WO2025119392A1 - Macrocyclic compound containing amide substitution - Google Patents

Abstract

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

Description

Macrocyclic compounds containing amide substitution

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority and rights of Chinese patent application with application number 202311693410.4 filed with the State Intellectual Property Office of China on December 8, 2023 and Chinese patent application with application number 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

The present invention belongs to the field of medical technology, and relates to amide-substituted macrocyclic compounds, stereoisomers or pharmaceutically acceptable salts thereof, preparation methods thereof, pharmaceutical compositions containing the compounds, and uses thereof in treating diseases.

Background Art

The discovery of small molecule inhibitors relies on the presence of suitable binding pockets on the surface of proteins. Approximately 90% of proteins in the human body lack this function. Such targets are generally considered undruggable and still require innovative therapeutic targeting strategies. It is 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 vital role in a variety of human cancers, making them suitable targets for anticancer therapy. Specifically, dysregulation of Ras proteins caused by activating mutations, overexpression, or upstream activation can lead to the growth and proliferation of human tumor cells. For example, KRAS, as a small guanosine triphosphatase (GTPase), can cycle between an inactive [guanosine diphosphate (GDP)-bound, OFF] state and an active (GTP-bound, ON) state, while KRAS in the active state can bind to and activate a variety of effector proteins to regulate cell growth and proliferation. KRAS mutations stimulate excessive downstream signaling and proliferation, and are important oncogenic drivers that are closely related to the occurrence and development of a variety of 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 literature reports that drugs targeting the active state (ON) of RAS can inactivate oncogenic signals and lead to tumor regression in a variety of human cancer models, but no such drugs have been approved for marketing, and more attempts are still needed in this field to discover drugs for various Ras mutation-driven cancers.

Summary of the invention

The present disclosure relates to 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 heterocyclyl, wherein the C _6-10 aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclyl is optionally substituted independently by 1, 2 or 3 R ^a ;

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, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 heteroalkyl, _C3-6 cycloalkyl or 3-6 membered heterocyclyl, said _C3-6 cycloalkyl or 3-6 membered heterocyclyl being optionally independently substituted with one or more substituents selected from halogen, =O, _-NH2 , -OH, -SH or -CN; or, R and R' together with the attached carbon atom form C=O, _C3-6 cycloalkyl or 3-6 membered heterocyclyl, said _C3-6 cycloalkyl or 3-6 membered heterocyclyl being optionally independently substituted with 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 heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl, wherein the C _3-14 cycloalkyl, C _3-14 cycloalkenyl, 3-14 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl is optionally substituted independently by 1, 2 or 3 R ^b ;

^Ra and ^Rb are each independently selected from halogen, =O, _-NH2 , -OH, -SH, -CN, _C1-12 alkyl, _C1-12 heteroalkyl, _C2-12 alkenyl, _C2-12 alkynyl, C3-8 cycloalkyl, _3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the _C1-12 alkyl, _C1-12 heteroalkyl, _C2-12 alkenyl or _C2-12 alkynyl is optionally independently substituted with one or more substituents selected from halogen, _-NH2 , -OH, -SH, -CN; the _C3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with one or more substituents selected from halogen, =O, _-NH2 , -OH, -SH, -CN, -COOH, _C1-6 alkyl, _{C1-6 heteroalkyl} , hydroxyl; Substituted by a _{C 1-6} haloalkyl or amino substituted C _1-6 alkyl substituent;

R ¹ is 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 heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl, wherein 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, -NH ₂ , -OH, -SH, -CN or -COOH; the C _3-14 cycloalkyl, C _4-14 cycloalkenyl, 4-14 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl is optionally substituted independently by one or more substituents selected from halogen, -NH ₂ , -OH, -SH, -CN, -COOH, C _1-6 alkyl, _{C 1-6} heteroalkyl, hydroxyl Substituted by a _{C 1-6} haloalkyl or amino substituted C _1-6 alkyl substituent;

Each R ² is independently selected from halogen, -NH ₂ , -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) ₂ C _1-6 alkyl, -S(O) ₂ NHC _1-6 alkyl, -S(O) ₂ N(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 heterocyclyl, C 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, _{-NH 2 ,} -OH, -SH, -CN, -COOH; the C _3-14 cycloalkyl, C _4-14 cycloalkenyl, 4-14 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl is optionally substituted independently by one or more substituents selected from halogen _, =O, -NH ₂ , -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;

^X1 and ^X3 are each independently selected from CH or N;

^X2 is 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 is selected from hydrogen, halogen, -NH ₂ , -OH, -SH, -CN, C _1-6 alkyl or C _1-6 heteroalkyl, wherein the C _1-6 alkyl or C _1-6 heteroalkyl is optionally substituted independently with 1, 2 or 3 substituents selected from halogen, -NH ₂ , -OH, -SH or -CN.

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

When the structure fragment Selected from And ring A is selected from when R ¹ is not C _1-6 heteroalkyl and C _2-6 alkenyl optionally and independently substituted by one or more substituents selected from halogen, -NH ₂ , -OH, -SH, -CN, -COOH; and R ¹ is not methyl and -CH ₂ CH(CH ₃ ) ₂ ; and R ¹ is not C 3-14 cycloalkyl, _4-14 membered saturated heterocyclyl, pyridyl, optionally and independently substituted by one or more substituents selected from halogen, =O, -NH ₂ , -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. 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.

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

When the structure fragment Selected from And ring A is selected from When ^R1 is not a _C3-5 cycloalkyl or a 6-membered heterocycloalkyl, the _C3-5 cycloalkyl or the 6-membered heterocycloalkyl is optionally substituted by 1 or 2 selected from CN, _C1-3 alkyl, halogenated _C1-3 alkyl, or pyrimidinyl; wherein * 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.

In some embodiments, Ring A is selected from C _6-10 aryl, _5-10 membered heteroaryl, or 5-10 membered heterocyclyl, which is optionally substituted independently with 1, 2, or 3 ^Ra , wherein ^Ra is as defined in the disclosure.

In some embodiments, Ring A is selected from C _6-10 aryl or _5-10 membered heteroaryl, which is optionally substituted independently with 1 or 2 ^Ra , wherein said ^Ra is as defined in the disclosure.

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 substituted independently with 1 or 2 ^Ra , wherein the ^Ra is as defined in the disclosure.

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 substituted independently with 1 or 2 ^Ra , wherein the ^Ra is as defined in the disclosure.

In some embodiments, Ring A is selected from a 5-membered or 9-membered heteroaryl, which is optionally substituted independently with 1 or 2 ^Ra , wherein ^Ra is as defined in the disclosure.

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 ring A is optionally substituted with 1 or 2 ^Ra , wherein ^Ra is as defined in the present disclosure.

In some embodiments, Ring A is selected from indolyl or pyrrolyl, said indolyl or pyrrolyl being optionally substituted independently with 1 or 2 ^Ra , wherein said ^Ra is as defined in the disclosure.

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 with 1 or 2 substituents selected from halogen, C _1-4 alkyl, C _2-4 alkynyl, -NH ₂ , -OH, -SH or -CN.

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 with 1 or 2 C _1-3 alkyl or C _2-4 alkynyl.

In some embodiments, Ring A is selected from 5-6 or 9-10 membered heteroaryl, which is optionally substituted independently with 1 or 2 C _1-3 alkyl or C _2-4 alkynyl.

In some embodiments, Ring A is selected from 5-membered or 9-membered heteroaryl, which is optionally substituted independently with 1 or 2 C _1-3 alkyl or C _2-4 alkynyl.

