Pan-RAS inhibitor compound

Abstract

The invention relates to a compound with a pan-RAS inhibition effect as shown in a formula (A), or an isotope derivative, a stereoisomer or pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing the compound, and the use of the compound of formula (A) for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Description

A pan-RAS inhibitor compound Technical Field

[0001] The present invention relates to a compound, in particular to a highly active pan-RAS inhibitor and use thereof. Background Art

[0002] RAS is one of the most frequently mutated genes in human tumors, occurring in approximately 30% of cancer patients, with KRAS accounting for approximately 85% of RAS mutations. KRAS mutations are found in 88% of pancreatic cancers, 50% of colorectal adenocarcinomas, and 32% of lung adenocarcinomas. The development of inhibitors targeting KRAS has significant clinical significance and value.

[0003] KRAS is a membrane-bound protein with GTPase activity. It cycles between a GDP-bound, inactive conformation and a GTP-bound, active conformation through nucleotide exchange, acting as a "molecular switch." KRAS in the GTP-bound state can activate multiple downstream signaling pathways, including RAF-MEK-ERK and PI3K-AKT, regulating vital processes such as cell growth, proliferation, differentiation, and apoptosis.

[0004] KRAS mutations (such as G12C, G12D, G12V, and G13D) affect GTP hydrolysis mediated by GTPase activating proteins (GAPs), increasing the amount of KRAS in the GTP-bound activated state and overactivating downstream signaling pathways, ultimately leading to tumor development and progression. However, because the KRAS protein lacks a corresponding hydrophobic pocket suitable for drug binding and its affinity for GTP and GDP is at the picomolar level (~20pM), the development of inhibitors that competitively bind to KRAS is extremely difficult. For the past few decades, KRAS has been considered an undruggable target.

[0005] In May 2021, AMG510 was approved by the FDA for the treatment of KRAS G12C Locally advanced or metastatic non-small cell lung cancer with KRAS mutations has broken the history of KRAS being "undruggable." However, G12C mutations only account for a small fraction of KRAS mutations. Currently, there is a lack of effective inhibitor compounds for mutations at other KRAS sites, as well as other RAS types (NRAS and HRAS). This creates a significant unmet clinical need, and therefore, the development of effective pan-RAS inhibitor compounds is a technological necessity. Summary of the Invention

[0006] The present invention provides a pan-RAS inhibitor. This structure is different from the existing KRAS that works by covalent binding. G12C Instead of being an inhibitor, it works by mediating the formation of a ternary complex between ubiquitous intracellular chaperone proteins (such as Cyclophilin A) and RAS proteins. The formation of the ternary complex can block the binding of RAS and its downstream effector molecules (such as RAF) through steric hindrance, inhibiting the activation of MAPK and PI3K-AKT signaling pathways, thereby inhibiting the occurrence and development of tumors and playing a role in treating tumors and other diseases.

[0007] In one aspect, the present invention provides a compound of formula (A), or its isotopic derivatives, stereoisomers or pharmaceutically acceptable salts thereof:

[0008] in:

[0009] Cya said or which may optionally be substituted by 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl;

[0010] R2 represents halogen, cyano, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl), which may be optionally substituted by 0, 1 or 2 substituents selected from the group consisting of -ORa, -SRa or -NRaRa';

[0011] R3 represents hydrogen, hydroxyl, -(C1-C3 alkylene)-OR a or C1-C3 alkyl;

[0012] Cy1 represents C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl, Cy1 can be a monocyclic, spirocyclic, bridged or fused ring;

[0013] R4 each independently represents hydrogen, halogen, oxo, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C6)cycloalkyl, -(C0-C6 alkylene)(4-8 membered)heterocycloalkyl, -(C0-C6 alkylene)ORa, -(C0-C6 alkylene)SRa, -(C0-C6 alkylene)NRaRa', -(C0-C6 alkylene)CORa, -(C0-C6 alkylene)COORa, -(C0-C6 alkylene) CONRaRa', -(C0-C6 alkylene)NRaCORa', -(C0-C6 alkylene)OCONRaRa', -(C0-C6 alkylene)NRaCONRaRa', -(C0-C6 alkylene)SORa, -(C0-C6 alkylene)S(O)2Ra, -(C0-C6 alkylene)NRaS(O)2Ra', -(C0-C6 alkylene)CN, -(C0-C6 alkylene)(C6-C 10 wherein R4 on two C atoms of Cy1 together with the C atom to which they are attached and the atom between the two C atoms may form a 3-8 membered ring, and the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or two R4 on the same C atom of Cy1 together with the C atom to which they are attached may form a 3-8 membered ring, and the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0014] Optionally, R3 and R4 may form a ring;

[0015] Cy2 represents a 5-membered heteroaryl group;

[0016] Cy3 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, the ring may be a monocyclic, spirocyclic, bridged or fused ring;

[0017] R6 and R7 are each independently selected from: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; the above C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl are each independently substituted by 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -ORa, -SRa, -NRaRa', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl;

[0018] W is H or formula (II), wherein * represents linkage with Cy3:

[0019] Cy4 is selected from C3-C 12Cycloalkyl or 4-12 membered heterocycloalkyl, the ring may be a monocyclic, spirocyclic, bridged or fused ring;

[0020] R8 are each independently selected from: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, wherein the C1-C6 alkyl may be substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo, -ORa, -NRaRa' or cyano;

[0021] L1 and L2 each independently represent a single bond or -(C1-C6)alkylene-, any methylene group on the -(C1-C6)alkylene- may be replaced by a carbonyl, NRa, O or S, the -(C1-C6)alkylene- may be substituted by 0, 1, 2, 3 or 4 substituents selected from halogen or C1-C3 alkyl, and two substituents on the same C atom may form a 3-6 membered ring with the C atom to which they are connected, and the 3-6 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0022] Cy0 represents a 5-12 membered aromatic ring or heteroaromatic ring;

[0023] R A Each is independently selected from H, halogen, CN, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl), -(C0-C6 alkylene)-ORa, -(C0-C6 alkylene)-SRa or -(C0-C6 alkylene)-NRaRa', and optionally, RA on two adjacent or non-adjacent atoms on Cy0 together with the ring atoms of Cy0 can form a 6-10 membered ring, and the 6-10 membered ring can be further substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl, -ORa, -SRa or -NRaRa';

[0024] L0 is selected from a single bond, -(C1-C6)alkylene, -(C2-C6)alkenylene, any methylene group on the -(C1-C6)alkylene or -(C2-C6)alkenylene may be replaced by a carbonyl, NRa, O or S, and the -(C1-C6)alkylene or -(C2-C6)alkenylene may be optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl;

[0025] R B are each independently selected from H, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-ORa, -(C0-C6 alkylene)-SRa or -(C0-C6 alkylene)-NRaRa', and optionally, R BIt can form a ring with the substituent R4 of Cy1;

[0026] R C is selected from H, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-ORa, -(C0-C6 alkylene)-SRa or -(C0-C6 alkylene)-NRaRa';

[0027] R D Selected from H, C1-C6 alkyl, -(C1-C6 alkylene)-ORa, -(C1-C6 alkylene)-SRa or -(C1-C6 alkylene)-NRaRa';

[0028] R E 、R F are each independently selected from H, C1-C6 alkyl, halogen, -(C0-C6 alkylene)-ORa, -(C0-C6 alkylene)-SRa or -(C0-C6 alkylene)-NRaRa'; and optionally, R E 、R F can form a 3-6 membered ring with the C atom to which they are attached, and the 3-6 membered ring may additionally contain 0, 1 or 2 heteroatoms selected from N, O and S;

[0029] Z represents N or CR5, Z' represents N or CR5', wherein R5 and R5' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C8)cycloalkyl or -(C0-C6 alkylene)CN;

[0030] Wherein, m, n, o, p, and q each independently represent 0, 1, 2, 3, or 4;

[0031] Ra and Ra' each independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; when Ra and Ra' are connected to the same N atom, said Ra and Ra' and the commonly connected N atom may form a 4-8 membered ring, and said 4-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0032] The alkyl, cycloalkyl, heterocycloalkyl and alkylene groups may each independently be substituted by 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

[0033] In some embodiments, the compound represented by formula (A), or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof has the structure represented by formula (A'):

[0034] where R A 、R B 、RC 、R D 、R E 、R F , Z, Z', R2, R3, R4, R6, R7, Cya, Cy0, Cy1, Cy2, Cy3, L0, L1, W, m, n, p, and q are defined as described in formula (A).

[0035] In some embodiments, R B For H.

[0036] In some embodiments, R C 、R D For H.

[0037] In some embodiments, Z represents CR5 and Z' represents CR5'.

[0038] In some embodiments, L0 is vinylene, -(C1-C3)alkylene, or a single bond; more preferably, L0 is a single bond.

[0039] In some embodiments, R E 、R F are each independently selected from H, C1-C6 alkyl, and optionally, R E 、R F can form a 3-6 membered ring with the C atom to which they are attached, and the ring can additionally contain 0, 1 or 2 heteroatoms selected from N, O, and S; more preferably, R E 、R F Each is independently selected from C1-C3 alkyl.

[0040] In one aspect, the present invention provides a compound having a structure represented by formula (B), or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof:

[0041] in:

[0042] Indicates a single bond or a double bond;

[0043] X1 and X2 each independently represent C or N;

[0044] Y1, Y2, and Y3 each independently represent no bond, a 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 Y3 is CR AWhen, R1 can optionally be connected to R of Y3 A The substituent group together with the N, X1 and C atoms to which it is attached forms a 6-10 membered ring, and the 6-10 membered ring may be further substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl, -ORa, -SRa or -NRaRa';

[0045] 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';

[0046] t is selected from 0, 1, 2 or 3;

[0047] R A 、R B 、R C 、R D 、R E 、R F , Z, Z', R2, R3, R4, R6, R7, Cya, Cy1, Cy2, Cy3, L1, W, m, n, and p are defined as described above.

[0048] In some embodiments, the compound represented by formula (B), or its isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof has a structure represented by formula (B'):

[0049] in, X1, X2, Y1, Y2, Y3, R A 、R B 、R C 、R D 、R E 、R F , Z, Z', R1, R2, R3, R4, R6, R7, Cya, Cy1, Cy2, Cy3, L1, W, m, n, p, and t are defined as described in formula (B).

[0050] In some embodiments, X1 and X2 each independently represent C.

[0051] In some embodiments, Selected from Among them, Q represents CR A or N, T represents NR1', O or S, and optionally, when Y3 is CR A When R1 can be connected to R AThe substituents together with the ring atoms on Cy0 form a 6-10 membered ring, which may be further substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl, -ORa, -SRa or -NRaRa'.

[0052] In some embodiments, express And optionally, R1 can be combined with R A The substituent, together with the N, X1 and C atoms to which it is attached, forms a 6-10 membered ring, which may be further substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl, -OH.

[0053] In some embodiments, express

[0054] In some embodiments, R A are each independently selected from H, halogen, CN, C1-C3 alkyl; more preferably, R A Each independently represents H or F.

[0055] In one aspect, the present invention provides a compound having the structure of formula (I), or its isotopic derivatives, stereoisomers or pharmaceutically acceptable salts thereof:

[0056] in:

[0057] 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';

[0058] R2 represents halogen, cyano, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl), which may be optionally substituted by 0, 1 or 2 of the following substituents: -ORa, -SRa or -NRaRa';

[0059] R3 represents hydrogen, hydroxyl, -(C1-C3 alkylene)-OR a , or C1-C3 alkyl;

[0060] Cy1 represents C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl, Cy1 can be a monocyclic, spirocyclic, bridged or fused ring;

[0061] R4 each independently represents hydrogen, halogen, oxo, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C6)cycloalkyl, -(C0-C6 alkylene)(4-8 membered)heterocycloalkyl, -(C0-C6 alkylene)ORa, -(C0-C6 alkylene)SRa, -(C0-C6 alkylene)NRaRa', -(C0-C6 alkylene)CORa, -(C0-C6 alkylene)COORa, -(C0-C6 alkylene)CONRaRa', -(C0-C6 alkylene)NRaCORa', -(C0-C6 alkylene)OCONRaRa', -(C0-C6 alkylene)NRaCONRaRa', -(C0-C6 alkylene)SORa, -(C0-C6 alkylene) wherein R4 on two C atoms of Cy1 together with the C atom to which they are attached and the atom between the two C atoms may form a 3-8 membered ring, and the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or two R4 on the same C atom of Cy1 together with the C atom to which they are attached may form a 3-8 membered ring, and the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0062] R5 and R5' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C8)cycloalkyl or -(C0-C6 alkylene)CN;

[0063] Cy2 represents a 5-membered heteroaryl group;

[0064] Cy3 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, the ring may be a monocyclic, spirocyclic, bridged or fused ring;

[0065] R6 and R7 are each independently selected from: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; the above C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl are each independently substituted by 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -ORa, -SRa, -NRaRa', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl;

[0066] W is H or formula (II), wherein * represents linkage with Cy3:

[0067] Cy4 is selected from C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, the ring may be a monocyclic, spirocyclic, bridged or fused ring;

[0068] R8 are each independently selected from: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, wherein the C1-C6 alkyl may be substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo, -ORa, -NRaRa', cyano;

[0069] L1 and L2 each independently represent a single bond or -(C1-C6)alkylene-, any methylene group on the -(C1-C6)alkylene- may be replaced by a carbonyl, NRa, O or S, the -(C1-C6)alkylene- may be substituted by 0, 1, 2, 3 or 4 substituents selected from halogen or C1-C3 alkyl, and two substituents on the same C atom may form a 3-6 membered ring with the C atom to which they are connected, and the 3-6 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0070] Wherein, m, n, o, and p each independently represent 0, 1, 2, 3, or 4;

[0071] Ra and Ra' each independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; wherein, when Ra and Ra' are connected to the same N atom, said Ra and Ra' and the commonly connected N atom may form a 4-8 membered ring, and said 4-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0072] The alkyl, cycloalkyl, heterocycloalkyl and alkylene groups may each independently be substituted by 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

[0073] In some embodiments, the compound represented by formula (I), or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof has a structure represented by formula (I'):

[0074] wherein, the definitions of R1, R2, R3, R4, R5, R5', R6, R7, Cya, Cy1, Cy2, Cy3, L1, W, m, n, and p are as described in formula (I).

[0075] In some embodiments of the present invention, Cya represents or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl.

[0076] In some preferred embodiments of the present invention, Cya represents It may optionally be substituted by 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; more preferably, Cya represents

[0077] In some embodiments of the present invention, Cya represents or It may optionally be substituted by 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; preferably, Cya represents

[0078] In some embodiments of the present invention, W is of formula (II).

[0079] In some embodiments of the present invention, L1 and L2 each independently represent a single bond or -(C1-C6)alkylene-, any methylene group on the -(C1-C6)alkylene- can be replaced by a carbonyl group, NRa, O or S, and the -(C1-C6)alkylene- can be substituted by 0, 1, 2, 3 or 4 C1-C3 alkyl substituents, and two substituents on the same C atom can form a 3-6 membered ring with the C atom to which they are connected, and the 3-6 membered ring optionally can contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0080] In some embodiments of the present invention, R1 represents C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl), halogenated C1-C6 alkyl, halogenated-(C0-C6 alkylene)-(C3-C8 cycloalkyl), halogenated-(C0-C6 alkylene)-(4-8 membered heterocycloalkyl).

[0081] In some embodiments of the present invention, R1 represents C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl).

[0082] In some embodiments of the present invention, R1 represents a C1-C6 alkyl group or a halogenated C1-C6 alkyl group; more preferably, R1 represents an ethyl group or -CH2CF3.

[0083] In some embodiments of the present invention, R2 represents a C1-C6 alkyl group, which may be substituted with 0 or 1 C1-C3 alkoxy groups; preferably, R2 represents a 1-methoxyethyl group; more preferably, R2 represents Wherein, * represents the position where R2 is connected to the portion to which it is connected in the general formula.

[0084] In some embodiments of the present invention, R3 is preferably H.

[0085] In some embodiments of the present invention, Cy1 represents a C3-C8 cycloalkyl group or a 4-8 membered heterocycloalkyl group; preferably, Cy1 represents a C3-C8 cycloalkyl group; more preferably, Cy1 represents a cyclopropyl group.

[0086] In some embodiments of the present invention, R4 each independently represents hydrogen, halogen or C1-C3 alkyl.

[0087] In some embodiments of the present invention, the structure of -Cy1-(R4)p is selected from the following:

[0088] Wherein, * represents the site where -Cy1-(R4)p is connected to the site to which it is connected in the general formula.

[0089] In some preferred embodiments of the present invention, express or Wherein, * indicates the site where Cy1 is connected to the site connected thereto in the general formula.

[0090] In some embodiments of the present invention, R5 and R5' each independently represent hydrogen, halogen, or C1-C6 alkyl; preferably, R5 and R5' are H.

[0091] In some embodiments of the present invention, Selected from or

[0092] In some embodiments of the invention, Cy2 is not pyrazole or isoxazole.

[0093] In some embodiments of the invention, Cy2 is not or

[0094] In some embodiments of the present invention, no or

[0095] In some embodiments of the present invention, Selected from or Preferably, Selected from or

[0096] In some embodiments of the present invention, Cy3 represents a 4-12 membered heterocycloalkyl group, and the ring can be a monocyclic ring, a spirocyclic ring, a bridged ring, or a fused ring; preferably, Cy3 represents a 4-8 membered heterocycloalkyl group, and the ring can be a monocyclic ring, a spirocyclic ring, a bridged ring, or a fused ring.

[0097] In some embodiments of the present invention, Cy3 represents or And Cy3 may have n substituents selected from R7; more preferably, Cy3 represents or And Cy3 may have n substituents selected from R7.

[0098] In some embodiments of the present invention, R6 is each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, and the above C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl are each independently substituted by 0, 1 or 2 halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; preferably, R6 is each independently selected from hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl, and the above C1-C6 alkyl, C3-C8 cycloalkyl are each independently substituted by 0, 1 or 2 halogen, C1-C6 alkyl or C3-C6 cycloalkyl; more preferably, R6 is each independently selected from hydrogen and methyl.

[0099] In some embodiments of the present invention, R7 is independently selected from: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, wherein the C1-C6 alkyl can be substituted by 0, 1 or 2 substituents selected from halogen, oxo, -ORa, -NRaRa', cyano; preferably, R7 is independently selected from: hydrogen, halogen, oxo, hydroxyl, cyano or C1-C6 alkyl.

[0100] In some embodiments of the present invention, L1 represents a single bond, -CH2-, -O- or -NH-.

[0101] In some embodiments of the present invention, express or And Cy3 may have n substituents selected from R7.

[0102] In some embodiments of the present invention, Cy4 is C5-C6 cycloalkyl or 5-6 membered heterocycloalkyl, o≥1 and R8 is not hydrogen.

[0103] In some embodiments of the present invention, Cy4 is selected from C3-C4 cycloalkyl or 4-membered heterocycloalkyl.

[0104] In some embodiments of the present invention, Cy4 is selected from or And Cy4 may have o substituents selected from R8; preferably, Cy4 is selected from or And Cy4 may have o substituents selected from R8; more preferably, Cy4 is selected from or Cy4 may have o substituents selected from R8.

[0105] In some embodiments of the present invention, L2 represents a single bond, -CH2- or -O-; preferably, L2 represents a single bond.

[0106] In some embodiments of the present invention, R8 is independently selected from hydrogen, halogen or C1-C6 alkyl.

[0107] In some embodiments of the present invention, express or And Cy3 may have n substituents selected from R7.

[0108] In some embodiments of the present invention, express or

[0109] In some embodiments of the present invention, m, n, o, p, q, and t each independently represent 0, 1, or 2.

[0110] In some embodiments of the present invention, Ra and Ra' each independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; preferably, Ra and Ra' each independently represent hydrogen or C1-C6 alkyl; preferably, Ra and Ra' each independently represent hydrogen or C1-C3 alkyl.

[0111] In one aspect, the present invention provides a compound having the structure of formula (III), or its isotopic derivatives, stereoisomers or pharmaceutically acceptable salts thereof:

[0112] in:

[0113] R1 represents ethyl or -CH2CF3;

[0114] R2 represents a C1-C6 alkyl group, which may be substituted by 0 or 1 C1-C3 alkoxy group;

[0115] Cy1 represents a C3-C8 cycloalkyl group or a 4-8 membered heterocycloalkyl group; preferably, Cy1 represents a C3-C8 cycloalkyl group;

[0116] R4 each independently represents hydrogen, halogen or C1-C3 alkyl;

[0117] Cy2 represents a 5-membered heteroaryl group;

[0118] Cy3 represents a 4-12 membered heterocycloalkyl group;

[0119] R6 is each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, and the above C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl are each independently substituted by 0, 1 or 2 halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl;

[0120] R7 is each independently selected from: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, wherein the C1-C6 alkyl may be substituted by 0, 1 or 2 substituents selected from halogen, oxo, -ORa, -NRaRa', cyano;

[0121] L1 represents a single bond or -(C1-C6)alkylene-, and any methylene group on the -(C1-C6)alkylene- can be replaced by a carbonyl group, NRa, O or S;

[0122] Cy4 is selected from C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C3-C 12 Cycloalkyl and 4-12 membered heterocycloalkyl may be monocyclic, spirocyclic, bridged, or fused, and when Cy4 is C5-C6 cycloalkyl or 5-6 membered heterocycloalkyl, o≥1 and R8 is not hydrogen;

[0123] L2 represents a single bond or -(C1-C6)alkylene-, wherein any methylene group on the -(C1-C6)alkylene- can be replaced by a carbonyl, NRa, O or S;

[0124] R8 are each independently selected from: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, wherein the C1-C6 alkyl may be substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo, -ORa, -NRaRa', cyano;

[0125] m, n, o, and p each independently represent 0, 1, or 2.

[0126] Ra and Ra' each independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl.

[0127] The alkyl, cycloalkyl, heterocycloalkyl and alkylene groups may each independently be substituted by 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

[0128] In some embodiments, the compound represented by formula (III), or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof has the structure represented by formula (III'):

[0129] wherein R1, R2, R4, R6, R7, R8, Cya, Cy1, Cy2, Cy3, Cy4, L1, L2, m, n, o, and p are defined as in formula (III).

[0130] In some embodiments of the present invention, Cya represents It may optionally be substituted by 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; preferably, Cya represents

[0131] In some embodiments of the present invention, Cya represents or It may optionally be substituted by 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; preferably, Cya represents

[0132] In some embodiments of the present invention, R2 represents 1-methoxyethyl; preferably, R2 represents Wherein, * represents the site where R2 is connected to the site to which it is connected in formula (III).

