97 - 2.91 (m, 1H), 2.81 - 2.75 (m, 1H), 2.56 - 2.52 (m, 4H), 2.42 - 2.38 (m, 1H), 2.37 (s, 3H), 2.12 - 2.06 (m, 1H), 1.84 - 1.76 (m, 2H), 1.57 - 1.45 (m, 2H), 1.36 (d, J = 6.0 Hz, 3H), 0.92 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.36 (s, 3H).

[0920] Example 12

[0921] 2-cyclopropyl-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-oxoacetamide

[0922] Compound 12 was synthesized by replacing N,N-dimethyl oxamic acid with 2-cyclopropyl-2-oxoacetic acid in the compound 1 synthesis procedure, using similar methods and reaction procedures. ESI-MS (m / z): 850.8 [M+H] + ; LC-MS retention time RT = 1.89 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.02 - 8.97 (m, 1H), 8.83 - 8.79 (m, 1H), 8.52 - 8.47 (m, 1H), 7.88 - 7.85 (m, 1H), 7.82 (s, 1H), 7.78 - 7.73 (m, 1H), 7.61 - 7.56 (m, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.26 - 5.18 (m, 1H), 4.37 - 4.19 (m, 4H), 4.11 - 4.03 (m, 1H), 3.63 - 3.55 (m, 8H), 3.32 - 3.28 (m, 1H), 3.25 (s, 3H), 2.98 - 2.91 (m, 1H), 2.83 - 2.75 (m, 2H), 2.56 - 2.52 (m, 4H), 2.42 - 2.36 (m, 1H), 2.13 - 2.06 (m, 1H), 1.85 - 1.77 (m, 2H), 1.56 - 1.48 (m, 2H), 1.38 - 1.34 (m, 3H), 1.20 - 1.15 (m, 2H), 1.10 - 1.02 (m, 2H), 0.92 (s, 3H), 0.90 - 0.84 (m, 3H), 0.36 (s, 3H).

[0923] Example 13

[0924] N 1 -((6 3 S,4S,Z)-11 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-N 2 ,N 2 -dimethyloxalamide

[0925] Compound 13 was obtained by replacing INT-4 with INT-12 in the synthesis of Compound 1 using similar procedures and reaction steps. ESI-MS (m / z): 872.8 [M+H] + ; LC-MS retention time RT = 1.62 min. HPLC retention time RT = 11.40 min. 1H NMR (500 MHz, DMSO-d6) δ 9.21 - 9.15 (m, 1H), 8.50 - 8.47 (m, 1H), 8.47 - 8.44 (m, 1H), 7.87 - 7.82 (m, 1H), 7.77 - 7.72 (m, 1H), 7.59 - 7.54 (m, 1H), 7.22 - 7.20 (m, 1H), 5.57 - 5.52 (m, 1H), 5.26 - 5.17 (m, 1H), 4.33 - 4.11 (m, 5H), 3.62 - 3.53 (m, 2H), 3.50 - 3.46 (m, 2H), 3.42 - 3.37 (m, 1H), 3.32 - 3.29 (m, 3H), 3.28 - 3.26 (m, 2H), 3.25 (s, 3H), 3.22 (s, 3H), 3.03 (s, 3H), 2.91 (s, 3H), 2.83 - 2.76 (m, 1H), 2.62 - 2.53 (m, 6H), 2.49 - 2.44 (m, 1H), 2.14 - 2.06 (m, 1H), 1.86 - 1.76 (m, 2H), 1.58 - 1.46 (m, 1H), 1.34 (d, J = 6.0 Hz, 3H), 1.30 - 1.20 (m, 1H), 0.95 - 0.87 (m, 6H), 0.36 (s, 3H).

[0926] Example 14

[0927] N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-morpholino-2-oxoacetamide

[0928] Compound 14 was obtained by replacing N,N-dimethyl oxamic acid with INT-14 in the synthesis of Compound 1, using similar methods and reaction procedures. ESI-MS (m / z): 895.8 [M+H] + ; LC-MS retention time RT = 1.69 min. HPLC retention time RT = 10.70 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.21 (d, J = 8.5 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 8.45 - 8.39 (m, 1H), 7.82 - 7.75 (m, 2H), 7.72 - 7.67 (m, 1H), 7.55 - 7.48 (m, 1H), 5.46 (t, J = 8.5 Hz, 1H), 5.18 - 5.12 (m, 1H), 4.32 - 4.08 (m, 4H), 4.06 - 3.97 (m, 1H), 3.63 - 3.39 (m, 16H), 3.35 - 3.30 (m, 1H), 3.24 - 3.21 (m, 1H), 3.18 (s, 3H), 2.92 - 2.85 (m, 1H), 2.77 - 2.68 (m, 1H), 2.52 - 2.45 (m, 4H), 2.37 - 2.28 (m, 1H), 2.06 - 1.99 (m, 1H), 1.77 - 1.67 (m, 2H), 1.49 - 1.40 (m, 1H), 1.29 (d, J = 6.0 Hz, 3H), 0.85 (s, 3H), 0.81 (t, J = 7.0 Hz, 3H), 0.28 (s, 3H).

[0929] Example 15

[0930] N 1 -((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,66-hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-N 2 ,N2 -dimethyloxalamide

[0931] Example 15 was prepared by the following steps:

[0932] Step 1: INT-1 (109 mg, 0.16 mmol), INT-15 (60 mg, 0.16 mmol), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (11 mg, 0.016 mmol), and potassium phosphate (100 mg, 0.48 mmol) were dissolved in a mixed solution of 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was stirred overnight at 70 °C under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 30 / 1) to obtain a brown oily compound 15a (109 mg, yield 79.9%). ESI-MS (m / z): 869.8 [M+H] + ;

[0933] Step 2: Compound 15a (109 mg, 0.13 mmol), cesium carbonate (123 mg, 0.38 mmol), and iodoethane (59 mg, 0.38 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was extracted with ethyl acetate. The organic phases were then combined, dried, and concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 30 / 1) to give a white solid compound 15b (36 mg, yield 32%, LC-MS retention time RT = 1.81 min) and its axial chiral isomer, compound 15b' (51 mg, yield 45%, LC-MS retention time RT = 1.82 min). ESI-MS (m / z): 897.8 [M+H] + ;

[0934] Step 3: Compound 15b (33 mg, 0.037 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, a saturated aqueous sodium bicarbonate solution was added to the reaction solution. The mixture was extracted with dichloromethane, and the combined organic phases were dried and concentrated to give compound 15c (29 mg, yield 98.9%). ESI-MS (m / z): 797.8 [M+H] + ;