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 ring A is optionally substituted with 1 or 2 C _1-3 alkyl or C _2-4 alkynyl.

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.

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

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 substituted independently by 1 or 2 C _1-3 alkyl or C _2-4 alkynyl groups.

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 substituted with 1 or 2 ^Ra .

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.

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.

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.

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 disclosure.

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

In some embodiments, L is a bond.

In some embodiments, L is -CH=CH-.

In some embodiments, R and R' are each independently selected from hydrogen, deuterium, halogen, _-NH2 , -OH, _C1-3 alkyl, _C1-3 haloalkyl, or _C1-3 heteroalkyl. Alternatively, in some embodiments, R and R' together with the attached carbon atom form C=O or cyclopropyl.

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

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

In some embodiments, Ring B is selected from _C5-10 cycloalkyl, _C5-10 cycloalkenyl, 5-10 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl, and the _C5-10 cycloalkyl, C5-10 cycloalkenyl, _5-10 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2 or 3 R ^b , wherein the R ^b is as defined in the present disclosure.

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 substituted independently with 1 or 2 R ^b , wherein the R ^b is as defined in the disclosure.

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 R ^b , wherein the R ^b is as defined in the disclosure.

In some embodiments, Ring B is selected from 5-6 membered heteroaryl, which is optionally substituted with 1 or 2 R ^b , wherein R ^b is as defined in the disclosure.

In some embodiments, ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl, and is optionally substituted with 1 or 2 R ^b , wherein R ^b is as defined in the present disclosure.

In some embodiments, Ring B is thiazolyl, which is optionally substituted with 1 or 2 R ^b , wherein R ^b is as defined in the disclosure.

In some embodiments, Ring B is selected from _C5-10 cycloalkyl, _C5-10 cycloalkenyl, 5-10 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl, wherein said _C5-10 cycloalkyl, C5-10 cycloalkenyl, _5-10 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl is optionally substituted independently with 1 or 2 substituents selected from -F, -Cl, _-NH2 , -OH, -SH or -CN.

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, -CN.

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.

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

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.

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, -NH ₂ , -OH, -SH, and -CN.

In some embodiments, Ring B is Among them, * indicates that the bond at this position is connected to L.

In some embodiments, ^Ra and ^Rb are each independently selected from halogen, =O, _-NH2 , -OH, -SH, -CN, _C1-8 alkyl, _C1-8 heteroalkyl, _C2-8 alkenyl, _C2-8 alkynyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, and the _C1-8 alkyl, _C1-8 heteroalkyl, _C2-8 alkenyl or _C2-8 alkynyl is optionally independently substituted with one or more substituents selected from halogen, -NH2, _-OH , -SH, -CN; the _C3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with one or more substituents selected from halogen, =O, _-NH2 , -OH, -SH, -CN, -COOH, _C1-4 alkyl, _C1-4 heteroalkyl, hydroxy-substituted _C1-4 alkyl, _C1-4 haloalkyl or amino-substituted C1-4 The substituents are substituted with _1-4 alkyl groups.

In some embodiments, ^Ra is selected from halogen, =O, _-NH2 , -OH, -SH, -CN, _C1-3 alkyl, _C1-3 heteroalkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein the _C1-3 alkyl, _C1-3 heteroalkyl, _C2-4 alkenyl, or _C2-4 alkynyl is optionally substituted independently with one or more substituents selected from halogen, _-NH2 , -OH, -SH, or -CN; and the _C3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted independently with one or more substituents selected from halogen, =O, _-NH2 , -OH, -SH, -CN, _C1-3 alkyl, _C1-3 heteroalkyl, or _C1-3 haloalkyl.

In some embodiments, ^Ra is selected from halogen, _C1-3 alkyl, _-OC1-3 alkyl, -NH( _C1-3 alkyl), -N( _C1-3 alkyl) ₂ , _C2-4 alkenyl or _C2-4 alkynyl, and the _C1-3 alkyl, _-OC1-3 alkyl, -NH( _C1-3 alkyl), -N( _C1-3 alkyl) ₂ , _C2-4 alkenyl or _C2-4 alkynyl are optionally substituted independently with one or more halogen.

In some embodiments, ^Ra is selected from F, Cl, _C1-3 alkyl, _-OC1-3 alkyl, -NH( _C1-2 alkyl), -N( _C1-2 alkyl) ₂ or _C2-4 alkynyl, wherein the _C1-3 alkyl, _-OC1-3 alkyl, -NH( _C1-2 alkyl), -N( _C1-2 alkyl) ₂ or _C2-4 alkynyl is optionally substituted independently with one or more halogens.

In some embodiments, ^Ra is selected from F, Cl, _C1-3 alkyl, _-OC1-3 alkyl, -NH( _C1-2 alkyl), -N( _C1-2 alkyl) ₂ , or _C2-4 alkynyl.

In some embodiments, ^Ra is selected from _C1-3 alkyl or _C2-4 alkynyl.

In some embodiments, ^Ra is selected from ethyl or ethynyl.

In some embodiments, R ^b is selected from halogen, ＝O, —NH ₂ , —OH, —SH, —CN, C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, or C _{2-6 alkynyl} , which is optionally substituted independently with one _{or more} substituents selected _from halogen, —NH ₂ , —OH, —SH, or —CN.

In some embodiments, R ^b is selected from halogen, =0, -NH ₂ , -OH, -SH, -CN, C _1-4 alkyl, or C _1-4 heteroalkyl, wherein the C _1-4 alkyl or C _1-4 heteroalkyl is optionally substituted independently with one or more substituents selected from F, Cl, -NH ₂ , -OH, -SH, or -CN.

In some embodiments, R ^b is selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, -NH(C _1-2 alkyl) or -N(C _1-2 alkyl) ₂ , wherein the C _1-3 alkyl, -OC _1-3 alkyl, -NH(C _1-2 alkyl) or -N(C _1-2 alkyl) ₂ is optionally substituted independently with 1, 2 or 3 F atoms.

In some embodiments, R ^b is selected from halogen, -NH ₂ , -OH, -SH, -CN, or C _1-3 alkyl.

In some embodiments, R ^b is selected from F, Cl or -OH.

In some embodiments, R ¹ is 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 heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein 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, -NH ₂ , -OH, -SH, -CN or -COOH; the C _3-10 cycloalkyl, C _5-10 cycloalkenyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl is optionally substituted independently with one or more substituents selected from halogen, =O, -NH 2 , -OH, -SH, -CN, -COOH, C _1-6 alkyl, C _1-6 heteroalkyl or C _2-6 alkynyl is optionally substituted independently with one or more substituents _selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, -COOH, The substituents are substituted with _{1 to 6} haloalkyl groups.

In some embodiments, R ¹ is 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 heterocyclyl, wherein the C _1-4 alkyl, C _1-4 heteroalkyl, C _2-4 alkenyl or C _2-4 alkynyl is optionally substituted independently with one or more substituents selected from halogen, -NH ₂ , -OH, -SH, -CN or -COOH; the C _3-8 cycloalkyl, C _5-8 cycloalkenyl or 4-8 membered heterocyclyl is optionally substituted independently with one or more substituents selected from halogen, ＝O, -NH ₂ , -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 .

In some embodiments, R ¹ is selected from C _1-4 alkyl, C _1-4 heteroalkyl, C _3-6 cycloalkyl, C _5-8 cycloalkenyl, or 5-8 membered heterocyclyl, wherein the C _1-4 alkyl or C _1-4 heteroalkyl is optionally substituted independently with one or more substituents selected from halogen, -NH ₂ , -OH, -SH, or -CN; the C _3-6 cycloalkyl, C _5-8 cycloalkenyl, 5-8 membered heterocyclyl is optionally substituted independently with one or more substituents selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, C _1-3 haloalkyl, -NH(CH ₃ ) or -N(CH ₃ ) ₂ .