[0133] In some embodiments of the present invention, Cy1 represents a C3-C8 cycloalkyl group. Preferably, Cy1 represents a cyclopropyl group.

[0134] In some embodiments of the present invention, express or Wherein, * indicates the site where Cy1 is connected to the site connected thereto in formula (III).

[0135] In some embodiments of the invention, Cy2 is not or

[0136] In some embodiments of the invention, Cy2 is not pyrazole or isoxazole.

[0137] In some embodiments of the present invention, Selected from or Preferably, Selected from or

[0138] In some embodiments of the present invention, R6 is independently selected from hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl, and the above C1-C6 alkyl and C3-C8 cycloalkyl can be substituted by 0, 1 or 2 substituents selected from halogen, C1-C6 alkyl or C3-C6 cycloalkyl; more preferably, R6 is independently selected from hydrogen and methyl.

[0139] In some embodiments of the present invention, R7 is independently selected from hydrogen, halogen, oxo, hydroxyl, cyano or C1-C6 alkyl.

[0140] In some embodiments of the present invention, L1 represents a single bond, -CH2-, -O- or -NH-.

[0141] In some embodiments of the present invention, Cy4 is C5-C6 cycloalkyl or 5-6 membered heterocycloalkyl, o≥1 and R8 is not hydrogen.

[0142] In some embodiments of the present invention, Cy4 is selected from C3-C4 cycloalkyl or 4-membered heterocycloalkyl.

[0143] In some embodiments of the present invention, L2 represents a single bond, -CH2- or -O-; preferably, L2 represents a single bond.

[0144] In some embodiments of the present invention, R8 is independently selected from hydrogen, halogen or C1-C6 alkyl.

[0145] In some embodiments of the present invention, Ra and Ra' each independently represent hydrogen or a C1-C6 alkyl group; preferably, Ra and Ra' each independently represent hydrogen or a C1-C3 alkyl group.

[0146] In another aspect, the present invention provides a compound having the structure of formula (IV), or its isotopic derivatives, stereoisomers or pharmaceutically acceptable salts thereof:

[0147] in:

[0148] R1 represents ethyl or -CH2CF3;

[0149] R4 each independently represents hydrogen, halogen or C1-C3 alkyl;

[0150] Selected from or

[0151] Cy3 is selected from 4-8 membered heterocycloalkyl;

[0152] Cy4 is selected from C3-C4 cycloalkyl or 4-membered heterocycloalkyl;

[0153] R6 are each independently selected from hydrogen, methyl;

[0154] R7 are each independently selected from: hydrogen, halogen, oxo or C1-C6 alkyl;

[0155] R8 are each independently selected from: hydrogen, halogen or C1-C6 alkyl;

[0156] L1 represents a single bond, -CH2- or -O-;

[0157] L2 represents a single bond, -CH2- or -O-;

[0158] Wherein, n, o, and p each independently represent 0, 1, or 2;

[0159] Ra and Ra' each independently represent hydrogen or C1-C6 alkyl; preferably, Ra and Ra' each independently represent hydrogen or C1-C3 alkyl;

[0160] The alkyl, cycloalkyl, heterocycloalkyl and alkylene groups may each independently be substituted by 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

[0161] In some embodiments, the compound represented by formula (IV), or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof has the structure represented by formula (IV'):

[0162] wherein R1, R4, R6, R7, R8, Cya, Cy2, Cy3, Cy4, L1, L2, m, n, o, and p are defined as in formula (IV).

[0163] In some embodiments of the present invention, express or Wherein, * indicates the site where Cy1 is connected to the site connected thereto in the general formula.

[0164] In some preferred embodiments of the present invention, Cya represents or.

[0165] In another aspect, the present invention provides a compound having the following structure, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof:

[0166] In yet another aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0167] In another aspect, the present invention provides the use of the aforementioned compounds, or their isotopic derivatives, stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions in the preparation of drugs for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

[0168] In another aspect, the present invention provides the use of the aforementioned compounds, or their isotopic derivatives, stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions in preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

[0169] In another aspect, the present invention provides a method for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases, comprising administering a therapeutically effective amount of the aforementioned compound, or its isotopic derivatives, stereoisomers or pharmaceutically acceptable salts and / or pharmaceutical compositions thereof to a patient in need.

[0170] In some embodiments, the disease, tumor, inflammatory disease, autoimmune disease or immune-mediated disease described in the above-mentioned uses or methods is a RAS protein-related disease; in some preferred embodiments, the RAS protein is one or more of KRAS protein, NRAS protein or HRAS protein.

[0171] In some embodiments, the disease, tumor, inflammatory disease, autoimmune disease or immune-mediated disease described in the above-mentioned uses or methods includes a RAS mutation; in some preferred embodiments, the RAS mutation includes one or more of a KRAS mutation, a NRAS mutation or a HRAS mutation; specifically, the RAS mutation is located at position 12, 13 and / or 61; more specifically, the RAS mutation includes one or more of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G13D or NRAS Q61L.

[0172] It is particularly noted that, herein, when referring to a "compound" of the structure of Formula (A), Formula (A'), Formula (B), Formula (B'), Formula (I), Formula (I'), Formula (III), Formula (III'), Formula (IV), or Formula (IV') , it generally also encompasses stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives thereof.

[0173] It is well known to those skilled in the art that the salts, solvates and hydrates of a compound are alternative forms of existence of the compound, and they can all be converted into the compound under certain conditions. Therefore, it is particularly noted that when referring to the compounds of formula (A), formula (A'), formula (B), formula (B'), formula (I), formula (I'), formula (III), formula (III'), formula (IV) and formula (IV') herein, they generally also include their pharmaceutically acceptable salts, and further include their solvates and hydrates.

[0174] Similarly, reference herein to a compound generally also includes prodrugs, metabolites, and N-oxides thereof.

[0175] Pharmaceutically acceptable salts of the present invention may be formed using, for example, the following inorganic or organic acids: "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, or the like, within the scope of sound medical judgment, and at a reasonable benefit / risk ratio. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent, as outlined below. For example, the free base function may be reacted with a suitable acid. Examples of pharmaceutically acceptable inorganic acid addition salts are salts formed of an amino group 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 by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0176] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol and acetonitrile), adding an excess of an organic acid or an aqueous inorganic acid solution thereto to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt.

[0177] The precursors or metabolites described herein may be those known in the art, as long as the precursors or metabolites are converted to compounds through in vivo metabolism. For example, "prodrugs" refer to those prodrugs of the compounds of the present invention that, within the scope of reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and are considered to have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly converted in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism or N-demethylation of the compounds of the present invention.

[0178] As used herein, "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of isolation. The solvent molecules in the solvate may exist in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0179] "Stereoisomerism" as used herein is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism and optical isomerism (i.e., optical isomerism). Conformational isomerism refers to the stereoisomerism phenomenon in which the atoms or atomic groups of an organic molecule with a certain configuration have different spatial arrangements due to the rotation or distortion of carbon-carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair and boat conformations that occur in the structure of cyclohexane. "Stereoisomers" refer to compounds of the present invention that contain one or more asymmetric centers and can therefore exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers. The compounds of the present invention have asymmetric centers, and each asymmetric center can produce two optical isomers. The scope of the present invention includes all possible optical isomers and diastereomeric mixtures, as well as pure or partially purified compounds. The compounds of the present invention may exist as tautomers, which have different hydrogen attachment points due to the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. Enantiomers, diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of all compounds of formula (A), formula (A'), formula (B), formula (B'), formula (I), formula (I'), formula (III), formula (III'), formula (IV), and formula (IV') are included within the scope of the present invention.

[0180] The "isotopic derivative" of the present invention refers to a molecule in which the compound is isotopically labeled. The isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; Carbon isotope: 11 C, 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 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 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 3 H and carbon 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H), substitution can enhance metabolic stability and prolong half-life, thereby achieving a reduction in dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques similar to those used for synthesizing non-isotope-labeled compounds.

[0181] The present invention also provides use of the compound of the present invention in preparing a medicament for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

[0182] In addition, the present invention provides a pharmaceutical composition for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases, or immune-mediated diseases, comprising a compound of the present invention as an active ingredient. The pharmaceutical composition may optionally contain a pharmaceutically acceptable carrier.

[0183] Furthermore, the present invention provides a method for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases or immune-mediated diseases, which comprises administering a compound of the present invention to a mammal in need thereof.

[0184] Representative examples of inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, atopic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic inflammatory lung 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, Sjögren's syndrome, autoimmune thyroid disease, disease, urticaria (rubella), 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 sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0185] Representative examples of cancer 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 carcinoma, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral Neuroectodermal tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, or plasmacytoma.

[0186] When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for treating cancer or tumors, the compound of the present invention or a pharmaceutically acceptable salt thereof may provide enhanced anticancer effects.

[0187] Representative examples of anticancer agents for treating cancer or tumors may include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, 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, ixapram ... lon, tamoxifen, flutamide, gonadorelin analogs, megestrol acetate, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danuceritinib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib Tinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracutinib, saridegib, sorafenib, sunitinib, telatinib, tivantinib, Tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, berentuzumab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, 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.

[0188] When the compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered in combination with another therapeutic agent for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may provide enhanced therapeutic effects.

[0189] Representative examples of therapeutic agents for treating inflammatory diseases, autoimmune diseases and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, hydroprednisolone, methylhydroprednisolone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα 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 may be contained in the pharmaceutical composition of the present invention.

[0190] Other features of the present invention will become apparent as the present invention describes exemplary embodiments, which are given to illustrate the present invention and are not intended to be limiting thereof. The following examples are prepared, isolated, and characterized using the methods disclosed herein.

[0191] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the following methods and synthetic methods known in the field of organic synthetic chemistry or variations thereof known to those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and for the desired transformation. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule is consistent with the proposed transformation. This sometimes requires judgment to change the order of the synthesis steps or the raw materials to obtain the desired compounds of the present invention.

[0192] Unless otherwise indicated, the terms used in this application, including the specification and claims, are defined as follows. Unless otherwise indicated, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology will be used. Throughout this application, unless otherwise indicated, the use of "or" or "and" means "and / or."

[0193] In the specification and claims, a given chemical formula or name shall encompass all stereoisomers and optical isomers thereof and racemates thereof in which such isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereoisomers) and racemic forms are within the scope of the present invention. Multiple geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. may also exist in the compounds, and all such stable isomers are encompassed by the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, and they can be separated into mixtures of isomers or separate isomeric forms. The compounds of the present invention can be isolated in optically active or racemic form. All methods for preparing the compounds of the present invention and the intermediates prepared therein are considered part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization). Depending on the process conditions, the final products of the present invention are obtained in free (neutral) or salt form. Both the free forms and salts of these final products are within the scope of the present invention. If desired, one form of the compound can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into a free compound or another salt; and a mixture of isomeric compounds of the present invention can be separated into its individual isomers. The compounds of the present invention, their free forms, and salts can exist in multiple 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. It should be understood that all tautomeric forms that may exist are included in the present invention.

[0194] In the present invention, when the linking group listed does not specify its connection direction, its connection direction is arbitrary, for example Where L is -C(O)NH-, in which case -C(O)NH- can be connected to form a phenyl group and a cyclohexyl group in the order of reading from left to right. It is also possible to connect phenyl and cyclohexyl groups in the reverse reading order from left to right to form Combinations of linking groups and linked groups are permitted only if they result in stable compounds. In some preferred embodiments of the present invention, the sequences are read from left to right.

[0195] Unless otherwise defined, the definitions of the substituents of the present invention are independent of each other and not interrelated. For example (listing but not exhaustive), in one aspect, for a substituent R a (or R a '), they are independent of each other in the definitions of different substituents. Specifically, for R a (or R a ') When a definition is selected in a substituent, it does not mean that the R a (or R a') have the same definition in other substituents. More specifically, for example (listing only non-exhaustive) for NR a R a ', when R a (or R a ') is selected from hydrogen, it does not mean that in -C(O)-NR a R a 'In, R a (or R a ') must be hydrogen. In another aspect, when more than one R is present in a substituent a (or R a '), these R a (or R a ') are also independent of each other. For example, in the substituent -(CR a R a’ ) m -O-(CR a R a’ ) n -, when m+n is greater than or equal to 2, the m+n R a (or R a ') are independent of each other and can have the same or different meanings.

[0196] Unless otherwise defined, the meaning of "substituted by x A substituents or B substituents" described in the present invention is the same as "substituted by x substituents selected from A and B", and when the number of substituents is greater than 1, the x substituents may be the same or different. For example, "R1 may be 0, 1 or 2 R x "Substituted" means that R1 can be optionally replaced by 0, 1 or 2 selected from R x When the number of substituents is greater than 1, these substituents may be R x For example, "R1 may be substituted with 0, 1 or 2 H, C1-C3 alkyl or C3-C6 cycloalkyl" means that R1 may optionally be substituted with 0, 1 or 2 substituents selected from H, C1-C3 alkyl or C3-C6 cycloalkyl, and when the number of substituents is greater than 1, these substituents may be the same or different. For example, when the number of substituents is 2, these two substituents may be, for example, 2 H, 2 C1-C3 alkyl, one H and the other C1-C3 alkyl, or one C1-C3 alkyl and the other C3-C6 cycloalkyl.

[0197] Unless otherwise defined, when a substituent is indicated as "optionally substituted", the substituent is selected, for example, from substituents such as alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, aryl In some embodiments, the present invention further comprises an alkylthiocarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, an arylalkylsulfonyl group, an aminosulfonyl group such as -SO2NH2, a substituted sulfonylamino group, a nitro group, a cyano group, a carboxyl group, a carbamoyl group such as -CONH2, a substituted carbamoyl group such as -CONHalkyl, -CONHaryl, -CONHarylalkyl or a case where the nitrogen has two substituents selected from alkyl, aryl or arylalkyl, an alkoxycarbonyl group, an aryl group, a substituted aryl group, a guanidino group, a heterocyclic group such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like and a substituted heterocyclic group.

[0198] Unless otherwise defined, the term "single bond," "bond," or "direct bond" as used herein means two atoms are connected by a saturated covalent bond. For example, when L represents a single bond, "ALB" means that A and B are connected by a saturated covalent bond, i.e., "AB"; 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-."

[0199] As used herein, the term "alkyl" is intended to include side chains and straight chain saturated aliphatic hydrocarbon groups with a specified number of carbon atoms. For example, "C1-C6 alkyl" represents an alkyl group with 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl) and pentyl (such as n-pentyl, isopentyl, neopentyl). Alkyl can be unsubstituted or substituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In this article, alkyl is preferably an alkyl group with 1 to 6, more preferably 1 to 4 carbon atoms.

[0200] As used herein, the term "alkylene" is intended to include saturated aliphatic hydrocarbon groups, branched, straight, containing or not containing cyclic alkyl groups, having a specified number of carbon atoms, which are residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms. For example, "C0-C6 alkylene" means an alkylene group 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 this article, alkylene groups are preferably alkylene groups having 0-6, 0-4, 0-3, 1-6, 1-4, or 1-3 carbon atoms. In this article, alkylene groups preferably do not contain alkylene groups that are cyclic alkyl groups.

[0201] The term "cycloalkyl" refers to a monocyclic, polycyclic or branched cyclic alkyl group. For example, C3-C 12 Cyclic alkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyls such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Herein, cycloalkyl can be a saturated or partially unsaturated carbocyclic ring, for example, a 6-membered cycloalkyl can include 0-2 double bonds, and a 12-membered cycloalkyl can include 0-5 double bonds or triple bonds. Polycyclic cycloalkyls such as bicyclic and tricyclic cycloalkyls include cycloalkyls of bridged rings, spiro rings or condensed rings. Cyclic alkyl can be unsubstituted or substituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In the invention, cycloalkyl is preferably C3-C 12 Cycloalkyl, more preferably C3-C8 cycloalkyl. According to common practice in the art, it is generally not specifically emphasized in the text that the cycloalkyl group can be a monocyclic ring. For example, unless otherwise specified, "the C3-C8 cycloalkyl group can be a spirocyclic ring, a bridged ring, or a fused ring" is equivalent to "the C3-C8 cycloalkyl group can be a monocyclic ring, a spirocyclic ring, a bridged ring, or a fused ring". For another example, unless otherwise specified, "the C3-C8 cycloalkyl group" can be a monocyclic ring, a spirocyclic ring, a bridged ring, or a fused ring, and is preferably a monocyclic ring.

[0202] Similarly, the term "heterocycloalkyl" refers to a ring structure in which at least one carbon atom of a cycloalkyl ring structure is replaced by a heteroatom selected from N, O, S and P. Herein, heterocycloalkyl can be a saturated or partially unsaturated heterocycle, for example, a 6-membered heterocycloalkyl can include 0-2 double bonds, and a 12-membered heterocycloalkyl can include 0-5 double bonds or triple bonds. The N atom can be optionally quaternized, and the N and S atoms can be optionally oxidized (i.e., NO, SO and SO2). It includes monocyclic heterocycles, bicyclic heterocycles and tricyclic heterocycle systems, wherein the bicyclic heterocycles and tricyclic heterocycle systems include spirocyclic heterocycles, annular heterocycles and bridged heterocycles. Heterocycloalkyl can be unsubstituted or substituted. When substituted, it can be substituted at any usable point of attachment, and the substituents are preferably selected from one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In the present invention, the heterocycloalkyl group is preferably a 4-12-membered heterocycloalkyl group, and more preferably a 4-8-membered heterocycloalkyl group. According to common practice in the art, when a heterocycloalkyl group may be a monocyclic ring, it is usually not specifically emphasized in the text. For example, unless otherwise specified, "the 3-8-membered heterocycloalkyl group may be a spirocyclic ring, a bridged ring, or a fused ring" is equivalent to "the 3-8-membered heterocycloalkyl group may be a monocyclic ring, a spirocyclic ring, a bridged ring, or a fused ring". For another example, unless otherwise specified, "the 3-8-membered heterocycloalkyl group" may be a monocyclic ring, a spirocyclic ring, a bridged ring, or a fused ring, and is preferably a monocyclic ring.

[0203] In the present invention, the term "paracyclic" refers to a polycyclic group formed by two or more cyclic structures sharing two adjacent atoms.

[0204] In the present invention, the term "bridged ring" refers to a polycyclic group in which two rings in the system share two or more ring atoms.

[0205] In the present invention, the term "spirocycle" refers to a polycyclic group in which single rings share a carbon atom (called a spiro atom).

[0206] The term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl includes, but is not limited to, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, etc. In this article, alkenyl is preferably C2-C6 alkenyl.

[0207] The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl. Monocyclic cyclic alkenyl refers to a C3-C8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornyl. Branched cycloalkenyls such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyls include cyclic alkenyls of bridged rings, spirocycles or condensed rings.

[0208] The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, etc. In this article, alkynyl is preferably C2-C6 alkynyl.

[0209] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, C6 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) and tert-butoxy. In this article, alkoxy is preferably an alkoxy having 1 to 6, more preferably 1 to 4 carbon atoms. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above connected by a sulfur bridge having a specified number of carbon atoms; for example, methyl-S- and ethyl-S-. Alkoxy can be unsubstituted or substituted, and when substituted, it can be substituted at any usable point of attachment, the substituent preferably being one or more selected from deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0210] The term "carbonyl" refers to an organic functional group composed of carbon and oxygen atoms connected by a double bond (C=O).

[0211] The term "aryl", alone or as part of a larger moiety such as "aralkyl", "arylalkoxy" or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to 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" refers to an alkyl residue attached to an aryl ring, non-limiting examples of which include benzyl, phenethyl and the like. The fused aryl group may be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring. The dotted line drawn from the ring system indicates that the bond may be attached to any suitable ring atom. The aryl group may be unsubstituted or substituted, and when substituted, it may be substituted at any available point of attachment, preferably one or more of deuterium, halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0212] When the term "heterocycle" is used, it refers to fully saturated, partially saturated, and fully unsaturated heteroatom-containing ring structures, including heteroaromatic rings.

[0213] The term "heteroaryl" means a stable 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic polycyclic heterocyclic ring containing carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; it includes a structure in which a cycloalkane or heterocycloalkane is fused to an aromatic ring such as a benzene ring or a heteroaromatic ring such as pyridine, and the site of the substituent can be located on the cycloalkane, heterocycloalkane, aromatic ring, or heteroaromatic ring. The nitrogen and sulfur heteroatoms may be optionally oxidized. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, wherein R is H or, if defined, another substituent). The heterocycle may be attached to its side group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic group described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. The heteroaryl group may be unsubstituted or substituted, and when substituted, it may be substituted at any available point of attachment, the substituent being preferably selected from one or more of halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.Examples of aromatic 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-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolenyl, 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, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidone 4-Piperidinyl, Pteridinyl, Purinyl, Pyranyl, Pyrazinyl, Pyrazolidinyl, Pyrazolinyl, Pyrazolopyridinyl, Pyrazolyl, Pyridazinyl, Pyridooxazolyl, Pyridoimidazolyl, Pyridothiazolyl, Pyridinyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2-Pyrrolidinonyl, 2H-Pyrrolyl, Pyrrolyl, Quinazolinyl, Quinolinyl, 4H-Qulolidinyl, Quinoxalinyl, Quinuclidinyl, Tetrazolyl, Tetrahydrofuranyl, Tetrahydroisoquinolinyl, Tetrahydroquinolinyl, 6H-1,2,5-Thiadiazinyl, 1,2,3-Thiadiazolyl, 1,2,4-Thiadiazolyl, 1,2,5-Thiadiazolyl, 1,3,4-Thiadiazolyl, Thianthryl, Thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, dihydroindolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-quinolyl, 2,3-dihydro-benzofuranyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", "-pyrimidylbiphenyl-"; the present invention also includes fused ring and spiro compounds containing, for example, the above-mentioned heterocycles.

[0214] As used herein, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valence is maintained and the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0215] In the present disclosure, one or more halogens may each be independently selected from fluorine, chlorine, bromine and iodine.

[0216] "Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" / "haloalkylene" is intended to include branched and straight-chain saturated alkyl / alkylene groups having a specified number of carbon atoms substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms substituted with one or more fluorine atoms. "Halocycloalkyl" / "haloheterocycloalkyl" is intended to include cycloalkyl / heterocycloalkyl groups having a specified number of carbon atoms substituted with one or more halogens. In the present invention, the halogen atom is preferably fluorine or chlorine, more preferably fluorine. In this document, unless it is specifically stated that an 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 halogenation, or it is considered that the group is not suitable for being halogenated according to common knowledge in the art, the group is considered to be halogenated.