[0935] Step 4: Compound 15c (29 mg, 0.037 mmol), N,N-dimethyl oxamic acid (9 mg, 0.074 mmol), N,N-diisopropyl ethylamine (24 mg, 0.18 mmol) were dissolved in N,N-dimethyl formamide (2 mL), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (15 mg, 0.04 mmol) was added to the above reaction solution at 0 °C, and the reaction solution was reacted at 0 °C for 2 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the combined organic phase was dried and concentrated to obtain a crude product, which was purified by preparative liquid chromatography to obtain compound 15 (14 mg, yield 42.9%). ESI-MS (m / z): 896.7 [M+H] + ; LC-MS retention time RT = 1.54 min. 1 H NMR (500 MHz, DMSO) δ 9.35 (d, J = 2.0 Hz, 1H), 9.18 (d, J = 8.5 Hz, 1H), 8.93 (s, 1H), 8.52 (s, 1H), 8.37 (d, J = 2.0 Hz, 1H), 7.87 (s, 1H), 7.81 - 7.77 (m, 1H), 7.64 - 7.60 (m, 1H), 5.53 (t, J = 8.5 Hz, 1H), 5.23 - 5.18 (m, 1H), 4.44 - 4.31 (m, 2H), 4.28 - 4.20 (m, 2H), 4.18-4.10 (m, 1H), 3.68 - 3.50 (m, 8H), 3.41 - 3.37 (m, 1H), 3.32 - 3.25 (m, 7H), 3.03 - 2.97 (m, 3H), 2.90 (s, 2H), 2.83 - 2.74 (m, 1H), 2.48 - 2.43 (m, 4H), 2.12 - 2.06 (m, 1H), 1.84 - 1.76 (m, 2H), 1.55 - 1.49 (m, 1H), 1.41 (d, J = 6.0 Hz, 3H), 0.97 - 0.84 (m, 6H), 0.38 (s, 3H).

[0936] Example 16

[0937] N 1 -((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(morpholinomethyl)-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,62 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-N 2 ,N 2 -dimethyloxalamide

[0938] Compound 16 was obtained by replacing INT-15 with INT-16 in the synthesis of compound 15, using similar methods and reaction procedures. ESI-MS (m / z): 897.8 [M+H] + ; LC-MS retention time RT = 1.69 min. HPLC retention time RT = 11.99 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.36 (d, J = 2.0 Hz, 1H), 9.12 (d, J = 8.5 Hz, 1H), 8.48 - 8.43 (m, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.75 - 7.72 (m, 1H), 7.58 - 7.54 (m, 1H), 5.47 (t, J = 8.5 Hz, 1H), 5.17 - 5.11 (m, 1H), 4.36 - 4.29 (m, 2H), 4.21 - 4.14 (m, 2H), 4.06 - 4.01 (m, 1H), 3.71 - 3.68 (m, 2H), 3.55 - 3.48 (m, 6H), 3.34 - 3.31 (m, 2H), 3.25 - 3.22 (m, 3H), 2.97 - 2.90 (m, 4H), 2.83 (s, 3H), 2.75 - 2.69 (m, 1H), 2.49 - 2.45 (m, 4H), 2.41 - 2.38 (m, 1H), 2.06 - 2.00 (m, 1H), 1.78 - 1.71 (m, 2H), 1.49 - 1.42 (m, 1H), 1.34 (d, J = 6.0 Hz, 3H), 0.89 - 0.79 (m, 6H), 0.30 (s, 3H).

[0939] Example 17

[0940] N 1 -((6 3 S,4S,Z)-1 2-(5-(4-benzyl-1,4-diazepan-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-N 2 ,N 2 -dimethyloxalamide

[0941] Compound 17 was synthesized by replacing INT-15 with INT-17 in the synthesis of compound 15, using similar methods and reaction procedures. ESI-MS (m / z): 918.8 [M+H] + ; LC-MS retention time RT = 2.02 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.10 (d, J = 8.5 Hz, 1H), 8.42 - 8.38 (m, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.76 (s, 1H), 7.68 - 7.63 (m, 1H), 7.50 - 7.46 (m, 1H), 7.24 - 7.12 (m, 5H), 6.87 (d, J = 2.5 Hz, 1H), 5.47 (t, J = 8.5 Hz, 1H), 5.17 - 5.12 (m, 1H), 4.25 - 4.09 (m, 4H), 4.07 - 4.01 (m, 1H), 3.58 - 3.45 (m, 8H), 3.33 - 3.31 (m, 1H), 3.24 - 3.19 (m, 3H), 3.14 (s, 3H), 2.95 (s, 3H), 2.89 - 2.84 (m, 1H), 2.83 (s, 3H), 2.74 - 2.62 (m, 3H), 2.42 - 2.38 (m, 1H), 2.05 - 2.00 (m, 1H), 1.82 - 1.70 (m, 4H), 1.48 - 1.40 (m, 1H), 1.27 (d, J = 6.0 Hz, 3H), 0.87 - 0.78 (m, 6H), 0.30 (s, 3H).

[0942] Example 18

[0943] N 1 -(cyclopropylmethyl)-N 2 -((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-N 1 -methyloxalamide

[0944] Compound 18 was synthesized by replacing N,N-dimethyl oxamic acid in the compound 1 synthesis step with INT-18, in a similar manner and reaction sequence. ESI-MS (m / z): 893.8 [M+H] + ; LC-MS retention time RT = 1.83 min. HPLC retention time RT = 13.0 min. 1H NMR (500 MHz, DMSO-d6) δ 9.19 (d, J = 8.5 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.52 - 8.49 (m, 1H), 7.90 - 7.85 (m, 2H), 7.79 - 7.76 (m, 1H), 7.62 - 7.57 (m, 1H), 5.59 - 5.50 (m, 1H), 5.26 - 4.20 (m, 1H), 4.40 - 4.32 (m, 1H), 4.31 - 4.20 (m, 3H), 4.15 - 4.03 (m, 1H), 3.65 - 3.59 (m, 4H), 3.58 - 3.52 (m, 4H), 3.34 - 3.30 (m, 2H), 3.27 (s, 3H), 3.26 - 3.22 (m, 1H), 3.18 - 3.12 (m, 1H), 3.08 - 3.06 (m, 1H), 2.99 - 2.93 (m, 3H), 2.84 - 2.77 (m, 1H), 2.58 - 2.52 (m, 4H), 2.43 - 2.38 (m, 1H), 2.14 - 2.08 (m, 1H), 1.85 - 1.77 (m, 2H), 1.60 - 1.49 (m, 1H), 1.37 (d, J = 6.0 Hz, 3H), 1.08 - 0.97 (m, 1H), 0.93 (s, 3H), 0.89 (t, J = 7.0 Hz, 3H), 0.52 - 0.46 (m, 2H), 0.35 (s, 3H), 0.31 - 0.21 (m, 2H).

[0945] Example 19

[0946] N 1 -((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-N 2 ,N 2 -dimethyloxalamide

[0947] Compound 19 was obtained by replacing INT-4 with INT-13 in the synthesis of Compound 1, using similar methods and reaction procedures. ESI-MS (m / z): 828.8 [M+H] + ; LC-MS retention time RT = 1.59 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.13 - 9.07 (m, 1H), 8.42 - 8.39 (m, 1H), 8.39 - 8.35 (m, 1H), 7.77 (s, 1H), 7.70 - 7.64 (m, 1H), 7.53 - 7.46 (m, 1H), 7.17 - 7.12 (m, 1H), 5.46 (t, J = 9.0 Hz, 1H), 5.20 - 5.09 (m, 1H), 4.25 - 4.03 (m, 5H), 3.55 - 3.40 (m, 2H), 3.34 - 3.29 (m, 1H), 3.24 - 3.18 (m, 5H), 3.14 (s, 3H), 2.97 - 2.92 (m, 3H), 2.87 - 2.79 (m, 4H), 2.41 - 2.34 (m, 6H), 2.15 (s, 3H), 2.06 - 1.99 (m, 1H), 1.77 - 1.70 (m, 2H), 1.49 - 1.39 (m, 1H), 1.29 - 1.21 (m, 3H), 0.90 - 0.77 (m, 6H), 0.29 (s, 3H).

