Macrocyclic compound containing amide substitution

Abstract

This application relates to the technical field of medicines and relates to a macrocyclic compound containing an amide substitution, in particular to a compound shown in formula (I) or a pharmaceutically acceptable salt thereof, as well as to a method of preparation, a pharmaceutical composition containing the compound and its use in the treatment of diseases.

Description

Macrocyclic compounds containing amide substitution

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese patent application No. 202311693410.4 filed with the State Intellectual Property Office of China on December 8, 2023 and Chinese patent application No. 202400000000.0 filed with the State Intellectual Property Office of China on December 5, 2024, and the contents disclosed in said applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure belongs to the field of medical technology and relates to macrocyclic compounds containing amide substitutions, stereoisomers or pharmaceutically acceptable salts thereof, preparation methods thereof, pharmaceutical compositions containing the compounds, and uses thereof in treating diseases. Background Art

[0004] The discovery of small molecule inhibitors relies on the presence of suitable binding pockets on protein surfaces. Approximately 90% of proteins in the human body lack this functional binding pocket, making such targets generally considered undruggable and requiring innovative therapeutic targeting strategies. It has been reported that approximately 30% of human cancers are caused by mutations in Ras proteins (including K-Ras, H-Ras, and N-Ras). Ras proteins play a crucial role in various human cancers, making them suitable targets for anticancer therapies. Specifically, dysregulation of Ras proteins due to activating mutations, overexpression, or upstream activation can contribute to the growth and proliferation of human tumor cells. For example, KRAS, a small guanosine triphosphatase (GTPase), cycles between an inactive (guanosine diphosphate (GDP)-bound, OFF) state and an active (GTP-bound, ON) state. The active KRAS state binds to and activates a variety of effector proteins to regulate cell growth and proliferation. KRAS mutations stimulate excessive downstream signaling and proliferation, making it a key oncogenic driver closely associated with the development and progression of various human cancers. In addition, mutations at codons 13 (e.g., G13D) and 61 (e.g., Q61K) in Ras also cause oncogenic activity in some cancers. Currently, there are reports that drugs targeting the active state (ON) of RAS can inactivate oncogenic signals and lead to tumor regression in various human cancer models. However, no such drugs have been approved for marketing, and more efforts are needed in this field to discover drugs targeting various Ras mutation-driven cancers. Summary of the Invention

[0005] The present disclosure relates to compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof,

[0006] in,

[0007] Ring A is selected from C 6-10 aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclic group, the C 6-10 Aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclyl is optionally independently substituted by 1, 2 or 3 R a replace;

[0008] L is selected from -(CRR') q -、-NH-(CRR') q -、-O-(CRR') q -、-S-(CRR') q -、-(CRR') q -(CH=CH) i -、-NH-(CH=CH) i -、-O-(CH=CH) i -、-S-(CH=CH) i -、-(CRR') q -(C≡C) i -、-NH-(C≡C) i -、-O-(C≡C) i -or-S-(C≡C) i -;

[0009] R and R' are each independently selected from hydrogen, deuterium, halogen, -NH2, -OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 3-6 Cycloalkyl or 3-6 membered heterocyclic group is optionally substituted independently by one or more substituents selected from halogen, =O, -NH2, -OH, -SH or -CN; or, R and R' and the attached carbon atom together form C=O, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 3-6 Cycloalkyl or 3-6 membered heterocyclyl is optionally substituted independently with one or more substituents selected from halogen, =O, -NH2, -OH, -SH or -CN;

[0010] Ring B is selected from C 3-14 Cycloalkyl, C 3-14 Cycloalkenyl, 3-14 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl, the C 3-14 Cycloalkyl, C 3-14 Cycloalkenyl, 3-14 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl is optionally independently substituted by 1, 2 or 3 Rb replace;

[0011] R a and R b Each independently selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, the C 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 Alkenyl or C 2-12 Alkynyl is optionally substituted independently by one or more substituents selected from halogen, -NH2, -OH, -SH, -CN; said C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl or amino substituted C 1-6 Substitution of alkyl groups;

[0012] R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, C 4-14 Cycloalkenyl, 4-14 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted independently with one or more substituents selected from halogen, -NH2, -OH, -SH, -CN or -COOH; said C 3-14 Cycloalkyl, C 4-14 Cycloalkenyl, 4-14 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl are optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl or amino substituted C 1-6Substitution of alkyl groups;

[0013] Each R 2 Each independently selected from halogen, -NH2, -OH, -SH, -CN, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -NHS(O)2C 1-6 Alkyl, -S(O)2NHC 1-6 Alkyl, -S(O)2N(C 1-6 Alkyl)2, -P(O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, C 4-14 Cycloalkenyl, 4-14 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted independently by one or more substituents selected from halogen, -NH2, -OH, -SH, -CN, -COOH; said C 3-14 Cycloalkyl, C 4-14 Cycloalkenyl, 4-14 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl are optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl or amino substituted C 1-6 Substitution of alkyl groups;

[0014] X 1 and X 3 are each independently selected from CH or N;

[0015] X 2 Selected from CH2 or NH;

[0016] n is selected from 1, 2, 3 or 4;

[0017] m is selected from 0, 1, 2, 3 or 4;

[0018] i is selected from 1 or 2;

[0019] q is selected from 0, 1, 2 or 3;

[0020] R 3 Selected from hydrogen, halogen, -NH2, -OH, -SH, -CN, C 1-6 Alkyl or C 1-6 heteroalkyl, the C 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted independently with 1, 2, or 3 substituents selected from halogen, -NH2, -OH, -SH, or -CN.

[0021] In some embodiments, the compound of formula (I) satisfies the following conditions:

[0022] When the structural fragment Selected from and Ring A is selected from When R 1 is not optionally independently substituted with one or more substituents selected from halogen, -NH2, -OH, -SH, -CN, -COOH 1-6 Heteroalkyl and C 2-6 alkenyl; and R 1 is not methyl and -CH2CH(CH3)2; and R 1 is not optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl or amino substituted C 1-6 Alkyl substituents substituted C 3-14 Cycloalkyl, 4-14 membered saturated heterocyclic group, pyridyl, Where * indicates that the bond at this position is connected to L, and ** indicates that the bond at this position is connected to the structural fragment. are connected.

[0023] In some embodiments, the compound of formula (I) satisfies the following conditions:

[0024] When the structural fragment Selected from and Ring A is selected from When R 1 Not for C 3-5 Cycloalkyl or 6-membered heterocycloalkyl, the C 3-5 Cycloalkyl or 6-membered heterocycloalkyl is optionally substituted by 1 or 2 groups selected from CN, C 1-3 Alkyl, halogenated C1-3 Alkyl, or pyrimidinyl substituted; where * indicates that the bond at this position is connected to L, and ** indicates that the bond at this position is connected to a structural fragment are connected.

[0025] In some embodiments, Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclic group, the C 6-10 Aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclic group is optionally independently substituted by 1, 2 or 3 R a Substituted, wherein the R a The definition of is as described in this disclosure.

[0026] In some embodiments, Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl, the C 6-10 Aryl or 5-10 membered heteroaryl is optionally independently substituted by 1 or 2 R a Substituted, wherein the R a The definition of is as described in this disclosure.

[0027] In some embodiments, ring A is selected from phenyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl, wherein the phenyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl is optionally independently substituted by 1 or 2 R a Substituted, wherein the R a The definition of is as described in this disclosure.

[0028] In some embodiments, Ring A is selected from 5-6 membered heteroaryl or 9-10 membered heteroaryl, wherein the 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally independently substituted by 1 or 2 R a Substituted, wherein the R a The definition of is as described in this disclosure.

[0029] In some embodiments, Ring A is selected from 5-membered or 9-membered heteroaryl, which is optionally independently substituted by 1 or 2 R a Substituted, wherein the R a The definition of is as described in this disclosure.

[0030] In some embodiments, ring A is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl or indazolyl, and the ring A is optionally substituted by 1 or 2 R a Substituted, wherein the R a The definition of is as described in this disclosure.

[0031] In some embodiments, Ring A is selected from indolyl or pyrrolyl, which are optionally independently substituted with 1 or 2 R a Substituted, wherein the R a The definition of is as described in this disclosure.

[0032] In some embodiments, ring A is selected from phenyl, 5-6-membered or 9-10-membered heteroaryl, wherein the phenyl, 5-6-membered or 9-10-membered heteroaryl is optionally substituted independently by 1 or 2 groups selected from halogen, C 1-4 Alkyl, C 2-4 The alkynyl group is substituted with a substituent of -NH2, -OH, -SH or -CN.

[0033] In some embodiments, ring A is selected from phenyl, 5-6-membered or 9-10-membered heteroaryl, wherein the phenyl, 5-6-membered or 9-10-membered heteroaryl is optionally independently substituted by 1 or 2 C 1-3 Alkyl or C 2-4 Alkynyl substitution.

[0034] In some embodiments, Ring A is selected from 5-6 or 9-10 membered heteroaryl, wherein the 5-6 or 9-10 membered heteroaryl is optionally independently substituted by 1 or 2 C 1-3 Alkyl or C 2-4 Alkynyl substitution.

[0035] In some embodiments, Ring A is selected from 5-membered or 9-membered heteroaryl, which is optionally independently substituted with 1 or 2 C 1-3 Alkyl or C 2-4 Alkynyl substitution.

[0036] In some embodiments, ring A is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl or indazolyl, and the ring A is optionally substituted by 1 or 2 C 1-3 Alkyl or C 2-4 Alkynyl substitution.

[0037] In some embodiments, Ring A is selected from indolyl or pyrrolyl, said indolyl or pyrrolyl being substituted with 1 or 2 ethyl or ethynyl groups.

[0038] In some embodiments, Ring A is selected from indolyl substituted with 1 or 2 ethyl or ethynyl groups.