[0217] "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above having the specified number of carbon atoms attached via an oxygen bridge. For example, "halo C1-C6 alkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a haloalkyl group as defined above having the specified number of carbon atoms attached via a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0218] In this disclosure, C is used when referring to certain substituent groups. x1 -C x2, which means that the number of carbon atoms in the substituent group can be x1 to x2. For example, C0-C8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C1-C8 means that the group contains 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C2-C8 means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C3-C8 means that the group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C4-C8 means that the group contains 4, 5, 6, 7 or 8 carbon atoms, C0-C6 means that the group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C1-C6 means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C2-C6 means that the group contains 2, 3, 4, 5 or 6 carbon atoms, and C3-C6 means that the group contains 3, 4, 5 or 6 carbon atoms.

[0219] In the present disclosure, when referring to a cyclic group (such as an aryl, heteroaryl, cycloalkyl and heterocycloalkyl), the expression "x1-x2 membered ring" is used, which means that the number of ring atoms of the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; the 3-6 membered ring means that the cyclic group can be a 3-, 4-, 5- or 6-membered ring, and the number of its ring atoms can be 3, 4, 5 or 6; the 3-8 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7- or 8-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7 or 8; the 3-9 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7, 8 or 9-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, The term "4-7 membered ring" refers to a 4-, 5-, 6-, or 7-membered ring having 4, 5, 6, or 7 ring atoms; a 5-, 8-, or 5-membered ring refers to a 5-, 6-, 7-, or 8-membered ring having 5, 6, 7, or 8 ring atoms; a 5-, 12-, or 5-membered ring refers to a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; and a 6-, 12-, or 6-membered ring refers to a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 6, 7, 8, 9, 10, 11, or 12 ring atoms. The ring atoms may be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, such as heteroatoms selected from N, O and S.

[0220] Where nitrogen atoms (e.g., amines) are present on the compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the invention. Thus, the shown and claimed nitrogen atoms are considered to encompass both the shown nitrogen and its N-oxide to obtain the derivatives of the invention.

[0221] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group may be optionally substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0222] The term "patient" as used herein refers to an organism to be treated by the method of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., mice, apes, monkeys, horses, cows, pigs, dogs, cats, etc.) and most preferably refer to humans.

[0223] As used herein, the term "effective amount" means an amount of a drug or pharmaceutical agent (i.e., a compound of the present invention) that will cause a biological or medical response in a tissue, system, animal, or human being, such as that sought by a researcher or clinician. In addition, the term "therapeutically effective amount" means an amount that results in improved treatment, cure, prevention, or alleviation of a disease, condition, or side effect, or reduces the rate of progression of a disease or condition, compared to a corresponding subject that has not received the above amount. An effective amount can be given in one or more administrations, applications, or dosages and is not intended to be limited by a specific formulation or route of administration. The term also includes within its scope an effective amount that enhances normal physiological function.

[0224] As used herein, the term "treating" includes any effect that results in improvement of a condition, disease, disorder, etc., such as alleviation, reduction, modulation, improvement, or elimination, or amelioration of the symptoms thereof.

[0225] The term "pharmaceutically acceptable" is used herein to refer to those compounds, substances, 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 problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0226] As used herein, the phrase "pharmaceutically acceptable carrier" or "pharmaceutical carrier" means a pharmaceutical substance, 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 stearic acid), or solvent encapsulating substance, which is involved in carrying or transporting the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0227] The term "pharmaceutical composition" means a composition comprising a compound of the present invention and at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals (particularly mammals), including (i.e.) adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the mode of administration and the nature of the dosage form.

[0228] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0229] The term "cancer," as used herein, refers to an abnormal, uncontrolled growth of cells that can metastasize (spread) under certain conditions. This type of cancer includes, but is not limited to, solid tumors (such as those of the bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (such as the thyroid), prostate, skin (melanoma), or blood tumors (such as non-leukemic leukemias).

[0230] The term "combination administration" or its like, as used herein, refers to the administration of several selected therapeutic agents to a single patient, using the same or different administration routes at the same or different times.

[0231] The terms "enhance" or "capable of enhancing," as used herein, refer to the ability to increase or prolong the potency or duration of a desired outcome. Thus, in the context of enhancing the therapeutic effect of a drug, the term "capable of enhancing" refers to the ability of the drug to increase or prolong the potency or duration of the drug in a system. "Potentiation," as used herein, refers to the ability of another therapeutic agent to maximize its effectiveness in an ideal system.

[0232] The term "immune disease" refers to a disease or condition that results from an adverse or deleterious response to an endogenous or exogenous antigen. The result is usually cellular dysfunction, or the resulting damage and malfunction of, or destruction of, organs or tissues that may be responsible for the immune condition.

[0233] The term "subject" or "patient" includes both mammals and non-mammals. Mammals include, but are not limited to, mammals such as humans, non-human primates such as gorillas, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs; livestock such as rabbits and dogs; and laboratory animals including rodents such as rats, mice, and guinea pigs. Non-mammals include, but are not limited to, birds and fish. In a preferred aspect, the selected mammal is a human.

[0234] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of a disease or symptom; alleviating complications caused by a disease or symptom, or preventing and / or treating signs caused by a disease or symptom.

[0235] The terms "inhibit" or "reduce," or any variation of these terms, include any measurable reduction or complete inhibition to achieve the desired result. For example, the activity can be reduced by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derivable therein, compared to normal.

[0236] The term "wild-type" refers to an entity having a structure or activity as found in nature in a "normal" (as opposed to mutated, diseased, altered, etc.) state or situation. Those skilled in the art will appreciate that wild-type genes and polypeptides typically exist in a variety of different forms (e.g., alleles).

[0237] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds that have the ability to inhibit the biological function of a target protein by inhibiting the activity or expression of a protein such as K-Ras, H-Ras, or N-Ras G12C. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological effects of the target protein. Although preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included in this definition. The preferred biological activity inhibited by the antagonist is related to the occurrence, growth, or spread of a tumor.

[0238] As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration, regardless of whether the administration is fixed or temporary, continuous or intermittent, and can be attributed to or related to the administration.

[0239] The composition can be prepared according to conventional mixing, granulation or coating methods, and the pharmaceutical composition of the present invention can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the compound of the present invention or its pharmaceutically acceptable salt by weight or volume. In some embodiments, the compound described herein or its pharmaceutically acceptable salt is present in an amount of 1-95% by weight of the total amount of the composition, for example, the pharmaceutical composition.

[0240] The composition can be provided in the dosage form suitable for following administration: intra-articular, oral, parenteral (such as intravenous, intramuscular), rectum, skin, subcutaneous, surface, percutaneous, sublingual, nasal, vaginal, intracapsular, intraurethral, ​​intrathecal, epidural, ear or eye administration, or by injection, suction or direct contact with nose, urogenital, genital or oral mucosa. Therefore, pharmaceutical composition can be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, syrups, osmotic delivery devices, suppositories, enemas, injections, implants, sprays, preparations suitable for iontophoresis delivery or aerosols. The composition can be prepared according to conventional medical practice.

[0241] As used herein, the term "administering" refers to administering a composition (e.g., a compound or a formulation comprising a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be performed by any appropriate route. For example, in some embodiments, administration can be bronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intracapsular, transmucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, or vitreous administration.

[0242] The formulation can be suitable for systemic administration or surface or topical application. Systemic formulations include formulations designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or can be prepared for transdermal, transmucosal or oral administration. The formulation will generally include a diluent and, in some cases, adjuvants, buffers, preservatives, etc. The compound or its pharmaceutically acceptable salt can also be administered in the form of a lipid particle composition or a microemulsion.

[0243] For injection, the formulation can be prepared in conventional forms, such as liquid solutions or suspensions, or solid forms suitable for preparation as solutions or suspensions in liquids prior to injection, or in the form of emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol, and the like. These compositions may also contain a certain amount of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, and the like, for example, sodium acetate, sorbitan monolaurate, and the like.

[0244] Systemic administration can also include relatively non-invasive methods such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or pharmaceutically acceptable salts thereof. It will be appreciated in the art that suitable forms include syrups, capsules, and tablets.

[0245] Each compound described herein or its pharmaceutically acceptable salt can be formulated in a variety of ways known in the art. For example, the first agent and the second agent in the combination therapy can be formulated together or separately. Other modes of combination therapy are also described herein.

[0246] Individual or separately formulated medicaments can be packaged together in a kit form. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, one pill and a powder, a suppository or a liquid in a vial, two topical creams, etc. The kit may include optional components that help administer the unit dose to the subject, such as vials for reconstitution of the powder form, syringes for injection, custom IV delivery systems, inhalers, etc. In addition, the unit dose kit may contain instructions for the preparation and administration of the composition. The kit can be manufactured as a disposable unit dose for one subject, for multiple uses (constant dose, or wherein the efficacy of an individual compound or its pharmaceutically acceptable salt can vary as the treatment progresses) for a specific subject; or the kit may contain multiple doses suitable for administration to multiple subjects ("whole package"). The kit components can be assembled in cartons, blister packs, bottles, tubes, etc.

[0247] Formulations for oral use include tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients. The excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrants (e.g., cellulose derivatives including microcrystalline cellulose, starch including potato starch, cross-linked sodium carboxymethylcellulose, alginates, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, optionally substituted hydroxypropyl methylcellulose, ethylcellulose, polyvinyl pyrrolidone, or polyethylene glycol); and lubricants, glidants, and anti-adherents (e.g., magnesium stearate, zinc stearate, stearic acid, silicon dioxide, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients may be colorants, flavorings, plasticizers, humectants, buffers, and the like.

[0248] Two or more compounds can be mixed together in tablets, capsules or other vehicles, or can be separated. In one example, the first compound is contained on the inside of the tablet, and the second compound is on the outside, thereby making the vast majority of the second compound release before the first compound releases.

[0249] Formulations for oral use may also be provided in the form of chewable tablets, or in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin); or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. Powders, granules and pellets may be prepared using the ingredients mentioned above for tablets and capsules in a conventional manner, using, for example, a mixer, a fluidized bed apparatus or a spray drying device.

[0250] Dissolution or diffusion controlled release can be achieved by appropriately coating tablets, capsules, pellets or granular formulations of the compound, or by incorporating the compound or its pharmaceutically acceptable salt into a suitable matrix. The controlled release coating can include one or more of the above-mentioned coating materials, such as shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxymethylacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate or polyethylene glycol. In controlled release matrix formulations, matrix materials may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, tristearin, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbons.

[0251] Liquid forms for oral administration that may incorporate the compounds of the present invention, or pharmaceutically acceptable salts thereof, and compositions include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0252] In general, when administered to a person, the oral dosage of any compound of the present invention or its pharmaceutically acceptable salt will depend on the properties of the compound, and can be easily determined by those skilled in the art. Dosage can be, for example, from about 0.001 mg to about 2000 mg per day, from about 1 mg to about 1000 mg per day, from about 5 mg to about 500 mg per day, from about 100 mg to about 1500 mg per day, from about 500 mg to about 1500 mg per day, from about 500 mg to about 2000 mg per day, or any range derived therefrom. In some embodiments, the daily dosage for oral administration can be, for example, in the range of about 0.001 mg to about 2000 mg per kilogram of human body weight, administered in single doses or divided doses. On the other hand, in some cases, it may be necessary to use a dosage outside the limit.

[0253] In some embodiments, the pharmaceutical composition may further comprise an additional compound having antiproliferative activity. Depending on the mode of administration, the compound or its pharmaceutically acceptable salt will be formulated into a suitable composition for ease of delivery. Each compound or its pharmaceutically acceptable salt in the combination therapy can be formulated in a variety of ways known in the art. For example, the first agent and the second agent in the combination therapy can be formulated together or separately. Desirably, the first agent and the second agent are formulated together so that these agents are administered simultaneously or nearly simultaneously.

[0254] It will be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and used in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, before, or after administration of one or more other desired therapeutic agents or medical procedures. The specific combination of therapies (therapeutics or procedures) used in a combination regimen should take into account the compatibility of the desired therapeutic agents or procedures with the desired therapeutic effect to be achieved. It will also be understood that the therapies employed may achieve the desired effect for the same condition, or they may achieve different effects (e.g., control any adverse effects).

[0255] As described herein, administration of each drug in the combination therapy can independently be one to four times daily for one day to one year, and can even be continued for the life of the subject. Chronic (long-term) administration may also be applicable.

[0256] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only. DETAILED DESCRIPTION

[0257] Example

[0258] General Process

[0259] When the preparation route is not included, the raw materials and reagents used in the present invention are all known products, which can be synthesized according to methods known in the art, or can be obtained by purchasing commercial products. No further purification is required for the commercially available reagents used.

[0260] Room temperature refers to 20-30℃.

[0261] Unless otherwise specified in the reaction examples, all reactions were carried out under a nitrogen atmosphere, which means that the reaction flask was connected to a nitrogen balloon of approximately 1 L.

[0262] The hydrogenation reaction is usually carried out by evacuating the flask and filling it with hydrogen, and this operation is repeated three times. The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1L.

[0263] Microwave reaction use Initiator + microwave reactor.

[0264] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker Ascend TMThe NMR spectra were obtained using a 500 nm NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard. The following abbreviations are used for NMR signal multiplicities: s = singlet, brs = broad, d = doublet, t = triplet, and m = multiplet. Coupling constants are listed as J values ​​and are measured in Hz.

[0265] Reverse phase preparative chromatography was performed using a Thermo (UltiMate 3000) reverse phase preparative chromatograph. Flash column chromatography was performed using an Aeger (FS-9200T) automatic column machine, and silica gel prepacked columns were performed using a Santai Pre-packed columns. Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for thin layer chromatography separation and purification products are 0.4mm to 0.5mm.

[0266] The LC-MS analysis method is as follows:

[0267] 1) Mass spectrometry: Thermo Fisher MSQ PLUS mass spectrometer, ESI source, positive ion mode. Ion source parameters: drying gas temperature, 350°C; drying gas flow rate, 10 L / min; MS range: 120–1000.

[0268] 2) Liquid phase conditions: Chromatographic column: Waters XBridge (3.5 μm, 50 mm × 4.6 mm); mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, linear gradient elution according to Table 1 below; flow rate: 2 mL / min; column temperature: 30°C; UV detection wavelengths: 214 nm, 254 nm, 280 nm; injection volume: 2 μL.

[0269] Table 1. Gradient elution conditions

[0270] The HPLC analysis method is as follows:

[0271] Chromatographic column: Waters XBridge phenyl (3.5 μm, 150 mm × 4.6 mm); mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, linear gradient elution according to Table 2; flow rate: 1 mL / min; column temperature: 30°C; UV detection wavelengths: 214 nm, 254 nm, 280 nm; injection volume: 2 μL.

[0272] Table 2. Gradient elution conditions

[0273] The synthetic methods of some intermediates in the invention are as follows:

[0274] Intermediate 1

[0275] Intermediate 1 was prepared by the following steps:

[0276] Step 1: Dissolve 2,2-dimethyl-3-hydroxypropionic acid methyl ester INT-1a (100 g, 756.67 mmol) in N,N-dimethylformamide (1 L). Add imidazole (128.79 g, 1.89 mol) and stir to dissolve. Add tert-butyldiphenylsilyl chloride (228.78 g, 832.34 mmol) dropwise at 20°C. Continue stirring for 4 hours. After the reaction is complete, pour the reaction solution into 3 L of ice water. The suspension is extracted with ethyl acetate (1 L x 2). The organic phase is washed three times with water and concentrated under reduced pressure to obtain INT-1b as a colorless oil, which is used directly in the next step without purification. ESI-MS (m / z): 371.2 [M+H]. + ;

[0277] Step 2: The residual liquid INT-1b obtained in the previous step was added to methanol (2 L), and 360 g of a prepared 33% aqueous sodium hydroxide solution was added, and stirred at 20°C for 17 hours. After the reaction was completed, 1 L of water was added, and the methanol was removed under reduced pressure. The residual liquid was extracted with petroleum ether (1 L * 5). After extraction, the pH value of the aqueous phase was adjusted to 4-5 with hydrochloric acid. A large amount of white solid precipitated. Stirring was continued for 30 minutes, filtered, and dried to obtain a white solid INT-1c (269 g, yield 90%). ESI-MS (m / z): 357.8 [M+H] + ;

[0278] Step 3: INT-1c (130 g, 364.63 mmol) was dissolved in dichloromethane (500 mL), and thionyl chloride (130.14 g, 1.09 mol, 79.35 mL) was added at room temperature. N,N-dimethylformamide (0.05 mL) was added dropwise, and the mixture was stirred at 60°C for 3 hours. After the reaction was completed, dichloromethane and the remaining thionyl chloride were removed under reduced pressure. Petroleum ether (300 mL) was added to the residual liquid and distilled until no fraction was evaporated to obtain a light yellow oil INT-1d, which was directly used in the next reaction without purification.

[0279] Step 4: Dissolve 5-bromoindole INT-1e (64.8 g, 331 mmol) in dichloromethane (400 mL). Add diethylaluminum chloride solution (198 mL, 2 M in hexanes) at 0°C. Stir for 30 minutes after addition. Add the dichloromethane solution of INT-1d obtained in the previous step dropwise to the reaction flask. Continue stirring for 2 hours. After the reaction is complete, slowly pour the reaction mixture into an ice-cold aqueous solution of potassium sodium tartrate (1 L) and stir for 16 hours. Once the system stabilizes, concentrate under reduced pressure to remove the dichloromethane. The residue is extracted with ethyl acetate (1 L x 2), washed with water, and the organic phase is rotary evaporated to yield a brown oil. This oil is added to a mixture of petroleum ether / ethyl acetate (10 / 1) (2 L). Stir at 20°C to precipitate a solid, which is then filtered to yield INT-1f (139 g, 78% yield) as a yellow solid. ESI-MS (m / z): 534.8 [M+H] + ;

[0280] Step 5: 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 mixture was stirred for 20 minutes. After the system stabilized, the temperature was raised to 60°C and stirred overnight. After the raw materials disappeared, the reaction solution was slowly added to ice water (200 mL) for quenching, and extracted with ethyl acetate (500 mL*3). The organic phase was washed with water, dried, and concentrated under reduced pressure. The residual liquid was dissolved in dichloromethane (500 mL). Add diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (28.43 g, 112.24 mmol) and p-toluenesulfonic acid (21.35 g, 112.24 mmol) and stir at room temperature for 3 hours. After the reaction is complete, concentrate under reduced pressure to remove dichloromethane. The residue is dissolved in methanol (500 mL) and a pre-prepared 14% aqueous lithium hydroxide solution (100 mL) is added. Stir at room temperature for 3 hours, filter, and air-dry at room temperature to obtain a yellow solid INT-1g (84 g, yield 86.26%). ESI-MS (m / z): 520.2 [M+H] + ;

[0281] Step 6: Dissolve INT-1g (50g, 96mmol) in tetrahydrofuran (250mL), add tetrabutylammonium fluoride (197mL, 1M in THF), and stir overnight at 60°C. After the reaction is complete, add the reaction solution to water (300mL), extract with ethyl acetate (200mL*3), wash with water, and concentrate under reduced pressure to obtain a brown oil. The resulting residue is dissolved in methanol (40mL), and water (20mL) is added. The mixed solution is washed with petroleum ether (40mL*5) and concentrated under reduced pressure to remove the methanol. The residue is extracted with ethyl acetate (50mL*2), the organic phase is washed with water, and dried to obtain INT-1h as a light yellow oil (25g, yield 90.40%). ESI-MS (m / z): 282.8 [M+H] + ;

[0282] Step 7: Dissolve compound INT-1h (25 g, 88.7 mmol) in dioxane (250 mL), add potassium acetate (21.7 g, 221.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.24 g, 4.4 mmol), and neopentyl glycol diboron (24.1 g, 106.4 mmol), and react at 90 ° C under nitrogen protection for 4 hours. LCMS monitoring shows that the reaction of the raw materials is complete. Celite was filtered and the filtrate was concentrated. Dichloromethane (200 mL) was added to the concentrate, and 15% aqueous sodium hydroxide solution (17.7 g, 3548 mmol) was added and the mixture was concentrated under reduced pressure until the aqueous phase was clear. The mixture was filtered and extracted once with dichloromethane. The pH of the aqueous phase was adjusted to 3-4 with hydrochloric acid under ice bath conditions. A large amount of yellow solid precipitated. Stirring was continued for 30 minutes and filtered to obtain the yellow solid compound INT-1i (17.96 g, yield 82.1%). ESI-MS (m / z): 248.4 [M+H] + ;

[0283] Step 8: 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 reacted at 90°C under nitrogen for 17 hours. LCMS monitored the complete reaction of the raw materials. The reaction solution was filtered through celite and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water, and dried to obtain a brown oily compound INT-1j, which was used directly in the next reaction without treatment. ESI-MS (m / z): 488.4 [M+H] + ;

[0284] Step 9: Dissolve the crude compound INT-1j in dichloromethane (700 mL). Add 4-dimethylaminopyridine (866 mg, 7.1 mmol) and triethylamine (43.0 g, 426 mmol). Add acetic anhydride (14.5 g, 142 mmol) dropwise at 0°C. After the addition is complete, remove the ice bath and allow the mixture to warm naturally. Stir for 1-2 hours. Once the reaction is complete, wash the reaction solution with water, dry it, and concentrate it to obtain a brown oil. Purify it by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain INT-1l as a light yellow oil (62.3 g, 83.2% yield). ESI-MS (m / z): 530.5 [M+H]. + ;

[0285] Step 10: Dissolve compound INT-11 (62.3 g, 117.9 mmol) in N,N-dimethylformamide (620 mL), add N-iodosuccinimide (26.5 g, 117.9 mmol), and react overnight at 10°C. LCMS monitoring confirmed the complete reaction of the raw materials. The reaction solution was slowly poured into ice water (3000 mL). Stirring resulted in the precipitation of solids, which were filtered, washed with water, and air-dried to obtain yellow solid compound INT-1m (64.2 g, yield 87%). ESI-MS (m / z): 656.3 [M+H] + ;

[0286] Step 11: Dissolve compound INT-1m (64 g, 99.1 mmol) in tetrahydrofuran (640 mL) and water (128 mL), add lithium hydroxide monohydrate (11.86 g, 282.4 mmol), stir at 70°C for 1 hour, monitor the reaction of the starting material by LCMS, add water (300 mL) to the reaction solution, and concentrate under reduced pressure. Then add methyltetrahydrofuran (200 mL), adjust the pH to 4-5 with 4M hydrochloric acid, and then extract with methyltetrahydrofuran (200 mL*3). Combine the organic phases, wash three times with brine, and thoroughly spin dry to obtain yellow solid compound INT-1n (56.5 g, yield 95%). ESI-MS (m / z): 600.5 [M+H] + ;

[0287] Step 12: Compound INT-1n (57 g, 95.0 mmol), 1-methylimidazole (38.9 g, 475 mmol) and (S)-hexahydropyridazine-3-carboxylic acid methyl ester trifluoroacetate (52.7 g, 142.5 mmol) were dissolved in acetonitrile (800 mL). A solution of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (40.0 g, 142.5 mmol) in acetonitrile (400 mL) was added dropwise at 0°C and stirred for 1 hour. LCMS monitored the complete reaction of the raw materials. Water (1000 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (1000 mL*3). The mixture was dried to obtain a yellow solid compound INT-1o (56.5 g, 95% yield). ESI-MS (m / z): 726.3 [M+H] + ;

[0288] Step 13: Dissolve compound INT-1o (56.5 g, 77.8 mmol) in tetrahydrofuran (560 mL) and water (112 mL), add lithium hydroxide (4.66 g, 194.7 mmol), and react at 10°C for 2 hours. LCMS monitoring shows that the reaction is complete. Add water (300 mL) and adjust the pH to 5-6 with 4M hydrochloric acid. Concentrate, extract with methyltetrahydrofuran, wash with brine, and after thorough separation, completely remove the solvent by rotary evaporation to obtain compound INT-1p (55.4 g, yield 88.16%) as a yellow solid. ESI-MS (m / z): 712.6 [M+H] + ;

[0289] Step 14: Add N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (59.1 g, 210.8 mmol) and 1-methylimidazole (26.5 g, 323.2 mmol) to acetonitrile (2000 mL) and stir to dissolve. Add a THF solution of compound INT-1p (100 g / 1000 mL, 140.5 mmol) dropwise at 10-20°C. Stir and react for 1-2 hours. LCMS monitoring indicates complete reaction of the starting material. Rotary evaporation removes the solvent, and the residue is added with water (1000 mL). Extract with dichloromethane (1000 mL*3), adjust the pH to 3-4 with hydrochloric acid, and spin-dry the organic phase to obtain a yellow solid. Recrystallize from isopropanol to obtain compound INT-1q (59 g, 60% yield). ESI-MS (m / z): 694.6 [M+H] + ;

[0290] Step 15: Dissolve compound INT-1q (37 g, 53.35 mmol), 2-dicyclohexylphosphine-2′,6′-dimethylbiphenyl (6.6 g, 16.0 mmol), tris(dibenzylideneacetone)dipalladium (5.86 g, 6.40 mmol), and potassium acetate (18.3 g, 186.7 mmol) in toluene (370 mL). Add pinacol borane (34.1 g, 266.7 mmol, 38.7 mL) dropwise under nitrogen. React at 50°C under nitrogen for 3 hours. Complete reaction of the starting materials was monitored by LCMS. The reaction solution was filtered and purified by silica gel column chromatography to obtain compound INT-1 (31 g, 82% yield) as a yellow solid. ESI-MS (m / z): 694.8 [M+H] + .