[0948] Example 20

[0949] N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,66-hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-oxo-2-(pyrrolidin-1-yl)acetamide

[0950] Compound 20 was obtained by replacing N,N-dimethyl oxamic acid with INT-19 in the synthesis of Compound 1, using similar methods and reaction procedures. ESI-MS (m / z): 879.8 [M+H] + ; LC-MS retention time RT = 1.80 min. HPLC retention time RT = 13.03 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.05 (d, J = 8.5 Hz, 1H), 8.83 - 8.80 (m, 1H), 8.51 - 8.48 (m, 1H), 7.88 - 7.82 (m, 2H), 7.78-7.74 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.33 (t, J = 9.0 Hz, 1H), 5.23 - 5.17 (m, 1H), 4.37 - 4.20 (m, 4H), 4.12 - 4.02 (m, 1H), 3.65 - 3.58 (m, 5H), 3.57 - 3.53 (m, 5H), 3.45 - 3.38 (m, 4H), 3.25 (s, 3H), 3.00 - 2.92 (m, 1H), 2.82 - 2.73 (m, 1H), 2.55 - 2.51 (m, 4H), 2.41 - 2.35 (m, 1H), 2.13 - 2.06 (m, 1H), 1.90 - 1.78 (m, 6H), 1.56 - 1.47 (m, 1H), 1.36 (d, J = 6.0 Hz, 3H), 0.92 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.35 (s, 3H).

[0951] Example 21

[0952] N 1 -cyclopropyl-N 2 -((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)oxalamide

[0953] Compound 21 was obtained by replacing N,N-dimethyl oxamic acid with INT-20 in the synthesis of Compound 1, using similar procedures and reaction steps. ESI-MS (m / z): 865.8 [M+H] + ; LC-MS retention time RT = 1.80 min. 1 H NMR (500 MHz, DMSO-d6) δ 8.96 (d, J = 9.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.78 (d, J = 5.5 Hz, 1H), 8.51 - 8.47 (m, 1H), 7.89 - 7.86 (m, 1H), 7.81 (s, 1H), 7.77 - 7.73 (m, 1H), 7.58 (d, J = 9.0 Hz, 1H), 5.51 (t, J = 9.0 Hz, 1H), 5.22 - 5.17 (m, 1H), 4.36 - 4.30 (m, 1H), 4.28 - 4.19 (m, 3H), 4.10 - 4.03 (m, 1H), 3.67 - 3.52 (m, 9H), 3.36 - 3.33 (m, 1H), 3.25 (s, 3H), 2.99 - 2.92 (m, 1H), 2.83 - 2.73 (m, 2H), 2.57 - 2.52 (m, 4H), 2.42 - 2.35 (m, 1H), 2.12 - 2.07 (m, 1H), 1.85 - 1.76 (m, 2H), 1.56 - 1.47 (m, 1H), 1.36 (d, J = 6.0 Hz, 3H), 0.92 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.68-0.62 (m, 4H), 0.35 (s, 3H).

[0954] Example 22

[0955] N 1 -cyclohexyl-N 2 -((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,63 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)oxalamide

[0956] Compound 22 was obtained by replacing N,N-dimethyl oxamic acid with INT-21 in the synthesis of Compound 1, using similar methods and reaction procedures. ESI-MS (m / z): 907.8 [M+H] + ; LC-MS retention time RT = 2.02 min. 1 H NMR (500 MHz, DMSO) δ 8.96 (d, J = 9.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.52 - 8.44 (m, 2H), 7.87 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.72 (m, 1H), 7.58 (d, J = 9.0 Hz, 1H), 5.52 (t, J = 9.0 Hz, 1H), 5.23 - 5.17 (m, 1H), 4.39 - 4.16 (m, 4H), 4.11-4.02 (m, 1H), 3.66 - 3.54 (m, 10H), 3.24 (s, 3H), 2.99 - 2.92 (m, 1H), 2.81 - 2.72 (m, 1H), 2.55 - 2.51 (m, 4H), 2.42 - 2.37 (m, 1H), 2.12 - 2.07 (m, 1H), 1.83 - 1.77 (m, 2H), 1.75 - 1.66 (m, 4H), 1.62 - 1.46 (m, 3H), 1.36 (d, J = 6.0 Hz, 3H), 1.32 - 1.23 (m, 3H), 1.15 - 1.03 (m, 2H), 0.92 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.36 (s, 3H).

[0957] Example 23

[0958] 2-(azetidin-1-yl)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-oxoacetamide

[0959] Compound 23 was obtained by replacing N,N-dimethyl oxamic acid with INT-22 in the synthesis of Compound 1, using similar procedures and reaction steps. ESI-MS (m / z): 865.8 [M+H] + ; LC-MS retention time RT = 1.77 min. 1 H NMR (500 MHz, DMSO) δ 8.96 (d, J = 9.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.50 - 8.48 (m, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.78 - 7.73 (m, 1H), 7.58 (d, J = 9.0 Hz, 1H), 5.52 (t, J = 9.0 Hz, 1H), 5.19 - 5.14 (m, 1H), 4.42 - 4.37 (m, 2H), 4.36 - 4.18 (m, 4H), 4.12 - 3.99 (m, 3H), 3.64 - 3.55 (m, 8H), 3.30 - 3.28 (m, 1H), 3.25 (s, 3H), 2.98 - 2.92 (m, 1H), 2.79 - 2.73 (m, 1H), 2.56 - 2.52 (m, 4H), 2.41 - 2.37 (m, 1H), 2.29 - 2.22 (m, 2H), 2.12 - 2.07 (m, 1H), 1.83 - 1.76 (m, 2H), 1.58 - 1.45 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 0.92 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.35 (s, 3H).