In some embodiments, R ¹ is selected from C _1-4 haloalkyl, C _1-4 heteroalkyl, C _5-8 cycloalkenyl, or 5-8 membered partially unsaturated heterocyclyl, wherein the C _1-4 haloalkyl, C _1-4 heteroalkyl is optionally substituted independently with one or more substituents selected from halogen, -NH ₂ , -OH, -SH, or -CN; the C _5-8 cycloalkenyl or 5-8 membered partially unsaturated heterocyclyl is optionally substituted independently with one or more substituents selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, C _1-3 haloalkyl, -NH(CH ₃ ) or -N(CH ₃ ) ₂ .

In some embodiments, R ¹ is selected from C _5-8 cycloalkenyl or 5-8 membered partially unsaturated heterocyclyl, _which is optionally substituted independently with one or more substituents selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, C _1-3 haloalkyl, -NH(CH ₃ ) or -N(CH ₃ ) ₂ .

In some embodiments, R ¹ is selected from C _3-6 cycloalkyl, n is 1, and the C _3-6 cycloalkyl is optionally substituted with one or more substituents selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, C _1-3 haloalkyl, -NH(CH ₃ ) or -N(CH ₃ ) _2. In some embodiments, R ¹ is selected from cyclopropyl, n is 1, and the cyclopropyl is optionally substituted with one or more substituents selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, C _1-3 haloalkyl, -NH(CH ₃ ) or -N(CH ₃ ) ₂ .

In some embodiments, R ¹ is selected from C _3-6 cycloalkyl, and Ring A is not The C _3-6 cycloalkyl group is optionally substituted by one or more substituents selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, C _1-3 haloalkyl, -NH(CH ₃ ) or -N(CH ₃ ) ₂ , wherein * 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. In conjunction with each other, the definition of ^Ra is as described in the present disclosure.

In some embodiments, R ¹ is selected from cyclopropyl, and Ring A is not The cyclopropyl group is optionally substituted by one or more substituents selected from halogen, =O, _-NH2 , -OH, -SH, -CN, _C1-3 alkyl, _-OC1-3 alkyl, _C1-3 haloalkyl, -NH( _CH3 ) or -N( _CH3 ) ₂ , wherein * 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. In conjunction with each other, the definition of ^Ra is as described in the present disclosure.

In some embodiments, R ¹ is selected from C _1-3 haloalkyl, C _3-6 cycloalkyl or C _5-7 cycloalkenyl, said C _3-6 cycloalkyl or C _5-7 cycloalkenyl optionally substituted independently with 1 or 2 substituents selected from halogen, -NH ₂ , C _1-3 alkyl or C _1-3 haloalkyl.

In some embodiments, R ¹ is selected from C _1-3 haloalkyl or C _5-7 cycloalkenyl, said C _5-7 cycloalkenyl being optionally substituted with 1 or 2 substituents selected from halogen, -NH ₂ , C _1-3 alkyl or C _1-3 haloalkyl.

In some embodiments, R ¹ is selected from _{C 5-7} cycloalkenyl, which is optionally substituted with 1 or 2 substituents selected from halogen, -NH ₂ , C _1-3 alkyl, or C _1-3 haloalkyl.

In some embodiments, R ¹ is selected from halomethyl, cyclopropyl, cyclohexenyl, cyclopentenyl, or bicyclo[2.2.1]hept-2-enyl, optionally substituted independently with 1 or 2 F, Cl, -NH ₂ , CHF ₂ , or methyl.

In some embodiments, R ¹ is selected from cyclohexenyl, cyclopentenyl, or bicyclo[2.2.1]hept-2-enyl, optionally substituted independently with 1 or 2 F, Cl, -NH ₂ , CHF ₂ , or methyl.

In some embodiments, R ¹ is selected from cyclohexenyl, optionally substituted independently with 1 or 2 F, Cl, -NH ₂ , CHF ₂ , or methyl.

In some embodiments, R ¹ is selected from halomethyl, Said Optionally substituted independently with 1 or 2 substituents selected from halogen, -NH ₂ , C _1-3 alkyl or C _1-3 haloalkyl.

In some embodiments, ^R is selected from Said Optionally substituted independently with 1 or 2 substituents selected from halogen, -NH ₂ , C _1-3 alkyl or C _1-3 haloalkyl.

In some embodiments, R ¹ is selected from halomethyl or Said Optionally substituted with 1 or 2 substituents selected from halogen, -NH ₂ , C _1-3 alkyl or C _1-3 haloalkyl. In some embodiments, R ¹ is selected from Said Optionally substituted with 1 or 2 substituents selected from halogen, -NH ₂ , C _1-3 alkyl or C _1-3 haloalkyl.

In some embodiments, R ¹ is selected from cyclopropyl, n is 1, and the cyclopropyl is optionally substituted with one or more C _1-3 haloalkyl.

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 groups, wherein * 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.

In some embodiments, R ¹ is selected from halo-substituted C _1-3 alkyl.

In some embodiments, R ¹ is selected from _{C 5-7} cycloalkenyl, which is optionally substituted with 1 or 2 substituents selected from halogen, -NH ₂ , C _1-3 alkyl, haloC _1-3 alkyl, -OH, or CN.

In some embodiments, R ¹ is selected from _{C 3-5} cycloalkyl, which is optionally substituted with 1 or 2 substituents selected from halogen, -NH ₂ , C _1-3 alkyl, C _1-3 haloalkyl, -OH, or CN.

In some embodiments, R ¹ is selected from halogenated C _1-3 alkyl, C _5-7 cycloalkenyl or C _3-5 cycloalkyl, wherein the C _5-7 cycloalkenyl or C _3-5 cycloalkyl is optionally substituted with 1 or 2 substituents selected from halogen, methyl, -NH ₂ or -CHF ₂ .

In some embodiments, R ¹ is selected from methyl, cyclohexenyl, cyclopropyl, cyclopentenyl or bicyclo[2.2.1]hept-2-enyl, wherein the methyl, cyclohexenyl, cyclopropyl, cyclopentenyl or bicyclo[2.2.1]hept-2-enyl is optionally substituted with 1 or 2 F or Cl, and the cyclohexenyl, cyclopropyl, cyclopentenyl or bicycloheptenyl is optionally substituted with 1 or 2 methyl, -NH ₂ or -CHF ₂ substituents.

In some embodiments, ^R is selected from

In some embodiments, ^R is selected from

In some embodiments, ^R is selected from

In some embodiments, ^R is selected from

In some embodiments, ^R is selected from

In some embodiments, ^R is selected from

In some embodiments, ^R is selected from n is 1.

In some embodiments, ^R is 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.

In some embodiments, ^X1 is selected from N, ^X2 is selected from _CH2 or NH, and ^X3 is selected from CH or N.

In some embodiments, ^X1 and ^X3 are N, and ^X2 is _CH2 or NH.

In some embodiments, X ¹ and X ³ are N, and X ² is CH ₂ .

In some embodiments, ^X1 and ^X3 are N, and ^X2 is NH.

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

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

In some embodiments, n is 1. In some embodiments, n is 2.