[0291] Intermediate 2

[0292] Intermediate 2 was prepared by the following steps:

[0293] Step 1: Compound INT-2a (43 g, 199 mmol), pinacol diboron (55.6 g, 219 mmol), methoxy(cyclooctadiene)iridium dimer (1.30 g, 1.99 mmol), and 4,4-di-tert-butylbipyridine (2.67 g, 9.95 mmol) were added to tetrahydrofuran (500 mL). The temperature was raised to 75°C under nitrogen and the reaction was stirred for 16 hours. LCMS monitoring showed complete conversion of the starting materials. Excess tetrahydrofuran was removed by rotary evaporation to obtain a brown residue, INT-2b, which was used directly in the next reaction without purification. ESI-MS (m / z): 358.3 [M+H] + .

[0294] Step 2: The residual liquid INT-2b obtained in the previous step was added to methanol (200 mL), and concentrated hydrochloric acid (100 mL) was added thereto. The reaction solution was refluxed for 3 hours. LCMS monitoring showed the disappearance of the starting material. The methanol was removed by rotary evaporation. The residual liquid was added to water (200 mL), and the pH was adjusted to 13 with 30% sodium hydroxide solution. The solution 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 continued stirring, filtered, and dried to obtain the white solid compound INT-2c (41.3 g, 80% yield). ESI-MS (m / z): 276.3 [M+H] + .

[0295] Step 3: Compound INT-2c (41.3 g, 159 mmol) was added to acetonitrile (400 mL) and dissolved. N-iodosuccinimide (35.8 g, 239 mmol) was added and the mixture was heated to 80°C and stirred overnight. LCMS showed that the starting material disappeared. The reaction solution was evaporated to remove acetonitrile, and the residue was added with ethyl acetate (300 mL). The mixture was washed with water, dried, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain a white solid compound INT-2d (45.6 g, yield 85%). ESI-MS (m / z): 358.1 [M+H] + .

[0296] Step 4: Dissolve compound INT-2d (5 g, 14.6 mmol) in N,N-dimethylformamide (50 mL), and add zinc cyanide (1.03 g, 8.8 mmol) and tetrakis(triphenylphosphine)palladium (1.69 g, 1.46 mmol) sequentially. Stir at 100°C overnight under nitrogen protection. LCMS monitoring shows that the reaction is complete. Ammonia water (5 mL) is added to quench the reaction, and the mixture is extracted with ethyl acetate (200 mL*2). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound INT-2e (2.1 g, yield 59.6%) as a colorless oil. ESI-MS (m / z): 241.2 [M+H] + .

[0297] Step 5: Compound INT-2e (2.1 g, 8.7 mmol) was dissolved in a mixture of ethanol (20 mL) and water (4 mL). Potassium hydroxide (0.54 g, 9.6 mmol) was added. The reaction mixture was refluxed for 16 hours. LCMS monitoring revealed the disappearance of the starting material. The reaction mixture was concentrated to afford compound INT-2f (2.26 g, 100% yield) as a white solid. ESI-MS (m / z): 259.3 [M+H] + .

[0298] Step 6: Dissolve compound INT-2f (770 mg, 2.96 mmol) in methanol (10 mL) and add thionyl chloride (1.06 g, 8.9 mmol). The reaction mixture was stirred at 70°C for 3 hours. LCMS confirmed the complete reaction. The reaction mixture was concentrated to afford compound INT-2g (800 mg, 98.6% yield) as a pale yellow solid. ESI-MS (m / z): 274.1 [M+H] + .

[0299] Step 7: Dissolve compound INT-2g (600 mg, 2.19 mmol) in ethanol (6 mL) and add hydrazine hydrate (329 mg, 6.57 mmol). The reaction mixture was stirred at 90°C for 16 hours. LCMS confirmed the complete reaction of the starting material. The reaction mixture was concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 20:1) to obtain compound INT-2h (550 mg, 91.7% yield) as a colorless oil. ESI-MS (m / z): 274.2 [M+H] + .

[0300] Step 8: Compound INT-2h (300 mg, 1.09 mmol) was dissolved in N,N-dimethylformamide (3 mL). INT-2i (376 mg, 1.64 mmol), 1-hydroxybenzotriazole (222 mg, 1.64 mmol), N,N-diisopropylethylamine (424 mg, 3.28 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (315 mg, 1.64 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 16 hours. LCMS confirmed the complete reaction. Water was added to the mixture, and 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 (dichloromethane / methanol = 10:1) to afford compound INT-2j (480 mg, 90.4% yield) as a pale yellow oil. ESI-MS (m / z): 485.3 [M+H] + .

[0301] Step 9: Dissolve compound INT-2j (480 mg, 0.99 mmol) in tetrahydrofuran (5 mL) and add Burgess reagent (354 mg, 1.48 mmol). The reaction mixture was stirred at 80°C for 16 hours. LCMS confirmed the complete reaction of the starting material. The reaction mixture was concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 20:1) to afford compound INT-2 (320 mg, 69.2% yield) as a colorless oil. ESI-MS (m / z): 467.2 [M+H] + .

[0302] Intermediate 3

[0303] Intermediate 3 was prepared by the following steps:

[0304] Step 1: Dissolve compound INT-1q (1.7 g, 2.45 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (5 mL), and react at room temperature for 2 hours. LCMS monitored the reaction until complete. The reaction solution was directly concentrated under reduced pressure, and the residue was dissolved in DCM (50 mL) and washed twice with saturated NaHCO3 aqueous solution. The organic phase was washed with water, dried over sodium sulfate, filtered, and concentrated to obtain a yellow solid compound INT-3a (1.3 g, yield 89.4%). ESI-MS (m / z): 594.7 [M+H] + .

[0305] Step 2: Compound INT-3a (1.3 g, 2.19 mmol) and compound INT-3b (0.24 g, 2.41 mmol) were dissolved in acetonitrile (30 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (922 mg, 3.29 mmol) and 1-methylimidazole (414 mg, 5.04 mmol) were added at 0°C. The mixture was reacted at 0°C for 1 hour. LCMS confirmed the complete reaction of the starting materials. The reaction solution was poured into water (50 mL) and extracted with dichloromethane (50 mL*3). The organic phase was washed with water and purified by column chromatography to obtain compound INT-3c (1.3 g, yield 87.9%) as a white solid. ESI-MS (m / z): 675.7 [M+H] + .

[0306] Step 3: Compound INT-3c (1.1 g, 1.63 mmol), 2-dicyclohexylphosphine-2′,6′-dimethylbiphenyl (200 mg, 0.188 mmol), tris(dibenzylideneacetone)dipalladium (179 mg, 0.195 mmol), and potassium acetate (559 mg, 5.7 mmol) were dissolved in toluene (30 mL). Pinacolborane (1.04 g, 8.14 mmol) was added dropwise under nitrogen. The mixture was reacted at 50°C under nitrogen for 3 hours. LCMS monitored the reaction for complete reaction. The reaction solution was filtered and purified by silica gel column chromatography to obtain INT-3 as a yellow solid (990 mg, 90% yield). ESI-MS (m / z): 676.9 [M+H] + .

[0307] Intermediate 4

[0308] Intermediate 4 was prepared by the following steps:

[0309] Step 1: Dissolve compound INT-3a (2.2 g, 3.71 mmol) and compound INT-4a (0.47 g, 4.08 mmol) in dichloromethane (50 mL). Add N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.56 g, 5.56 mmol) and 1-methylimidazole (0.70 g, 8.53 mmol) at 0°C. React at 0°C for 1 hour. LCMS monitoring indicates complete reaction. Pour the reaction solution into water (50 mL) and extract with dichloromethane (50 mL*3). Wash the organic phase with water and purify by column chromatography to obtain compound INT-4b (2.3 g, 90.0% yield) as a white solid. ESI-MS (m / z): 690.2 [M+H] + .

[0310] Step 2: Compound INT-4b (2.1 g, 3.05 mmol), 2-dicyclohexylphosphine-2′,6′-dimethylbiphenyl (375 mg, 0.91 mmol), tris(dibenzylideneacetone)dipalladium (335 mg, 0.365 mmol), and potassium acetate (1.05 g, 10.7 mmol) were dissolved in toluene (30 mL). Pinacolborane (1.95 g, 15.2 mmol) was added dropwise under nitrogen. The mixture was reacted at 50°C under nitrogen for 3 hours. LCMS monitored the reaction for complete reaction. The reaction mixture was filtered and purified by silica gel column chromatography to obtain INT-4 (1.8 g, 85.7% yield) as a yellow solid. ESI-MS (m / z): 690.3 [M+H] + .

[0311] Intermediate 5

[0312] Intermediate 5 was prepared by the following steps:

[0313] Step 1: INT-5a (663 mg, 2.92 mmol) was dissolved in ethanol (8 mL), sodium ethoxide (199 mg, 2.92 mmol) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. The solid was removed by filtration, and then an ethanol solution of INT-2h (400 mg, 1.46 mmol) was added to the filtrate. The reaction mixture was stirred at 85°C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain a light yellow solid compound INT-5b (516 mg, yield 75.8%). ESI-MS (m / z): 466.3 [M+H] + .

[0314] Step 2: INT-5b (516 mg, 1.11 mmol) was dissolved in acetonitrile (8 mL). Potassium carbonate (459 mg, 3.33 mmol) and iodomethane (236 mg, 1.66 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain INT-5 (382 mg, yield 71.9%) as a colorless oil. ESI-MS (m / z): 480.3 [M+H] + .

[0315] Intermediate 6

[0316] Intermediate 6 was prepared by the following steps:

[0317] Step 1: Dissolve INT-2h (2.1 g, 7.66 mmol) and methyl 2-chloroacetimidate hydrochloride (2.0 g, 13.79 mmol) in anhydrous ethanol (40 mL). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain INT-6a (2.1 g, 82.4% yield) as a colorless oil. ESI-MS (m / z): 332.4 [M+H] + .

[0318] Step 2: INT-6a (188 mg, 0.57 mmol), 1-tert-butyloxycarbonylpiperazine (211 mg, 1.13 mmol), potassium carbonate (156 mg, 1.13 mmol), and potassium iodide (47 mg, 0.28 mmol) were dissolved in acetonitrile (5 mL). The reaction mixture was stirred at 70°C for 3 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (40 mL). The organic phase was dried and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain INT-6 (218 mg, 80.0% yield) as a colorless oil. ESI-MS (m / z): 482.2 [M+H] + .

[0319] Intermediate 7

[0320] By replacing INT-2i in the synthesis step of intermediate INT-2 with 1-tert-butyloxycarbonyl-4-piperidinylacetic acid, compound INT-7 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 481.2 [M+H] + .

[0321] Intermediate 8

[0322] Intermediate 8 was prepared by the following steps:

[0323] Step 1: Dissolve compound INT-8a (1 g, 7.93 mmol) in ethanol (10 mL) and water (5 mL). Add hydroxylamine hydrochloride (2.2 g, 31.7 mmol) and sodium carbonate (2.52 g, 23.8 mmol) sequentially. The reaction mixture was stirred at 90°C overnight. LCMS monitored the complete reaction. The reaction mixture was concentrated, and the residue was purified by column chromatography (dichloromethane / methanol = 10:1) to obtain compound INT-8b (901 mg, 71.4% yield) as a white solid. ESI-MS (m / z): 160.2 [M+H] + .

[0324] Step 2: Compound INT-2f (409 mg, 1.40 mmol) was dissolved in N,N-dimethylformamide (6 mL). INT-8b (202 mg, 1.68 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (639 mg, 1.68 mmol), and N,N-diisopropylethylamine (543 mg, 4.20 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 4 hours. LCMS confirmed the complete reaction of the starting materials. Water was added to the system, and the mixture was 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 afford compound INT-8c (407 mg, 59.9% yield) as a colorless oil. ESI-MS (m / z): 485.4 [M+H] + .

[0325] Step 3: Compound INT-8c (407 mg, 0.84 mmol) was dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (325 mg, 2.52 mmol) was added. The reaction solution was stirred at 90°C for 16 hours. LCMS monitored the complete reaction of the starting material. Water was added to the system, extracted with dichloromethane, and the organic phase was dried, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2:3) to obtain INT-8 (149 mg, yield 38.0%) as a colorless oil. ESI-MS (m / z): 467.4 [M+H] + .

[0326] Intermediate 9

[0327] Intermediate 9 was prepared by the following steps:

[0328] Step 1: Dissolve compound INT-2e (150 mg, 0.62 mmol) in ethanol (6 mL), and add hydroxylamine hydrochloride (86 mg, 1.24 mmol) and triethylamine (126 mg, 1.24 mmol) sequentially. The reaction mixture was stirred at 80°C for 3 hours. LCMS monitored the complete reaction of the starting materials. The reaction mixture was concentrated to obtain the crude product of compound INT-9a as a colorless oil, which was used directly in the next reaction without purification. ESI-MS (m / z): 274.2 [M+H] + .

[0329] Step 2: Compound INT-9a (350 mg, 1.28 mmol) was dissolved in N,N-dimethylformamide (5 mL). INT-2i (293 mg, 1.28 mmol), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (533 mg, 1.40 mmol), and N,N-diisopropylethylamine (495 mg, 3.83 mmol) were added sequentially. The reaction mixture was stirred at 100°C for 16 hours. LCMS confirmed the reaction was complete. Water was added to the mixture, and 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 = 1:2) to afford compound INT-16 (315 mg, 52.8% yield) as a colorless oil. ESI-MS (m / z): 467.4 [M+H] + .

[0330] Intermediate 10

[0331] Intermediate 10 was prepared by the following steps:

[0332] Step 1: Compound INT-10a (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. The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, water (50 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (50 mL x 2). The organic phases were 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 afford INT-10b (3.1 g, 64.2% yield) as a pale yellow oil. ESI-MS (m / z): 186.2 [M+H] + .

[0333] Step 2: Dissolve compound INT-10b (2.0 g, 10.8 mmol) in tetrahydrofuran (5 mL) and water (5 mL). Add lithium hydroxide monohydrate (544 mg, 13.0 mmol) under ice-cooling. Stir the reaction mixture at room temperature for 2 hours. After the reaction is complete, lyophilize the reaction mixture to obtain compound INT-10c (1.85 g, 100% yield) as a white solid. ESI-MS (m / z): 172.2 [M+H] + .

[0334] Step 3: Compound INT-2h (150 mg, 0.55 mmol) was dissolved in N,N-dimethylformamide (8 mL). INT-10c (187 mg, 1.09 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (427 mg, 0.82 mmol), and N,N-diisopropylethylamine (212 mg, 1.64 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 4 hours. LCMS confirmed the complete reaction of the starting material. Water was added to the system, and the mixture was extracted with dichloromethane. The organic phase was dried, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 10:1) to afford compound INT-10d (200 mg, 85.5% yield) as a pale yellow oil. ESI-MS (m / z): 427.2 [M+H] + .

[0335] Step 4: Compound INT-10d (200 mg, 0.47 mmol) was dissolved in dichloromethane (5 mL), and p-toluenesulfonyl chloride (448 mg, 2.35 mmol) and triethylamine (476 mg, 4.70 mmol) were added sequentially. The reaction solution was stirred at room temperature for 4 hours. LCMS monitoring showed that the reaction of the raw material was complete. Water was added to the system, and the mixture was 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-10 (140 mg, yield 73.0%) as a light yellow oil. ESI-MS (m / z): 409.2 [M+H] + .

[0336] Intermediate 11

[0337] By replacing INT-2i in the synthesis step of intermediate INT-2 with (S)-1-(tert-butyloxycarbonyl)piperidine-3-carboxylic acid, compound INT-11 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 467.2 [M+H] + .

[0338] Intermediate 12

[0339] By replacing INT-2i in the synthesis step of intermediate INT-2 with (R)-1-(tert-butyloxycarbonyl)piperidine-3-carboxylic acid, compound INT-12 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 467.2 [M+H] + .

[0340] Intermediate 13

[0341] By replacing INT-2i in the synthesis step of intermediate INT-2 with (S)-1-(tert-butyloxycarbonyl)-2-piperidinic acid, compound INT-13 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 467.2 [M+H] + .

[0342] Intermediate 14

[0343] By replacing INT-2i in the synthesis step of intermediate INT-2 with (R)-1-(tert-butyloxycarbonyl)piperidine-2-carboxylic acid, compound INT-14 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 467.2 [M+H] + .

[0344] Intermediate 15

[0345] By replacing INT-2i in the synthesis step of intermediate INT-2 with (2R)-1-[(tert-butyloxy)carbonyl]pyrrolidine-2-carboxylic acid, compound INT-15 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 453.2 [M+H] + .

[0346] Intermediate 16

[0347] By replacing INT-2i in the synthesis step of intermediate INT-2 with (S)-1-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylic acid, compound INT-16 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 453.2 [M+H] + .

[0348] Intermediate 17

[0349] By replacing INT-2i in the synthesis step of intermediate INT-2 with (R)-1-(tert-butyloxycarbonyl)pyrrolidine-3-carboxylic acid, compound INT-17 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 453.2 [M+H]+ .

[0350] Intermediate 18

[0351] By replacing INT-2i in the synthesis step of intermediate INT-2 with (S)-1-(tert-butyloxycarbonyl)pyrrolidine-3-carboxylic acid, compound INT-18 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 453.2 [M+H] + .

[0352] Intermediate 30

[0353] Intermediate 30 was prepared by the following steps:

[0354] Step 1: Dissolve compound INT-30a (5.0 g, 39.0 mmol) in dichloromethane (50 mL) and methanol (10 mL). Add trimethylsilylated diazomethane (2 M, 29.3 mL) dropwise at 0°C. Stir for 1 hour after addition. TLC confirms complete reaction. Concentrate to afford compound INT-30b (5.6 g, 100% yield) as a colorless oil. ESI-MS (m / z): 143.4 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ3.70(s,3H),3.32–3.20(m,2H),2.87–2.77(m,3H),2.68–2.60(m,2H).

[0355] Step 2: Compound INT-30b (5.6 g, 39.4 mmol) was dissolved in n-heptane (60 mL), and tert-butyl carbazate (5.5 g, 41.4 mmol) was added. The reaction mixture was heated to 70°C and stirred for 16 hours. LCMS confirmed the complete reaction. The reaction mixture was concentrated, and the resulting residue was recrystallized from (n-heptane / isopropanol = 30 / 1) to afford compound INT-30c (9.0 g, 89.1% yield) as a white solid. ESI-MS (m / z): 257.3 [M+H] + .

[0356] Step 3: Compound INT-30c (3.0 g, 11.7 mmol) was dissolved in methanol (30 mL), and platinum dioxide (300 mg, 10% wt) was added. The reaction mixture was stirred under a hydrogen atmosphere for 16 hours. LC-MS confirmed the complete reaction. The reaction mixture was filtered through celite, and the filtrate was concentrated to afford compound INT-30d (3.0 g, 99.2% yield) as a colorless oil. ESI-MS (m / z): 259.3 [M+H]+ .

[0357] Step 4: Compound INT-30d (3.0 g, 11.6 mmol) was dissolved in tetrahydrofuran (30 mL). Di-tert-butyl dicarbonate (3.0 g, 14.0 mmol), triethylamine (3.5 g, 34.8 mmol), and 4-dimethylaminopyridine (0.14 g, 1.2 mmol) were added sequentially at 0°C. The reaction was allowed to warm to room temperature and stirred for 2 hours. LCMS confirmed the complete reaction. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford compound INT-30e (3.2 g, 75.7% yield) as a colorless oil. ESI-MS (m / z): 359.2 [M+H] + .