[0039] In some embodiments, Ring A is selected from Among them, * indicates that the bond at this position is connected to L, and ** indicates that the bond at this position is connected to the structural fragment. The ring A is optionally independently connected to one or two C1-3 Alkyl or C 2-4 Alkynyl substitution.

[0040] In some embodiments, Ring A is selected from Among them, * indicates that the bond at this position is connected to L, and ** indicates that the bond at this position is connected to the structural fragment. connected, the ring A is optionally independently substituted by 1 or 2 R a replace.

[0041] In some embodiments, Ring A is selected from Among them, * indicates that the bond at this position is connected to L, and ** indicates that the bond at this position is connected to the structural fragment. are connected.

[0042] In some embodiments, Ring A is selected from Among them, * indicates that the bond at this position is connected to L, and ** indicates that the bond at this position is connected to the structural fragment. are connected.

[0043] In some embodiments, L is selected from -(CRR') q -、-(CRR') q -(CH=CH) i -or-(CRR') q -(C≡C) i -, wherein R, R', q or i are as defined in the present disclosure.

[0044] In some embodiments, L is selected from -(CRR') q -or-(CRR') q -(CH=CH) i -, wherein R, R', q or i are as defined in the present disclosure.

[0045] In some embodiments, L is selected from a bond or -CH=CH-.

[0046] In some embodiments, L is a bond.

[0047] In some embodiments, L is -CH=CH-.

[0048] In some embodiments, R and R' are each independently selected from hydrogen, deuterium, halogen, -NH2, -OH, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alternatively, in some embodiments, R and R', together with the attached carbon atom, form C=O or cyclopropyl.

[0049] In some embodiments, R and R' are each independently selected from hydrogen, F, Cl, -NH2, -OH, or methyl.

[0050] In some embodiments, R and R' are each independently hydrogen.

[0051] In some embodiments, Ring B is selected from C 5-10 Cycloalkyl, C 5-10 Cycloalkenyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 5-10 Cycloalkyl, C 5-10 Cycloalkenyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R b Substituted, wherein the R b The definition of is as described in this disclosure.

[0052] In some embodiments, Ring B is selected from phenyl, 5-6-membered or 9-10-membered heteroaryl, wherein the phenyl, 5-6-membered or 9-10-membered heteroaryl is optionally independently substituted by 1 or 2 R b Substituted, wherein the R b The definition of is as described in this disclosure.

[0053] In some embodiments, Ring B is selected from phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally independently substituted by 1 or 2 R b Substituted, wherein the R b The definition of is as described in this disclosure.

[0054] In some embodiments, Ring B is selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted by 1 or 2 R b Substituted, wherein the R b The definition of is as described in this disclosure.

[0055] In some embodiments, ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl, and the ring B is optionally substituted by 1 or 2 R b Substituted, wherein the R b The definition of is as described in this disclosure.

[0056] In some embodiments, Ring B is thiazolyl, which is optionally substituted with 1 or 2 R b Substituted, wherein the R b The definition of is as described in this disclosure.

[0057] In some embodiments, Ring B is selected from C 5-10 Cycloalkyl, C5-10 Cycloalkenyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 5-10 Cycloalkyl, C 5-10 Cycloalkenyl, 5-10 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl is optionally substituted independently with 1 or 2 substituents selected from -F, -Cl, -NH2, -OH, -SH or -CN.

[0058] In some embodiments, Ring B is selected from phenyl, naphthyl, 5-6-membered or 9-10-membered heteroaryl, wherein the phenyl, naphthyl, 5-6-membered or 9-10-membered heteroaryl is optionally substituted independently with 1 or 2 substituents selected from -F, -Cl, -NH2, -OH, -SH, and -CN.

[0059] In some embodiments, Ring B is selected from phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted independently with 1 or 2 substituents selected from -F, -Cl, -NH2, -OH, -SH, -CN.

[0060] In some embodiments, Ring B is selected from phenyl or thiazolyl, said phenyl being optionally substituted with 1 -OH.

[0061] In some embodiments, Ring B is selected from phenyl or thiazolyl. In some embodiments, Ring B is selected from 5-6 membered heteroaryl. In some embodiments, Ring B is thiazolyl.

[0062] In some embodiments, Ring B is Wherein, * indicates that the bond at this position is connected to L, and the ring B is optionally substituted by one or two substituents selected from -F, -Cl, -NH2, -OH, -SH, and -CN.

[0063] In some embodiments, Ring B is Wherein, * indicates that the bond at this position is connected to L.

[0064] In some embodiments, R a and R b Each independently selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-8 Alkyl, C 1-8 Heteroalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, the C 1-8 Alkyl, C 1-8 Heteroalkyl, C 2-8 Alkenyl or C 2-8Alkynyl is optionally substituted independently by one or more substituents selected from halogen, -NH2, -OH, -SH, -CN; said C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-4 Alkyl, C 1-4 Heteroalkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Haloalkyl or amino substituted C 1-4 The alkyl group is substituted with a substituent.

[0065] In some embodiments, R a Selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, C 1-3 Heteroalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Heteroalkyl, C 2-4 Alkenyl or C 2-4 Alkynyl is optionally substituted independently with one or more substituents selected from halogen, -NH2, -OH, -SH or -CN; said C 3-6 Cycloalkyl or 3-6 membered heterocyclic group is optionally independently substituted by one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, C 1-3 Heteroalkyl or C 1-3 The substituents of the haloalkyl group are substituted.

[0066] In some embodiments, R a Selected from halogen, C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 2-4 Alkenyl or C 2-4 Alkynyl, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 2-4 Alkenyl or C 2-4 Alkynyl groups are optionally substituted independently with one or more halogens.

[0067] In some embodiments, R a Selected from F, Cl, C 1-3 Alkyl, -OC1-3 Alkyl, -NH(C 1-2 Alkyl), -N(C 1-2 Alkyl)2 or C 2-4 Alkynyl, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-2 Alkyl), -N(C 1-2 Alkyl)2 or C 2-4 Alkynyl groups are optionally substituted independently with one or more halogens.

[0068] In some embodiments, R a Selected from F, Cl, C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-2 Alkyl), -N(C 1-2 Alkyl)2 or C 2-4 Alkynyl.

[0069] In some embodiments, R a Selected from C 1-3 Alkyl or C 2-4 Alkynyl.

[0070] In some embodiments, R a Selected from ethyl or ethynyl.

[0071] In some embodiments, R b Selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups are optionally substituted independently with one or more substituents selected from halogen, -NH2, -OH, -SH or -CN.

[0072] In some embodiments, R b Selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-4 Alkyl or C 1-4 heteroalkyl, the C 1-4 Alkyl or C 1-4 Heteroalkyl is optionally substituted independently with one or more substituents selected from F, Cl, -NH2, -OH, -SH or -CN.

[0073] In some embodiments, R b Selected from halogen, =O, -NH2, -OH, -SH, -CN, C1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-2 alkyl) or -N(C 1-2 Alkyl) 2, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-2 alkyl) or -N(C 1-2 alkyl)2 are optionally substituted independently with 1, 2 or 3 F atoms.

[0074] In some embodiments, R b Selected from halogen, -NH2, -OH, -SH, -CN or C 1-3 alkyl.

[0075] In some embodiments, R b Selected from F, Cl or -OH.

[0076] In some embodiments, R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 5-10 Cycloalkenyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted independently with one or more substituents selected from halogen, -NH2, -OH, -SH, -CN or -COOH; said C 3-10 Cycloalkyl, C 5-10 Cycloalkenyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl are optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl or C 1-6 The substituents of the haloalkyl group are substituted.

[0077] In some embodiments, R 1 Selected from C 1-4 Alkyl, C 1-4 Heteroalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, C 5-8 Cycloalkenyl or 4-8 membered heterocyclic group, the C 1-4 Alkyl, C 1-4Heteroalkyl, C 2-4 Alkenyl or C 2-4 Alkynyl is optionally substituted independently with one or more substituents selected from halogen, -NH2, -OH, -SH, -CN or -COOH; said C 3-8 Cycloalkyl, C 5-8 Cycloalkenyl or 4-8 membered heterocyclic group is optionally independently substituted by one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl)2 is substituted with a substituent.

[0078] In some embodiments, R 1 Selected from C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, C 5-8 Cycloalkenyl or 5-8 membered heterocyclic group, the C 1-4 Alkyl or C 1-4 Heteroalkyl is optionally substituted independently with one or more substituents selected from halogen, -NH2, -OH, -SH or -CN; said C 3-6 Cycloalkyl, C 5-8 Cycloalkenyl, 5-8 membered heterocyclic group are optionally independently substituted by one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, C 1-3 The substituents are substituted with haloalkyl, -NH(CH3) or -N(CH3)2.

[0079] In some embodiments, R 1 Selected from C 1-4 Halogenated alkyl, C 1-4 Heteroalkyl, C 5-8 Cycloalkenyl or 5-8 membered partially unsaturated heterocyclic group, the C 1-4 Halogenated alkyl, C 1-4 Heteroalkyl is optionally substituted independently with one or more substituents selected from halogen, -NH2, -OH, -SH or -CN; said C 5-8 Cycloalkenyl or 5-8 membered partially unsaturated heterocyclic group is optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, C 1-3 The substituents are substituted with haloalkyl, -NH(CH3) or -N(CH3)2.

[0080] In some embodiments, R 1 Selected from C 5-8 Cycloalkenyl or 5-8 membered partially unsaturated heterocyclic group, the C 5-8 Cycloalkenyl or 5-8 membered partially unsaturated heterocyclic group is optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, C 1-3 The substituents are substituted with haloalkyl, -NH(CH3) or -N(CH3)2.

[0081] In some embodiments, R 1 Selected from C 3-6 Cycloalkyl, n is 1, the C 3-6 Cycloalkyl is optionally substituted by one or more alkyl radicals selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, C 1-3 In some embodiments, R 1 is selected from cyclopropyl, n is 1, and the cyclopropyl is optionally substituted by one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, C 1-3 The substituents are substituted with haloalkyl, -NH(CH3) or -N(CH3)2.