[0960] Example 24

[0961] N 1 -((6 3(S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(2-oxooxazolidin-3-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-N 2 ,N 2 -dimethyloxalamide

[0962] Compound 24 was synthesized by replacing INT-15 in the synthesis procedure of compound 15 with INT-23, using similar methods and reaction procedures. ESI-MS (m / z): 815.8 [M+H] + ; LC-MS retention time RT = 1.58 min. HPLC retention time RT = 11.1 min. 1H NMR (500 MHz, DMSO-d6) δ 9.18 (d, J = 8.5 Hz, 1H), 8.87 (d, J = 2.5 Hz, 1H), 8.53 - 8.50 (m, 1H), 8.05 (d, J = 2.5 Hz, 1H), 7.85 (s, 1H), 7.79 - 7.75 (m, 1H), 7.59 (d, J = 8.5 Hz, 1H), 5.53 (t, J = 8.5 Hz, 1H), 5.22 - 5.17 (m, 1H), 4.51 (t, J = 8.0 Hz, 2H), 4.37 - 4.32 (m, 1H), 4.28 - 4.11 (m, 6H), 3.60 - 3.52 (m, 2H), 3.42 - 3.35 (m, 1H), 3.32 - 3.27 (m, 1H), 3.25 (s, 3H), 3.03 (s, 3H), 2.98 - 2.92 (m, 1H), 2.90 (s, 3H), 2.81 - 2.75 (m, 1H), 2.48 - 2.43 (m, 1H), 2.13 - 2.08 (m, 1H), 1.84 - 1.78 (m, 2H), 1.55 - 1.48 (m, 1H) 1.37 (d, J = 6.0 Hz, 3H), 0.92 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.35 (s, 3H).

[0963] Example 25

[0964] 2-cyclopropyl-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-oxoacetamide

[0965] Compound 25 was obtained by replacing INT-4 with INT-13 in the synthesis of Compound 1, 2-cyclopropyl-2-oxoacetic acid in place of N,N-dimethyl oxamic acid, using similar methods and reaction procedures. ESI-MS (m / z): 869.8 [M+H] + ; LC-MS retention time RT = 1.84 min. 1 H NMR (500 MHz, DMSO-d6) δ 8.94 - 8.89 (m, 1H), 8.44 - 8.40 (m, 1H), 8.40 - 8.34 (m, 1H), 7.73 (s, 1H), 7.68 - 7.63 (m, 1H), 7.51 - 7.46 (m, 1H), 7.17 - 7.10 (m, 1H), 5.49 (t, J = 9.0 Hz, 1H), 5.18 - 5.13 (m, 1H), 4.25 - 4.12 (m, 3H), 4.10 - 4.03 (m, 2H), 3.54 - 3.47 (m, 4H), 3.41 - 3.38 (m, 2H), 3.30 - 3.25 (m, 1H), 3.20 - 3.16 (m, 7H), 3.14 (s, 3H), 2.88 - 2.82 (m, 1H), 2.76 - 2.69 (m, 2H), 2.52 - 2.48 (m, 4H), 2.49 - 2.42 (m, 1H), 2.41 - 2.36 (m, 1H), 2.06 - 1.99 (m, 1H), 1.76 - 1.69 (m, 2H), 1.51 - 1.41 (m, 1H), 1.26 (d, J = 6.0 Hz, 3H), 1.13 - 1.08 (m, 2H), 1.03 - 0.96 (m, 2H), 0.88 - 0.81 (m, 6H), 0.29 (s, 3H).

[0966] Example 26

[0967] 2-(((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)amino)-2-oxoacetic acid

[0968] Example 26 was prepared from the following steps:

[0969] First step: Compound INT-4 (25 mg, 0.033 mmol) was dissolved in dichloromethane (2 mL), oxalyl chloride monoethyl ester (7 mg, 0.05 mmol) and triethylamine (10 mg, 0.1 mmol) were added under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain compound 26a (28 mg, yield 99%) as colorless oil. ESI-MS (m / z): 854.8 [M+H] + .

[0970] Second step: Compound 26a (28 mg, 0.033 mmol) was dissolved in tetrahydrofuran (2 mL) and water (0.2 mL), lithium hydroxide (0.8 mg, 0.033 mmol) was added under ice bath. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was completed, water (5 mL) was added for dilution, the pH was adjusted to 6 with hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to obtain compound 26 (10 mg, yield 36.9%) as white solid. ESI-MS (m / z): 826.8 [M+H] + . LC-MS retention time RT = 1.43 min. HPLC retention time RT = 9.52 min. 1H NMR (500 MHz, DMSO-d6) δ 8.89 - 8.80 (m, 2H), 8.51 - 8.49 (m, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.78 - 7.73 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.35 - 7.10 (m, 1H), 5.53 (t, J = 9.0 Hz, 1H), 5.19 - 5.14 (m, 1H), 4.39 - 4.19 (m, 4H), 4.12 - 4.04 (m, 1H), 3.63 - 3.56 (m, 8H), 3.50 - 3.45 (m, 1H), 3.34 - 3.31 (m, 1H), 3.25 (s, 3H), 3.00 - 2.92 (m, 1H), 2.81 - 2.74 (m, 1H), 2.57 - 2.52 (m, 4H), 2.42 - 2.36 (m, 1H), 2.12 - 2.06 (m, 1H), 1.84 - 1.77 (m, 2H), 1.56 - 1.47 (m, 1H), 1.36 (d, J = 6.0 Hz, 3H), 0.95 - 0.83 (m, 6H), 0.35 (s, 3H).

[0971] Example 27

[0972] 2-cyclobutyl-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-oxoacetamide

[0973] Compound 27 was synthesized by replacing N,N-dimethyl oxamic acid with 2-cyclobutyl-2-oxoacetic acid in the step of synthesizing compound 1, using similar methods and reaction procedures. ESI-MS (m / z): 864.8 [M+H] +LC-MS retention time RT = 1.99 min. HPLC retention time RT = 14.66 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.03 (d, J = 9.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.51 - 8.48 (m, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.73 (m, 1H), 7.58 (d, J = 9.0 Hz, 1H), 5.54 (t, J = 9.0 Hz, 1H), 5.21 - 5.15 (m, 1H), 4.36 - 4.19 (m, 4H), 4.13 - 4.04 (m, 1H), 3.94 - 3.86 (m, 1H), 3.66 - 3.55 (m, 10H), 3.25 (s, 3H), 3.00 - 2.92 (m, 1H), 2.80 - 2.74 (m, 1H), 2.55 - 2.52 (m, 4H), 2.43 - 2.34 (m, 1H), 2.20 - 2.07 (m, 5H), 2.03 - 1.96 (m, 1H), 1.84 - 1.75 (m, 3H), 1.56 - 1.46 (m, 1H), 1.35 (d, J = 6.0 Hz, 3H), 0.94 - 0.85 (m, 6H), 0.34 (s, 3H).

[0974] Example 28

[0975] N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-(furan-2-yl)-2-oxoacetamide

[0976] Compound 28 was synthesized by replacing N,N-dimethyl oxamic acid with 2-cyclobutyl-2-oxoacetic acid in the step of synthesizing compound 1, using similar methods and reaction procedures. ESI-MS (m / z): 876.9 [M+H] + ; LC-MS retention time RT = 1.88 min. HPLC retention time RT = 13.78 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.39 (d, J = 8.5 Hz, 1H), 8.82 - 8.80 (m, 1H), 8.52 - 8.49 (m, 1H), 8.22 - 8.19 (m, 1H), 7.88 - 7.86 (m, 1H), 7.83 (s, 1H), 7.81 - 7.74 (m, 2H), 7.58 (d, J = 8.5 Hz, 1H), 6.88 - 6.79 (m, 1H), 5.65 (t, J = 9.0 Hz, 1H), 5.27 - 5.20 (m, 1H), 4.38 - 4.22 (m, 4H), 4.13 - 4.05 (m, 1H), 3.62 - 3.51 (m, 10H), 3.25 (s, 3H), 3.00 - 2.93 (m, 1H), 2.84 - 2.76 (m, 1H), 2.56 - 2.51 (m, 4H), 2.42 - 2.35 (m, 1H), 2.14 - 2.08 (m, 1H), 1.86 - 1.78 (m, 2H), 1.58 - 1.48 (m, 1H), 1.36 (d, J = 6.0 Hz, 3H), 0.95 - 0.84 (m, 6H), 0.36 (s, 3H).