[0358] Step 5: Dissolve compound INT-30e (2.0 g, 5.6 mmol) in anhydrous tetrahydrofuran (20 mL) and add lithium bis(trimethylsilyl)amide (1 M, 16.7 mL) dropwise at -70°C under a nitrogen atmosphere. After the addition is complete, stir at this temperature for 30 minutes. Then, add trimethylsilyl chloride (1.8 g, 16.7 mmol). After stirring for 1 hour, add N-bromosuccinimide (3.0 g, 16.7 mmol). The reaction solution is warmed to room temperature and stirred for 16 hours. LC-MS monitoring indicates that the reaction of the starting material is complete. Water is added to the system to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product INT-30f is used directly in the next reaction. ESI-MS (m / z): 509.3 [M+H] + .

[0359] Step 6: Dissolve the crude compound INT-30f in methanol (20 mL) and add potassium carbonate (1.5 g, 11.2 mmol) at 0°C. The reaction is allowed to warm to room temperature and stirred for 2 hours. LCMS confirms the reaction is complete. Water is added to quench the reaction, followed by extraction with ethyl acetate. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford INT-30g (1.4 g, 57.4% yield over two steps) as a colorless oil. ESI-MS (m / z): 437.2 [M+H] + .

[0360] Step 7: Compound INT-30g (1.4 g, 3.2 mmol) was dissolved in acetonitrile (140 mL) and cesium carbonate (3.1 g, 9.6 mmol) was added. The reaction mixture was heated to 60°C and stirred for 16 hours. LCMS monitoring confirmed the complete reaction. Water was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative liquid chromatography and SFC to obtain compound INT-30 (0.21 g, 18.4% yield) as a white solid. ESI-MS (m / z): 357.2 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ5.24–4.93(m,1H),4.52–4.42(m,1H),3.78–3.71(m,3H),2.93 –2.84(m,1H),2.42–2.35(m,1H),2.17–2.09(m,1H),1.61–1.55(m,2H),1.55–1.46(m,18H).

[0361] Intermediate 31

[0362] Intermediate 31 was prepared by the following steps:

[0363] Step 1: Dissolve compound INT-1k (1.0 g, 2.7 mmol) in tetrahydrofuran (5 mL) and water (5 mL). Add lithium hydroxide monohydrate (230 mg, 5.5 mmol) at 0°C and continue stirring for 2 hours. LCMS monitoring indicates complete reaction. Dilute with water, adjust the pH to 5 with dilute hydrochloric acid, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford compound INT-31a (900 mg, 93.6% yield) as a yellow solid. ESI-MS (m / z): 350.8 [M+H] + .

[0364] Step 2: Dissolve compound INT-30 (100 mg, 0.24 mmol) in dichloromethane (1 mL) and add trifluoroacetic acid (1 mL) under ice. Stir the reaction mixture at room temperature for 2 hours. After the reaction is complete, concentrate the reaction mixture to obtain the trifluoroacetate salt of compound INT-31b (91 mg, 100% yield) as a colorless oil. ESI-MS (m / z): 157.3 [M+H] + .

[0365] Step 3: Dissolve compound INT-31b (91 mg, 0.24 mmol) in dichloromethane (5 mL). Diisopropylethylamine (118 mg, 0.91 mmol), compound INT-31a (80 mg, 0.23 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (104 mg, 0.27 mmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 2 hours. LCMS confirmed the complete reaction. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound INT-31 (100 mg, 89.7% yield) as a colorless oil. ESI-MS (m / z): 489.2 [M+H] + .

[0366] Intermediate 32

[0367] Intermediate 32 was prepared by the following steps:

[0368] Step 1: Dissolve compound INT-2 (10 g, 21.4 mmol) in 1,4-dioxane (300 mL), and add potassium acetate (4.2 g, 42.8 mmol), neopentyl glycol diboron (7.3 g, 32.1 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene] palladium dichloride (1.4 g, 2.14 mmol) in sequence. Stir and react at 85°C under a nitrogen atmosphere for 16 hours. LCMS monitoring indicates the reaction is complete. Water is added to the system, extracted with ethyl acetate, and the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude brown oil, INT-32a, which is used directly in the next step without purification. ESI-MS (m / z): 501.2 [M+H] + .

[0369] Step 2: The crude compound INT-32a obtained above was dissolved in 1,4-dioxane (150 mL) and water (15 mL). INT-32b (8.5 g, 13.2 mmol), potassium carbonate (5.5 g, 39.4 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.96 g, 1.3 mmol) were added sequentially. The reaction solution was stirred at 85°C under a nitrogen atmosphere for 16 hours. LCMS monitored the reaction for completion. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford INT-32c (4.1 g, 20.5% yield over two steps) as a colorless oil. ESI-MS (m / z): 906.7 [M+H] + .

[0370] Step 3: Dissolve compound INT-32c (1.4 g, 1.5 mmol) in N,N-dimethylformamide (15 mL), and add cesium carbonate (1.5 g, 4.5 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 g, 4.5 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (150 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, 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-32d (770 mg, 51.3% yield) as a pale yellow solid. ESI-MS (m / z): 988.7 [M+H] + .

[0371] Step 4: Dissolve compound INT-32d (770 mg, 0.78 mmol) in tetrahydrofuran (3 mL) and add tetrabutylammonium fluoride (1 M, 3.9 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (20 mL) was added to the reaction system and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, 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 = 1 / 3) to obtain compound INT-32e (526 mg, 90.0% yield) as a pale yellow solid. ESI-MS (m / z): 750.6 [M+H] + .

[0372] Step 5: Dissolve compound INT-32e (400 mg, 0.54 mmol) in acetonitrile (4 mL) and add trimethylsilyl iodide (190 mg, 0.8 mmol) under ice-cooling. Stir the reaction mixture under ice-cooling for 1 hour. After the reaction is complete, add aqueous sodium bicarbonate solution (20 mL) to the reaction system, extract with ethyl acetate (20 mL x 2). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound INT-32f (325 mg, 93.8% yield) as a pale yellow solid. ESI-MS (m / z): 650.6 [M+H] + .

[0373] Step 6: Dissolve compound INT-32f (325 mg, 0.5 mmol) in dichloromethane (5 mL) and add 3-oxetanone (72 mg, 1.0 mmol) at room temperature. Stir the reaction mixture at room temperature for 10 minutes, then add sodium triacetoxyborohydride (318 mg, 1.5 mmol) and continue stirring for 2 hours. After the reaction is complete, add aqueous sodium bicarbonate (20 mL) to the reaction system, extract with dichloromethane (20 mL x 2). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound INT-32 (225 mg, 77.9% yield) as a pale yellow solid. ESI-MS (m / z): 706.6 [M+H] + .

[0374] Intermediate 33

[0375] Intermediate 33 was prepared by the following steps:

[0376] Step 1: Compound INT-32 (220 mg, 0.31 mmol) was dissolved in 1,4-dioxane (5 mL). Potassium acetate (92 mg, 0.94 mmol), pinacol diboron (118 mg, 0.47 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (20 mg, 0.031 mmol) were added sequentially. The mixture was stirred at 70°C under a nitrogen atmosphere for 16 hours. LCMS monitored the reaction for completion. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound INT-33a (173 mg, 73.9% yield) as a pale yellow solid. ESI-MS (m / z): 754.6 [M+H] + .

[0377] Step 2: Compound INT-33a (101 mg, 0.13 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). INT-31 (66 mg, 0.13 mmol), potassium carbonate (46 mg, 0.34 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (8.7 mg, 0.013 mmol) were added sequentially. The reaction mixture was stirred at 70°C under a nitrogen atmosphere for 16 hours. LCMS monitored the reaction for completion. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound INT-33b (118 mg, 85.0% yield) as a pale yellow solid. ESI-MS (m / z): 1036.7 [M+H] + .

[0378] Step 3: Dissolve compound INT-33b (118 mg, 0.11 mmol) in tetrahydrofuran (2 mL) and water (1 mL). Add lithium hydroxide monohydrate (14 mg, 0.33 mmol) at 0°C and continue stirring for 1 hour. LCMS monitoring indicates complete reaction. Dilute with water, adjust the pH to 5 with dilute hydrochloric acid, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford compound INT-33c (101 mg, 90.0% yield) as a pale yellow solid. ESI-MS (m / z): 1022.7 [M+H] + .

[0379] Step 4: Add N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (56 mg, 0.2 mmol) and 1-methylimidazole (41 mg, 0.5 mmol) to acetonitrile (3 mL) and stir to dissolve. Add a solution of compound INT-1p (101 mg, 0.1 mmol) in THF (1 mL) dropwise at room temperature. Stir and react for 1 hour after addition. LCMS monitoring indicates complete reaction of the starting material. Add water to the system, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The resulting residue is purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain a light yellow solid compound INT-33d (72 mg, yield 65.0%). ESI-MS (m / z): 1004.7 [M+H] + .

[0380] Step 5: Dissolve compound INT-33d (30 mg, 0.03 mmol) in dichloromethane (2 mL) and add trifluoroacetic acid (1 mL) under ice-cooling. Stir the reaction mixture at room temperature for 2 hours. After the reaction is complete, add saturated sodium bicarbonate solution to the reaction system under ice-cooling to adjust the pH to 8. Extract with dichloromethane (20 mL x 2). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound INT-33 (25 mg, 92.6% yield) as a pale yellow solid. ESI-MS (m / z): 904.7 [M+H] + .

[0381] Intermediate 34

[0382] Intermediate 34 was prepared by the following steps:

[0383] Step 1: INT-5b (300 mg, 0.64 mmol) was dissolved in N,N-dimethylformamide (6 mL). Cesium carbonate (629 mg, 1.93 mmol) and 3-iodooxetane (355 mg, 1.93 mmol) were added at room temperature. The reaction solution was stirred at 90°C for 48 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. 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 = 2:3) to obtain INT-34 (287 mg, 85.4% yield) as a colorless oil. ESI-MS (m / z): 522.5 [M+H] + .

[0384] Intermediate 35

[0385] By replacing 3-iodooxetane in the synthesis step of intermediate INT-34 with tert-butyl-(2-iodoethoxy)dimethylsilane, compound INT-35 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 624.7 [M+H] + .

[0386] Intermediate 36

[0387] By replacing INT-2i in the synthesis step of intermediate INT-2 with cis-1-[(tert-butoxy)carbonyl]-3-methylpiperidine-4-carboxylic acid, compound INT-36 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 481.3 [M+H] + .

[0388] Intermediate 37

[0389] By replacing 3-oxetanone in the synthesis step of intermediate INT-32 with cyclopropanecarboxaldehyde, compound INT-37 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 704.3 [M+H] + .

[0390] Intermediate 38

[0391] Using INT-32 from the synthesis step of INT-37 intermediate INT-33, similar methods and reaction steps can be used to obtain compound INT-38. ESI-MS (m / z): 902.6 [M+H] + .

[0392] Intermediate 39

[0393] By replacing the (S)-hexahydropyridazine-3-carboxylic acid methyl ester trifluoroacetate in the synthesis step of the intermediate INT-1q with INT-31b, the compound INT-39 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 706.4 [M+H] + .

[0394] Intermediate 40

[0395] By replacing INT-1q in the synthesis step of intermediate INT-3 with INT-39 and INT-3b with INT-4a, compound INT-40 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 702.6 [M+H] + .

[0396] Intermediate 41

[0397] By replacing (S)-hexahydropyridazine-3-carboxylic acid methyl ester trifluoroacetate in the synthesis step of intermediate INT-1 with INT-31b, compound INT-41 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 706.6 [M+H] + .

[0398] Intermediate 42

[0399] Intermediate 42 was prepared by the following steps:

[0400] Step 1: Dissolve compound INT-42a (400 mg, 2.55 mmol) in tetrahydrofuran (8 mL). Add cyclopropylboronic acid (1.31 g, 15.27 mmol), copper acetate (1.39 g, 7.64 mmol), pyridine (805 mg, 10.18 mmol), and triethylamine (2.06 g, 20.36 mmol) in this order. The reaction mixture was stirred at 65°C under an oxygen atmosphere for 24 hours. Water and ethyl acetate were added, and the reaction mixture was filtered through celite. The organic phase was separated, 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 = 1 / 4) to obtain compound INT-42b (366 mg, 72.9% yield) as a brown oil. ESI-MS (m / z): 198.4 [M+H] + .

[0401] Step 2: Dissolve compound INT-42b (550 mg, 2.19 mmol) in methanol (2 mL) and add hydrazine hydrate (0.5 mL). The reaction mixture was stirred at 70°C for 16 hours. LCMS monitored the reaction until complete. The reaction mixture was concentrated to obtain crude compound INT-42c (438 mg). ESI-MS (m / z): 198.4 [M+H] + .

[0402] Step 3: Compound INT-42c (370 mg, 1.88 mmol) was dissolved in dichloromethane (8 mL). INT-2f (488 mg, 1.88 mmol), 1-hydroxybenzotriazole (431 mg, 2.81 mmol), N,N-diisopropylethylamine (727 mg, 5.63 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (539 mg, 2.81 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete. Water was added to the mixture, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water = 1:1) to afford INT-42d (517 mg, 62.7% yield) as a white solid. ESI-MS (m / z): 439.7 [M+H] + .

[0403] Step 4: Dissolve compound INT-42d (517 mg, 1.18 mmol) in tetrahydrofuran (8 mL) and add Burgess reagent (421 mg, 1.77 mmol). The reaction mixture was stirred at 70°C for 16 hours. LCMS confirmed the complete reaction of the starting material. The reaction mixture was concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water = 7:3) to afford compound INT-42 (265 mg, 53.5% yield) as a colorless oil. ESI-MS (m / z): 421.5 [M+H] + .

[0404] Intermediate 43

[0405] By replacing INT-2i in the synthesis step of intermediate INT-2 with 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.2.1]heptane-5-carboxylic acid, compound INT-43 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 479.3 [M+H] + .

[0406] Intermediate 44

[0407] Intermediate 44 was prepared by the following steps:

[0408] Step 1: Compound INT-2h (280 mg, 1.02 mmol) was dissolved in dichloromethane (5 mL). INT-44a (249 mg, 1.02 mmol), 1-hydroxybenzotriazole (235 mg, 1.53 mmol), N,N-diisopropylethylamine (396 mg, 3.06 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.53 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete. Water was added to the mixture, and 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 (dichloromethane / methanol = 20:1) to afford compound INT-44b (420 mg, 82.3% yield) as a white solid. ESI-MS (m / z): 499.3 [M+H] + .

[0409] Step 2: Dissolve compound INT-44b (50 mg, 0.10 mmol) in toluene (5 mL) and add Lawesson's reagent (49 mg, 0.12 mmol). The reaction mixture was stirred at 110°C for 16 hours. LCMS monitored the complete reaction of the starting material. Saturated sodium bicarbonate solution (30 mL) was added and stirred for 30 minutes. Extract with ethyl acetate, dry the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate. The residue was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound INT-44 (40 mg, yield 80.3%) as a colorless oil. ESI-MS (m / z): 497.3 [M+H] + .

[0410] Intermediate 45

[0411] By replacing INT-2i in the synthesis step of intermediate INT-2 with 1-tert-butyloxycarbonylpyrrolidine-3-carboxylic acid, compound INT-45 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 453.2 [M+H] + .

[0412] Intermediate 46

[0413] Intermediate 46 was prepared by the following steps:

[0414] Step 1: Under a nitrogen atmosphere and an ice bath, sodium hydride (48 mg, 1.2 mmol, 60% dispersion in oil) was added to a tetrahydrofuran solution of compound INT-5b (160 mg, 0.343 mmol). The reaction solution was stirred at room temperature for 2 hours, then cooled to 0°C and 2-(trimethylsilyl)ethoxymethyl chloride (114 mg, 0.686 mmol) was added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred for 16 hours. LCMS monitored the complete reaction of the raw material. Water (40 mL) was added and the mixture was extracted with ethyl acetate (40 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to obtain compound INT-46 (134 mg, 65.6% yield). ESI-MS (m / z): 596.4 [M+H] + .

[0415] Example 1

[0416] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-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-methylcyclopropane-1-carboxamide

[0417] Example 1 was prepared by the following steps:

[0418] Step 1: Compound INT-3 (111 mg, 0.16 mmol) was dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL). INT-2 (70 mg, 0.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.015 mmol), and potassium phosphate (95 mg, 0.45 mmol) were added sequentially. The reaction mixture was stirred at 70°C under nitrogen for 16 hours. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20:1) to afford compound 1a (67 mg, 47.8% yield) as a pale yellow solid. ESI-MS (m / z): 936.7 [M+H] + .

[0419] Step 2: Compound 1a (67 mg, 0.072 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (47 mg, 0.144 mmol) and iodoethane (22 mg, 0.144 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (ethyl acetate) to obtain compound 1b (20 mg, 29.0% yield) as a pale yellow solid. ESI-MS (m / z): 964.7 [M+H] + .

[0420] Step 3: Compound 1b (20 mg, 0.021 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction system under ice-cooling to adjust the pH to 8. The mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a light yellow solid compound 21c (17 mg, yield 95.0%). ESI-MS (m / z): 864.7 [M+H] + .

[0421] Step 4: The crude product of compound 1c (17 mg, 0.02 mmol) was dissolved in dichloromethane (2 mL), and 3-oxetanone (4 mg, 0.06 mmol) was added at room temperature. The reaction solution was stirred at room temperature for 10 minutes. Sodium acetate borohydride (21 mg, 0.10 mmol) was then slowly added to the reaction solution, and the reaction solution was continued to stir at room temperature for 3 hours. LCMS detection showed that the reaction was complete. Saturated aqueous ammonium chloride was added to the reaction system to quench the reaction, extracted with dichloromethane, and the organic phases were combined and concentrated. The residue was purified by preparative liquid chromatography to obtain white solid compound 1 (8 mg, yield 43.5%). ESI-MS (m / z): 920.7 [M+H] + ; LC-MS retention time RT = 1.63 min. HPLC retention time RT = 13.45 min.

[0422] 11H NMR (500 MHz, DMSO-d6) δ 9.33 (d, J = 2.0 Hz, 1H), 8.57–8.52 (m, 2H), 8.30 (d, J = 2.0 Hz, 1H), 7.84 (s, 1H), 7.78 (dd, J = 8.5, 1.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 5.56 (t, J = 9.0 Hz, 1H), 5.12–5.08 (m, 1H), 4.53 (t, J = 6.0 Hz, 2H), 4.43 (t, J = 6.0 Hz, 2H), 4.41–4.35 (m, 2H), 4.25–4.17 (m, 2H), 4.15–4.08 (m, 1H), 3.58 (s, 2H), 3.42–3.39 (m, 1H), 3.34–3.32 (m, 1H), 3.30 (s, 3H), 3.15–3.06 (m, 2H), 3.03–2.99 (m, 1H), 2.79–2.69 (m, 3H), 2.46–2.41 (m, 1H), 2.11–2.06 (m, 3H), 1.99–1.92 (m, 2H), 1.86–1.76 (m, 5H), 1.53–1.48 (m, 2H), 1.40 (d, J = 6.0 Hz, 3H), 1.10–1.05 (m, 4H), 0.93–0.82 (m, 6H), 0.58–0.54 (m, 1H), 0.36 (s, 3H).

[0423] Example 2

[0424] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-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)-2,3-dimethylcyclopropane-1-carboxamide

[0425] By replacing INT-3 in the synthesis step of compound 1 with INT-4, compound 2 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 934.8 [M+H] + ; LC-MS retention time RT = 1.68 min.

[0426] 1 H NMR(500MHz,DMSO-d6)δ9.33(d,J=2.0Hz,1H),8.53(d,J=1.5Hz,1H),8.42(d, J=8.5Hz,1H),8.31(d,J=2.0Hz,1H),7.84(s,1H),7.80–7.77(m,1H),7.62(d, J=8.5Hz,1H),5.55(t,J=9.0Hz,1H),5.11–5.06(m,1H),4.53(t,J=6.0Hz,2H) ,4.43(t,J=6.0Hz,2H),4.40–4.35(m,2H),4.25–4.17(m,2H),4.14–4.07(m,1H ),3.58(s,2H),3.43–3.40(m,2H),3.30(s,3H),3.18–3.14(m,1H),3.11–3.06 (m,1H),3.02–2.98(m,1H),2.77–2.70(m,3H),2.47–2.41(m,1H),2.12–2.06(m ,3H),2.00–1.92(m,3H),1.86–1.77(m,4H),1.55–1.49(m,1H),1.40(d,J=6.0 Hz,3H),1.20–1.14(m,2H),1.10–1.05(m,6H),0.93–0.86(m,6H),0.36(s,3H).

[0427] Example 3

[0428] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(1-methyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,4-triazol-3-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)-2-methylcyclopropane-1-carboxamide

[0429] By replacing INT-2 in the synthesis step of compound 1 with INT-5, compound 3 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 933.8 [M+H] + ; LC-MS retention time RT = 1.64 min.

[0430] 1 H NMR(500MHz,DMSO-d6)δ9.28(d,J=2.0Hz,1H),8.57–8.50(m,2H),8.14(d,J=2.0Hz,1H),7.83(s,1H),7.77(dd,J=8.5,2.0Hz,1H),7.60(d,J=8.5Hz,1H ),5.56(t,J=9.0Hz,1H),5.12–5.06(m,1H),4.54(t,J=6.5Hz,2H),4.43(t, J=6.5Hz,2H),4.39–4.31(m,2H),4.26–4.18(m,2H),4.16–4.08(m,1H),3.9 0(s,3H),3.58(s,2H),3.44–3.39(m,1H),3.32–3.30(m,1H),3.28(s,3H),3 .18–3.10(m,1H),3.03–2.94(m,2H),2.81–2.75(m,3H),2.42–2.35(m,1H), 2.12–2.05(m,1H),1.94–1.74(m,9H),1.55–1.47(m,2H),1.40(d,J=6.0Hz, 3H),1.09–1.04(m,4H),0.91–0.84(m,6H),0.59–0.53(m,1H),0.37(s,3H).

[0431] Example 4

[0432] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 1 -ethyl-12 -(2-((S)-1-methoxyethyl)-5-(1-methyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,4-triazol-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)-2,3-dimethylcyclopropane-1-carboxamide

[0433] Compound 4 can be obtained by replacing INT-2 in the synthesis step of compound 1 with INT-5 and replacing INT-3 with INT-4 using similar methods and reaction steps. ESI-MS (m / z): 947.8 [M+H] + ; LC-MS retention time RT = 1.69 min. HPLC retention time RT = 12.09 min.