[0082] In some embodiments, R 1 Selected from C 3-6 Cycloalkyl, and Ring A is not The C 3-6 Cycloalkyl is optionally substituted by one or more alkyl radicals selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, C 1-3 Substituted by haloalkyl, -NH(CH3)2, or -N(CH3)2, where * indicates that the bond at this position is connected to L, and ** indicates that the bond at this position is connected to the structural fragment. connected, the R a The definition of is as described in this disclosure.

[0083] In some embodiments, R 1 is selected from cyclopropyl, and ring A is not The cyclopropyl group is optionally substituted by one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, C1-3 Substituted by haloalkyl, -NH(CH3)2, or -N(CH3)2, where * indicates that the bond at this position is connected to L, and ** indicates that the bond at this position is connected to the structural fragment. connected, the R a The definition of is as described in this disclosure.

[0084] In some embodiments, R 1 Selected from C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl or C 5-7 Cycloalkenyl, the C 3-6 Cycloalkyl or C 5-7 Cycloalkenyl is optionally substituted independently by 1 or 2 groups selected from halogen, -NH2, C 1-3 Alkyl or C 1-3 The substituents of the haloalkyl group are substituted.

[0085] In some embodiments, R 1 Selected from C 1-3 Haloalkyl or C 5-7 Cycloalkenyl, the C 5-7 Cycloalkenyl is optionally substituted by 1 or 2 groups selected from halogen, -NH2, C 1-3 Alkyl or C 1-3 The substituents of the haloalkyl group are substituted.

[0086] In some embodiments, R 1 Selected from C 5-7 Cycloalkenyl, the C 5-7 Cycloalkenyl is optionally substituted by 1 or 2 groups selected from halogen, -NH2, C 1-3 Alkyl or C 1-3 The substituents of the haloalkyl group are substituted.

[0087] In some embodiments, R 1 is selected from halomethyl, cyclopropyl, cyclohexenyl, cyclopentenyl or bicyclo[2.2.1]hept-2-enyl, wherein the cyclopropyl, cyclohexenyl, cyclopentenyl or bicyclo[2.2.1]hept-2-enyl is optionally substituted independently with 1 or 2 F, Cl, -NH2, CHF2 or methyl groups.

[0088] In some embodiments, R 1 is selected from cyclohexenyl, cyclopentenyl or bicyclo[2.2.1]hept-2-enyl, wherein the cyclohexenyl, cyclopentenyl or bicyclo[2.2.1]hept-2-enyl is optionally substituted independently with 1 or 2 F, Cl, -NH2, CHF2 or methyl groups.

[0089] In some embodiments, R 1is selected from cyclohexenyl, said cyclohexenyl being optionally substituted independently with 1 or 2 F, Cl, -NH2, CHF2 or methyl.

[0090] In some embodiments, R 1 Selected from halomethyl, described Optionally independently substituted by 1 or 2 selected from halogen, -NH2, C 1-3 Alkyl or C 1-3 The substituents of the haloalkyl group are substituted.

[0091] In some embodiments, R 1 Selected from described Optionally independently substituted by 1 or 2 selected from halogen, -NH2, C 1-3 Alkyl or C 1-3 The substituents of the haloalkyl group are substituted.

[0092] In some embodiments, R 1 Selected from halomethyl or described Optionally, 1 or 2 selected from halogen, -NH2, C 1-3 Alkyl or C 1-3 In some embodiments, R 1 Selected from described Optionally, 1 or 2 selected from halogen, -NH2, C 1-3 Alkyl or C 1-3 The substituents of the haloalkyl group are substituted.

[0093] In some embodiments, R 1 Selected from cyclopropyl, n is 1, the cyclopropyl is optionally substituted by one or more C 1-3 Haloalkyl substitution.

[0094] In some embodiments, R 1 is selected from cyclopropyl, and ring A is not The cyclopropyl group is optionally substituted by one or more C 1-3 Haloalkyl substitution, where * indicates that the bond at this position is connected to L, and ** indicates that the bond at this position is connected to a structural fragment are connected.

[0095] In some embodiments, R 1 Selected from halogenated C 1-3 alkyl.

[0096] In some embodiments, R 1 Selected from C 5-7 Cycloalkenyl, the C 5-7Cycloalkenyl is optionally substituted by 1 or 2 groups selected from halogen, -NH2, C 1-3 Alkyl, halogenated C 1-3 The substituent is substituted with an alkyl, -OH or CN substituent.

[0097] In some embodiments, R 1 Selected from C 3-5 Cycloalkyl, the C 3-5 Cycloalkyl is optionally substituted by 1 or 2 groups selected from halogen, -NH2, C 1-3 Alkyl, C 1-3 The substituent is substituted with a haloalkyl, -OH or CN substituent.

[0098] In some embodiments, R 1 Selected from halogenated C 1-3 Alkyl, C 5-7 Cycloalkenyl or C 3-5 Cycloalkyl, the C 5-7 Cycloalkenyl or C 3-5 The cycloalkyl group is optionally substituted with 1 or 2 substituents selected from halogen, methyl, -NH2 or -CHF2.

[0099] In some embodiments, R 1 is selected from methyl, cyclohexenyl, cyclopropyl, cyclopentenyl or bicyclo[2.2.1]hept-2-enyl, said methyl, cyclohexenyl, cyclopropyl, cyclopentenyl or bicyclo[2.2.1]hept-2-enyl, said methyl being optionally substituted with 1 or 2 F or Cl groups, said cyclohexenyl, cyclopropyl, cyclopentenyl or bicycloheptenyl being optionally substituted with 1 or 2 methyl, -NH2 or -CHF2 substituents.

[0100] In some embodiments, R 1 Selected from

[0101] In some embodiments, R 1 Selected from

[0102] In some embodiments, R 1 Selected from

[0103] In some embodiments, R 1 Selected from

[0104] In some embodiments, R 1 Selected from

[0105] In some embodiments, R 1 Selected from

[0106] In some embodiments, R 1 Selected from n is 1.

[0107] In some embodiments, R 1 Selected from And ring A is not Where * indicates that the bond at this position is connected to L, and ** indicates that the bond at this position is connected to the structural fragment. are connected.

[0108] In some embodiments, X 1 Selected from N, X 2 is selected from CH2 or NH, and X 3 is selected from CH or N.

[0109] In some embodiments, X 1 and X 3 is N, and X 2 is CH2 or NH.

[0110] In some embodiments, X 1 and X 3 is N, and X 2 For CH2.

[0111] In some embodiments, X 1 and X 3 is N, and X 2 For NH.

[0112] In some embodiments, n is selected from 1, 2, or 3.

[0113] In some embodiments, n is selected from 1 or 2.

[0114] In some embodiments, n is 1. In some embodiments, n is 2.

[0115] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from

[0116] In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, each R 2Each independently selected from halogen, -NH2, -OH, -SH, -CN, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -N(C 1-3 alkyl)C(O)(C 1-3 Alkyl), -NHS(O)2(C 1-3 alkyl), -S(O)2NH(C 1-3 alkyl), -S(O)2N(C 1-3 Alkyl)2, -P(O)(C 1-3 Alkyl)2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is optionally substituted independently by one or more substituents selected from halogen, -NH2, -OH, -SH, -CN, -COOH; said C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl are optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-4 Alkyl, C 1-4 Heteroalkyl or C 1-4 The substituents of the haloalkyl group are substituted.

[0117] In some embodiments, each R 2 Each independently selected from F, Cl, -NH2, -OH, -SH, -CN, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-8 Cycloalkyl, C 5-8 Cycloalkenyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the C 1-4 Alkyl or C 1-4 Heteroalkyl is optionally substituted independently with one or more substituents selected from halogen, -NH2, -OH, -SH, -CN, -COOH; said C 3-8 Cycloalkyl, C 5-8Cycloalkenyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl are optionally independently substituted with one or more halogen, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, C 1-3 Haloalkyl, -NH(C 1-2 alkyl) or -N(C 1-2 alkyl)2 substituted.

[0118] In some embodiments, each R 2 Each independently selected from C 3-8 Cycloalkyl, C 5-8 Cycloalkenyl or 5-8 membered heterocyclic group, the C 3-8 Cycloalkyl, C 5-8 Cycloalkenyl or 5-8 membered heterocyclic group are optionally independently substituted with one or more halogen, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, C 1-3 Substituted with haloalkyl, -NH(CH3) or -N(CH3)2.

[0119] In some embodiments, each R 2 Each independently selected from 5-8 membered heterocyclic groups, wherein the 5-8 membered heterocyclic groups are optionally substituted by one or more selected from halogen, -NH2, -OH, -SH, -CN, C 1-3 Alkyl or C 1-3 The substituents of the haloalkyl group are substituted.

[0120] In some embodiments, each R 2 Each is independently selected from a 5-6 membered heterocyclic group containing 1 or 2 N or O atoms, wherein the 5-6 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-3 Alkyl or C 1-3 The substituents of the haloalkyl group are substituted.

[0121] In some embodiments, each R 2 Each is independently selected from a 5-6 membered partially unsaturated heterocyclic group containing 1 or 2 nitrogen atoms, wherein the 5-6 membered partially unsaturated heterocyclic group is optionally substituted by 1 or 2 selected from F, Cl or C 1-3 The alkyl group is substituted with a substituent.

[0122] In some embodiments, each R 2 Each independently selected from 5-8 membered heterocycloalkyl, the 5-8 membered heterocycloalkyl being optionally substituted by one or more selected from halogen, C 1-3 Alkyl or C 1-3 The substituents of the haloalkyl group are substituted.

[0123] In some embodiments, each R 2 Each is independently selected from a 5-6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N or O, wherein the 5-6 membered heterocycloalkyl is optionally substituted by one or more halogens, C 1-3 Alkyl or C 1-3 The substituents of the haloalkyl group are substituted.