[0977] Example 29

[0978] N 1 -((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-N 2N 2 -dimethyloxalamide

[0979] Compound 29 was obtained by replacing INT-15 with INT-24 in the synthesis of compound 15, using similar methods and reaction procedures. ESI-MS (m / z): 842.8 [M+H] + ; LC-MS retention time RT = 1.49 min. HPLC retention time RT = 10.19 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.18 (d, J = 8.5 Hz, 1H), 8.50 - 8.47 (m, 1H), 8.45 - 8.42 (m, 1H), 7.85 (s, 1H), 7.76 - 7.72 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.33 - 7.28 (m, 1H), 5.55 (t, J = 8.5 Hz, 1H), 5.23 - 5.18 (m, 1H), 4.33 - 4.28 (m, 1H), 4.25 - 4.20 (m, 2H), 4.20 - 4.12 (m, 3H), 3.94 - 3.86 (m, 2H), 3.66 - 3.61 (m, 2H), 3.59 - 3.53 (m, 3H), 3.38 - 3.34 (m, 1H), 3.33 - 3.28 (m, 1H), 3.23 (s, 3H), 3.03 (s, 3H), 2.96 - 2.93 (m, 1H), 2.92 - 2.87 (m, 6H), 2.82 - 2.76 (m, 1H), 2.48 - 2.44 (m, 1H), 2.14 - 2.07 (m, 1H), 1.85 - 1.77 (m, 2H), 1.57 - 1.49 (m, 1H), 1.35 (d, J = 6.0 Hz, 3H), 0.94 - 0.88 (m, 6H), 0.38 (s, 3H).

[0980] Example 30

[0981] N 1 -((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6- hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-N 2 -((1S,2S)-2-methylcyclopropyl)oxalamide

[0982] Compound 30 was obtained by replacing N,N-dimethyl oxamic acid with INT-25 in the synthesis of Compound 1, using similar methods and reaction procedures. ESI-MS (m / z): 879.8 [M+H] + ; LC-MS retention time RT = 1.88 min. HPLC retention time RT = 13.75 min. 1 H NMR (500 MHz, DMSO-d6) δ 8.97 - 8.93 (m, 1H), 8.84 - 8.80 (m, 1H), 8.77 - 8.74 (m, 1H), 8.52 - 8.48 (m, 1H), 7.90 - 7.86 (m, 1H), 7.82 (s, 1H), 7.78 - 7.74 (m, 1H), 7.62 - 7.55 (m, 1H), 5.52 (t, J = 9.0 Hz, 1H), 5.24 - 5.17 (m, 1H), 4.38 - 4.20 (m, 4H), 4.12 - 4.03 (m, 1H), 3.67 - 3.54 (m, 10H), 3.32 - 3.29 (m, 1H), 3.25 (s, 3H), 3.00 - 2.92 (m, 1H), 2.83 - 2.73 (m, 1H), 2.58 - 2.52 (m, 4H), 2.43 - 2.35 (m, 1H), 2.14 - 2.07 (m, 1H), 1.82 - 1.77 (m, 2H), 1.57 - 1.48 (m, 1H), 1.37 (d, J = 6.0 Hz, 3H), 1.07 - 1.00 (m, 4H), 0.93 (s, 3H), 0.91 - 0.86 (m, 3H), 0.85 - 0.80 (m, 1H), 0.51 - 0.46 (m, 1H), 0.36 (s, 3H).

[0983] Example 31

[0984] 2-cyclohexyl-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-oxoacetamide

[0985] Compound 31 was synthesized by replacing N,N-dimethyl oxamic acid with 2-cyclohexyl-2-oxoacetic acid in the compound 1 synthesis procedure, using similar methods and reaction procedures. ESI-MS (m / z): 892.8 [M+H] + ; LC-MS retention time RT = 2.13 min. HPLC retention time RT = 15.89 min. 1 H NMR (500 MHz, DMSO-d6) δ 9.02 (d, J = 8.5 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.51 - 8.48 (m, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.84 (s, 1H), 7.77 - 7.74 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.22 - 5.17 (m, 1H), 4.36 - 4.20 (m, 4H), 4.12-3.05 (m, 1H), 3.63 - 3.59 (m, 4H), 3.57 - 3.54 (m, 3H), 3.53 - 3.47 (m, 1H), 3.37 - 3.34 (m, 1H), 3.19 (s, 3H), 3.15 - 3.10 (m, 1H), 2.98 - 2.92 (m, 1H), 2.82 - 2.74 (m, 1H), 2.58 - 2.51 (m, 4H), 2.40 - 2.35 (m, 1H), 2.13 - 2.07 (m, 1H), 1.85 - 1.70 (m, 6H), 1.65 - 1.60 (m, 1H), 1.55 - 1.47 (m, 1H), 1.35 (d, J = 6.0 Hz, 3H), 1.32 - 1.15 (m, 6H), 0.92 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.35 (s, 3H).

[0986] Example 32

[0987] N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-3,3-dimethyl-2-oxobutanamide

[0988] Compound 32 was synthesized by replacing N,N-dimethyl oxamic acid with 3,3-dimethyl-2-oxobutanoic acid in the step of compound 1, using similar methods and reaction procedures. ESI-MS (m / z): 866.8 [M+H]; LC-MS retention time RT = 2.02 min. + 1 ​H NMR (500 MHz, DMSO) δ 9.04 (d, J = 9.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.50 - 8.48 (m, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.85 (s, 1H), 7.78 - 7.74 (m, 1H), 7.59 (d, J = 8.5 Hz, 1H), 5.60 - 5.53 (m, 1H), 5.23 - 5.18 (m, 1H), 4.39 - 4.19 (m, 4H), 4.13 - 4.02 (m, 1H), 3.63 - 3.55 (m, 7H), 3.39 - 3.35 (m, 2H), 3.33 - 3.29 (m, 1H), 3.26 (s, 3H), 3.00 - 2.94 (m, 1H), 2.83 - 2.74 (m, 1H), 2.59 - 2.52 (m, 4H), 2.41 - 2.35 (m, 1H), 2.13 - 2.06 (m, 1H), 1.85 - 1.77 (m, 2H), 1.57 - 1.47 (m, 1H), 1.36 (d, J = 6.0 Hz, 3H), 1.24 (s, 9H), 0.93 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.34 (s, 3H).

[0989] Example 33

[0990] N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-oxo-3-phenylpropanamide

[0991] Compound 33 was obtained by replacing N,N-dimethyl oxamic acid with phenylpyruvic acid in the synthesis of C...