[0434] 11H NMR (500 MHz, DMSO-d6) δ 9.27 (d, J = 2.0 Hz, 1H), 8.53–8.50 (m, 1H), 8.42 (d, J = 9.0 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.84 (s, 1H), 7.77 (dd, J = 8.5, 1.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.11–5.05 (m, 1H), 4.54 (t, J = 6.0 Hz, 2H), 4.43 (t, J = 6.0 Hz, 2H), 4.37–4.31 (m, 2H), 4.25–4.17 (m, 2H), 4.16–4.09 (m, 1H), 3.90 (s, 3H), 3.58 (s, 2H), 3.42–3.41 (m, 1H), 3.28 (s, 3H), 3.17–3.12 (m, 1H), 3.03–2.96 (m, 2H), 2.80–2.74 (m, 3H), 2.43–2.37 (m, 1H), 2.10–2.05 (m, 1H), 1.92–1.78 (m, 9H), 1.55–1.48 (m, 1H), 1.40 (d, J = 6.0 Hz, 3H), 1.19–1.14 (m, 3H), 1.10–1.05 (m, 6H), 0.90–0.85 (m, 6H), 0.37 (s, 3H).

[0435] Example 5

[0436] (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-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-methylcyclopropane-1-carboxamide

[0437] By replacing the iodoethane in the synthesis step of compound 1 with 2,2,2-trifluoroethyl trifluoromethanesulfonate, compound 5 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 974.8 [M+H] + ; LC-MS retention time RT = 1.70 min.

[0438] 1 H NMR (500MHz, DMSO-d6) δ9.34(d,J=2.0Hz,1H),8.60–8.52(m,2H),8.27(d,J=2.0Hz,1H),7.91–7.85(m,2H),7.80(d,J=8.5Hz,1H),5.74–5.61( m,1H),5.54(t,J=9.0Hz,1H),5.11–5.04(m,1H),4.92–4.81(m,1H),4.5 6–4.51(m,2H),4.46–4.41(m,2H),4.38–4.32(m,1H),4.27–4.20(m,2H) ,3.58(s,2H),3.43–3.40(m,2H),3.33(s,3H),3.18–3.04(m,3H),2.78– 2.70(m,3H),2.47–2.42(m,1H),2.13–2.05(m,3H),2.00–1.93(m,2H),1 .86–1.76(m,4H),1.54–1.48(m,2H),1.42(d,J=6.0Hz,3H),1.10–1.03( m,4H),0.93(s,3H),0.90–0.84(m,1H),0.59–0.53(m,1H),0.32(s,3H).

[0439] Example 6

[0440] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 ,6 2 ,6 3 ,6 4 ,65 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0441] Compound 6 can be obtained by replacing INT-3 in the synthesis step of compound 1 with INT-4 and iodoethane with 2,2,2-trifluoroethyl trifluoromethanesulfonate using similar methods and reaction steps. ESI-MS (m / z): 988.8 [M+H] + ; LC-MS retention time RT = 1.75 min.

[0442] 1 H NMR(500MHz,DMSO-d6)δ9.34(d,J=2.0Hz,1H),8.54(d,J=1.5Hz,1H),8.43(d, J=9.0Hz,1H),8.27(d,J=2.0Hz,1H),7.91(s,1H),7.87(dd,J=8.5,1.5Hz,1H) ,7.81(d,J=8.5Hz,1H),5.71–5.61(m,1H),5.53(t,J=9.0Hz,1H),5.10–5.04( m,1H),4.91–4.82(m,1H),4.55–4.52(m,2H),4.45–4.41(m,2H),4.37–4.32(m, 1H),4.26–4.19(m,2H),3.58(s,2H),3.44–3.39(m,2H),3.33(s,3H),3.18–3. 04(m,3H),2.77–2.70(m,3H),2.47–2.42(m,1H),2.12–2.06(m,3H),2.00–1.94 (m,2H),1.87–1.77(m,4H),1.56–1.48(m,1H),1.42(d,J=6.0Hz,3H),1.20–1. 15(m,3H),1.09(d,J=6.0Hz,3H),1.08–1.05(m,3H),0.93(s,3H),0.32(s,3H).

[0443] Example 7

[0444] (1S,2S)-N-((6 3 S,4S,Z)-1 1-ethyl-1 2 -(5-(5-(1-(1-isopropylazetidin-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-2-((S)-1-methoxyethyl)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-methylcyclopropane-1-carboxamide

[0445] Example 7 was prepared by the following steps:

[0446] Step 1: Compound 1c (50 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL). 1-tert-Butyloxycarbonyl-3-azetidinone (31 mg, 0.18 mmol) was added at room temperature, and the reaction solution was stirred at room temperature for 10 minutes. Sodium acetate borohydride (38 mg, 0.18 mmol) was then slowly added to the reaction solution, and the reaction solution was continued to stir at room temperature for 16 hours. LCMS confirmed the reaction was complete. Saturated aqueous ammonium chloride was added to the reaction system to quench the reaction, and the mixture was extracted with dichloromethane. The organic phases were combined and concentrated, and the residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30:1) to obtain compound 7a (49 mg, 80.0% yield) as a white solid. ESI-MS (m / z): 1019.7 [M+H] + ;

[0447] Step 2: Compound 7a (49 mg, 0.048 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction system under ice-cooling to adjust the pH to 8. The mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a light yellow solid compound 7b (42 mg, yield 95.0%). ESI-MS (m / z): 919.7 [M+H] + .

[0448] Step 3: The crude product of compound 7b (42 mg, 0.046 mmol) was dissolved in dichloromethane (2 mL), and acetone (13 mg, 0.23 mmol) was added at room temperature. The reaction solution was stirred at room temperature for 10 minutes. Sodium acetate borohydride (29 mg, 0.138 mmol) was then slowly added to the reaction solution, and the reaction solution continued to stir at room temperature for 3 hours. LCMS detection showed that the reaction was complete. Saturated aqueous ammonium chloride solution was added to the reaction system to quench the reaction, extracted with dichloromethane, and the organic phases were combined and concentrated. The residue was purified by preparative liquid chromatography to obtain white solid compound 7 (8 mg, yield 18.1%). ESI-MS (m / z): 961.7 [M+H] + ; LC-MS retention time RT = 1.70 min.

[0449] 1 H NMR(500MHz,DMSO-d6)δ9.32(d,J=2.0Hz,1H),8.57–8.50(m,2H),8.30(d,J=2.0Hz,1H),7.83(s,1H),7.78(dd,J=8.5,1.5Hz,1H),7.61( d,J=8.5Hz,1H),5.56(t,J=9.0Hz,1H),5.12–5.06(m,1H),4.42–4.34(m,2H),4.25–4.19(m,2H),4.13–4.07(m,1H),3.58(s,2H),3.30(s ,3H),3.17–3.13(m,1H),3.07–2.99(m,2H),2.75–2.70(m,5H),2.45–2.41(m,1H),2.27–2.22(m,1H),2.11–1.90(m,7H),1.83–1.75(m,4 H),1.53–1.47(m,2H),1.40(d,J=6.0Hz,3H),1.24–1.22(m,3H),1.08–1.05(m,3H),0.92–0.83(m,12H),0.58–0.53(m,1H),0.36(s,3H).

[0450] Example 8

[0451] Example 8 was prepared by the following steps:

[0452] Step 1: Compound INT-33 (25 mg, 0.028 mmol) and compound INT-4a (6.3 mg, 0.056 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (11 mg, 0.084 mmol) and (2-oximino-cyanoacetic acid ethyl)-N,N-dimethyl-morpholinourea hexafluorophosphate (18 mg, 0.041 mmol) were added at room temperature. The mixture was allowed to react for 1 hour. LCMS confirmed the complete reaction of the starting materials. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to afford compound 8 (8 mg, 28.9% yield) as a white solid. ESI-MS (m / z): 1000.7 [M+H] + LC-MS retention time RT = 1.80 min.

[0453] 1 H NMR(500MHz,DMSO-d6)δ9.34(d,J=2.0Hz,1H),8.49–8.42(m,2H),8.30–8.24(m,1H), 7.91(s,1H),7.89–7.85(m,1H),7.83–7.78(m,1H),5.96–5.90(m,1H),5.70–5.60(m,1 H),5.37–5.29(m,1H),4.91–4.82(m,1H),4.75–4.69(m,1H),4.54(t,J=6.5Hz,2H),4 .51–4.46(m,1H),4.43(t,J=6.5Hz,2H),4.37–4.31(m,1H),3.59–3.53(m,2H),3.44–3 .41(m,1H),3.32(s,3H),3.29–3.25(m,1H),3.19–3.04(m,3H),2.76–2.70(m,2H),2. 67–2.61(m,1H),2.49–2.43(m,1H),2.38–2.30(m,1H),2.18–2.12(m,1H),2.11–2.05( m,2H),2.00–1.93(m,2H),1.88–1.79(m,2H),1.66–1.58(m,1H),1.42(d,J=6.0Hz,3H ),1.31–1.25(m,2H),1.20–1.16(m,2H),1.12–1.05(m,6H),0.90(s,3H),0.31(s,3H).

[0454] Example 9

[0455] By replacing INT-4a in the synthesis step of compound 8 with INT-3b, compound 9 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 986.8 [M+H] + ; LC-MS retention time RT = 1.75 min.

[0456] 1 H NMR(500MHz,DMSO-d6)δ9.34(d,J=2.0Hz,1H),8.56(d,J=9.0Hz,1H),8.48–8.45(m,1H) ,8.30–8.25(m,1H),7.90(s,1H),7.89–7.85(m,1H),7.82–7.78(m,1H),5.98–5.91(m,1 H),5.69–5.60(m,1H),5.38–5.32(m,1H),4.91–4.82(m,1H),4.75–4.70(m,1H),4.53(t ,J=6.5Hz,2H),4.51–4.47(m,1H),4.43(t,J=6.5Hz,2H),4.38–4.31(m,1H),3.58–3.52( m,2H),3.44–3.38(m,1H),3.32(s,3H),3.27–3.24(m,1H),3.17–3.02(m,3H),2.76–2.7 0(m,2H),2.66–2.62(m,1H),2.38–2.31(m,2H),2.18–2.12(m,1H),2.12–2.05(m,2H),2 .01–1.93(m,2H),1.88–1.79(m,3H),1.66–1.60(m,1H),1.52–1.48(m,1H),1.42(d,J=6 .0Hz,3H),1.29–1.24(m,2H),1.08(s,3H),0.92(s,3H),0.60–0.55(m,1H),0.30(s,3H).

[0457] Example 10

[0458] (1r,2R,3S)-N-((6 3 S,4S,Z)-1 2 -(5-(5-(1-(1-isopropylazetidin-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1-(2,2,2-trifluoroethyl)-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)-2,3-dimethylcyclopropane-1-carboxamide

[0459] Example 10 was prepared by the following steps:

[0460] Compound 10d was obtained by replacing INT-4 with INT-3 in the synthesis step of compound 1, 2,2,2-trifluoroethyl trifluoromethanesulfonate with iodoethane, and 1-tert-butyloxycarbonyl-3-azetidinone with 3-oxetanone using similar methods and synthetic steps. Compound 10d was obtained by replacing 7a in the synthesis step of compound 7 using similar methods and synthetic steps. ESI-MS (m / z): 1029.8 [M+H] + ; LC-MS retention time RT = 1.90 min.

[0461] 11H NMR (500 MHz, DMSO-d6) δ 9.37–9.31 (m, 1H), 8.58–8.52 (m, 1H), 8.43 (d, J = 9.0 Hz, 1H), 8.29–8.24 (m, 1H), 7.92–7.89 (m, 1H), 7.89–7.85 (m, 1H), 7.83–7.78 (m, 1H), 5.71–5.60 (m, 1H), 5.53 (t, J = 9.0 Hz, 1H), 5.11–5.03 (m, 1H), 4.91–4.80 (m, 1H), 4.38–4.30 (m, 1H), 4.28–4.17 (m, 2H), 3.62–3.52 (m, 2H), 3.37–3.34 (m, 2H), 3.33 (s, 3H), 3.20–3.12 (m, 1H), 3.09–3.01 (m, 2H), 2.80–2.69 (m, 4H), 2.69–2.62 (m, 2H), 2.47–2.41 (m, 1H), 2.23–2.16 (m, 1H), 2.13–2.02 (m, 3H), 1.98–1.89 (m, 2H), 1.86–1.72 (m, 4H), 1.57–1.47 (m, 1H), 1.44–1.39 (m, 3H), 1.27–1.15 (m, 4H), 1.13–1.04 (m, 6H), 0.97–0.89 (m, 3H), 0.86–0.79 (m, 6H), 0.32 (s, 3H).

[0462] Example 18

[0463] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-((S)-1-(oxetan-3-yl)piperidin-3-yl)-1,3,4-oxadiazol-2-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-methylcyclopropane-1-carboxamide

[0464] By replacing INT-2 in the synthesis step of compound 1 with INT-11, compound 18 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 920.8 [M+H] + ; LC-MS retention time RT = 1.72 min.

[0465] 1 H NMR(500MHz,DMSO-d6)δ9.34(d,J=2.0Hz,1H),8.57–8.51(m,2H),8.29(d,J=2.0 Hz,1H),7.83(s,1H),7.80–7.76(m,1H),7.61(d,J=8.5Hz,1H),5.56(t,J=9.0Hz, 1H),5.12–5.06(m,1H),4.56–4.49(m,2H),4.45–4.35(m,4H),4.26–4.18(m,2H), 4.14–4.08(m,1H),3.58(s,2H),3.49–3.43(m,1H),3.33–3.28(m,1H),3.30(s,3H ),3.28–3.23(m,1H),3.18–3.13(m,1H),3.03–2.97(m,1H),2.92–2.85(m,1H),2. 80–2.72(m,1H),2.46–2.40(m,1H),2.39–2.31(m,1H),2.12–2.04(m,2H),2.03–1 .97(m,1H),1.82–1.73(m,4H),1.65–1.58(m,1H),1.53–1.47(m,2H),1.41(d,J=6 .0Hz,3H),1.09–1.04(m,4H),0.94–0.85(m,8H),0.59–0.52(m,1H),0.36(s,3H).

[0466] Example 26

[0467] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(1-(oxetan-3-yl)-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,4-triazol-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)-2-methylcyclopropane-1-carboxamide

[0468] By replacing INT-2 in the synthesis step of compound 1 with INT-33, compound 26 can be obtained using similar methods and reaction steps. ESI-MS (m / z): 975.1 [M+H] + ; LC-MS retention time RT = 1.64 min.

[0469] 11H NMR (500 MHz, DMSO-d6) δ 9.35 (d, J = 2.0 Hz, 1H), 8.54–8.50 (m, 2H), 8.24 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.77 (dd, J = 8.5, 1.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 5.88–5.82 (m, 1H), 5.57 (t, J = 9.0 Hz, 1H), 5.10–5.06 (m, 1H), 5.01–4.92 (m, 4H), 4.56–4.52 (m, 2H), 4.45–4.41 (m, 2H), 4.38–4.34 (m, 2H), 4.25–4.14 (m, 3H), 3.60 (s, 2H), 3.43–3.39 (m, 1H), 3.36–3.34 (m, 1H), 3.29 (s, 3H), 3.18–3.12 (m, 1H), 3.06–3.01 (m, 1H), 2.96–2.92 (m, 1H), 2.79–2.73 (m, 3H), 2.43–2.38 (m, 1H), 2.11–2.06 (m, 1H), 2.03–1.96 (m, 1H), 1.92–1.87 (m, 2H), 1.83–1.77 (m, 6H), 1.52–1.48 (m, 2H), 1.41 (d, J = 6.0 Hz, 3H), 1.08–1.06 (m, 4H), 0.91 (s, 3H), 0.89–0.86 (m, 3H), 0.57–0.53 (m, 1H), 0.39 (s, 3H).

[0470] Example 27

[0471] (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(1-(2-(dimethylamino)ethyl)-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,4-triazol-3-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 1H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide

[0472] Example 27 was prepared by the following steps:

[0473] Step 1: Compound INT-3 (157 mg, 0.23 mmol) was dissolved in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL). INT-35 (104 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (24 mg, 0.024 mmol), and potassium phosphate (106 mg, 0.50 mmol) were added sequentially. The reaction mixture was stirred at 70°C under nitrogen for 16 hours. After the reaction was complete, the reaction solution was concentrated and the residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20:1) to obtain compound 27a (138 mg, 75.8% yield) as a pale yellow solid. ESI-MS (m / z): 1093.8 [M+H] + .

[0474] Step 2: Compound 27a (138 mg, 0.126 mmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (123 mg, 0.378 mmol) and iodoethane (59 mg, 0.378 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (40 mL*3). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 27b. ESI-MS (m / z): 1121.8 [M+H] + .

[0475] Step 3: Dissolve the crude compound 27b in tetrahydrofuran (4 mL) and add tetrabutylammonium fluoride (0.25 mL, 1.0 M in THF). The reaction mixture is stirred at room temperature for 16 hours. After the reaction is complete, it is diluted with ethyl acetate (60 mL), washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by preparative thin-layer chromatography (dichloromethane / methanol = 15:1) to afford a pale yellow solid, compound 27c (72 mg, 56.6% yield over two steps). ESI-MS (m / z): 1007.8 [M+H] + .

[0476] Step 4: Dissolve compound 27c (72 mg, 0.071 mmol) and N,N-diisopropylethylamine (28 mg, 0.22 mmol) in dichloromethane (3 mL). Add methanesulfonic anhydride (19 mg, 0.11 mmol) under ice-cooling. Stir the reaction mixture at room temperature for 4 hours. After the reaction is complete, dilute with dichloromethane (60 mL), wash with water, then with saturated brine, dry over anhydrous sodium sulfate, and filter and concentrate to obtain compound 27d. ESI-MS (m / z): 1085.9 [M+H] + .

[0477] Step 5: Dissolve the crude compound 27d in acetonitrile (3 mL) and add potassium carbonate (30 mg, 0.22 mmol), potassium iodide (12 mg, 0.071 mmol), and dimethylamine (0.11 mL, 2.0 M in MeOH). The reaction mixture was stirred at 70°C for 24 hours. After the reaction was complete, water (20 mL) was added to the reaction system and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 15:1) to afford compound 27e (50 mg, 67.6% yield for two steps) as a pale yellow solid. ESI-MS (m / z): 1034.7 [M+H] + .

[0478] Step 6: Compound 27e (20 mg, 0.021 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction system under ice-cooling to adjust the pH to 8. The mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 27f as a pale yellow solid. ESI-MS (m / z): 934.7 [M+H]. + .

[0479] Step 7: The crude compound 27f was dissolved in dichloromethane (3 mL), 3-oxetanone (11 mg, 0.15 mmol) was added at room temperature, and the reaction solution was stirred at room temperature for 10 minutes. Sodium acetate borohydride (51 mg, 0.24 mmol) was then slowly added to the reaction solution, and the reaction solution was continued to stir at room temperature for 3 hours. LCMS detection showed that the reaction was complete. Saturated sodium bicarbonate solution was added to the reaction system to quench the reaction, extracted with dichloromethane, and the organic phases were combined and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 13:1) to give a white solid compound 27 (10 mg, yield 20.3%). ESI-MS (m / z): 990.9 [M+H] +; LC-MS retention time RT = 1.68 min. HPLC retention time RT = 10.76 min.

[0480] 1 H NMR(500MHz,DMSO-d6)δ9.32(s,1H),8.55–8.50(m,2H),8.18(d,J=2.0Hz,1H),7.83(s,1H),7.77(dd,J=8.5,1.5Hz,1H),7.61(d,J=8.5Hz,1 H),5.57(t,J=9.0Hz,1H),5.11–5.06(m,1H),4.62–4.40(m,6H),4.38–4.32(m,2H),4.25–4.11(m,3H),3.59(s,2H),3.46–3.39(m,1H),3.32 –3.30(m,2H),3.28(s,3H),3.18–3.13(m,1H),3.06–2.98(m,2H),2.8 5–2.72(m,4H),2.51–2.51(m,6H),2.42–2.38(m,1H),2.10–2.06(m,1H ),1.95–1.73(m,9H),1.53–1.48(m,2H),1.40(d,J=6.0Hz,3H),1.07(s ,4H),0.90(s,3H),0.88–0.85(m,3H),0.57–0.53(m,1H),0.38(s,3H).

[0481] Example 38

[0482] Compound 38 can be obtained by replacing INT-3 in the synthesis step of compound 1 with INT-40 and INT-2 with INT-36, 2,2,2-trifluoroethyl trifluoromethanesulfonate using a similar method and synthesis steps. ESI-MS (m / z): 1014.8 [M+H] + ; LC-MS retention time RT = 1.80 min.

[0483] 1H NMR(500MHz,DMSO-d6)δ9.39–9.29(m,1H),8.52–8.39(m,2H),8.29–8.20(m ,1H),7.91(s,1H),7.90–7.84(m,1H),7.83–7.77(m,1H),5.93(d,J=11.0Hz, 1H),5.70–5.60(m,1H),5.37–5.30(m,1H),4.90–4.80(m,1H),4.75–4.69(m ,1H),4.58–4.51(m,2H),4.50–4.43(m,2H),4.42–4.32(m,2H),3.58–3.54(m ,2H),3.31(s,3H),3.29–3.24(m,2H),3.18–3.12(m,1H),3.07–3.00(m,1H) ,2.69–2.60(m,2H),2.46–2.29(m,4H),2.25–2.12(m,3H),2.11–2.02(m,2H) ,1.99–1.92(m,1H),1.66–1.57(m,1H),1.42(d,J=6.0Hz,3H),1.30–1.22(m ,2H),1.20–1.14(m,2H),1.12–1.04(m,6H),0.98–0.88(m,6H),0.31(s,3H).

[0484] Example 39

[0485] Compound 39 can be obtained by replacing INT-33 in the synthesis steps of compound 8 with INT-38 and INT-4a with (1R,2S)-2-fluorocyclopropanecarboxylic acid using similar methods and synthesis steps. ESI-MS (m / z): 988.8 [M+H] + ; LC-MS retention time RT = 1.85 min.