[0124] In some embodiments, each R 2 Each is independently selected from a 5-6 membered heterocycloalkyl containing 1 or 2 N atoms, wherein the 5-6 membered heterocycloalkyl is optionally substituted by 1 or 2 selected from F, Cl or C 1-3 The alkyl group is substituted with a substituent.

[0125] In some embodiments, each R 2 Each independently selected from piperazinyl, said piperazinyl being optionally substituted by C 1-3 Alkyl substitution.

[0126] In some embodiments, each R 2 are each independently selected from piperazinyl, said piperazinyl being optionally substituted with methyl.

[0127] In some embodiments, each R 2 Each independently selected from

[0128] In some embodiments, each R 2 Each independently

[0129] In some embodiments, m is selected from 0, 1 or 2.

[0130] In some embodiments, m is selected from 0 or 1.

[0131] In some embodiments, m is 0.

[0132] In some embodiments, m is 1.

[0133] In some embodiments, i is 1.

[0134] In some embodiments, q is selected from 0, 1 or 2.

[0135] In some embodiments, q is selected from 0 or 1. In some embodiments, q is 0.

[0136] In some embodiments, R 3 Selected from hydrogen, halogen, -NH2, -OH, -SH, -CN, C 1-4 Alkyl or C 1-4 heteroalkyl, the C 1-4 Alkyl or C1-4 Heteroalkyl is optionally substituted independently with 1, 2, or 3 substituents selected from halogen, -NH2, -OH, -SH, or -CN.

[0137] In some embodiments, R 3 Selected from F, Cl, -NH2, -OH, -CN, C 1-3 Alkyl or C 1-3 heteroalkyl, the C 1-3 Alkyl or C 1-3 Heteroalkyl groups are optionally substituted independently with 1 or 2 F atoms.

[0138] In some embodiments, R 3 Selected from C 1-3 In some embodiments, R 3 Selected from C3 heteroalkyl.

[0139] In some embodiments, R 3 Selected from C 1-3 Alkoxy-substituted C 1-3 alkyl.

[0140] In some embodiments, R 3 for In some embodiments, R 3 for

[0141] In some embodiments, the structural fragment Selected from

[0142] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) described in the present disclosure is selected from the hydrochloride salt of the compound of formula (I).

[0143] In some embodiments, the compound of formula (I) described in the present disclosure, its stereoisomer or pharmaceutically acceptable salt thereof is selected from the compound of formula (I-1), the compound of formula (I-1A), the compound of formula (I-2), the compound of formula (I-2A), the compound of formula (I-3), the compound of formula (I-3A), the compound of formula (I-4), the compound of formula (I-4A), the compound of formula (I-5) or the compound of formula (I-5A), its stereoisomer or pharmaceutically acceptable salt thereof,

[0144] wherein p is selected from 1, 2 or 3;

[0145] The X 2 、R 1 、R 2 、R a , m and n are as defined in this disclosure;

[0146] Each R c Each independently selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl or amino substituted C 1-6 alkyl.

[0147] In some embodiments, each R c Each independently selected from -NH2 or C 1-6 alkyl.

[0148] In some embodiments, each R c Each independently selected from -NH2 or C 1-3 alkyl.

[0149] In some embodiments, each R c Each is independently selected from -NH2 or methyl.

[0150] It is to be understood that any of the embodiments of the compounds of the present disclosure as described above and the descriptions herein with respect to a particular X in the compounds of the present disclosure as described above 1 、X 2 、X 3 , Ring A, L, Ring B, R 1 、R 2 、R 3 、R a 、R b 、R c Any specific substituents described for X, R, and R' can be independently combined with other embodiments of the present disclosure and / or substituents of compounds to form embodiments of the present disclosure not specifically described above. 1 、X 2 、X 3 , Ring A, L, Ring B, R 1 、R 2 、R 3 、R a 、R b 、R c Where a range of substituents is disclosed for R, R and R' substituents, it is understood that one or more substituents may be deleted from the range and the remaining substituent range is also considered an embodiment of the disclosure.

[0151] The present disclosure provides the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof,

[0152] In another aspect, the present disclosure provides a pharmaceutical composition comprising the above-mentioned compound of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0153] In another aspect, the present disclosure provides a method for treating a disease associated with Ras protein in a mammal, comprising administering a therapeutically effective amount of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0154] In another aspect, the present disclosure provides use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating diseases associated with Ras protein.

[0155] In another aspect, the present disclosure provides use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in treating diseases associated with Ras protein.

[0156] In another aspect, the present disclosure provides the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or pharmaceutical composition thereof for treating a disease associated with Ras protein. In some embodiments, the disease associated with Ras protein is selected from cancer.

[0157] Technical Effects

[0158] The disclosed compound has good AsPc-1 cell and Capan-1 cell proliferation inhibitory activity, stable in vitro liver microsome metabolism, good in vivo pharmacodynamics, and good pharmacokinetic properties.

[0159] definition

[0160] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0161] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0162] The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (-CH2CH3), monosubstituted (e.g., -CH2CH2F), polysubstituted (e.g., -CHFCH2F, -CH2CHF2, etc.), or fully substituted (-CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0163] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; "C 1-3 ” means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0164] As used herein, "one or more" refers to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" refers to one, two, three, four, five, or six; or, "one or more" refers to one, two, or three.

[0165] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0166] When a substituent's bond crosses between two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0167] In this application, the groups or structural parts such as -NH-(CRR') q -、-O-(CRR') q -、-S-(CRR') q -、-(CRR') q -(CH=CH) i -、-NH-(CH=CH) i -、-O-(CH=CH) i -、-S-(CH=CH) i -、-(CRR') q -(C≡C)i -、-NH-(C≡C) i -、-O-(C≡C) i -or-S-(C≡C) i - and its specific options, optionally in a reading order from left to right, are connected to the group or part of the left side group and the right side group in the general formula, such as -(CRR') q -(CH=CH) i -In the order of reading from left to right, -(CRR') q - is connected to the ring A on the left side of the general formula, -(CH=CH) i - is connected to the ring B on the right. Optionally, for example, the above groups or structural parts can also be read from right to left, specifically -(CRR') q -(CH=CH) i -, according to the reading order from right to left, -(CH=CH) i - connected to the left ring A, -(CRR') q - is connected to the ring B on the right side of the general formula.

[0168] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0169] The term "hydroxy" refers to an -OH group.

[0170] The term "amino" refers to a -NH2 group.

[0171] The term "nitro" refers to a -NO2 group.

[0172] The term "cyano" refers to a -CN group.

[0173] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.

[0174] The term "heteroalkyl" refers to a straight or branched chain alkyl group consisting of a certain number of carbon atoms and at least one backbone heteroatom or heteroatom group, preferably having 1 to 14 carbons, more preferably 1 to 10 carbons, further more preferably 1 to 6 carbons, and most preferably 1 to 3 carbons in the chain. The heteroatoms are preferably selected from S, O and N heteroatoms, and the number is preferably 1, 2 or 3, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom may also be optionally quaternized. The heteroatom group is preferably selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-. The numerical range (e.g., C 1-6 Heteroalkyl) refers to the number of carbons in the chain, in this case 1-6 carbon atoms. For example, a -CH2OCH2CH3 group is referred to as a C3 heteroalkyl. The heteroatom or heteroatom group may be located at any internal position of the heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule. In the heteroalkyl group, the portion directly attached to the parent structure may optionally be a carbon atom, a heteroatom or a heteroatom group. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, alkyl sulfides, tertiary amine alkyls or secondary aminoalkyls, including alkoxy, alkylthio, alkylamino; unless otherwise specified, C 1-6 Heteroalkyl groups include C1, C2, C3, C4, C5 and C6 heteroalkyl groups, such as C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino.

[0175] The term "alkoxy" refers to an -O-alkyl group.

[0176] The term "bicyclic" refers to a cyclic group containing two rings, which may be fully saturated, partially saturated or aromatic. The bicyclic ring may consist entirely of C atoms or may contain one or more heteroatoms selected from, for example, N, O, S or P. The bicyclic ring may be a fused ring, a bridged ring or a spiro ring.

[0177] The term "cycloalkyl" refers to a fully saturated carbocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring. Unless otherwise indicated, the cycloalkyl group may be monocyclic, bicyclic, or tricyclic. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

[0178] The term "heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially undersaturated (but not fully unsaturated heteroaromatic) and can exist as a monocycle, a bridged ring, and a ring or a spirocycle. Unless otherwise indicated, the heterocycle is typically 3 to 20 rings, 3 to 15 rings, 3 to 12 rings or 3 to 10 rings (such as 3, 4, 5, 6, 7, 8, 9 or 10 rings), 4 to 8 rings, 5 to 8 rings or 5 to 6 rings containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulphur, oxygen, nitrogen, phosphorus, silicon and / or boron. The limiting examples of heterocyclic radical include but are not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc.

[0179] The term "cycloalkenyl" refers to an incompletely saturated, non-aromatic carbocyclic ring that can exist as a monocycle, a bicyclic bridged ring or a spirocycle. Unless otherwise indicated, the carbocyclic ring is typically 4 to 16 rings, 4 to 12 rings, 4 to 10 rings or 4 to 8 rings (specifically, for example, 5, 6, 7, 8, 9, 10 or 11 rings). Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl etc.

[0180] The term "heterocyclenyl" includes cycloalkenyl groups in which one or more carbon atoms are replaced by heteroatoms, specifically cycloalkenyl groups in which up to 3 carbon atoms, up to 2 carbon atoms, in one embodiment 1 carbon atom is independently replaced by N, O or S (O), with the condition that at least one cycloalkenyl carbon-carbon double bond is retained. Heterocyclenyl can be a cyclic group existing with a monocycle, a bridged ring or a spirocycle, and can be a 3 to 16-membered ring (e.g., 3 to 12 members, 5 to 8-membered ring, specifically 5 members, 6 members, 7 members, 8 members, 9 members, 10 members or 11-membered ring). Examples of heterocyclenyl include, but are not limited to, dihydropyridyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazepine or azaspirooctene.