Claims

1. A compound having the structure of Formula (A), or an isotopic derivative, stereoisomer, or a pharmaceutically acceptable salt thereof: ###00001### (A). wherein: Cya denotes or which is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; A represents an optionally substituted 4- to 8-membered heterocycloalkylene group, an optionally substituted phenylene group or an optionally substituted 5- to 6-membered heteroarylene group; B represents a single bond, an optionally substituted 4- to 12-membered heterocycloalkylene group, an optionally substituted 5- to 6-membered heteroarylene group or an optionally substituted phenylene group; X represents O, NR6or CR7R7'; W represents halogen, optionally substituted amino, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkyl, optionally substituted 4 to 12 membered heterocycloalkyl, optionally substituted C3-C 12 membered heteroaryl, or optionally substituted phenyl; L represents a single bond or -(C1-C6)alkylene-, each of the methylene groups in said -(C1-C6)alkylene- being optionally replaced with a carbonyl, NR a , O, or S; each of the methylene groups in said -(C1-C6)alkylene- being independently optionally substituted with 0, 1, 2, 3, or 4 C1-C3alkyl groups, and two substituents on the same C atom can form a 3-8 membered ring with said C atom; R2represents C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), or -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), which optionally can be substituted with 0, 1, or 2 substituents selected from: -OR a , -SR a , or -NR a R a ’; R4represents hydrogen, -(C0-C6alkylene)OR a , -(C0-C6alkylene)SR a , or -(C0-C6alkylene)NR a R a ', 3-8 membered cycloalkyl, or 4-12 membered heterocycloalkyl, each of which C0-C6alkylene, 3-8 membered cycloalkyl, or 4-12 membered heterocycloalkyl is independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halo, oxo, -OR a , -SR a , -NR a R a ', cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl; R5represents -OR a , -NR a R a ' or -Cy1-(R8) m ; Cy1represents C3-C 12 cycloalkyl or 4-12 membered heterocycloalkyl, which ring can be spiro, bridged, fused; R6represents -OR a , -NR a R a ’; R7, R7' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl); said R7and R7' with the common C atom can form a 4-8 membered ring, said 4-8 membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S; each R8independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a , cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R a , C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl; Cy0represents a 5- to 12-membered aromatic or heteroaromatic ring; R A each independently is selected from H, halogen, CN, C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C0-C6alkylene)-ORa, -(C0-C6alkylene)-SRa, or -(C0-C6alkylene)-NRaRa’, and optionally, 2 adjacent or non-adjacent atoms on Cy0are substituted with R A together with the ring atoms of Cy0may form a 6-10 membered ring, which can be further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, C1-C3alkyl, -ORa, -SRa, or -NRaRa’; L0is selected from a single bond, -(C1-C6) alkylene, -(C2-C6) alkenylene, any methylene of said -(C1-C6) alkylene or -(C2-C6) alkenylene being optionally replaced by a carbonyl, NRa, O or S, and said -(C1-C6) alkylene or -(C2-C6) alkenylene being optionally substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, C1-C3 alkyl; R C is selected from H, halogen, Ci-C6alkyl, -(Co-C6alkylene)-ORa, -(Co-C6alkylene)-SRa, or -(Co-C6alkylene)-NRaRa'; R D is selected from H, C1-C6alkyl, -(C1-C6alkylene)-ORa, -(C1-C6alkylene)-SRa, or -(C1-C6alkylene)-NRaRa'; R E , R F each independently is selected from H, C1-C6alkyl, halogen, -(C0-C6alkylene)-ORa, -(C0-C6alkylene)-SRa, or -(C0-C6alkylene)-NRaRa'; and optionally, R E , R F may form, with the C atom to which they are attached, a 3-6 membered ring which can additionally contain 0, 1, or 2 heteroatoms selected from N, O, S; Z represents N or CR3, Z' represents N or CR3', wherein R3, R3' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C8) cycloalkyl or -(C0-C6 alkylene)CN; wherein m, q each independently represent 0, 1, 2 or 3; R a , R a each independently represent hydrogen, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; when R a , R a are attached to the same N atom, said R a and R a together with the N atom to which they are both attached can form a 4-8 membered ring, which optionally can contain 1, 2 or 3 heteroatoms selected from N, O or S; said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene each independently can be substituted with 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

2. The compound of claim 1, or an isotopic derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof, having the structure of Formula (A’): wherein A, X, W, B, L, R A , R C , R D , R E , R F , Z, Z', R2, R4, R5, Cya, Cy0, L0, q are as defined in claim 1.

3. The compound of any preceding claim, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, R C , R D is H.

4. The compound of any preceding claim, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, Z represents CR3, Z' represents CR3'.

5. The compound of any preceding claim, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, L0is selected from a single bond, -(C1-C6) alkylene, -(C2-C6) alkenylene, any methylene of said -(C1-C6) alkylene or -(C2-C6) alkenylene being optionally replaced by a carbonyl, NRa, O or S, and said -(C1-C6) alkylene or -(C2-C6) alkenylene being optionally substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, C1-C3 alkyl; 6. The compound of any preceding claim, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, R E , R F are each independently selected from the group consisting of H, C1-C6 alkyl, and optionally, R E , R F may form, together with the C atom to which they are attached, a 3-6 membered ring, which ring can additionally contain 0, 1 or 2 heteroatoms selected from N, O, S; more preferably, R E , R F are each independently selected from the group consisting of C1-C3 alkyl.

7. The compound of any preceding claim, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, having the structure of Formula (B): represents a single bond or a double bond; X1, X2each independently represent C or N; R1represents C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6 alkylene)-ORa, -(C1-C6 alkylene)-SRaor -(C1-C6 alkylene)-NRaRa'; Y1, Y2, Y3each independently represent non-bond, single bond, CR A , N, NR1', O, S, wherein R1' represents C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6 alkylene)-ORa, -(C1-C6 alkylene)-SRa, or -(C1-C6 alkylene)-NRaRa'; wherein when Y3is CR A , optionally R1may be taken together with R A of Y3to form a 6-10 membered ring, which can be further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, C1-C3 alkyl, -ORa, -SRa, or -NRaRa'; t is selected from 0, 1, 2 or 3; X1, X2each independently represent C. A, X, W, B, L, R C , R D , R E , R F , Z, Z', R2, R4, R5, Cya are defined as in any of the preceding claims.

8. The compound of claim 7, or an isotopic derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof, having the structure of formula (B’): wherein X1, X2, Y1, Y2, Y3, A, X, W, B, L, R C , R D , R E , R F , Z, Z', R2, R4, R5, Cya, t are as defined in claim 7.

9. The compound of any one of claims 7-8, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, wherein:

10. The compound of any one of claims 7-9, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, selected from wherein Q represents CR A or N, T represents NR1', O or S, and optionally, when Y3is CR A R1may be taken together with R A substituents together with the ring atoms on Cy0form a 6-10 membered ring, which can be further substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, C1-C3alkyl, -ORa, -SRaor -NRaRa'.

11. The compound of any one of claims 7-10, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, denotes and optionally, R1may be taken together with R A substituents together with the N, X1and C atoms to which they are attached form a 6-10 membered ring, which can be further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, C1-C3alkyl, -OH.

