Macrocyclic compound, preparation method therefor, and use thereof

Abstract

The present disclosure belongs to the field of medicinal chemistry, and relates to a macrocyclic compound, a preparation method therefor, and use thereof, particularly, to a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition comprising the compound, and use thereof in the treatment of a disease (such as cancer).

Description

Macrocyclic compounds, their preparation methods and uses Technical Field

[0001] This disclosure pertains to the field of medicinal chemistry and relates to macrocyclic compounds, their preparation methods and uses, specifically to compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing the compound, and their use in the treatment of diseases (e.g., cancer). Background Technology

[0002] The discovery of small molecule inhibitors relies on the presence of suitable binding pockets on the protein surface. Approximately 90% of proteins in the human body lack this function, and such targets are often considered untreatable, requiring innovative therapeutic targeting strategies. It has been reported that approximately 30% of human cancers are caused by mutations in Ras proteins (including K-Ras, H-Ras, and N-Ras). Ras proteins play a crucial role in various human cancers, making them suitable targets for anticancer therapies. Specifically, Ras protein dysregulation caused by activating mutations, overexpression, or upstream activation can lead to the growth and proliferation of human tumor cells. For example, KRAS, a small guanosine triphosphatase (GTPase), cycles between an inactive [GDP-bound, OFF] state and an active (GTP-bound, ON) state. The active state of KRAS can bind to and activate various effector proteins to regulate cell growth and proliferation. KRAS mutations stimulate excessive downstream signaling and proliferation, making them an important oncogenic driver closely related to the development and progression of various human cancers. Furthermore, mutations at codons 13 (e.g., G13D) and 61 (e.g., Q61K) in Ras also induce oncogenic activity in some cancers. Currently, there are reports in the literature that drugs targeting the RAS active state (ON) can inactivate oncogenic signals and lead to tumor regression in various human cancer models; however, no such drugs have yet been approved for marketing, and further efforts are needed in this field to discover drugs targeting various Ras mutation-driven cancers. Summary of the Invention

[0003] This disclosure relates to compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0004] in,

[0005] Ring A is selected from C 6-10 aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclic, wherein C 6-10 Aryl, 5-14-membered heteroaryl, or 5-14-membered heterocyclic group may be independently bonded by one, two, or three R groups. a replace;

[0006] 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 -;

[0007] R and R' are each independently selected from hydrogen, deuterium, halogen, -NH2, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 The cycloalkyl or 3-6 membered heterocyclic group is optionally and independently substituted by one or more substituents selected from halogens, =O, -NH2, -OH, -SH, or -CN; or, R and R' together with the attached carbon atom form C=O, ... 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 The cycloalkyl or 3-6 membered heterocyclic group may be independently substituted by one or more substituents selected from halogen, =O, -NH2, -OH, -SH or -CN;

[0008] Ring B is selected from C 3-14 cycloalkyl, C 3-14 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-14 heteroaryl, wherein C 3-14 cycloalkyl, C 3-14 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-14 heteroaryl groups are optionally and independently bound by one, two, or three R groups. b replace;

[0009] R a and R b Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C3-8 Cycloalkyl, 3-8 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein C 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 alkenyl or C 2-12 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, and -CN; the C 3-8 Cycloalkyl, 3-8-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups are optionally and independently bound by one or more groups selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or amino-substituted C 1-6 Alkyl substituents;

[0010] Each R 2 Each is independently selected from halogens, -NH2, -OH, -SH, -CN, and -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 group, -NHS(O)2C 1-6 Alkyl group, -S(O)2NHC 1-6 Alkyl group, -S(O)2N(C) 1- 6-alkyl)2、-P(O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 cycloalkyl, C 4-14 Cycloalkenyl, 4-14 membered heterocyclic groups, C 6-10 Aryl or 5-14 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, -CN, and -COOH, wherein the C 3-14 cycloalkyl, C 4-14 Cycloalkenyl, 4-14 membered heterocyclic groups, C 6-10 Aryl or 5-14 heteroaryl groups are optionally and independently constituting one or more R groups. d replace;