[0181] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. Unless otherwise indicated, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms or 6-10 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl and 1,2,3,4-tetrahydronaphthalene, etc., preferably phenyl. In some embodiments, the aryl group may be a phenyl group fused with a heterocyclic group or a cycloalkyl group to form two or more rings (e.g., 2, 3, 4 rings, etc.), and the ring directly connected to the parent structure in the aryl group is a benzene ring, and non-limiting examples include, but are not limited to wait.

[0182] The term "heteroaryl" refers to a monocyclic or polycyclic ring system containing at least one ring selected from N, O, S(O) n 、P(O) n (wherein n is 0, 1 or 2) ring atoms, the remaining ring atoms are C, and there is an aromatic ring of at least one heteroaromatic ring. Unless otherwise indicated, the heteroaryl can be a monocyclic, bicyclic or tricyclic radical. Unless otherwise indicated, the heteroaryl can have a single 5 to 8-membered ring, or comprise 6 to 14, especially multiple fused rings of 6 to 10 ring atoms. Non-limiting examples of heteroaryl include but are not limited to pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl etc. In some embodiments, the heteroaryl can be a 6-membered heteroaryl fused with a heterocyclic radical or a cycloalkyl to form 2 or more rings (such as 2, 3, 4 rings etc.), and the ring directly connected to the parent structure in the heteroaryl is a heteroaromatic ring, and non-limiting examples include but are not limited to wait.

[0183] Unless otherwise specified, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing these heteroatoms. For example, heteroatoms include, but are not limited to, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), and boron (B). Specific heteroatoms or heteroatom groups include: -O-, -S-, -N=, =O, =S, -P(=O)-, -P(=O)2-, -P(=O)O-, -P(=O)2O-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, and optionally substituted -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, or -S(=O)N(H)-. Preferably, the term "hetero" denotes a heteroatom or a heteroatom group (ie a group containing a heteroatom) wherein the heteroatom is selected from oxygen, nitrogen or sulfur.

[0184] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0185] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0186] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0187] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a specific disease, condition, or disorder described herein, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder described herein, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0188] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0189] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0190] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure, their stereoisomers, or salts thereof, and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0191] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0192] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0193] Unless otherwise specifically stated, singular terms encompass plural terms and plural terms encompass the singular. Unless otherwise specifically stated, the words "a" or "an" mean "at least one" or "at least one." Unless otherwise specified, the use of "or" means "and / or."

[0194] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0195] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0196] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicates the relative configuration of a stereocenter.

[0197] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomers are recovered. In addition, separation of enantiomers and diastereoisomers is typically accomplished using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., to form carbamates from amines).

[0198] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N.15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0199] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0200] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H or D)) substitution can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and complete deuterium substitution means that all hydrogens on the group are replaced by deuterium, for example, complete replacement of a methyl group (-CH3) by deuterium yields -CD3.

[0201] The compounds of the present disclosure may exist in their tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer can be an imidazole moiety, in which a proton can migrate between two ring nitrogens.

[0202] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0203] Typical routes of administration of the disclosed compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, topical, inhalation, parenteral, intranasal, intraocular, intramuscular, subcutaneous, and intravenous administration.

[0204] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0205] In all methods of administration of the compounds of (I) disclosed herein, the dosage administered per day is 0.001 to 2000 mg / kg body weight, in single or divided doses.

[0206] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the same with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0207] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0208] An important consideration in synthetic route planning in the art is the selection of a suitable protecting group for a reactive functional group (such as the amino group in the present disclosure). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc., all references cited in the present disclosure are hereby incorporated into the present disclosure in their entirety.

[0209] For the purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present disclosure. All statements regarding the dates of these documents or representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications are part of the common general knowledge in the art in any country.

[0210] This disclosure uses the following abbreviations:

[0211] PE represents petroleum ether; EA represents ethyl acetate; DCM represents dichloromethane; THF represents tetrahydrofuran; DMF represents N,N-dimethylformamide; TBDPSCl represents tert-butyldiphenylchlorosilane; DMAP represents 4-dimethylaminopyridine; dtbpy represents 4,4-di-tert-butylbipyridine; NIS represents N-iodosuccinimide; XantPhos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; t-BuOK represents potassium tert-butoxide; Pd(dppf)Cl2·CH2Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium dichloromethane complex; DIPEA represents N,N-diisopropylethylamine; HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HOAT represents N-hydroxy-7-azobenzotriazole; MeCN represents acetonitrile; Pd(dtbpf)Cl2 represents [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride; EDCI represents 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; Boc represents tert-butyloxycarbonyl; Cbz represents benzyloxycarbonyl; OAc represents acetoxy; and TFA represents trifluoroacetic acid. DETAILED DESCRIPTION

[0212] Intermediate Example 1-A: Preparation of Intermediate A

[0213] Step 1:

[0214] Compound A-0 (50 g) and imidazole (32 g) were dissolved in dichloromethane (1 L), cooled to 0°C, and TBDPSCl (120 mL) was added dropwise. The mixture was stirred at room temperature for reaction. After the reaction was complete, 2N hydrochloric acid (1.2 L) was added to the reaction solution to quench the mixture. The mixture was stirred and separated. The aqueous layer was extracted once with dichloromethane (1.2 L). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain compound A-1 (154 g).

[0215] Step 2:

[0216] Compound A-1 (154 g) was dissolved in toluene (500 mL), and dichlorothionyl (40 mL) and DMF (1-3 drops) were added. The mixture was stirred and reacted at 80°C. After the reaction was complete, the reaction solution was evaporated to dryness under reduced pressure to obtain a crude compound A-2 (162 g), which was used directly in the next step without purification.

[0217] Step 3:

[0218] The crude compound A-2 (162 g) obtained in the previous step was dissolved in dichloromethane (360 mL), cooled to 0 ° C in an ice bath, and a dichloromethane solution (400 mL) of anhydrous tin tetrachloride (117 g) was slowly added dropwise. After the addition was completed, stirring was continued at 0 ° C for 0.5 h, and then a dichloromethane solution (120 mL) of 5-bromoindole (75 g) was added dropwise. After stirring for 45 min in an ice-water bath, the mixture was transferred to room temperature and stirred for reaction. After the reaction was complete, the reaction solution was evaporated to dryness under reduced pressure, ethyl acetate (500 mL) was added and stirred to dissolve, saturated brine (300 mL * 3) was added and washed three times, the aqueous layers were combined, extracted twice with ethyl acetate (200 mL * 2), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and the crude product was slurried 3 times with PE: EA = 2: 1 (300 mL * 3) at room temperature, filtered, and evaporated to dryness to obtain compound A-3 (189 g).

[0219] Step 4:

[0220] Compound A-3 (189 g) was dissolved in THF (372 mL), stirred and cooled in an ice-water bath, and sodium borohydride (52.4 g) was added in 6 batches. After the addition, the reaction was stirred at 60-65 ° C. After the reaction was complete, methanol (200-300 mL) was added dropwise to the reaction solution to quench the reaction, and then water (200 mL) was added dropwise. The mixture was allowed to stand and filtered, and the filter cake was washed with EA (20 mL). The filtrate was concentrated under reduced pressure, EA (500 mL) was added, stirred and filtered to remove insoluble matter, and the organic layer was washed twice with saturated brine (150 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound A-4 (122 g). Step 5:

[0221] Compound A-4 (122 g) and triethylamine (179 mL) were dissolved in DCM (1 L). The mixture was cooled in an ice-water bath for 1 h, and acetic anhydride (66.1 g) was added. After the reaction for 1 h, DMAP (4.1 g) was added. After the reaction for 0.5 h, the ice bath was removed and the reaction was stirred at room temperature. After the reaction was complete, water (200 mL) was added to the reaction solution, the mixture was stirred and separated, and the resulting aqueous layer was extracted twice with DCM (100 mL * 2). The organic layers were combined and washed three times with saturated brine (200 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography to obtain compound A-5 (69 g).

[0222] Step 6:

[0223] Compound A-5 (10 g) was dissolved in THF (200 mL), and sodium bicarbonate (3.1 g), silver trifluoromethanesulfonate (9.5 g), and I2 (7.8 g) were added under ice bath conditions, and the reaction was stirred at 0°C. After the reaction was complete, purified water (100 mL) was added to the reaction solution to quench the reaction, and EA (300 mL*2) was added and extracted twice. The organic phases were combined and washed with sodium sulfite solution (200 mL) and sodium chloride solution (200 mL) in sequence, dried over anhydrous sodium sulfate, filtered, concentrated and sanded, and separated by silica gel column chromatography to obtain intermediate A (11.34 g). LC-MS: m / z: 449.9 (MH) - .

[0224] Intermediate Example 1-B: Preparation of a mixture of intermediates B and B-4

[0225] Step 1:

[0226] Compound B-0 (80g), bipyridyl borate (141g), dtbpy (14.9g), (1,5-cyclooctadiene) methoxyiridium (I) dimer (7.5g) were dissolved in THF (400mL), replaced with nitrogen three times, and stirred at 75°C for reaction. After the reaction was complete, the reaction solution was cooled to room temperature, and sodium carbonate (40g) and sodium hydroxide (10g) were added to water (600mL) to dissolve the solution and obtain an alkaline aqueous solution. Ethyl acetate (200mL) was added to the reaction solution, and the pH was adjusted to 10 with the prepared alkaline aqueous solution. The mixture was separated and the aqueous phase was retained. The aqueous phase was extracted once with ethyl acetate (800mL), the aqueous phase was cooled in an ice bath, and the pH was adjusted to 6 with a 6N dilute hydrochloric acid aqueous solution. The solid was precipitated and filtered to obtain compound B-1 (62g).