In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from

In some embodiments, the structural fragment Selected from In some embodiments, the structural fragment Selected from In some embodiments, each R ² is independently selected from halogen, -NH ₂ , -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) ₂ NH(C _1-3 alkyl), -S(O) ₂ N(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 heterocyclyl, 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 heterocyclyl, C 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, -NH ₂ , -OH, -SH, -CN, -COOH; the C _3-10 cycloalkyl, C _3-10 cycloalkenyl, _3-10 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl is optionally substituted independently with one or more substituents selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, C _1-4 alkyl, C _1-4 heteroalkyl or C _1-4 haloalkyl.

In some embodiments, each R ² is independently selected from F, Cl, -NH ₂ , -OH, -SH, -CN, C _1-4 alkyl, C _1-4 heteroalkyl, C _3-8 cycloalkyl, C _5-8 cycloalkenyl, 5-10 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl, wherein the C _1-4 alkyl or C _1-4 heteroalkyl is optionally independently substituted with one or more substituents selected from halogen, -NH ₂ , -OH, -SH, -CN, -COOH; the C _3-8 cycloalkyl, C _5-8 cycloalkenyl, 5-10 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl is optionally independently substituted with one or more halogen, -NH ₂ , -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.

In some embodiments, each R ² is independently selected from C _3-8 cycloalkyl, C _5-8 cycloalkenyl, or 5-8 membered heterocyclyl, which is optionally independently substituted with one or more halogen, -NH _{2 ,} -OH, -SH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, C _1-3 haloalkyl, -NH(CH ₃ ) or -N(CH _{3 ) 2} .

In some embodiments, each R ² is independently selected from 5-8 membered heterocyclyl, which is optionally substituted with one or more substituents selected from halogen, -NH ₂ , -OH, -SH, -CN, C _1-3 alkyl, or C _1-3 haloalkyl.

In some embodiments, each R ² is independently selected from a 5-6 membered heterocyclyl containing 1 or 2 N or O atoms, wherein the 5-6 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, C _1-3 alkyl or C _1-3 haloalkyl.

In some embodiments, each R ² 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 with 1 or 2 substituents selected from F, Cl or C _1-3 alkyl.

In some embodiments, each R ² is independently selected from 5-8 membered heterocycloalkyl, which is optionally substituted with one or more substituents selected from halogen, C _1-3 alkyl, or C _1-3 haloalkyl.

In some embodiments, each R ² 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 with one or more substituents selected from halogen, C _1-3 alkyl or C _1-3 haloalkyl.

In some embodiments, each R ² is independently selected from 5-6 membered heterocycloalkyl containing 1 or 2 N atoms, which is optionally substituted with 1 or 2 substituents selected from F, Cl or C _1-3 alkyl.

In some embodiments, each R ² is independently selected from piperazinyl, which is optionally substituted with C _1-3 alkyl.

In some embodiments, each R ² is independently selected from piperazinyl, which is optionally substituted with methyl.

In some embodiments, each R ² is independently selected from

In some embodiments, each R ² is independently

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

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

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, i is 1.

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

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

In some embodiments, R ³ is selected from hydrogen, halogen, -NH ₂ , -OH, -SH, -CN, C _1-4 alkyl, or C _1-4 heteroalkyl, which is optionally substituted independently with 1, 2, or ₃ substituents selected from halogen, -NH ₂ , -OH, -SH _, or -CN.

In some embodiments, R ³ is selected _from F, Cl, -NH ₂ , -OH, -CN, C _1-3 alkyl, or C _1-3 heteroalkyl _, which are optionally substituted independently with 1 or 2 F atoms.

In some embodiments, R ³ is selected from C _1-3 heteroalkyl. In some embodiments, R ³ is selected from C ₃ heteroalkyl.

In some embodiments, R ³ is selected from C _1-3 alkoxy substituted C _1-3 alkyl.

In some embodiments, ^R3 is In some embodiments, ^R3 is

In some embodiments, the structural fragment Selected from

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).

In some embodiments, the compound of formula (I) described in the present disclosure, its stereoisomer or its pharmaceutically acceptable salt 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 its pharmaceutically acceptable salt,

wherein p is selected from 1, 2 or 3;

The definitions of X ² , R ¹ , R ² , ^Ra , m and n are as described in the present disclosure;

Each R ^c is independently selected from halogen, =O, -NH ₂ , -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.

In some embodiments, each R ^c is independently selected from -NH ₂ or C _1-6 alkyl.

In some embodiments, each R ^c is independently selected from -NH ₂ or C _1-3 alkyl.

In some embodiments, each R ^c is independently selected from -NH ₂ or methyl.

It is understood that any embodiment of the compounds of the present disclosure as described above and any specific substituents described herein for specific X ¹ , X ² , X ³ , ring A, L, ring B, R ¹ , R ² , R ³ , ^Ra , R ^b , R ^c , R and R ' in the compounds of the present disclosure as described above can be independently combined with other embodiments of the present disclosure and/or substituents of the compounds to form embodiments of the present disclosure not specifically described above. In addition, where a substituent range is disclosed in a specific embodiment and/or claim for any specific X ¹ , X ² , X ³ , ring A, L, ring B, R ¹ , R ² , R ³ , ^Ra , R ^b , R ^c , R and R 'substituents, it is understood that one or more substituents can be deleted from the range and the remaining substituent range should also be considered an embodiment of the present disclosure.

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

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.

On the other hand, the present disclosure provides a method for treating a disease associated with Ras protein in a mammal, the method comprising administering a therapeutically effective amount of the above compound, its stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

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 a disease associated with Ras protein.

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.

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.

Technical Effects

The disclosed compounds have good AsPc-1 cell and Capan-1 cell proliferation inhibition activity, stable in vitro liver microsome metabolism, good in vivo pharmacodynamics, and good pharmacokinetic properties.

definition

Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be considered as indefinite or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced 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 oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted ( _-CH2CH3 ), _{monosubstituted} (such _{as -CH2CH2F} ), polysubstituted (such as _-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 is sterically impossible and/or cannot be synthesized will be introduced.

C _mn herein 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 may have 1 carbon atom, 2 carbon atoms or 3 carbon atoms.

The term "one or more" as used herein 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.

When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 2 R's, each R has an independent choice.

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

In the present 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 their specific options can be optionally read from left to right, and are connected to the left and right groups of the group or part in the general formula respectively. Specifically, in -(CRR' _{)q- (} CH=CH) _i- , according to the reading order from left to right, -(CRR')q-(CH=CH) _i- - is connected to the ring A on the left side of the general formula, and -(CH=CH) _i - is connected to the ring B on the right side. Optionally, for example, the above-mentioned groups or structural parts can also adopt a reading order from right to left, such as in -(CRR') _q -(CH=CH) _i -, according to the reading order from right to left, -(CH=CH) _i - is connected to the ring A on the left side, and -(CRR') _q - is connected to the ring B on the right side of the general formula.

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

The term "hydroxy" refers to an -OH group.

The term "amino" refers to a _-NH2 group.

The term "nitro" refers to the _-NO2 group.

The term "cyano" refers to a -CN group.

The term "alkyl" refers to a hydrocarbon group of the general formula _{CnH2n +1} . The alkyl group may be straight or branched. For example, the term " _C1-6 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.

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) ₂ N(H)- and -S(=O)N(H)-. Numerical ranges (e.g., C _1-6 heteroalkyl) refer to the number of carbons in the chain, and in this example, include 1-6 carbon atoms. For example, a -CH ₂ OCH ₂ CH ₃ group is referred to as a C ₃ 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, and the like, including alkoxy, alkylthio, alkylamino; unless otherwise specified, C _1-6 heteroalkyl groups include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ heteroalkyl groups, such as C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino.