[0011] Each R d Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, -COOH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1- 6-alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-10 Aryl, 5-14 membered heteroaryl, said C 1- 6-alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 The alkyl group (2) is optionally and independently substituted by one or more substituents selected from halogens, -OH, -SH, -NH2, -CN, -NH(CH3)2, or -N(CH3)2, wherein the C 6-10 The aryl or 5-14 heteroaryl group is optionally and independently bound by one or more elements selected from halogen, -OH, -SH, -NH2, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 The alkyl group is substituted with a substituent of (2), wherein the 3-14 membered cycloalkyl group or the 4-14 membered heterocyclic group is optionally independently replaced by one or more substituents selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Substitution of alkyl group 2;

[0012] X 3 Selected from CH or N;

[0013] m is selected from 0, 1, 2, 3 or 4;

[0014] i is selected from 1 or 2;

[0015] q is selected from 0, 1, 2, or 3;

[0016] R 3 Selected from hydrogen, halogens, -NH2, -OH, -SH, -CN, C 1-6 Alkyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6The heteroalkyl group may be independently substituted by one, two or three substituents selected from halogens, -NH2, -OH, -SH or -CN;

[0017] Structural fragments Choose from either (a) or (b) below:

[0018] (a) Structural fragments Selected from

[0019] R 1 Selected from C 2-6 alkenyl, C 2-6 alkynyl group, C 4-14 Cycloalkenyl or 5-14 membered heterocyclic alkenyl, wherein the C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, -CN, or -COOH, wherein the C 4-14 Cycloalkenyl or 5-14 membered heterocyclic alkenyl groups are independently bounded by one or more R groups. c replace;

[0020] Each R c Each is independently selected from C 3-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-10 Aryl, 5-14 membered heteroaryl, said C 6-10 The aryl or 5-14 heteroaryl group is optionally and independently bound by one or more elements selected from halogen, -OH, -SH, -NH2, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1- 6-alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 The alkyl group is substituted with a substituent of (2), wherein the 3-14 membered cycloalkyl group or the 4-14 membered heterocyclic group is optionally independently replaced by one or more substituents selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1- 6-alkyl) or -N(C 1-6 Substitution of alkyl group 2;

[0021] (b) Structural Fragments Selected from

[0022] R 1 Selected from C 2-6 alkenyl, C 2-6 alkynyl group, C 4-14Cycloalkenyl or 5-14 membered heterocyclic alkenyl, wherein the C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, -CN, or -COOH, wherein the C 4-14 The cycloalkenyl or 5-14 membered heterocyclic alkenyl group is optionally and independently surrounded by one or more R groups. c replace;

[0023] Each R c Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, -COOH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1- 6-alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-10 Aryl, 5-14 membered heteroaryl, said C 1- 6-alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 The alkyl group (2) is optionally and independently substituted by one or more substituents selected from halogens, -OH, -SH, -NH2, -CN, -NH(CH3)2, or -N(CH3)2, wherein the C 6-10 The aryl or 5-14 heteroaryl group is optionally and independently bound by one or more elements selected from halogen, -OH, -SH, -NH2, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 The alkyl group is substituted with a substituent of (2), wherein the 3-14 membered cycloalkyl group or the 4-14 membered heterocyclic group is optionally independently replaced by one or more substituents selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2 substituents.

[0024] In some implementations, ring A is selected from C. 6-10 Aryl or 5-13 heteroaryl, wherein C 6-10 Aryl or 5-13 heteroaryl groups are optionally and independently bound by one, two, or three R groups. a Instead, the Ra The definition is as described in this disclosure.

[0025] In some embodiments, ring A is selected from phenyl, 5-6-membered or 9-13-membered heteroaryl groups, wherein the phenyl, 5-6-membered or 9-13-membered heteroaryl group is optionally independently surrounded by one or two R groups. a Instead, the R a The definition is as described in this disclosure.