[0486] 1H NMR(500MHz,DMSO-d6)δ9.34(d,J=2.0Hz,1H),8.89(d,J=9.0Hz,1H),8.46(d,J =1.5Hz,1H),8.27(d,J=2.0Hz,1H),8.24(s,1H),7.91(s,1H),7.89–7.84(m,1H ),7.81(d,J=9.0Hz,1H),6.00(d,J=11.0Hz,1H),5.71–5.63(m,1H),4.90–4.81 (m,1H),4.72(d,J=11.0Hz,1H),4.51–4.48(m,1H),4.36–4.32(m,1H),3.55(s, 3H),3.15–3.08(m,2H),3.08–2.94(m,6H),2.66–2.63(m,1H),2.38–2.27(m,4H ),2.21(d,J=6.0Hz,3H),2.09–2.03(m,3H),2.03–1.97(m,1H),1.90–1.78(m,3 H),1.67–1.62(m,1H),1.43–1.41(m,3H),1.23(s,3H),1.17–1.12(m,1H),0.91 (s,3H),0.87–0.80(m,2H),0.48–0.45(m,2H),0.30(s,3H),0.09–0.06(m,2H).

[0487] Example 40

[0488] Example 40 was prepared by the following steps:

[0489] Step 1: Compound INT-41 (100 mg, 0.14 mmol) was dissolved in a mixture of 1,4-dioxane (4 mL) and water (0.4 mL). INT-42 (60 mg, 0.14 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 0.014 mmol), and potassium phosphate (90 mg, 0.43 mmol) were added sequentially. The reaction mixture was stirred at 70°C under nitrogen for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10:1) to obtain compound 40a (80 mg, 61.4% yield) as a pale yellow solid. ESI-MS (m / z): 920.2 [M+H] + .

[0490] Step 2: Compound 40a (80 mg, 0.087 mmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (85 mg, 0.261 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (61 mg, 0.261 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 40b. ESI-MS (m / z): 1002.7 [M+H] + .

[0491] Step 3: Dissolve the crude compound 40b in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and react at 0°C for 3 hours. LCMS monitoring indicates that the reaction is complete. Quench with saturated aqueous NaHCO3 solution and extract with dichloromethane (30 mL x 3). The organic phases are combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 40c. ESI-MS (m / z): 902.9 [M+H] + .

[0492] Step 4: Dissolve the crude compound 40c and compound INT-4a (14.9 mg, 0.130 mmol) in N,N-dimethylformamide (3 mL). Add N,N-diisopropylethylamine (45 mg, 0.348 mmol) and (2-oximino-cyanoacetic acid ethyl)-N,N-dimethyl-morpholinourea hexafluorophosphate (48 mg, 0.113 mmol) at room temperature. React at room temperature for 1 hour. LCMS monitoring indicates complete reaction. Water is added to the system, and extraction is performed with ethyl acetate (30 mL x 3). The organic phases are combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by preparative liquid chromatography to afford compound 40 (15 mg, 17.3% yield for three steps) as a white solid. ESI-MS (m / z): 998.4 [M+H] + LC-MS retention time RT = 1.75 min.

[0493] 1H NMR(500MHz,DMSO-d6)δ9.34(s,1H),8.54–8.42(m,3H),7.97–7.83(m,2H),7.79–7.68(m,1H),6.01–5.86(m,1H),5.38–5. 28(m,1H),5.04–4.89(m,2H),4.80–4.72(m,1H),4.56–4.46(m,1H),4.09–3.96(m,1H),3.68–3.58(m,4H),3.54–3.49(m,1H ),3.29–3.24(m,2H),3.19–3.09(m,5H),2.77–2.63(m,5H),2.37–2.26(m,2H),2.20–2.13(m,1H),2.06–1.97(m,1H),1.80 –1.74(m,1H),1.68–1.60(m,1H),1.35–1.19(m,8H),1.14–1.06(m,6H),0.74–0.65(m,2H),0.63–0.56(m,2H),0.46(s,3H).

[0494] Example 41

[0495] Compound 41 can be obtained by replacing INT-3 in the synthesis step of compound 1 with INT-40 and INT-2 with INT-7 using similar methods and synthesis steps. ESI-MS (m / z): 1014.8 [M+H] + ; LC-MS retention time RT = 1.72 min.

[0496] 1H NMR(500MHz,DMSO-d6)δ9.32(d,J=2.0Hz,1H),8.46(d,J=10.0Hz,2H),8.41(d,J=2.)Hz,1H),7.91(s,1H),7.86(d,J=8.5Hz,1H),7.72(d,J=8.5Hz, 1H),5.97–5.89(m,1H),5.31(t,J=8.0Hz,1H),5.00–4.91(m,2H),4.78–4. 71(m,1H),4.53–4.47(m,3H),4.39(t,J=6.)Hz,2H),4.00–3.94(m,1H),3. 65–3.59(m,1H),3.54–3.48(m,1H),3.31–3.23(m,1H),3.19–3.04(m,5H), 2.93(d,J=7.0Hz,2H),2.70–2.64(m,3H),2.48–2.43(m,1H),2.38–2.30(m ,1H),2.20–2.12(m,1H),1.89–1.79(m,1H),1.76–1.69(m,4H),1.67–1.59 (m,1H),1.36–1.17(m,10H),1.13–1.05(m,6H),0.92(s,3H),0.47(s,3H).

[0497] Example 42

[0498] Compound 42 can be obtained by replacing INT-3 in the synthesis step of compound 1 with INT-40 and INT-2 with INT-9 using similar methods and synthesis steps. ESI-MS (m / z): 1000.8 [M+H] + ; LC-MS retention time RT = 1.85 min.

[0499] 1H NMR(500MHz,DMSO-d6)δ9.35(d,J=2.0Hz,1H),8.49–8.43(m,2H),8.24–8.21(m,1H ),7.91(s,1H),7.90–7.86(m,1H),7.81(d,J=8.5Hz,1H),5.98–5.88(m,1H),5.71–5 .61(m,1H),5.37–5.31(m,1H),4.91–4.83(m,1H),4.74–4.69(m,1H),4.54(t,J=6.5 Hz,2H),4.51–4.48(m,1H),4.44(t,J=6.0Hz,2H),4.38–4.32(m,1H),3.57(s,2H),3 .44–3.40(m,2H),3.32(s,3H),3.29–3.25(m,1H),3.18–3.13(m,2H),3.08–3.02(m, 1H),2.76–2.70(m,2H),2.67–2.62(m,1H),2.49–2.41(m,2H),2.36–2.31(m,1H),2. 17–2.08(m,3H),1.99–1.93(m,2H),1.88–1.79(m,2H),1.65–1.59(m,1H),1.43(d,J =6.0Hz,3H),1.29–1.22(m,3H),1.20–1.17(m,2H),1.12–1.06(m,6H),0.90(s,3H).

[0500] Example 43

[0501] Compound 43 can be obtained by replacing INT-3 in the synthesis step of compound 1 with INT-40 and INT-2 with INT-43 using similar methods and synthesis steps. ESI-MS (m / z): 1012.8 [M+H] + ; LC-MS retention time RT = 1.73 min.

[0502] 1H NMR(500MHz,DMSO-d6)δ9.35–9.30(m,1H),8.50–8.41(m,3H),8.26–7.80(m,3 H),7.72(d,J=8.6Hz,1H),5.97–5.88(m,1H),5.38–5.27(m,1H),5.04–4.82(m ,2H),4.78–4.69(m,1H),4.61–4.52(m,2H),4.51–4.47(m,1H),4.42(t,J=5.8 Hz,1H),4.39–4.34(m,1H),4.04–3.95(m,1H),3.87–3.80(m,1H),3.63–3.55(m ,1H),3.52–3.48(m,1H),3.31–3.22(m,4H),3.19–3.06(m,4H),2.80–2.74(m, 1H),2.68–2.63(m,2H),2.60–2.55(m,1H),2.37–2.30(m,1H),2.19–2.12(m,1 H),2.07–1.95(m,2H),1.67–1.56(m,2H),1.56–1.50(m,1H),1.45–1.39(m,1H ),1.32–1.17(m,7H),1.12–1.05(m,6H),0.94–0.88(m,3H),0.49–0.28(m,3H).

[0503] Example 44

[0504] Compound 44 can be obtained by replacing INT-3 in the synthesis step of compound 1 with INT-40 and INT-2 with INT-44 using similar methods and synthesis steps. ESI-MS (m / z): 1030.5 [M+H] + ; LC-MS retention time RT = 1.84 min.

[0505] 1H NMR(500MHz,DMSO-d6)δ9.33–9.28(m,1H),8.49–8.40(m,3H),7.91(s,1H),7. 87–7.83(m,1H),7.72(d,J=8.6Hz,1H),5.95–5.89(m,1H),5.31(t,J=8.0Hz,1 H),4.98–4.91(m,2H),4.74(d,J=11.0Hz,1H),4.54(t,J=6.5Hz,2H),4.49(d, J=5.0Hz,1H),4.40(t,J=6.0Hz,2H),3.99–3.94(m,1H),3.71–3.65(m,1H),3. 63–3.56(m,2H),3.53–3.48(m,1H),3.28–3.25(m,1H),3.18–3.05(m,6H),2.6 8–2.63(m,1H),2.61–2.55(m,1H),2.48–2.46(m,2H),2.36–2.31(m,1H),2.22 –2.12(m,3H),2.01–1.92(m,2H),1.87–1.80(m,1H),1.76–1.68(m,1H),1.66– 1.59(m,1H),1.30–1.19(m,8H),1.12–1.06(m,6H),0.91(s,3H),0.47(s,3H).

[0506] Example 45

[0507] Example 45 was prepared by the following steps:

[0508] Step 1: Dissolve compound INT-32d (1 g, 1.01 mmol) in dichloromethane (4.5 mL), add trifluoroacetic acid (1.5 mL), and react at 0°C for 3 hours. LCMS monitoring confirmed the complete reaction of the starting material. Quench with saturated aqueous NaHCO3 solution and extract with dichloromethane (60 mL*3). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 45a (838 mg, yield 93.2%). ESI-MS (m / z): 888.6 [M+H] + .

[0509] Step 2: Compound 45a (1 g, 1.12 mmol) was dissolved in tetrahydrofuran (5 mL), and N,N-diisopropylethylamine (436 mg, 3.37 mmol) was added. Benzyl chloroformate (288 mg, 1.69 mmol) was then added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 16 hours, and then additional benzyl chloroformate (288 mg, 1.69 mmol) was added. The reaction mixture was stirred at room temperature for another 6 hours. Water was added to the reaction system, and the mixture was extracted with dichloromethane (60 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude, pale yellow solid, compound 45b. ESI-MS (m / z): 1022.6 [M+H]. + ;

[0510] Step 3: Dissolve the crude compound 45b in tetrahydrofuran (6 mL) and add tetrabutylammonium fluoride (1 M, 3.37 mL). Stir the reaction mixture at 60°C for 16 hours. After the reaction is complete, add water (30 mL) to the reaction system and extract with ethyl acetate (30 mL*3). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to obtain a light yellow solid compound 45c (551 mg, yield 62.5%). ESI-MS (m / z): 784.2 [M+H] + .

[0511] Step 4: Compound 45c (551 mg, 0.70 mmol) was dissolved in 1,4-dioxane (10 mL). Potassium acetate (207 mg, 2.11 mmol), pinacol diboron (267 mg, 1.05 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (51 mg, 0.070 mmol) were added sequentially. The mixture was stirred at 80°C under a nitrogen atmosphere for 16 hours. LCMS monitored the reaction for completion. Water was added to the mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, 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 = 1 / 3) to afford compound 45d (467 mg, 78.0% yield) as a pale yellow solid. ESI-MS (m / z): 832.8 [M+H]. + .

[0512] Step 5: Compound 45d (467 mg, 0.56 mmol) was dissolved in 1,4-dioxane (6 mL) and water (0.6 mL). INT-31 (261 mg, 0.53 mmol), potassium carbonate (233 mg, 1.68 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (36 mg, 0.056 mmol) were added sequentially. The reaction mixture was stirred at 50°C under a nitrogen atmosphere for 20 hours. LCMS confirmed the reaction was complete. Water was added to the mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, 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 / 9) to afford compound 45e (529 mg, 84.6% yield) as a pale yellow solid. ESI-MS (m / z): 1114.9 [M+H] + .

[0513] Step 6: Dissolve compound 45e (519 mg, 0.466 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL). Add lithium hydroxide monohydrate (58 mg, 1.4 mmol) at 0°C and continue stirring for 1 hour. LCMS monitoring indicates complete reaction. Dilute with water, adjust the pH to 5 with dilute hydrochloric acid, and extract with ethyl acetate (30 mL x 3). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield crude compound 45f as a pale yellow solid. ESI-MS (m / z): 1100.8 [M+H]. + .

[0514] Step 7: Add N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (261 mg, 0.93 mmol) and 1-methylimidazole (191 mg, 2.33 mmol) to acetonitrile (10 mL) and stir to dissolve. Add the crude compound 45f in THF (5 mL) dropwise at room temperature. Stir and react for 1 hour after addition. LCMS monitoring indicates complete reaction. Add water to the system and extract with ethyl acetate (30 mL x 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The resulting residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 9) to afford compound 45g (348 mg, 69.1% yield for two steps) as a pale yellow solid. ESI-MS (m / z): 1082.8 [M+H] + .

[0515] Step 8: Compound 45g (70 mg, 0.065 mmol), 10% palladium hydroxide (14 mg), 10% palladium on carbon (14 mg), and isopropanol (2 mL) were added to a reaction flask. Under a hydrogen atmosphere, the reaction mixture was stirred at 70°C for 20 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain crude compound 45h. ESI-MS (m / z): 948.8 [M+H] + .

[0516] Step 9: The crude compound 45h was dissolved in 1,2-dichloroethane (3 mL), and N-methyl-4-piperidone (22 mg, 0.194 mmol) was added at room temperature. The reaction solution was stirred at room temperature for 10 minutes. Sodium acetate borohydride (69 mg, 0.323 mmol) was then slowly added to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours. LCMS monitored the reaction completion. Saturated aqueous sodium bicarbonate solution was added to the reaction system to quench the reaction. The mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (dichloromethane / methanol = 8:1) to obtain a light yellow solid compound 45i (44 mg, two-step yield 65.1%). ESI-MS (m / z): 1045.8 [M+H] + .

[0517] Step 10: Compound 45i (44 mg, 0.042 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added under ice-cooling. The reaction mixture was stirred at 0°C for 3 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction system under ice-cooling to adjust the pH to 8. The mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 45j (38 mg, yield 95.5%) as a pale yellow solid. ESI-MS (m / z): 945.8 [M+H] + .

[0518] Step 11: Compound 45j (38 mg, 0.040 mmol) and compound 45k (7.7 mg, 0.06 mmol) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (21 mg, 0.16 mmol) and (ethyl 2-oximinocyanoacetate)-N,N-dimethylmorpholinouradium hexafluorophosphate (22 mg, 0.052 mmol) were added at room temperature. The mixture was allowed to react for 1 hour. LCMS confirmed the complete reaction. Water was added to the mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to afford 45 as a white solid (8 mg, 18.9% yield). ESI-MS (m / z): 1055.7 [M+H]. + LC-MS retention time RT = 1.50 min.

[0519] 1 H NMR(500MHz,DMSO-d6)δ9.36–9.31(m,1H),8.67–8.59(m,1H),8.46(s,1H) ,8.34–8.23(m,3H),7.91(s,1H),7.90–7.85(m,1H),7.83–7.78(m,1H),6. 00–5.91(m,1H),5.70–5.59(m,1H),5.41–5.30(m,1H),4.91–4.81(m,1H), 4.76–4.69(m,1H),4.52–4.45(m,1H),4.37–4.30(m,1H),3.90–3.85(m,2H ),3.67–3.65(m,2H),3.33–3.28(m,4H),3.16–3.11(m,1H),3.07–3.00(m, 2H),2.94–2.89(m,2H),2.84–2.80(m,2H),2.66–2.63(m,1H),2.37–2.28( m,4H),2.18–2.14(m,4H),2.08–2.01(m,3H),1.94–1.89(m,3H),1.82–1.7 5(m,2H),1.70–1.61(m,4H),1.50–1.40(m,5H),0.90(s,3H),0.31(s,3H).

[0520] Example 46

[0521] Compound 46 can be obtained by replacing INT-3 in the synthesis step of compound 1 with INT-40 and INT-2 with INT-45 using similar methods and synthesis steps. ESI-MS (m / z): 986.8 [M+H] + ; LC-MS retention time RT = 1.72 min.

[0522] 1 H NMR(500MHz,DMSO-d6)δ9.36–9.32(m,1H),8.52–8.42(m,3H),7.93–7.90( m,1H),7.90–7.71(m,2H),5.96–5.90(m,1H),5.37–5.29(m,1H),5.03–4.83 (m,2H),4.77–4.71(m,1H),4.62–4.56(m,2H),4.52–4.44(m,3H),4.38–3. 98(m,1H),3.81–3.73(m,1H),3.69–3.61(m,2H),3.57–3.49(m,1H),3.33–3 .31(m,1H),3.30–3.25(m,1H),3.19–3.04(m,4H),2.99–2.93(m,1H),2.89 –2.82(m,1H),2.68–2.59(m,3H),2.49–2.45(m,1H),2.37–2.21(m,3H),2.1 9–2.13(m,1H),1.67–1.61(m,1H),1.46–1.41(m,1H),1.33–1.22(m,4H),1 .21–1.16(m,2H),1.12–1.07(m,6H),0.94–0.90(m,3H),0.49–0.29(m,3H).

[0523] Example 47

[0524] Compound 47 can be obtained by replacing INT-3 in the synthesis step of compound 1 with INT-4 and replacing INT-2 with INT-46 using similar methods and synthesis steps. ESI-MS (m / z): 933.3 [M+H] + ; LC-MS retention time RT = 1.75 min.

[0525] Biological screening of RAS inhibitors and results

[0526] Test Example 1: In vitro cell proliferation inhibition test

[0527] Due to the diversity of RAS mutations and to evaluate the activity of compounds in cell lines with different RAS mutations, we selected KRASG12D 、KRAS G12V 、KRAS G12C NRAS Q61L 、KRAS G13D 、KRAS G12R and KRAS WT The in vitro activity of the compounds was evaluated and screened using the cell lines (see table below).

[0528] Experimental plan: Luminescent Viability Assay(Promega)

[0529] Depending on the doubling time of different cell lines, different numbers of cells (1000-5000 cells / well) were seeded into 96-well plates containing 180 μl of the corresponding culture medium and cultured overnight in a 37°C cell culture incubator with 5% CO2. The next day, the test compound was pre-diluted 3-fold with culture medium, with the highest concentration being 100 μM, for a total of 10 concentration gradients; then 20 μl of culture medium containing different concentrations of the compound was added to the cells in the 96-well plate to ensure that the final concentration of the compound was up to 10 μM, with 10 concentration gradients of 3-fold dilution. After the cells and compounds were co-incubated for 72 hours, the 96-well plate was removed from the incubator and equilibrated at room temperature for 30 minutes, after which 25 μl of the test compound was added to each well. Mix the reagent thoroughly and incubate at room temperature for 10 min. Then transfer 100 μl of sample to a white 96-well plate (OptiPlate TM -96, PerkinElmer), using a multifunctional microplate reader ( i3x, Molecular devices was used to read the fluorescence signal value. The signal value was then normalized and the curve was fitted using a four-parameter regression equation to calculate the half maximal inhibitory concentration (IC) of the compound on the cell line. 50 ).

[0530] Table 3: Antiproliferative activity of the compounds of the present invention against RAS cell mutants

[0531] 1. The reference molecule is synthesized in-house and characterized by structure and biological activity data.

[0532] Conclusion: The compounds of the present invention have significant inhibitory activity against different RAS mutation cell lines.

[0533] Experimental Example 2: Complex Binding Constant Test

[0534] 2.1 Binary complex binding assay

[0535] To determine the binding ability of test compounds to cyclophilin A (CypA), we used a bio-layer interferometry (Octet R8)-based method to monitor the binding kinetics of the compounds to CypA and calculate the affinity of the binary complex. First, a His-tagged CypA protein (3589-CAB, R&D) was immobilized on an NTA sensor and allowed to equilibrate for 120 seconds in assay buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM TCEP, 0.01% Tween20). Subsequently, the sensor was exposed to buffer containing varying concentrations of compound, and the association between the compound and protein was monitored in real time. After the binding reached a plateau at high concentrations, the sensor was transferred to compound-free buffer to measure dissociation. To ensure the accuracy of the experimental data, DMSO normalization was performed and buffer optimization was performed to reduce nonspecific binding. Negative and positive controls were also included to verify the specificity of the assay. Octet Analysis Studio 13.0 software was used to analyze the data. The 1:1 binding model was used to analyze the data and calculate the association rate constant (ka), dissociation rate constant (kdis), and equilibrium dissociation constant (K D1 ).

[0536] Table 4: Binary complex binding constants (K D1 )

[0537] 1. The reference molecule is synthesized in-house and characterized by structure and biological activity data.

[0538] Conclusion: The compounds of the present invention have a strong ability to form binary complexes with Cyclophilin A (CypA) protein.

[0539] 2.2 Ternary complex binding assay

[0540] To test the ability of test compounds to induce the formation of a ternary complex between RAS and CypA, we used a bio-layer interferometry (Octet R8)-based method to monitor the binding kinetics of the compounds, RAS, and CypA and calculate the affinity of the ternary complex. GMPPNPs were first incubated with RAS protein to allow GMPPNP loading onto the RAS protein. Different His-tagged RAS mutants were immobilized on an NTA sensor and allowed to equilibrate for 120 seconds in assay buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM TCEP, 5 μM GMPPNP, 0.01% Tween 20). Subsequently, the sensor was exposed to buffer containing varying concentrations of compound and a fixed concentration of CypA, and the association of the ternary complex was monitored in real time. After the binding reached a plateau, the sensor was transferred to a buffer without compound or CypA to measure dissociation. To ensure the accuracy of the experimental data, we performed DMSO standardization and reduced nonspecific binding by buffer optimization. At the same time, negative and positive controls were set to verify the specificity of the experiment. Octet Analysis Studio 13.0 analysis software was used to process the data. The 1:1 binding model was used to analyze the data and calculate the association rate constant (ka), dissociation rate constant (kdis) and equilibrium dissociation constant (K D2 ).

[0541] Table 5: Ternary complex binding constants (K D2 )

[0542] 1. The reference molecule is synthesized in-house and characterized by structure and biological activity data.

[0543] Conclusion: The compound of the present invention has a strong ability to form a ternary complex with Cyclophilin A (CypA) protein and RAS protein.

[0544] Experimental Example 3: Pharmacokinetic Test in Mice

[0545] To evaluate the pharmacokinetic behavior of compounds of the invention in male CD-1 mice, test compounds were dissolved in a vehicle (5% DMOS / 10% solutol / 85% water). Twelve male CD-1 mice were divided into two groups of six. Group 1 received a single intravenous (iv) bolus of compound; group 2 received a single oral (p.o.) bolus of compound. Whole blood samples were collected at 0.083 (iv bolus group only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-dose. Test compound concentrations in whole blood samples were determined using LC-MS / MS.