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

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.

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 may be a monocyclic, bicyclic or tricyclic ring. Non-limiting examples of cycloalkyl 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.

The term "heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, and ring or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring is generally 3 to 20 rings, 3 to 15 rings, 3 to 12 rings or 3 to 10 rings (e.g., 3, 4, 5, 6, 7, 8, 9 or 10), 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 sulfur, oxygen, nitrogen, phosphorus, silicon and/or boron. Non-limiting examples of heterocyclic radicals include but are not limited to oxirane, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc.

The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring or spirocyclic ring. 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.

The term "heterocycloalkenyl" includes cycloalkenyl groups in which one or more carbon atoms are replaced by heteroatoms, such as cycloalkenyl groups in which up to 3 carbon atoms, up to 2 carbon atoms, and 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. Heterocycloalkenyl groups can be cyclic groups existing as monocycles, bridged rings or spirocycles, and can be 3 to 16 rings (such as 3 to 12, 5 to 8 rings, such as 5, 6, 7, 8, 9, 10 or 11 rings). Examples of heterocycloalkenyl groups include but are not limited to dihydropyridine radicals, dihydropyrrolyls, tetrahydropyridine radicals, tetrahydroazepines or azaspirocyclooctene.

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 2 or more rings (e.g., 2, 3, 4 rings, etc.), and the ring in the aryl group that is directly connected to the parent structure is a benzene ring, and non-limiting examples include, but are not limited to wait.

The term "heteroaryl" refers to a monocyclic or polycyclic ring system containing at least one ring atom selected from N, O, S(O) _n , P(O) _n (wherein n is 0, 1 or 2), the remaining ring atoms being C, and having an aromatic ring of at least one heteroaromatic ring. Unless otherwise indicated, the heteroaryl may be a monocyclic, bicyclic or tricyclic ring. Unless otherwise indicated, the heteroaryl may have a single 5 to 8-membered ring, or a plurality of fused rings containing 6 to 14, especially 6 to 10, ring atoms. Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc. In some embodiments, the heteroaryl group may be a 6-membered heteroaryl group fused with a heterocyclyl group or a cycloalkyl group to form two or more rings (e.g., two, three, four rings, etc.), wherein the ring directly connected to the parent structure in the heteroaryl group is a heteroaromatic ring, non-limiting examples include but are not limited to wait.

Unless otherwise specified, the term "hetero" refers to a heteroatom or a heteroatom group (i.e., a group containing a heteroatom), 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) ₂ N(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.

The term "treatment" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

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

(ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

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 those skilled in the art based on their own knowledge and the present disclosure.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, 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.

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.

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.

The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

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

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 and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present disclosure.

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

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

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), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., the formation of a carbamate from an amine).

The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into 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, etc., respectively.

Certain isotopically labeled compounds of the present disclosure (e.g., those labeled with ³ H and ¹⁴ C) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e., 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 present disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.

Further, substitution with heavier isotopes such as deuterium (i.e., ² H or D) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, wherein deuterium substitution may be partial or full, partial deuterium substitution refers to replacement of at least one hydrogen with at least one deuterium, full deuterium substitution refers to replacement of all hydrogens on a group with deuterium, for example, complete replacement of a methyl group ( _-CH3 ) with deuterium yields _-CD3 .

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.

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

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, intravenous administration.

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.

In all administration methods disclosed herein, the compound (I) is administered at a dosage of 0.001 to 2000 mg/kg body weight per day in the form of single or divided doses.

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 embodiments with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.

The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes 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 the synthesis steps or reaction processes based on the existing embodiments.

An important consideration in synthetic route planning in the art is to select 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.

For the purpose of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided only because their disclosure precedes the filing date of the present disclosure. All statements regarding the dates of these documents or the 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 reference to these publications herein does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

This disclosure uses the following abbreviations:

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)Cl ₂ ·CH ₂ Cl ₂ represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride 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)Cl ₂ 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; TFA represents trifluoroacetic acid.

DETAILED DESCRIPTION

Intermediate Example 1-A: Preparation of Intermediate A

Step 1:

Compound A-0 (50 g) and imidazole (32 g) were dissolved in dichloromethane (1 L), cooled to 0 ° C, TBDPSCl (120 mL) was added, and 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, and the mixture was stirred and separated. The aqueous layer was extracted once with dichloromethane (1.2 L), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated to obtain compound A-1 (154 g).

Step 2:

Compound A-1 (154 g) was dissolved in toluene (500 mL), and dichlorothionyl (40 mL) and DMF (1-3 drops) were added, and 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.

Step 3:

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. The reaction was complete, the reaction solution was evaporated under reduced pressure to dry the solvent, 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, and extracted twice with ethyl acetate (200 mL * 2), the organic layers were combined, dried and filtered with anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and the crude product was slurried 3 times at room temperature with PE: EA = 2: 1 (300 mL * 3), filtered, and evaporated to dryness to obtain compound A-3 (189 g).

Step 4:

Compound A-3 (189 g) was dissolved in THF (372 mL), stirred and cooled in an ice-water bath, sodium borohydride (52.4 g) was added in 6 batches, and the reaction was stirred at 60-65°C after the addition. 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:

Compound A-4 (122 g) and triethylamine (179 mL) were dissolved in DCM (1 L). After the mixture was cooled in an ice-water bath for 1 h, acetic anhydride (66.1 g) was added. After reacting for 1 h, DMAP (4.1 g) was added. After reacting 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. The obtained 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).

Step 6:

Compound A-5 (10 g) was dissolved in THF (200 mL), sodium bicarbonate (3.1 g), silver trifluoromethanesulfonate (9.5 g), and I ₂ (7.8 g) were added under ice bath conditions, and the mixture was stirred at 0°C for reaction. 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 to extract twice, the organic phases were combined, 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) ^- .

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

Step 1:

Compound B-0 (80g), biboric acid pinacol ester (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 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), and the aqueous phase was cooled in an ice bath, and the pH was adjusted to 6 with a 6N dilute hydrochloric acid aqueous solution. Solids were precipitated and filtered to obtain compound B-1 (62g).

LC-MS: m/z: 260; 262.1 (M+H) ⁺ .

Step 2:

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

LC-MS: m/z: 341.91; 343.92(M+H) ⁺ .

Step 3:

Compound B-2 (9.88 g), benzyl-1-piperazine carbonate (15.73 g), XantPhos (1.68 g), Pd ₂ (dba) ₃ (530.74 mg), 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).

LC-MS: m/z: 434.21; 436.19 (M+H) ⁺ .

Step 4:

Compound B-3 (9.9 g), bipyraclostrobin (8.68 g), potassium acetate (5.59 g) and Pd(dppf)Cl ₂ ^. CH ₂ Cl ₂ (1.86 g) were 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, concentrated under reduced pressure to remove most of the toluene, and then directly sanded. After separation by neutral alumina column chromatography, a mixture of intermediate B and B-4 (13.6 g) was obtained.

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

Intermediate Example 1-C: Preparation of Intermediate C

Step 1:

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

Step 2:

Dissolve compound C-1 (23 g) in dichloromethane (230 mL), add trifluoroacetic acid (115 mL), and stir at room temperature to react. After the reaction is completed, the reaction solution is concentrated under reduced pressure to evaporate the solvent, and the residue is dried twice with toluene to obtain compound C-2 (25 g).

LC-MS: m/z: 145 (M+H) ⁺ .

Step 3:

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, DCM (100 mL) and water (50 mL) were added, and the pH was adjusted to 5-6 with a 2N dilute hydrochloric acid aqueous solution, and the liquid was extracted and separated. The aqueous phase was extracted again with DCM (100 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound C-3 (13.8 g).