[0227] LC-MS: m / z: 260; 262.1 (M+H) + .

[0228] Step 2:

[0229] Compound B-1 (16.3 g) and NIS (35.27 g) were added to acetonitrile (300 mL) and stirred at 80°C. After the reaction was complete, the reaction solution was cooled to room temperature. The reaction solution was washed twice with saturated sodium thiosulfate aqueous solution (300 mL*2) and extracted twice with EA (200 mL*2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (eluent: PE:EA = 20:1) to obtain compound B-2 (12 g).

[0230] LC-MS:m / z:341.91; 343.92(M+H) + .

[0231] Step 3:

[0232] Compound B-2 (9.88 g), benzyl-1-piperazine carbonate (15.73 g), XantPhos (1.68 g), Pd2(dba)3 (530.74 mg), and t-BuOK (4.88 g) were dissolved in toluene (200 mL), replaced with argon three times, and stirred at 120 ° C. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove most of the toluene. Water (150 mL) was added to the residue, extracted with EA (200 mL * 2), washed with saturated brine (200 mL * 2), and the organic phase was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: PE: EA = 1:1) to obtain compound B-3 (9.9 g).

[0233] LC-MS: m / z:434.21; 436.19(M+H) + .

[0234] Step 4:

[0235] Compound B-3 (9.9 g), pinacol diboron (8.68 g), potassium acetate (5.59 g) and Pd(dppf)Cl2 . CH2Cl2 (1.86 g) was dissolved in toluene (120 mL), replaced with argon three times, and stirred at 90°C. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to remove most of the toluene. The mixture was then directly sanded and separated by neutral alumina column chromatography to obtain a mixture of intermediates B and B-4 (13.6 g).

[0236] Intermediate B-4: LC-MS: m / z: 400.29 (M+H) + .

[0237] Intermediate Example 1-C: Preparation of Intermediate C

[0238] Step 1:

[0239] Compound C-0 (27 g) and potassium carbonate (22.5 g) were dissolved in THF (400 mL). After stirring, a solution of iodomethane (12.7 g) in tetrahydrofuran (100 mL) was added dropwise. The mixture was stirred at room temperature and reacted. After the reaction was complete, the reaction solution was directly filtered, the filter cake was washed, and the filtrate was collected, concentrated, and separated by silica gel column chromatography to obtain compound C-1 (23 g).

[0240] Step 2:

[0241] Compound C-1 (23 g) was dissolved in dichloromethane (230 mL), trifluoroacetic acid (115 mL) was added, and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dry the solvent, and the residue was dried twice with toluene to obtain compound C-2 (25 g).

[0242] LC-MS: m / z: 145 (M+H) + .

[0243] Step 3:

[0244] Compound SZ (10 g) and lithium hydroxide monohydrate (366.45 mg) were dissolved in tetrahydrofuran (50 mL) and water (25 mL) and stirred at 40°C for reaction. After the reaction was complete, the mixture was concentrated under reduced pressure to remove THF, and DCM (100 mL) and water (50 mL) were added. The pH was adjusted to 5-6 with 2N dilute hydrochloric acid aqueous solution, and the mixture was extracted and separated. The aqueous phase was extracted again with DCM (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound C-3 (13.8 g).

[0245] Step 4:

[0246] DIPEA (20 g) was added to a solution of compound C-2 (21.94 g) in dichloromethane (50 mL), and the resulting mixture was set aside. Compound C-3 (13.8 g) was dissolved in DCM (200 mL), cooled in an ice bath, and the above mixture, HATU (19.33 g), HOAT (2.67 g) and DIPEA (30.79 g) were added and stirred at 0-5°C for reaction. After the reaction was complete, water (500 mL) and DCM (200 mL) were added and stirred to separate the liquids. The organic phase was washed with 10% brine (500 mL), dried, filtered, and concentrated. The residue was separated by column chromatography on silica gel (eluent: PE:EA = 2:1) to obtain intermediate C (16.2 g).

[0247] LC-MS: m / z: 477.1 (M+H) + .

[0248] Intermediate Example 1-D: Preparation of Intermediate D

[0249] Step 1:

[0250] A mixture of Intermediates B and B-4 (8.38 g), Intermediate A (6.3 g), K2CO3 (3.86 g), and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (2.53 g) were dissolved in a mixture of toluene, 1,4-dioxane, and water (v / v / v = 3 / 1 / 1, 250 mL total). The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 70°C for reaction. After the reaction was complete, the reaction mixture was extracted twice with water (150 mL) and ethyl acetate (150 mL x 2). The organic phase was washed once with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (eluent: PE:EA = 1:2) to obtain compound D-1 (5.28 g).

[0251] LC-MS: m / z: 677.2 (M+H) + .

[0252] Step 2:

[0253] Compound D-1 (5.28 g) was added to DMF (50 mL) and stirred to dissolve. Cesium carbonate (7.61 g) was added, and the mixture was cooled to 5°C in an ice bath. Ethyl iodide (2.42 g) was added dropwise, and the mixture was stirred at 40°C to react. After the reaction was complete, water (125 mL) and EA (150 mL) were added for extraction. The organic phase was washed with 10% brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product D-2 (7 g).

[0254] LC-MS: m / z: 705.3 (M+H) + .

[0255] Step 3:

[0256] The crude product D-2 (7 g) obtained in the previous step was dissolved in methanol (50 mL), and LiOH (1.36 g) and K₃PO₄ (2.1 g) were added. The reaction was stirred at 40°C. After the reaction was complete, the presence of atropisomers was monitored under LC / MS conditions (column: Waters ACQUITY CSH C18; mobile phase A: 0.1% formic acid (FA) / H₂O; mobile phase B: MeCN; gradient elution (0-7 min, 15%-95%-5%-15%)). The retention times of the leading and trailing peaks were 4.23 and 4.40 min, respectively. The reaction mixture was cooled to room temperature and directly sanded and separated by silica gel column chromatography (eluent: PE:EA = 1:2) to afford the two atropisomers of D-3: the leading peak, compound D-3B (2.37 g), and the trailing peak, compound D-3A (2.53 g).

[0257] LC-MS: m / z: 663.4 (M+H) + .

[0258] Step 4:

[0259] Compound D-3A (2.5 g), pinacol diboronate (1.43 g), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (408.9 mg), and potassium acetate (736.96 mg) were dissolved in toluene (50 mL), replaced with nitrogen three times, and stirred at 90°C for reaction. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated, and separated by silica gel column chromatography (eluent: PE:EA = 1:1.5) to obtain 2.18 g of compound D-4A.

[0260] LC-MS: m / z 711.5 (M+H) + .

[0261] Step 5:

[0262] Compound D-4A (1.5 g), intermediate C (875.84 mg), Pd (dtbpf) Cl2 (137.51 mg) 、 K3PO4 (1.11 g) was dissolved in 25 mL of a mixed solvent of toluene / dioxane / water (v / v / v = 3 / 1 / 1), the atmosphere was replaced with nitrogen three times, and the mixture was stirred at 70°C. After the reaction was complete, the reaction solution was cooled, concentrated, and sanded. Compound D-5A (1.67 g) was isolated by silica gel column chromatography (eluent: PE:EA = 1:10) to obtain compound D-5A.

[0263] LC-MS: m / z 981.64 (M+H) + .

[0264] Step 6:

[0265] Compound D-5A (1.25 g) and LiOH (175.72 mg) were dissolved in 17.5 mL of a mixed solvent of THF and H2O (v / v = 2 / 1) and stirred at 35°C. After the reaction was complete, 80 mL each of water and DCM were added to the system. The pH of the system was adjusted to 5-6 with 2N dilute hydrochloric acid aqueous solution, and the mixture was separated by extraction. The aqueous phase was further extracted with DCM (80 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product D-6A (1.3 g), which was used directly in the next step.

[0266] LC-MS: m / z 967.9 (M+H) + .

[0267] Step 7:

[0268] Dissolve crude D-6A (1.3 g) in DCM (150 mL), add EDCI (7.72 g), DIPEA (4.91 g), and HOBT (185 mg), and stir at room temperature. Once the reaction is complete, add water (300 mL) and DCM (200 mL), extract and wash, and the organic phase is washed with water (300 mL) and saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product is purified by silica gel column chromatography (eluent: DCM:MeOH = 50:1) to afford compound D-7A (350 mg).

[0269] LC-MS: m / z 949.8 (M+H) + .

[0270] Step 8:

[0271] Compound D-7A (350 mg) was dissolved in methanol (10 mL), and 10% Pd / C (100 mg) was added. The atmosphere was initially purged with nitrogen and then replaced three times with a hydrogen balloon. The reaction mixture was stirred at 50°C. After the reaction was complete, the reaction mixture was cooled, filtered to remove the Pd / C powder, and the filtrate was concentrated under reduced pressure to obtain crude product D-8A, which was used directly in the next step.

[0272] LC-MS: m / z 815.4 (M+H) + .

[0273] Step 9:

[0274] The crude product D-8A obtained in the previous step was dissolved in methanol (15 mL), 2 drops of acetic acid were added, and the mixture was cooled in an ice bath. 37% aqueous formaldehyde solution (107.76 mg) was added dropwise, followed by sodium cyanoborohydride (68.27 mg), and the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and water (50 mL) and DCM (80 mL) were added for extraction. The organic phase was then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to dryness to obtain crude product D-9A (336 mg).

[0275] LC-MS: m / z 829.4 (M+H) + .

[0276] Step 10:

[0277] Dissolve the crude product D-9A (336 mg) obtained in the previous step in 1,4-dioxane (5 mL), cool to 5°C in an ice bath, and add a 4M 1,4-dioxane solution of hydrochloric acid (2 mL) dropwise. Stir the mixture at room temperature until the reaction is complete. After the reaction is complete, evaporate the solvent under reduced pressure to obtain Intermediate D (356 mg).

[0278] LC-MS: m / z 729.4 (M+H) + .