[0546] All animals tolerated the treatment well and showed no abnormalities. Detailed test results are shown in Table 6.

[0547] Table 6: Pharmacokinetic test results in mice

[0548] Conclusion: The compounds of the present invention have slow clearance, high exposure and good pharmacokinetic properties.

Claims

1. A compound of formula (A), or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof: in: Cya said or which may optionally be substituted by 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; R2 represents halogen, cyano, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl), which may be optionally substituted by 0, 1 or 2 substituents selected from the group consisting of -ORa, -SRa or -NRaRa'; R3 represents hydrogen, hydroxyl, -(C1-C3 alkylene)-OR a or C1-C3 alkyl; Cy1 represents C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl, Cy1 can be a monocyclic, spirocyclic, bridged or fused ring; R4 each independently represents hydrogen, halogen, oxo, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C6)cycloalkyl, -(C0-C6 alkylene)(4-8 membered)heterocycloalkyl, -(C0-C6 alkylene)ORa, -(C0-C6 alkylene)SRa, -(C0-C6 alkylene)NRaRa', -(C0-C6 alkylene)CORa, -(C0-C6 alkylene)COORa, -(C0-C6 alkylene) CONRaRa', -(C0-C6 alkylene)NRaCORa', -(C0-C6 alkylene)OCONRaRa', -(C0-C6 alkylene)NRaCONRaRa', -(C0-C6 alkylene)SORa, -(C0-C6 alkylene)S(O)2Ra, -(C0-C6 alkylene)NRaS(O)2Ra', -(C0-C6 alkylene)CN, -(C0-C6 alkylene)(C6-C 10 wherein, R4 on two C atoms of Cy1 together with the C atom to which they are attached and the atom between the two C atoms may form a 3-8 membered ring, and the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or two R4 on the same C atom of Cy1 together with the C atom to which they are attached may form a 3-8 membered ring, and the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; Optionally, R3 and R4 may form a ring; Cy2 represents a 5-membered heteroaryl group; Cy3 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, the ring may be a monocyclic, spirocyclic, bridged or fused ring; R6 and R7 are each independently selected from: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; the above C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl are each independently substituted by 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -ORa, -SRa, -NRaRa', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; W is H or formula (II), wherein * represents linkage with Cy3: Cy4 is selected from C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, the ring may be a monocyclic, spirocyclic, bridged or fused ring; R8 are each independently selected from: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, wherein the C1-C6 alkyl may be substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo, -ORa, -NRaRa' or cyano; L1 and L2 each independently represent a single bond or -(C1-C6)alkylene-, any methylene group on the -(C1-C6)alkylene- may be replaced by a carbonyl, NRa, O or S, the -(C1-C6)alkylene- may be substituted by 0, 1, 2, 3 or 4 substituents selected from halogen or C1-C3 alkyl, and two substituents on the same C atom may form a 3-6 membered ring with the C atom to which they are connected, and the 3-6 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; Cy0 represents a 5-12 membered aromatic ring or heteroaromatic ring; R A each independently selected from H, halogen, CN, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl), -(C0-C6 alkylene)-ORa, -(C0-C6 alkylene)-SRa or -(C0-C6 alkylene)-NRaRa', and optionally, RA on two adjacent or non-adjacent atoms on Cy0 together with the ring atoms of Cy0 can form a 6-10 membered ring, and the 6-10 membered ring can be further substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl, -ORa, -SRa or -NRaRa'; L0 is selected from a single bond, -(C1-C6)alkylene, -(C2-C6)alkenylene, any methylene group on the -(C1-C6)alkylene or -(C2-C6)alkenylene may be replaced by a carbonyl, NRa, O or S, and the -(C1-C6)alkylene or -(C2-C6)alkenylene may be optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl; R B are each independently selected from H, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-ORa, -(C0-C6 alkylene)-SRa or -(C0-C6 alkylene)-NRaRa', and optionally, R B It can form a ring with the substituent R4 of Cy1; R C is selected from H, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-ORa, -(C0-C6 alkylene)-SRa or -(C0-C6 alkylene)-NRaRa'; R D Selected from H, C1-C6 alkyl, -(C1-C6 alkylene)-ORa, -(C1-C6 alkylene)-SRa or -(C1-C6 alkylene)-NRaRa'; R E 、R F are each independently selected from H, C1-C6 alkyl, halogen, -(C0-C6 alkylene)-ORa, -(C0-C6 alkylene)-SRa or -(C0-C6 alkylene)-NRaRa'; and optionally, R E 、R F can form a 3-6 membered ring with the C atom to which they are attached, and the 3-6 membered ring may additionally contain 0, 1 or 2 heteroatoms selected from N, O and S; Z represents N or CR5, Z' represents N or CR5', wherein R5 and R5' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C8)cycloalkyl or -(C0-C6 alkylene)CN; Wherein, m, n, o, p, and q each independently represent 0, 1, 2, 3, or 4; Ra and Ra' each independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; when Ra and Ra' are connected to the same N atom, said Ra and Ra' and the commonly connected N atom may form a 4-8 membered ring, and said 4-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; The alkyl, cycloalkyl, heterocycloalkyl and alkylene groups may each independently be substituted by 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

2. The compound according to claim 1, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, having the structure represented by formula (A'): where R A 、R B 、R C 、R D 、R E 、R F , Z, Z', R2, R3, R4, R6, R7, Cya, Cy0, Cy1, Cy2, Cy3, L0, L1, W, m, n, p, q are defined as described in claim 1.

3. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R B For H.

4. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R C 、R D For H.

5. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Z represents CR5, and Z' represents CR5'.

6. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: L0 is vinylene, -(C1-C3)alkylene or a single bond; more preferably, L0 is a single bond.

7. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R E 、R F are each independently selected from H, C1-C6 alkyl, and optionally, R E 、R F can form a 3-6 membered ring with the C atom to which they are attached, and the ring can additionally contain 0, 1 or 2 heteroatoms selected from N, O, and S; more preferably, R E 、R F Each is independently selected from C1-C3 alkyl.

8. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, having the structure shown in formula (B): in: Indicates a single bond or a double bond; X1 and X2 each independently represent C or N; Y1, Y2, and Y3 each independently represent no bond, a 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 Y3 is CR A When, R1 can optionally be connected to R of Y3 A The substituent group together with the N, X1 and C atoms to which it is attached forms a 6-10 membered ring, and the 6-10 membered ring may be further substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl, -ORa, -SRa or -NRaRa'; 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'; t is selected from 0, 1, 2 or 3; R A 、R B 、R C 、R D 、R E 、R F , Z, Z', R2, R3, R4, R6, R7, Cya, Cy1, Cy2, Cy3, L1, W, m, n, and p are defined as described in any of the preceding claims.

9. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, having the structure represented by formula (B'): in, X1, X2, Y1, Y2, Y3, R A 、R B 、R C 、R D 、R E 、R F , Z, Z', R1, R2, R3, R4, R6, R7, Cya, Cy1, Cy2, Cy3, L1, W, m, n, p, and t are defined as described in claim 8.

10. The compound according to any one of claims 8 to 9, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: X1 and X2 each independently represent C.

11. The compound according to any one of claims 8 to 10, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Selected from Among them, Q represents CR A or N, T represents NR1', O or S, and optionally, when Y3 is CR A When R1 can be connected to R A The substituents together with the ring atoms on Cy0 form a 6-10 membered ring, which may be further substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl, -ORa, -SRa or -NRaRa'.

12. The compound according to any one of claims 8 to 11, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: express And optionally, R1 can be combined with R A The substituent, together with the N, X1 and C atoms to which it is attached, forms a 6-10 membered ring, which may be further substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl, -OH.

13. The compound according to any one of claims 8 to 10, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: express 14. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R A are each independently selected from H, halogen, CN, C1-C3 alkyl; more preferably, R A Each independently represents H or F.

15. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, having the structure of formula (I): in: Cya said or which may optionally be substituted by 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; 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'; R2 represents halogen, cyano, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl), which may be optionally substituted by 0, 1 or 2 substituents selected from the group consisting of -ORa, -SRa or -NRaRa'; R3 represents hydrogen, hydroxyl, -(C1-C3 alkylene)-OR a or C1-C3 alkyl; Cy1 represents C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl, Cy1 can be a monocyclic, spirocyclic, bridged or fused ring; R4 each independently represents hydrogen, halogen, oxo, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C6)cycloalkyl, -(C0-C6 alkylene)(4-8 membered)heterocycloalkyl, -(C0-C6 alkylene)ORa, -(C0-C6 alkylene)SRa, -(C0-C6 alkylene)NRaRa', -(C0-C6 alkylene)CORa, -(C0-C6 alkylene)COORa, -(C0-C6 alkylene) CONRaRa', -(C0-C6 alkylene)NRaCORa', -(C0-C6 alkylene)OCONRaRa', -(C0-C6 alkylene)NRaCONRaRa', -(C0-C6 alkylene)SORa, -(C0-C6 alkylene)S(O)2Ra, -(C0-C6 alkylene)NRaS(O)2Ra', -(C0-C6 alkylene)CN, -(C0-C6 alkylene)(C6-C 10 wherein, R4 on two C atoms of Cy1 together with the C atom to which they are attached and the atom between the two C atoms may form a 3-8 membered ring, and the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or two R4 on the same C atom of Cy1 together with the C atom to which they are attached may form a 3-8 membered ring, and the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; R5 and R5' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C8)cycloalkyl or -(C0-C6 alkylene)CN; Cy2 represents a 5-membered heteroaryl group; Cy3 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, the ring may be a monocyclic, spirocyclic, bridged or fused ring; R6 and R7 are each independently selected from: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; the above C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl are each independently substituted by 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -ORa, -SRa, -NRaRa', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; W is H or formula (II), wherein * represents linkage with Cy3: Cy4 is selected from C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, the ring may be a monocyclic, spirocyclic, bridged or fused ring; R8 are each independently selected from: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, wherein the C1-C6 alkyl may be substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo, -ORa, -NRaRa' or cyano; L1 and L2 each independently represent a single bond or -(C1-C6)alkylene-, any methylene group on the -(C1-C6)alkylene- may be replaced by a carbonyl, NRa, O or S, the -(C1-C6)alkylene- may be substituted by 0, 1, 2, 3 or 4 substituents selected from halogen or C1-C3 alkyl, and two substituents on the same C atom may form a 3-6 membered ring with the C atom to which they are connected, and the 3-6 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; Wherein, m, n, o, and p each independently represent 0, 1, 2, 3, or 4; Ra and Ra' each independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; when Ra and Ra' are connected to the same N atom, said Ra and Ra' and the commonly connected N atom may form a 4-8 membered ring, and said 4-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; The alkyl, cycloalkyl, heterocycloalkyl and alkylene groups may each independently be substituted by 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

16. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, having the structure of formula (I'): in, The definitions of R1, R2, R3, R4, R5, R5', R6, R7, Cya, Cy1, Cy2, Cy3, L1, W, m, n, and p are as described in claim 15.

17. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein Cya represents or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl.

18. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cya said It may optionally be substituted by 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; preferably, Cya represents 19. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cya said or It may optionally be substituted by 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; preferably, Cya represents 20. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: W is formula (II).

21. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: L1 and L2 each independently represent a single bond or -(C1-C6)alkylene-, any methylene group on the -(C1-C6)alkylene- can be replaced by a carbonyl group, NRa, O or S, and the -(C1-C6)alkylene- can be substituted by 0, 1, 2, 3 or 4 C1-C3 alkyl substituents, and two substituents on the same C atom can form a 3-6 membered ring with the C atom to which they are connected, and the 3-6 membered ring optionally can contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.

22. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R1 represents C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl), halogenated C1-C6 alkyl, halogenated-(C0-C6 alkylene)-(C3-C8 cycloalkyl) or halogenated-(C0-C6 alkylene)-(4-8 membered heterocycloalkyl); preferably, R1 represents C1-C6 alkyl or halogenated C1-C6 alkyl; more preferably, R1 represents ethyl or -CH2CF3.

23. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R2 represents a C1-C6 alkyl group, which may be substituted by 0 or 1 C1-C3 alkoxy group; preferably, R2 represents a 1-methoxyethyl group; more preferably, R2 represents Wherein, * represents the position where R2 is connected to the portion to which it is connected in the general formula.

24. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R3 is preferably H.

25. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cy1 represents a C3-C8 cycloalkyl group or a 4-8 membered heterocycloalkyl group; preferably, Cy1 represents a C3-C8 cycloalkyl group; more preferably, Cy1 represents a cyclopropyl group.

26. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R4 each independently represents hydrogen, halogen or C1-C3 alkyl.

27. A compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: -Cy1-(R4)p has a structure selected from the following: Wherein, * represents the site where -Cy1-(R4)p is connected to the site to which it is connected in the general formula.

28. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R5 and R5' each independently represent hydrogen, halogen or C1-C6 alkyl; preferably, R5 and R5' are H.

29. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Selected from or 30. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cy2 is not pyrazole or isoxazole.

31. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cy2 is not or 32. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: no or 33. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Selected from or Preferably, Selected from or 34. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cy3 represents a 4-12 membered heterocycloalkyl group, and the ring may be a monocyclic ring, a spirocyclic ring, a bridged ring, or a fused ring; preferably, Cy3 represents a 4-8 membered heterocycloalkyl group, and the ring may be a monocyclic ring, a spirocyclic ring, a bridged ring, or a fused ring.

35. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cy3 represents or And Cy3 may have n substituents selected from R7; more preferably, Cy3 represents or And Cy3 may have n substituents selected from R7.

36. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R6 is each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, and the above C1-C6 alkyl, C3-C8 cycloalkyl and 4-8 membered heterocycloalkyl are each independently substituted by 0, 1 or 2 substituents selected from halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; preferably, R6 is each independently selected from hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl, and the above C1-C6 alkyl and C3-C8 cycloalkyl are each independently substituted by 0, 1 or 2 substituents selected from halogen, C1-C6 alkyl or C3-C6 cycloalkyl; more preferably, R6 is each independently selected from hydrogen and methyl.

37. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R7 is independently selected from the group consisting of: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, wherein the C1-C6 alkyl group is independently substituted by 0, 1 or 2 substituents selected from the group consisting of: halogen, oxo, -ORa, -NRaRa', cyano; preferably, R7 is independently selected from the group consisting of: hydrogen, halogen, oxo, hydroxyl, cyano or C1-C6 alkyl.

38. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: L1 represents a single bond, -CH2-, -O- or -NH-.

39. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein, express or And Cy3 may have n substituents selected from R7.

40. The compound according to any preceding claim, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein Cy4 is C5-C6 cycloalkyl or 5-6 membered heterocycloalkyl, o≥1 and R8 is not hydrogen.

41. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cy4 is selected from C3-C4 cycloalkyl or 4-membered heterocycloalkyl.

42. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cy4 is selected from or And Cy4 may have o substituents selected from R8; preferably, Cy4 is selected from or And Cy4 may have o substituents selected from R8; more preferably, Cy4 is selected from or Cy4 may have o substituents selected from R8.

43. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: L2 represents a single bond, -CH2- or -O-; preferably, L2 represents a single bond.

44. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R8 are each independently selected from hydrogen, halogen or C1-C6 alkyl.

45. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: express or And Cy3 may have n substituents selected from R7.

46. ​​A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: express or 47. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: m, n, o, p, q, and t each independently represent 0, 1, or 2.

48. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Ra and Ra' each independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; preferably, Ra and Ra' each independently represent hydrogen or C1-C6 alkyl; preferably, Ra and Ra' each independently represent hydrogen or C1-C3 alkyl.

49. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, having the structure represented by formula (III): in: Cya said or which may optionally be substituted by 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; R1 represents ethyl or -CH2CF3; R2 represents a C1-C6 alkyl group, which may be substituted by 0 or 1 C1-C3 alkoxy group; Cy1 represents a C3-C8 cycloalkyl group or a 4-8 membered heterocycloalkyl group; R4 each independently represents hydrogen, halogen or C1-C3 alkyl; Cy2 represents a 5-membered heteroaryl group, and Cy2 is not or Cy3 represents a 4-12 membered heterocycloalkyl group; R6 is each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl, and the above C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl are each independently substituted by 0, 1 or 2 substituents selected from halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; R7 is each independently selected from: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, wherein the C1-C6 alkyl may be substituted by 0, 1 or 2 substituents selected from halogen, oxo, -ORa, -NRaRa', cyano; L1 represents a single bond or -(C1-C6)alkylene-, and any methylene group on the -(C1-C6)alkylene- can be replaced by a carbonyl group, NRa, O or S; Cy4 is selected from C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C3-C 12 Cycloalkyl and 4-12 membered heterocycloalkyl may be monocyclic, spirocyclic, bridged, or fused, and when Cy4 is C5-C6 cycloalkyl or 5-6 membered heterocycloalkyl, o≥1 and R8 is not hydrogen; L2 represents a single bond or -(C1-C6)alkylene-, wherein any methylene group on the -(C1-C6)alkylene- can be replaced by a carbonyl, NRa, O or S; R8 are each independently selected from: hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C1-C6 alkyl, wherein the C1-C6 alkyl may be substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, oxo, -ORa, -NRaRa', cyano; m, n, o, and p each independently represent 0, 1, or 2; Ra and Ra' each independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; The alkyl, cycloalkyl, heterocycloalkyl and alkylene groups may each independently be substituted by 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

50. The compound according to any preceding claim, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, having the structure represented by formula (III'): The definitions of R1, R2, R4, R6, R7, R8, Cya, Cy1, Cy2, Cy3, Cy4, L1, L2, m, n, o, and p are as described in claim 49.

51. The compound according to any one of claims 49 to 50, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cya said It may optionally be substituted by 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; preferably, Cya represents 52. The compound according to any one of claims 49-50, or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof, wherein: Cya said or It may optionally be substituted by 0, 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; preferably, Cya represents 53. The compound according to any one of claims 49 to 52, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R2 represents 1-methoxyethyl; preferably, R2 represents Wherein, * represents the position where R2 is connected to the portion to which it is connected in the general formula.

54. The compound according to any one of claims 49 to 53, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cy1 represents a C3-C8 cycloalkyl group; preferably, Cy1 represents a cyclopropyl group.

55. The compound according to any one of claims 49 to 54, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: express or Wherein, * indicates the site where Cy1 is connected to the site connected thereto in the general formula.

56. The compound according to any one of claims 49 to 55, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Selected from or Preferably, Selected from or 57. The compound according to any one of claims 49 to 56, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R6 is independently selected from hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl, and the above C1-C6 alkyl and C3-C8 cycloalkyl can be substituted by 0, 1 or 2 substituents selected from halogen, C1-C6 alkyl or C3-C6 cycloalkyl; more preferably, R6 is independently selected from hydrogen and methyl.

58. The compound according to any one of claims 49 to 57, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R7 is independently selected from hydrogen, halogen, oxo, hydroxy, cyano or C1-C6 alkyl.

59. The compound according to any one of claims 49 to 58, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: L1 represents a single bond, -CH2-, -O- or -NH-.

60. The compound according to any one of claims 49 to 59, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cy4 is a C5-C6 cycloalkyl group or a 5-6 membered heterocycloalkyl group, o≥1 and R8 is not hydrogen.

61. The compound according to any one of claims 49 to 60, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cy4 is selected from C3-C4 cycloalkyl or 4-membered heterocycloalkyl.

62. The compound according to any one of claims 49 to 61, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: L2 represents a single bond, -CH2- or -O-; preferably, L2 represents a single bond.

63. The compound according to any one of claims 49 to 62, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: R8 are each independently selected from hydrogen, halogen or C1-C6 alkyl.

64. The compound according to any one of claims 49 to 63, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Ra and Ra' each independently represent hydrogen or a C1-C6 alkyl group; preferably, Ra and Ra' each independently represent hydrogen or a C1-C3 alkyl group.

65. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, having the structure shown in formula (IV): in: Cya said or R1 represents ethyl or -CH2CF3; R4 each independently represents hydrogen, halogen or C1-C3 alkyl; Selected from or Cy3 is selected from 4-8 membered heterocycloalkyl; Cy4 is selected from C3-C4 cycloalkyl or 4-membered heterocycloalkyl; R6 are each independently selected from hydrogen, methyl; R7 are each independently selected from: hydrogen, halogen, oxo or C1-C6 alkyl; R8 are each independently selected from: hydrogen, halogen or C1-C6 alkyl; L1 represents a single bond, -CH2- or -O-; L2 represents a single bond, -CH2- or -O-; Wherein, n, o, and p each independently represent 0, 1, or 2; Ra and Ra' each independently represent hydrogen or C1-C6 alkyl; preferably, Ra and Ra' each independently represent hydrogen or C1-C3 alkyl; The alkyl, cycloalkyl, heterocycloalkyl and alkylene groups may each independently be substituted by 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

66. A compound according to any preceding claim, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, having the structure shown in formula (IV'): The definitions of R1, R4, R6, R7, R8, Cya, Cy2, Cy3, Cy4, L1, L2, m, n, o, and p are as described in claim 65.

67. The compound according to any one of claims 65-66, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: express or Wherein, * indicates the site where Cy1 is connected to the site connected thereto in the general formula.

68. The compound according to any one of claims 65 to 67, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cya said 69. The compound according to any one of claims 65 to 67, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Cya said 70. A compound having the following structure, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof:

71. A pharmaceutical composition comprising a compound according to any one of claims 1 to 70, or an isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

72. Use of a compound according to any one of claims 1 to 70, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 71 in the preparation of a medicament for preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

73. Use of a compound according to any one of claims 1 to 70, or its isotopic derivative, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 71 in preventing and / or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

74. A method for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 70, or its isotopic derivatives, stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 71.

75. The use of claim 72 or 73, or the method of claim 74, wherein The cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease is a RAS protein-related disease.

76. The use or method of claim 75, wherein The RAS protein is one or more of KRAS protein, NRAS protein or HRAS protein.

77. The use or method of claim 75 or 76, wherein The cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease comprises a RAS mutation.

78. The use or method of claim 77, wherein The RAS mutation includes one or more of KRAS mutation, NRAS mutation or HRAS mutation.

79. The use or method of claim 77 or 78, wherein The RAS mutation is located at position 12, 13 and / or 61.

80. The use or method of claim 77, 78 or 79, wherein The RAS mutation includes one or more of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G13D or NRAS Q61L.

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