Step 4:

DIPEA (20 g) was added to a dichloromethane (50 mL) solution of compound C-2 (21.94 g), 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 aforementioned mixture, HATU (19.33 g), HOAT (2.67 g) and DIPEA (30.79 g) were added, and stirred at 0-5°C for reaction. When the reaction was complete, water (500 mL) and DCM (200 mL) were added, stirred and separated, and 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).

LC-MS: m/z: 477.1 (M+H) ⁺ .

Intermediate Example 1-D: Preparation of Intermediate D

Step 1:

The mixture of intermediate B and B-4 (8.38 g), intermediate A (6.3 g), K ₂ CO ₃ (3.86 g), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (2.53 g) were dissolved in a mixed solvent of toluene, 1,4-dioxane and water (v/v/v=3/1/1, 250 mL in total), replaced with nitrogen three times, and stirred at 70°C for reaction. After the reaction was complete, water (150 mL) and ethyl acetate (150 mL*2) were added to the reaction solution for extraction twice, and 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).

LC-MS: m/z: 677.2 (M+H) ⁺ .

Step 2:

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

LC-MS: m/z: 705.3 (M+H) ⁺ .

Step 3:

The crude product D-2 (7 g) obtained in the previous step was dissolved in methanol (50 mL), and LiOH (1.36 g) and K ₃ PO ₄ (2.1 g) were added, and the mixture was stirred at 40°C for reaction. After the reaction was complete, the presence of atropisomers was monitored under LC-MS conditions (chromatographic column: Waters ACQUITY CSH C18; mobile phase A: 0.1% formic acid (FA)/H ₂ O; mobile phase B: MeCN; 0-7 min gradient elution (15%-95%-5%-15%)), and the retention times of the front peak and the back peak were 4.23 min and 4.40 min, respectively. The reaction solution was cooled to room temperature, and the sand was directly made and separated by silica gel column chromatography (eluent: PE:EA=1:2) to obtain two atropisomers of D-3, including the front peak compound D-3B (2.37 g) and the back peak compound D-3A (2.53 g).

LC-MS: m/z: 663.4 (M+H) ⁺ .

Step 4:

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

LC-MS: m/z 711.5 (M+H) ⁺ .

Step 5:

Compound D-4A (1.5 g), intermediate C (875.84 mg), Pd(dtbpf)Cl ₂ (137.51 mg) _, K ₃ PO ₄ (1.11 g) were dissolved in 25 mL of a mixed solvent of toluene/dioxane/water (v/v/v=3/1/1), replaced with nitrogen three times, and stirred at 70° C. After the reaction was complete, the reaction solution was cooled, concentrated and sanded, and separated by silica gel column chromatography (eluent: PE:EA=1:10) to obtain compound D-5A (1.67 g).

LC-MS: m/z 981.64 (M+H) ⁺ .

Step 6:

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

LC-MS: m/z 967.9 (M+H) ⁺ .

Step 7:

Dissolve the crude product of D-6A (1.3 g) in DCM (150 mL), add EDCI (7.72 g), DIPEA (4.91 g), HOBT (185 mg), and stir at room temperature to react. When the reaction is complete, add water (300 mL) and DCM (200 mL), extract and wash, wash the organic phase with water (300 mL) and saturated brine (200 mL*2), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate. The crude product is chromatographed on a silica gel column (eluent: DCM: MeOH = 50: 1) to obtain compound D-7A (350 mg).

LC-MS: m/z 949.8 (M+H) ⁺ .

Step 8:

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

LC-MS: m/z 815.4 (M+H) ⁺ .

Step 9:

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

LC-MS: m/z 829.4 (M+H) ⁺ .

Step 10:

The crude product D-9A (336 mg) obtained in the previous step was dissolved in 1,4-dioxane (5 mL), cooled to 5°C in an ice bath, and a 1,4-dioxane solution of hydrochloric acid (4M, 2 mL) was added dropwise. After the addition was completed, the reaction was stirred at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain intermediate D (356 mg).

LC-MS: m/z 729.4 (M+H) ⁺ .

Example 1: Preparation of Compound 1

Step 1:

Dissolve intermediate D (100 mg) in DMF (10 mL), add (R)-2-chloro-2-fluoroacetic acid (18.51 mg), DIPEA (88.59 mg) and HATU (78.18 mg), and stir at room temperature to react. After the reaction is complete, add purified water (50 mL) and DCM (40 mL*2) to extract twice, combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter and concentrate. The crude product was purified by preparative liquid chromatography (the 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); the second step: mobile phase A: 20 mM ammonium acetate, mobile phase B: methanol, gradient: 30% B-90% B (0-60 min); the 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).

LC-MS: m/z 823.6 (M+H) ⁺ .

Example 2: Preparation of Compound 2

Step 1:

Dissolve intermediate D (100 mg) in DMF (10 mL), add 4-methyl-3-cyclohexene-1-carboxylic acid (23.06 mg), DIPEA (88.59 mg) and HATU (78.18 mg), and stir at room temperature to react. After the reaction is complete, add purified water (50 mL) and DCM (40 mL*2) to extract twice, combine the organic phases, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and prepare the crude product by 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).

LC-MS: m/z 851.5 (M+H) ⁺ .

Example 3: Preparation of Compounds 3-A and 3-B

Step 1:

Dissolve intermediate D (100 mg) in DMF (10 mL), add 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), and stir at room temperature to react. After the reaction is complete, add purified water (50 mL), extract twice with DCM (40 mL*2), combine the organic phases, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter and concentrate to obtain a crude compound 3-1 (190 mg).

LC-MS: m/z 952.5 (M+H) ⁺ .

Step 2:

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 the mixture was stirred at room temperature for reaction. After the reaction was complete, the solvent was removed by evaporation under reduced pressure, and the crude product was subjected to 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), and 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 were obtained in turn.

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

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

Embodiment 4-A, 4-B

Step 1:

Dissolve intermediate D (48 mg, containing a mixture of atropisomers) in DMF (10 mL), add (1S, 4R)-4-(Boc-amino)-2-cyclopentenoic acid (17.03 mg), DIPEA (74.45 mg), HATU (28.36 mg), and stir at room temperature to react. The reaction is complete. Add purified water (30 mL), extract twice with EA (40 mL*2), wash twice with brine, dry with anhydrous sodium sulfate for 2 h, filter, and concentrate the filtrate to dryness under reduced pressure to obtain a crude compound 4-1 (68 mg).

Step 2:

The crude compound 4-1 (68 mg) was added to 1,4-dioxane (5 mL), and a 4M HCl solution in 1,4-dioxane (1 mL) was added, and the mixture was stirred at room temperature for reaction. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain 82 mg of the crude product. The purified column was prepared by chromatography: YMC AQ C18, 50*250 mm, 10 μm; mobile phase: A: 0.1% formic acid water, B: methanol; gradient: 10%-80% B (0-60 min). λ: 254 nm, V: 60 mL/min. The hydrochloride of compound 4-A (6 mg) was separated at RT 32.7 min, and the hydrochloride of compound 4-B (14 mg) was separated at RT 38.6 min.