[0279] Example 1: Preparation of Compound 1

[0280] Step 1:

[0281] Intermediate D (100 mg) was dissolved in DMF (10 mL), and (R)-2-chloro-2-fluoroacetic acid (18.51 mg), DIPEA (88.59 mg), and HATU (78.18 mg) were added. The reaction was stirred at room temperature. After the reaction was complete, purified water (50 mL) and DCM (40 mL x 2) were added and extracted twice. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative liquid chromatography (first step: YMC AQ C18 column, mobile phase A: 0.05% acetic acid / water, mobile phase B: acetonitrile, gradient: 10% B-50% B (0-60 min); second step: mobile phase A: 20 mM ammonium acetate, mobile phase B: methanol, gradient: 30% B-90% B (0-60 min); third step: mobile phase A: purified water, mobile phase B: acetonitrile, gradient: 10% B-10%-90%-90% B (0-20-21-60 min)) to give compound 1 (33 mg).

[0282] LC-MS: m / z 823.6 (M+H) + .

[0283] Example 2: Preparation of Compound 2

[0284] Step 1:

[0285] Intermediate D (100 mg) was dissolved in DMF (10 mL), and 4-methyl-3-cyclohexene-1-carboxylic acid (23.06 mg), DIPEA (88.59 mg), and HATU (78.18 mg) were added. The reaction was stirred at room temperature. After the reaction was complete, purified water (50 mL) and DCM (40 mL*2) were added and extracted twice. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative liquid chromatography (YMC AQ C18 column, mobile phase A: 0.05% acetic acid aqueous solution, mobile phase B: acetonitrile, gradient: 20% B-60% B, 0-60 min) to obtain compound 2 (65 mg).

[0286] LC-MS: m / z 851.5 (M+H) + .

[0287] Example 3: Preparation of Compounds 3-A and 3-B

[0288] Step 1:

[0289] Intermediate D (100 mg) was dissolved in DMF (10 mL), and Boc-(+ / -)-trans-2-amino-4-cyclohexene-1-carboxylic acid (CAS No.: 865689-24-3) (39.69 mg), DIPEA (88.59 mg), and HATU (78.18 mg) were added. The reaction was stirred at room temperature. After the reaction was complete, purified water (50 mL) was added and extracted twice with DCM (40 mL*2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product of compound 3-1 (190 mg).

[0290] LC-MS: m / z 952.5 (M+H) + .

[0291] Step 2:

[0292] The crude compound 3-1 (190 mg) obtained in the previous step was dissolved in 1,4-dioxane (5 mL), and a 4M hydrochloric acid solution in 1,4-dioxane (2 mL) was added and stirred at room temperature for reaction. After the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product was purified by preparative liquid chromatography (YMC AQ C18 column, mobile phase A: 0.05% acetic acid aqueous solution, mobile phase B: acetonitrile, gradient: 10% B-40% B, 0-60 min) to obtain compound 3-B (47 mg) with a retention time of 30 min and compound 3-A (40 mg) with a retention time of 36 min.

[0293] Compound 3-A LC-MS: m / z: 852.51 (M+H) + ;

[0294] Compound 3-B LC-MS: m / z: 852.48 (M+H) + .

[0295] Examples 4-A and 4-B

[0296] Step 1:

[0297] Intermediate D (48 mg, containing a mixture of atropisomers) was dissolved in DMF (10 mL). (1S,4R)-4-(Boc-amino)-2-cyclopentenoic acid (17.03 mg), DIPEA (74.45 mg), and HATU (28.36 mg) were added and stirred at room temperature. The reaction was complete. Purified water (30 mL) was added, and the mixture was extracted twice with EA (40 mL x 2). The mixture was washed twice with brine, dried over anhydrous sodium sulfate for 2 h, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain crude compound 4-1 (68 mg).

[0298] Step 2:

[0299] Crude compound 4-1 (68 mg) was added to 1,4-dioxane (5 mL), followed by a 4M HCl solution in 1,4-dioxane (1 mL), and the mixture was stirred at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to yield 82 mg of crude product. Purification was performed using a preparative chromatography column: YMC AQ C18, 50 x 250 mm, 10 μm; mobile phase: A: 0.1% formic acid in water, B: methanol; gradient: 10% to 80% B (0-60 min). λ: 254 nm, V: 60 mL / min. Compound 4-A (6 mg) as the hydrochloride salt was isolated at RT 32.7 min, and compound 4-B (14 mg) as the hydrochloride salt was isolated at RT 38.6 min.

[0300] Compound 4-A LC-MS: m / z=838.86 [M+H] + .

[0301] Compound 4-B LC-MS: m / z=838.88 [M+H] + .

[0302] Test Example 1 AsPc-1 cell proliferation inhibitory activity assay

[0303] Take AsPc-1 cells that are in good growth state, collect them into a centrifuge tube, and adjust the cell density to 3×10 4 Cells were inoculated at 100 μL / well in a 96-well plate. Compounds were added using a nanoliter pipette to a final concentration of 5000 nM to 0.31 nM in duplicate wells. A control was also set up. After 72 hours of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 3 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 The experimental results are shown in Table 1. Where A represents IC 50 <100nM; B means 100nM≤IC50 <500nM.

[0304] Test Example 2 Capan-1 cell proliferation inhibitory activity assay

[0305] Take Capan-1 cells that are in good growth condition, collect them into a centrifuge tube, and adjust the cell density to 1.5×10 4 Cells were plated at 100 μL / mL in a 96-well plate (100 μL / well). Compounds were added using a nanoliter pipette to a final concentration of 20,000 nM to 9.1 nM in duplicate wells. A control was also set up. After 5 days of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 4 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 The experimental results are shown in Table 1. Where A represents IC 50 <100nM; B means 100nM≤IC 50 <500nM.

[0306] Table 1 Cell proliferation inhibition test results of each compound

[0307] The test results show that the disclosed compounds have good proliferation inhibition activity on AsPc-1 cells and Capan-1 cells.

[0308] Test Example 3 In vitro liver microsome stability

[0309] Liver microsomal incubation samples (species: human and mouse) were prepared by mixing PBS buffer (pH = 7.4), liver microsomal solution (0.5 mg / mL), test compound, and NADPH + MgCl₂ solution at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH = 7.4), liver microsomal solution (0.5 mg / mL), and test compound. The sample was added to an acetonitrile solution containing an internal standard for protein precipitation, and the supernatant was prepared and diluted for LC / MS / MS analysis. The test results are shown in Table 2.

[0310] Table 2 In vitro liver microsome metabolic stability results

[0311] The experimental results show that the compounds disclosed herein are stable in liver microsome metabolism in vitro.

Claims

1. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, Ring A is selected from C 6-10 aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclic group, the C 6-10 Aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclyl is optionally independently substituted by 1, 2 or 3 R a replace; L is selected from -(CRR') q -, -NH-(CRR') q -, -O-(CRR') q -, -S-(CRR') q -, -(CRR') q -(CH=CH) i -, -NH-(CH=CH) i -, -O-(CH=CH) i -, -S-(CH=CH) i -, -(CRR') q -(C≡C) i -, -NH-(C≡C) i -, -O-(C≡C) i - or -S-(C≡C) i -; R and R' are each independently selected from hydrogen, deuterium, halogen, -NH2, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 3-6 Cycloalkyl or 3-6 membered heterocyclic group is optionally substituted independently by one or more substituents selected from halogen, =O, -NH2, -OH, -SH or -CN; or, R and R' and the attached carbon atom together form C=O, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 3-6 Cycloalkyl or 3-6 membered heterocyclyl is optionally substituted independently by one or more substituents selected from halogen, =O, -NH2, -OH, -SH or -CN; Ring B is selected from C 3-14 Cycloalkyl, C 3-14 Cycloalkenyl, 3-14 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl, the C 3-14 Cycloalkyl, C 3-14 Cycloalkenyl, 3-14 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R b replace; R a and R b Each is independently selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, the C 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 Alkenyl or C 2-12 Alkynyl is optionally substituted independently by one or more substituents selected from halogen, -NH2, -OH, -SH, -CN; 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl or amino substituted C 1-6 Substitution of alkyl groups; R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, C 4-14 Cycloalkenyl, 4-14 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted independently by one or more substituents selected from halogen, -NH2, -OH, -SH, -CN or -COOH; 3-14 Cycloalkyl, C 4-14 Cycloalkenyl, 4-14 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl is optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl or amino substituted C 1-6 Substitution of alkyl groups; Each R 2 Each independently selected from halogen, -NH2, -OH, -SH, -CN, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -N(C 1-6 Alkyl)C(O)C 1-6 Alkyl, -NHS(O)2C 1-6 Alkyl, -S(O)2NHC 1-6 Alkyl, -S(O)2N(C 1-6 Alkyl)2, -P(O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, C 4-14 Cycloalkenyl, 4-14 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted independently by one or more substituents selected from halogen, -NH2, -OH, -SH, -CN, -COOH; 3-14 Cycloalkyl, C 4-14 Cycloalkenyl, 4-14 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl is optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl or amino substituted C 1-6 Substitution of alkyl groups; X 1 and X 3 are each independently selected from CH or N; X 2 Selected from CH2 or NH; n is selected from 1, 2, 3 or 4; m is selected from 0, 1, 2, 3 or 4; i is selected from 1 or 2; q is selected from 0, 1, 2 or 3; R 3 Selected from hydrogen, halogen, -NH2, -OH, -SH, -CN, C 1-6 Alkyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted independently with 1, 2 or 3 substituents selected from halogen, -NH2, -OH, -SH or -CN.

2. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclic group, the C 6-10 Aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl is optionally independently substituted by 1, 2 or 3 R a replace; Alternatively, ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl, the C 6-10 Aryl or 5-10 membered heteroaryl is optionally independently substituted by 1 or 2 R a replace; Alternatively, Ring A is selected from phenyl, 5-6-membered heteroaryl or 9-10-membered heteroaryl, wherein the phenyl, 5-6-membered heteroaryl or 9-10-membered heteroaryl is optionally independently substituted by 1 or 2 R a replace; Alternatively, ring A is selected from phenyl, 5-6-membered or 9-10-membered heteroaryl, wherein the phenyl, 5-6-membered or 9-10-membered heteroaryl is optionally independently substituted by 1 or 2 selected from halogen, C 1-4 Alkyl, C 2-4 Alkynyl, -NH2, -OH, -SH or -CN substituent substitution; Alternatively, ring A is selected from indolyl or pyrrolyl, and the indolyl or pyrrolyl is substituted by 1 or 2 ethyl or ethynyl groups.

3. The compound of formula (I) according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: L is selected from -(CRR') q -、-(CRR') q -(CH=CH) i -or-(CRR') q -(C≡C) i -; Alternatively, L is selected from -(CRR') q -or-(CRR') q -(CH=CH) i -; Alternatively, L is selected from a bond or -CH=CH-; Optionally, q is selected from 0, 1 or 2; or, q is selected from 0 or 1; or, q is selected from 0; Optionally, i is selected from 1.

4. The compound of formula (I) according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R and R' are each independently selected from hydrogen, deuterium, halogen, -NH2, -OH, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 heteroalkyl; or, R and R' and the attached carbon atom together form C=O or cyclopropyl; Alternatively, R and R' are each independently selected from hydrogen, F, Cl, -NH2, -OH or methyl; Alternatively, R and R' are each independently hydrogen.

5. The compound of formula (I) according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from C 5-10 Cycloalkyl, C 5-10 Cycloalkenyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 5-10 Cycloalkyl, C 5-10 Cycloalkenyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R b replace; Alternatively, Ring B is selected from phenyl, 5-6-membered or 9-10-membered heteroaryl, wherein the phenyl, 5-6-membered or 9-10-membered heteroaryl is optionally independently substituted by 1 or 2 R b replace; Alternatively, Ring B is selected from phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally independently substituted by 1 or 2 R b replace; Alternatively, ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, and the ring B is optionally substituted by 1 or 2 R b replace; Alternatively, Ring B is selected from phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted independently by 1 or 2 substituents selected from -F, -Cl, -NH2, -OH, -SH, -CN; Alternatively, ring B is selected from phenyl or thiazolyl, wherein the phenyl is optionally substituted with 1 -OH; Alternatively, ring B is Among them, * indicates that the bond at this position is connected to L.

6. The compound of formula (I) according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R a and R b Each is independently selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-8 Alkyl, C 1-8 Heteroalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, the C 1-8 Alkyl, C 1-8 Heteroalkyl, C 2-8 Alkenyl or C 2-8 Alkynyl is optionally substituted independently by one or more substituents selected from halogen, -NH2, -OH, -SH, -CN; 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-4 Alkyl, C 1-4 Heteroalkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Haloalkyl or amino substituted C 1-4 Substitution of alkyl groups; Or, optionally, R a Selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, C 1-3 Heteroalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Heteroalkyl, C 2-4 Alkenyl or C 2-4 Alkynyl is optionally substituted independently by one or more substituents selected from halogen, -NH2, -OH, -SH or -CN; 3-6 Cycloalkyl or 3-6 membered heterocyclic group is optionally independently substituted by one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, C 1-3 Heteroalkyl or C 1-3 Substitution of haloalkyl groups; Or, R a Selected from F, Cl, C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-2 Alkyl), -N(C 1-2 Alkyl)2 or C 2-4 Alkynyl, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C 1-2 Alkyl), -N(C 1-2 Alkyl)2 or C 2-4 Alkynyl is optionally substituted independently with one or more halogens; Or, R a is selected from ethyl or ethynyl; Or, optionally, R b Selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is optionally substituted independently with one or more substituents selected from halogen, -NH2, -OH, -SH or -CN; Or, R b is selected from halogen, -NH2, -OH, -SH, -CN or C 1-3 alkyl.

7. A compound of formula (I) according to any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 5-10 Cycloalkenyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted independently by one or more substituents selected from halogen, -NH2, -OH, -SH, -CN or -COOH; 3-10 Cycloalkyl, C 5-10 Cycloalkenyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl or C 1-6 Substitution of haloalkyl groups; Or, R 1 Selected from C 3-6 Cycloalkyl, n is 1, the C 3-6 The cycloalkyl group is optionally substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, C 1-3 Substitution with haloalkyl, -NH(CH3) or -N(CH3)2; Or, R 1 Selected from C 3-6 Cycloalkyl, and Ring A is not The C 3-6 The cycloalkyl group is optionally substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, C 1-3 The substituents are substituted by haloalkyl, -NH(CH3)2, where * indicates that the bond at this position is connected to L, and ** indicates that the bond at this position is connected to the structural fragment. Connected; Or, R 1 Selected from C 5-8 Cycloalkenyl or 5-8 membered partially unsaturated heterocyclic group, the C 5-8 Cycloalkenyl or 5-8 membered partially unsaturated heterocyclic group is optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, C 1-3 Substitution with haloalkyl, -NH(CH3) or -N(CH3)2; Or, R 1 is selected from cyclohexenyl, cyclopentenyl or bicyclo[2.2.1]hept-2-enyl, wherein the cyclohexenyl, cyclopentenyl or bicyclo[2.2.1]hept-2-enyl is optionally substituted independently with 1 or 2 F, Cl, -NH2, CHF2 or methyl; Or, R 1 Selected from C 1-3 Haloalkyl or C 5-7 Cycloalkenyl, the C 5-7 Cycloalkenyl is optionally substituted by 1 or 2 radicals selected from halogen, -NH2, C 1-3 Alkyl or C 1-3 Substitution of haloalkyl groups; Or, R 1 Selected from halomethyl, Said Optionally independently substituted by 1 or 2 selected from halogen, -NH2, C 1-3 Alkyl or C 1-3 Substitution of haloalkyl groups; Or, R 1 Selected from Or, R 1 Selected from 8. The compound of formula (I) according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R 2 Each is independently selected from halogen, -NH2, -OH, -SH, -CN, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -N(C 1-3 alkyl)C(O)(C 1-3 Alkyl), -NHS(O)2(C 1-3 alkyl), -S(O)2NH(C 1-3 alkyl), -S(O)2N(C 1-3 Alkyl)2, -P(O)(C 1-3 Alkyl)2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is optionally substituted independently by one or more substituents selected from halogen, -NH2, -OH, -SH, -CN, -COOH; 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-4 Alkyl, C 1-4 Heteroalkyl or C 1-4 Substitution of haloalkyl groups; Or, each R 2 Each independently selected from C 3-8 Cycloalkyl, C 5-8 Cycloalkenyl or 5-8 membered heterocyclic group, the C 3-8 Cycloalkyl, C 5-8 Cycloalkenyl or 5-8 membered heterocyclic group is optionally independently substituted with one or more halogen, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, C 1-3 Substituted with haloalkyl, -NH(CH3) or -N(CH3)2; Or, each R 2 Each is independently selected from a 5-6 membered heterocyclic group containing 1 or 2 N or O atoms, wherein the 5-6 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-3 Alkyl or C 1-3 Substitution of haloalkyl groups; Or, each R 2 Each independently selected from 5-8 membered heterocycloalkyl, the 5-8 membered heterocycloalkyl is optionally substituted by one or more selected from halogen, C 1-3 Alkyl or C 1-3 Substitution of haloalkyl groups; Or, each R 2 are each independently selected from a 5-6 membered heterocycloalkyl group containing 1 or 2 N atoms, the 5-6 membered heterocycloalkyl group being optionally substituted by 1 or 2 groups selected from F, Cl or C 1-3 Substitution of alkyl groups; Or, each R 2 are each independently selected from piperazinyl, said piperazinyl being optionally substituted with methyl; Or, each R 2 Each independently selected from Optionally, m is selected from 0, 1 or 2; Alternatively, m is selected from 0 or 1; alternatively, m is selected from 0; alternatively, m is selected from 1.

9. The compound of formula (I) according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: X 1 Selected from N, X 2 is selected from CH2 or NH, and X 3 is selected from CH or N; Or, X 1 and X 3 Select from N, and X 2 Selected from CH2 or NH; Or, X 1 and X 3 Select from N, and X 2 Selected from CH2; Or, X 1 and X 3 Select from N, and X 2 Selected from NH; Optionally, n is selected from 1, 2 or 3; Alternatively, n is selected from 1 or 2; Alternatively, n is selected from 1; or, n is selected from 2.

10. The compound of formula (I) according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 3 Selected from hydrogen, halogen, -NH2, -OH, -SH, -CN, C 1-4 Alkyl or C 1-4 Heteroalkyl, the C 1-4 Alkyl or C 1-4 Heteroalkyl is optionally substituted independently with 1, 2 or 3 substituents selected from halogen, -NH2, -OH, -SH or -CN; Or, R 3 Selected from C 1-3 heteroalkyl; Or, R 3 Selected from F, Cl, -NH2, -OH, -CN, C 1-3 Alkyl or C 1-3 Heteroalkyl, the C 1-3 Alkyl or C 1-3 Heteroalkyl is optionally substituted independently with 1 or 2 F atoms; Or, R 3 Selected from 11. A compound of formula (I) according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from the following compounds of formula (I-1), formula (I-1A), formula (I-2), formula (I-2A), formula (I-3), formula (I-3A), formula (I-4), formula (I-4A), formula (I-5), or formula (I-5A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, p is selected from 1, 2 or 3; each R c Each is independently selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl or amino substituted C 1-6 alkyl.

12. The following compound, its stereoisomer or its pharmaceutically acceptable salt:

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, its stereoisomer or a pharmaceutically acceptable salt thereof.

14. Use of the compound according to any one of claims 1 to 12, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating a disease associated with Ras protein; optionally, the disease associated with Ras protein is selected from cancer.