12. The compound of any one of claims 7-11, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, denotes 13. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, R A each independently selected from H, halogen, CN, C1-C3 alkyl; more preferably, R A each independently represents H or F.

14. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, having the structure of Formula (I): which is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; Cya denotes or A represents an optionally substituted 4- to 6-membered heterocycloalkylene group, an optionally substituted phenylene group or an optionally substituted 5- to 6-membered heteroarylene group; an optionally substituted 4- to 12-membered heterocycloalkylene group, an optionally substituted 5- to 6-membered heteroarylene group or an optionally substituted phenylene group; B represents a single bond, X represents O, NR6or CR7R7'; ​ W represents halogen, optionally substituted amino, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkyl, optionally substituted 4 to 12 membered heterocycloalkyl, optionally substituted C3-C 12 membered heteroaryl, or optionally substituted phenyl; L represents a single bond or -(C1-C6)alkylene-, each of the methylene groups in said -(C1-C6)alkylene- being optionally replaced with a carbonyl, NR a , O, or S; each of the methylene groups in said -(C1-C6)alkylene- being independently optionally substituted with 0, 1, 2, 3, or 4 C1-C3alkyl groups, and two substituents on the same C atom can form a 3-8 membered ring with said C atom; R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ’; R2represents C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), or -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), which optionally can be substituted with 0, 1, or 2 substituents selected from: -OR a , -SR a , or -NR a R a ’; R3, R3' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-CN; R4represents hydrogen, -OR a , -SR a or -NR a R a ’; R5represents -OR a , -NR a R a ' or -Cy1-(R8) m ; Cy1represents C3-C 12 cycloalkyl or 4-12 membered heterocycloalkyl, which ring can be spiro, bridged, fused; R6represents -OR a , -NR a R a ’; R7, R7' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl); said R7 and R7' together with the common attached C atom can form a 4-8 membered ring, said 4-8 membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S; each R8independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a , cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R a , C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl; wherein m represents 0, 1, 2 or 3; R a , R a each independently represent hydrogen, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; when R a , R a are attached to the same N atom, said R a and R a together with the N atom to which they are attached can form a 4-8 membered ring, said 4-8 membered ring optionally can contain 1, 2 or 3 heteroatoms selected from N, O or S; each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be substituted with 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

15. The compound of claim 14, or an isotopic derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I’): wherein, R1, R2, R3, R3', R4, R5, Cya, A, B, L, X, W are as defined in claim 14.

16. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Cya represents or optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl.

17. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, Cya represents optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl; preferably, Cya represents 18. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, Cya represents or optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl; preferably, Cya represents 19. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, A represents an optionally substituted 4- to 6-membered heterocycloalkylene or an optionally substituted 5- to 6-membered heteroarylene; preferably, A represents an optionally substituted thiazolylene; more preferably, A represents an unsubstituted thiazolylene.

20. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, B represents a single bond, phenylene or optionally substituted 5-6 membered heteroarylene; preferably, B represents optionally substituted or more preferably, B represents or 21. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, X represents O or CH2.

22. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, W represents halogen, optionally substituted C1-C4 alkyl, optionally substituted 4- to 8-membered heterocycloalkyl or optionally substituted C3-C8 membered cycloalkyl.

23. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, L represents a single bond or -(C1-C6)alkylene-, any methylene of which can be replaced by a carbonyl, NR a , O or S; preferably, L represents a single bond, -C(O)-, -CH2- or -O-.

24. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl); preferably, R1 represents C1-C6 alkyl or C1-C6 haloalkyl; more preferably, R1 represents ethyl or -CH2CF3.

25. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, R2represents C1-C6alkyl, which can be substituted with 0 or 1 -ORa; preferably, R2represents 1-methoxyethyl; more preferably, R2represents wherein * indicates the point of attachment of R2to the rest of the formula.

26. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, R3, R3' each independently represent hydrogen, halogen, C1-C6 alkyl; preferably, R3, R3' are H.

27. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, R4 represents H.

28. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, R5represents -Cy1-(R8) m ; 29. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, Cy1 represents a 4- to 12-membered heterocycloalkyl, said ring can be spiro, bridged, fused; preferably, Cy1 represents a 4- to 8-membered heterocycloalkyl, said ring can be spiro, bridged, fused.

30. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, R7, R7' each independently represent hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl; preferably, R7, R7' each independently represent hydrogen, halogen, C1-C3 alkyl, C3-C6 cycloalkyl; said R7 and R7' together with the common attached C atom can form a 4-6 membered ring, said 4-6 membered ring optionally can contain 0 or 1 heteroatom selected from N, O or S.

31. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, each R8independently represents hydrogen, oxo, =NRa, -S(O)2Ra, -C(O)Ra, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently unsubstituted or substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -ORa, -SRa, -NRaRb, cyano, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; preferably each R8independently represents hydrogen, oxo, =NRa, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently unsubstituted or substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -ORa, -SRa, -NRaRb, cyano, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; preferably each R8independently represents hydrogen, oxo, =NRa, C1-C6alkyl; each of the above mentioned C1-C6alkyl is independently unsubstituted or substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -ORa, -SRa, -NRaRb, cyano, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl. a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl. a , C1-C6alkyl; each of the above mentioned C1-C6alkyl is independently unsubstituted or substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl. a , C1-C6alkyl; each of the above mentioned C1-C6alkyl is independently unsubstituted or substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl.

32. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, m represents 0, 1 or 2.

33. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, R a , R a each independently represent hydrogen, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; preferably, R a , R a each independently represent hydrogen or C1-C6alkyl; more preferably, R a , R a each independently represent hydrogen or C1-C3alkyl.

34. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, having the structure of Formula (II): wherein: Cya denotes or it can be optionally substituted with 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; X represents O, NR6 or CR7R7'; W represents halogen, optionally substituted amino, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkyl, optionally substituted 4 to 12 membered heterocycloalkyl, optionally substituted C3-C 12 membered heteroaryl, or optionally substituted phenyl; L represents a single bond or -(C1-C6)alkylene-, any methylene of which can be replaced by a carbonyl, NR a , O or S; R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ’; R5represents -OR a , -NR a R a ' or -Cy1-(R8) m ; Cy1represents C3-C 12 cycloalkyl or 4-12 membered heterocycloalkyl, which ring can be spiro, bridged, fused; R6represents -OR a , -NR a R a ’; R7, R7' each independently represent hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; said R7 and R7' together with the common attached C atom can form a 4-8 membered ring, said 4-8 membered ring optionally can contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; each R8independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a , cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R a , C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl; wherein m represents 0, 1, 2 or 3; each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be substituted with 0, 1, 2, 3, 4, 5 or 6 halogen atoms. R a , R a each independently represent hydrogen, Ci-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; when R a , R a are attached to the same N atom, said R a and R a together with the N atom to which they are both attached can form a 4-8 membered ring, which optionally can contain 1, 2 or 3 heteroatoms selected from N, O or S; each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene is independently optionally substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

35. The compound of claim 34, or an isotopic derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II’): wherein, R1, R5, Cya, L, X, W are as defined in claim 34.