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

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

Test Example 1 AsPc-1 cell proliferation inhibitory activity assay

Take AsPc-1 cells in good growth state, collect them into centrifuge tubes, adjust the cell density to 3×10 ⁴ cells/mL, inoculate them on 96-well plates (100μL/well), and use a nanoliter sampler to add compounds to make the final concentration of the compounds 5000nM-0.31nM, 2 replicates, and set controls at the same time. After continuing to culture in the cell culture incubator for 72 hours, add the detection reagent CCK-8 (manufacturer: Tongren Chemical, 10μL/well), incubate in the cell culture incubator for 3 hours, and detect its absorbance at 450nm with a PerkinElmer Envision microplate reader. Four-parameter analysis, fitting of the dose-effect curve, and calculation of IC ₅₀ . The experimental results are shown in Table 1. Among them, A means IC ₅₀ <100nM; B means 100nM≤IC ₅₀ <500nM.

Test Example 2 Capan-1 cell proliferation inhibitory activity assay

Capan-1 cells in good growth state were collected into centrifuge tubes, the cell density was adjusted to 1.5×10 ⁴ cells/mL, and the cells were inoculated on 96-well plates (100 μL/well). At the same time, the compound was added using a nanoliter pipette to make the final concentration of the compound 20000nM-9.1nM, 2 replicates, and a control was set at the same time. After 5 days of continuous culture in the cell culture incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL/well) was added. After incubation in the cell culture incubator for 4 hours, the absorbance value was detected at 450nm by PerkinElmer Envision microplate reader, and the four-parameter analysis was performed to fit the dose-effect curve and calculate IC ₅₀ . The experimental results are shown in Table 1. Among them, A means IC ₅₀ <100nM; B means 100nM≤IC ₅₀ <500nM.

Table 1 Results of cell proliferation inhibition test of each compound

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

Test Example 3 In vitro liver microsome stability

Liver microsome incubation samples (species: human and mouse) were prepared by mixing PBS buffer (pH = 7.4), liver microsome solution (0.5 mg/mL), test compound and NADPH + MgCl ₂ solution at 37 ° C and 300 rpm for 1 hour. 0 hour samples were prepared by mixing PBS buffer (pH = 7.4), liver microsome solution (0.5 mg/mL), test compound. The samples were added with acetonitrile solution containing internal standard to prepare supernatant by protein precipitation, and diluted for LC/MS/MS determination. The test results are shown in Table 2.

Table 2 In vitro liver microsome metabolic stability results

The test results show that the compounds disclosed herein are stable in vitro in the liver microsome metabolism.

Claims (14)