36. The compound of any one of claims 34-35, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, Cya represents optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl; preferably, Cya represents 37. The compound of any one of claims 34-36, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, Cya represents or optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl; preferably, Cya represents 38. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, having the structure of Formula (III): wherein: Cya denotes or X represents O, NR6, or CR7R7'; W represents halogen, C1-C4alkyl, 4- to 8-membered heterocycloalkyl, or C3-C8cycloalkyl, each independently of the other, unsubstituted or substituted by 0, 1, 2, 3, 4, 5, or 6 R b substituted; L represents a single bond, -C(O)-, -CH2-, or -O-; R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ’; Cy1represents a 4-8 membered heterocycloalkyl, which ring can be spiro, bridged, fused; R6represents -OR a , -NR a R a ’; each of R7, R7' independently represents hydrogen, halogen, C1-C3alkyl, C3-C6cycloalkyl; said R7and R7' together with the common C atom can form a 4-6 membered ring, which 4-6 membered ring optionally can contain 0 or 1 heteroatom selected from N, O, or S; R8 independently represents hydrogen, oxo, =NRa, or C1-C6 alkyl; each of the C1-C6 alkyl groups can be 0, 1, 2, 3, or 4 selected from halogen, oxo, -OR a -SR a -NR a R a Substituents of '; wherein m represents 0, 1, or 2; R a , R a each independently represent hydrogen, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; R b each independently represents hydrogen, halogen, C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl, C2-C6alkenyl or C2-C6alkynyl; each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene is independently optionally substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

39. The compound of claim 38, or an isotopic derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof, having the structure of Formula (III’): wherein, R1, R5, Cya, L, X, W are as defined in claim 34.

40. The compound of any one of claims 38-39, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, Cya denotes 41. The compound of any one of claims 38-40, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, Cya denotes 42. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, having the structure of Formula (IV): wherein: Cya denotes or which is optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl; Cy2represents optionally substituted 4-12 membered heterocycloalkylene, optionally substituted 5- to 6-membered heteroarylene, or optionally substituted phenylene; X represents O, NR6, or CR7R7'; W represents halogen, optionally substituted amino, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkyl, optionally substituted 4 to 12 membered heterocycloalkyl, optionally substituted C3-C 12 membered heteroaryl, or optionally substituted phenyl; L represents a single bond or -(C1-C6)alkylene-, any methylene of which can be replaced by a carbonyl, NR a , O or S; R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ’; R5represents -OR a , -NR a R a ' or -Cy1-(R8) m ; Cy1represents C3-C 12 cycloalkyl or 4-12 membered heterocycloalkyl, which ring can be spiro, bridged, fused; R6represents -OR a , -NR a R a ’; each of R7, R7' independently represents hydrogen, halogen, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; said R7and R7' together with the common C atom can form a 4-8 membered ring, which 4-8 membered ring optionally can contain 0, 1, 2, or 3 heteroatoms selected from N, O, or S; each R8independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a , cyano, -COOR a , -COR a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R a , C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl can be independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl; wherein m represents 0, 1, 2, or 3; R a , R a each independently represent hydrogen, Ci-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; when R a , R a are attached to the same N atom, said R a and R a together with the N atom to which they are both attached can form a 4-8 membered ring, which optionally can contain 1, 2 or 3 heteroatoms selected from N, O or S; each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene is independently optionally substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

43. The compound of claim 42, or an isotopic derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IV’): wherein, R1, X, W, Cya, R5, Cy2, L are as defined in claim 42.

44. The compound of any one of claims 42-43, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, Cya represents optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl; preferably, Cya represents 45. The compound of any one of claims 42-44, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, Cya represents or optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl; preferably, Cya represents 46. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, having the structure of Formula (V): wherein: Cya denotes or Cy2represents or X represents O, NR6, or CR7R7'; W represents halogen, C1-C4alkyl, 4- to 8-membered heterocycloalkyl, or C3-C8cycloalkyl, each independently of the other, unsubstituted or substituted by 0, 1, 2, 3, 4, 5, or 6 R b substituted; L represents a single bond, -C(O)-, -CH2-, or -O-; R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ’; Cy1represents a 4-8 membered heterocycloalkyl, which ring can be spiro, bridged, fused; R6represents -OR a , -NR a R a ’; each of R7, R7' independently represents hydrogen, halogen, C1-C3alkyl, C3-C6cycloalkyl; said R7and R7' together with the common C atom can form a 4-6 membered ring, which 4-6 membered ring optionally can contain 0 or 1 heteroatom selected from N, O, or S; R8each independently represents hydrogen, oxo, =NRa, -S(O)2R a , -COR a , C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl can be independently substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; wherein m represents 0, 1, or 2; R a , R a each independently represent hydrogen, Ci-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; R b each independently represents hydrogen, halogen, C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl, C2-C6alkenyl or C2-C6alkynyl; each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene is independently optionally substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

47. The compound of claim 46, or an isotopic derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof, having the structure of Formula (V’): wherein R1, X, W, Cya, Cy2, L, Cy1, R8, m are as defined in claim 46.

48. The compound of claim 29, or an isotopic derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, Cya denotes 49. The compound of any one of claims 47-48, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, Cya denotes 50. The compound of any one of the preceding claims, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, wherein, each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene is independently substituted with 0, 1, 2, 3, or 4 substituents selected from F, CI, Br; preferably, with 0, 1, 2, 3, or 4 substituents selected from F, CI; more preferably, with 0, 1, 2, 3, or 4 F.

51. A compound having the structure: ###0012### 51 or an isotopic derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof.

52. A pharmaceutical composition comprising a compound of any one of claims 1-51, or an isotopically enriched derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof.

53. Use of a compound of any one of claims 1-51, or an isotopically enriched derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 52, for the manufacture of a medicament for the prevention and / or treatment of a cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease.

54. Use of a compound of any one of claims 1-51, or an isotopically enriched derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 52, for the prevention and / or treatment of a cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease.

55. A method of use of a medicament for the prevention and / or treatment of a cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-51, or an isotopically enriched derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 52.

56. The use of claim 53 or 54, or the method of claim 55, wherein, The cancer, tumor, inflammatory disease, autoimmune disease, or immune-mediated disease is a RAS protein-related disease.

57. The use or method of claim 56, wherein, The RAS protein is one or more of a KRAS protein, a NRAS protein, or a HRAS protein.

58. The use or method of claim 56 or 57, wherein, The cancer, tumor, inflammatory disease, autoimmune disease, or immune-mediated disease comprises a RAS mutation.

59. The use or method of claim 58, wherein, The RAS mutation comprises one or more of a KRAS mutation, a NRAS mutation, or a HRAS mutation.

60. The use or method of claim 58 or 59, wherein, The RAS mutation is at position 12, 13, and / or 61.

61. The use or method of claim 58, 59, or 60, wherein, The RAS mutation comprises one or more of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G13D, NRAS Q61L, KRAS G12A, KRAS G12S, or NRAS Q61K.

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