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 heterocyclyl, wherein the C _6-10 aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclyl is optionally substituted independently by 1, 2 or 3 R ^a ; 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, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 heteroalkyl, _C3-6 cycloalkyl or 3-6 membered heterocyclyl, said _C3-6 cycloalkyl or 3-6 membered heterocyclyl being optionally independently substituted with one or more substituents selected from halogen, =O, _-NH2 , -OH, -SH or -CN; or, R and R' together with the attached carbon atom form C=O, _C3-6 cycloalkyl or 3-6 membered heterocyclyl, said _C3-6 cycloalkyl or 3-6 membered heterocyclyl being optionally independently substituted with 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 heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl, wherein the C _3-14 cycloalkyl, C _3-14 cycloalkenyl, 3-14 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl is optionally substituted independently by 1, 2 or 3 R ^b ; ^Ra and ^Rb are each independently selected from halogen, =O, _-NH2 , -OH, -SH, -CN, _C1-12 alkyl, _C1-12 heteroalkyl, _C2-12 alkenyl, _C2-12 alkynyl, C3-8 cycloalkyl, _3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the _C1-12 alkyl, _C1-12 heteroalkyl, _C2-12 alkenyl or _C2-12 alkynyl is optionally independently substituted with one or more substituents selected from halogen, _-NH2 , -OH, -SH, -CN; the _C3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with one or more substituents selected from halogen, =O, _-NH2 , -OH, -SH, -CN, -COOH, _C1-6 alkyl, _{C1-6 heteroalkyl} , hydroxyl; Substituted by a _{C 1-6} haloalkyl or amino substituted C _1-6 alkyl substituent; R ¹ is 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 heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl, wherein 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, -NH ₂ , -OH, -SH, -CN or -COOH; the C _3-14 cycloalkyl, C _4-14 cycloalkenyl, 4-14 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl is optionally substituted independently by one or more substituents selected from halogen, -NH ₂ , -OH, -SH, -CN, -COOH, C _1-6 alkyl, _{C 1-6} heteroalkyl, hydroxyl Substituted by a _{C 1-6} haloalkyl or amino substituted C _1-6 alkyl substituent; Each R ² is independently selected from halogen, -NH ₂ , -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) ₂ C _1-6 alkyl, -S(O) ₂ NHC _1-6 alkyl, -S(O) ₂ N(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 heterocyclyl, C 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, _{-NH 2 ,} -OH, -SH, -CN, -COOH; the C _3-14 cycloalkyl, C _4-14 cycloalkenyl, 4-14 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl is optionally substituted independently by one or more substituents selected from halogen _, =O, -NH ₂ , -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; ^X1 and ^X3 are each independently selected from CH or N; ^X2 is 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 is selected from hydrogen, halogen, -NH ₂ , -OH, -SH, -CN, C _1-6 alkyl or C _1-6 heteroalkyl, wherein the C _1-6 alkyl or C _1-6 heteroalkyl is optionally substituted independently with 1, 2 or 3 substituents selected from halogen, -NH ₂ , -OH, -SH or -CN. The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein Ring A is selected from C _6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl, and the C _6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl is optionally substituted independently by 1, 2 or 3 R ^a ; Alternatively, Ring A is selected from C _6-10 aryl or 5-10 membered heteroaryl, wherein the C _6-10 aryl or 5-10 membered heteroaryl is optionally substituted independently by 1 or 2 R ^a ; 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 substituted independently by 1 or 2 ^Ra ; 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 substituted independently with 1 or 2 substituents selected from halogen, C _1-4 alkyl, C _2-4 alkynyl, -NH ₂ , -OH, -SH or -CN; Alternatively, ring A is selected from indolyl or pyrrolyl, and the indolyl or pyrrolyl is substituted by 1 or 2 ethyl or ethynyl groups. The compound of formula (I) according to claim 1 or 2, its stereoisomer or 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. The compound of formula (I) according to any one of claims 1 to 3, its stereoisomer or pharmaceutically acceptable salt thereof, wherein R and R' are each independently selected from hydrogen, deuterium, halogen, -NH ₂ , -OH, C _1-3 alkyl, C _1-3 haloalkyl or C _1-3 heteroalkyl; or, R and R' together with the attached carbon atom form C=O or cyclopropyl; Alternatively, R and R' are each independently selected from hydrogen, F, Cl, -NH ₂ , -OH or methyl; Alternatively, R and R' are each independently hydrogen. 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 heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, and the C _5-10 cycloalkyl, C _5-10 cycloalkenyl, 5-10 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2 or 3 R ^b ; 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 substituted independently by 1 or 2 R ^b ; 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 R ^b ; 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 with 1 or 2 R ^b ; 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, -NH ₂ , -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. The compound of formula (I) according to any one of claims 1 to 5, its stereoisomer or pharmaceutically acceptable salt thereof, wherein ^Ra and ^Rb are each independently selected from halogen, =O, _-NH2 , -OH, -SH, -CN, _C1-8 alkyl, _C1-8 heteroalkyl, _C2-8 alkenyl, _C2-8 alkynyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, and the _C1-8 alkyl, C1-8 heteroalkyl, _C2-8 alkenyl or _C2-8 alkynyl is optionally independently substituted with one or more substituents selected from halogen, _-NH2 , -OH, -SH, -CN; the _C3-6 cycloalkyl, _3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with one or more substituents selected from halogen, =O, _-NH2 , -OH, -SH, -CN, -COOH, _C1-4 alkyl, C2-8 heteroalkyl, C2-8 alkenyl or C2-8 alkynyl substituted with a substituent selected from C _1-4 heteroalkyl, hydroxy substituted C _1-4 alkyl, C _1-4 haloalkyl or amino substituted C _1-4 alkyl; Or, optionally, ^Ra is selected from halogen, =O, _-NH2 , -OH, -SH, -CN, _C1-3 alkyl, _C1-3 heteroalkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl or 3-6 membered heterocyclyl, said _C1-3 alkyl, _C1-3 heteroalkyl, _C2-4 alkenyl or _C2-4 alkynyl being optionally independently substituted with one or more substituents selected from halogen, _-NH2 , -OH, -SH or -CN; said _C3-6 cycloalkyl or 3-6 membered heterocyclyl being optionally independently substituted with one or more substituents selected from halogen, =O, _-NH2 , -OH, -SH, -CN, _C1-3 alkyl, _C1-3 heteroalkyl or _C1-3 haloalkyl; Alternatively, ^Ra is selected from F, Cl, _C1-3 alkyl, _-OC1-3 alkyl, -NH( _C1-2 alkyl), -N( _C1-2 alkyl) ₂ or _C2-4 alkynyl, wherein the _C1-3 alkyl, _-OC1-3 alkyl, -NH( _C1-2 alkyl), -N( _C1-2 alkyl) ₂ or _C2-4 alkynyl is optionally substituted independently with one or more halogens; Alternatively, ^Ra is selected from ethyl or ethynyl; or, optionally, R ^b is selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkenyl or C _2-6 alkynyl, said C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkenyl or C _2-6 alkynyl being optionally substituted independently with one or more substituents selected from halogen, -NH ₂ , -OH, -SH or -CN; Alternatively, R ^b is selected from halogen, -NH ₂ , -OH, -SH, -CN or C _1-3 alkyl. The compound of formula (I) according to any one of claims 1 to 6, its stereoisomer or pharmaceutically acceptable salt thereof, wherein R ¹ is 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 heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, and the C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl is optionally independently substituted with one or more substituents selected from halogen, -NH ₂ , -OH, -SH, -CN or -COOH; the C _3-10 cycloalkyl, C _5-10 cycloalkenyl, 4-10 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, -COOH, C _1-6 alkyl, C _1-6 heteroalkyl or C _1-6 haloalkyl; Alternatively, R ¹ is selected from C _3-6 cycloalkyl, n is 1, and the C _3-6 cycloalkyl is optionally substituted by one or more substituents selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, C _1-3 haloalkyl, -NH(CH ₃ ) or -N(CH ₃ ) ₂ ; Alternatively, R ¹ is selected from C _3-6 cycloalkyl, and Ring A is not The C _3-6 cycloalkyl group is optionally substituted by one or more substituents selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, C _1-3 haloalkyl, -NH(CH ₃ ) or -N(CH ₃ ) ₂ , wherein * 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; Alternatively, R ¹ is selected from C _5-8 cycloalkenyl or 5-8 membered partially unsaturated heterocyclyl, wherein the C _5-8 cycloalkenyl or 5-8 membered partially unsaturated heterocyclyl is optionally substituted independently by one or more substituents selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, C _1-3 haloalkyl, -NH(CH ₃ ) or -N(CH ₃ ) ₂ ; Alternatively, 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, -NH ₂ , CHF ₂ or methyl; Alternatively, R ¹ is selected from C _1-3 haloalkyl or C _5-7 cycloalkenyl, wherein the C _5-7 cycloalkenyl is optionally substituted with 1 or 2 substituents selected from halogen, -NH ₂ , C _1-3 alkyl or C _1-3 haloalkyl; Alternatively, ^R1 is selected from halomethyl, Said optionally substituted independently by 1 or 2 substituents selected from halogen, -NH ₂ , C _1-3 alkyl or C _1-3 haloalkyl; Alternatively, ^R1 is selected from Alternatively, ^R1 is selected from The compound of formula (I) according to any one of claims 1 to 7, its stereoisomer or pharmaceutically acceptable salt thereof, wherein each R ² is independently selected from halogen, -NH ₂ , -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) ₂ NH(C _1-3 alkyl), -S(O) ₂ N(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 _1-6 alkyl, C _1-6 heteroalkyl, C 2-6 alkynyl, C _3-10 cycloalkyl, C _{C 3-10} cycloalkyl, C 3-10 cycloalkenyl, 3-10 membered heterocyclyl, 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 with one or more substituents selected from halogen, -NH ₂ , -OH, -SH, -CN, -COOH; the C _3-10 cycloalkyl, C _3-10 cycloalkenyl, 3-10 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl is optionally substituted independently with one or more substituents selected from halogen, =O, -NH ₂ , -OH, -SH, -CN, C _1-4 alkyl, C _1-4 heteroalkyl or C _1-4 haloalkyl; Alternatively, each R ² is independently selected from C _3-8 cycloalkyl, C _5-8 cycloalkenyl or 5-8 membered heterocyclyl, wherein the C _3-8 cycloalkyl, C _5-8 cycloalkenyl or 5-8 membered heterocyclyl is optionally independently substituted with one or more halogen, -NH ₂ , -OH, -SH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, C _1-3 haloalkyl, -NH(CH ₃ ) or -N(CH ₃ ) ₂ ; Alternatively, each R ² 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 substituents selected from halogen, C _1-3 alkyl or C _1-3 haloalkyl; Alternatively, each R ² is independently selected from 5-8 membered heterocycloalkyl, wherein the 5-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, C _1-3 alkyl or C _1-3 haloalkyl; Alternatively, each R ² is independently selected from a 5-6 membered heterocycloalkyl group containing 1 or 2 N atoms, wherein the 5-6 membered heterocycloalkyl group is optionally substituted with 1 or 2 substituents selected from F, Cl or C _1-3 alkyl; Alternatively, each R ² is independently selected from piperazinyl, which is optionally substituted with methyl; Alternatively, each ^R2 is 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. 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 is selected from N, ^X2 is selected from _CH2 or NH, and ^X3 is selected from CH or N; Alternatively, ^X1 and ^X3 are selected from N, and ^X2 is selected from _CH2 or NH; Alternatively, ^X1 and ^X3 are selected from N, and ^X2 is selected from _CH2 ; Alternatively, ^X1 and ^X3 are selected from N, and ^X2 is 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. 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 is selected from hydrogen, halogen, -NH ₂ , -OH, -SH, -CN, C _1-4 alkyl or C _1-4 heteroalkyl, and the C _1-4 alkyl or C _1-4 heteroalkyl is optionally substituted independently with 1, 2 or 3 substituents selected from halogen, -NH ₂ , -OH, -SH or -CN; Alternatively, R ³ is selected from C _1-3 heteroalkyl; Alternatively, R ³ is selected from F, Cl, -NH ₂ , -OH, -CN, C _1-3 alkyl or C _1-3 heteroalkyl, wherein the C _1-3 alkyl or C _1-3 heteroalkyl is optionally substituted independently by 1 or 2 F atoms; Alternatively, ^R3 is selected from The compound of formula (I) according to any one of claims 1 to 10, its stereoisomer 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), its stereoisomer or a pharmaceutically acceptable salt thereof:

wherein p is selected from 1, 2 or 3; each R ^c is independently selected from halogen, =O, -NH ₂ , -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. The following compound, its stereoisomer or a pharmaceutically acceptable salt thereof:

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