[0026] In some embodiments, ring A is selected from 5-6-membered or 9-13-membered heteroaryl groups, wherein the 5-6-membered or 9-13-membered heteroaryl group is optionally independently constituted by one or two R groups. a Instead, the R a The definition is as described in this disclosure.

[0027] In some embodiments, ring A is selected from 5-6 member monocyclic heteroaryl or 9-13 member bicyclic or tricyclic heteroaryl, wherein the 5-6 member monocyclic heteroaryl or 9-13 member bicyclic or tricyclic heteroaryl is optionally independently bounded by one or two R groups. a Instead, the R a The definition is as described in this disclosure.

[0028] In some embodiments, ring A is selected from 5-6-membered or 9-13-membered heteroaryl groups, wherein the 5-6-membered or 9-13-membered heteroaryl groups contain 1, 2, or 3 N atoms, and the 5-6-membered or 9-13-membered heteroaryl groups are optionally independently surrounded by 1 or 2 R atoms. a Instead, the R a The definition is as described in this disclosure.

[0029] In some embodiments, ring A is selected from 5-6 membered monocyclic heteroaryl or 9-13 membered bicyclic or tricyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl or 9-13 membered bicyclic or tricyclic heteroaryl contains 1, 2 or 3 N atoms, and the 5-6 membered monocyclic heteroaryl or 9-13 membered bicyclic or tricyclic heteroaryl is optionally independently bounded by 1 or 2 R atoms. a Instead, the R a The definition is as described in this disclosure.

[0030] In some embodiments, ring A is selected from 9-membered or 12-membered heteroaryl groups, wherein the 9-membered or 12-membered heteroaryl group is optionally independently surrounded by one or two R groups. a Instead, the R a The definition is as described in this disclosure.

[0031] In some embodiments, ring A is selected from 9-membered bicyclic heteroaryl or 12-membered tricyclic heteroaryl, wherein the 9-membered bicyclic heteroaryl or 12-membered tricyclic heteroaryl is optionally independently bounded by one or two R groups. a Instead, the R a The definition is as described in this disclosure.

[0032] In some embodiments, ring A is selected from a 9-membered bicyclic heteroaryl or a 12-membered tricyclic heteroaryl, wherein the 9-membered bicyclic heteroaryl or the 12-membered tricyclic heteroaryl contains 1, 2, or 3 N atoms, and the 9-membered bicyclic heteroaryl or the 12-membered tricyclic heteroaryl is optionally independently bounded by 1 or 2 R atoms. a Instead, the R a The definition is as described in this disclosure.

[0033] In some embodiments, ring A is selected from pyrroloyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, triazolyl, furanyl, thiophenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoyindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, indolyl, etc. The ring A is optionally bounded by one or two Rs. a Instead, the R a The definition is as described in this disclosure.

[0034] In some embodiments, ring A is selected from indolyl, isoyindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, indazolyl, etc. The ring A is optionally bounded by one or two Rs. a Instead, the R a The definition is as described in this disclosure.

[0035] In some embodiments, ring A is selected from indole or The indole group or Optionally and independently controlled by one or two R a Instead, the R a The definition is as described in this disclosure.

[0036] In some implementations, ring A is selected from... In this context, * indicates that the bond at that position is connected to L, and ** indicates that the bond at that position is connected to a structural segment. Connect, r is selected from 0, 1 or 2, R a The definition is as stated in this application.

[0037] In some implementations, r is selected from 0 or 1, R a The definition is as stated in this application.

[0038] In some implementations, ring A is selected from... Where * indicates that the bond at that position is connected to L, and ** indicates that the bond at that position is connected to a structural segment. Connected, R a The definition is as stated in this application.

[0039] In some implementations, ring A is selected from... Where * indicates that the bond at that position is connected to L, and ** indicates that the bond at that position is connected to a structural segment. Connected, R a The definition is as stated in this application.

[0040] In some implementations, ring A is Where * indicates that the bond at that position is connected to L, and ** indicates that the bond at that position is connected to a structural segment. Connected.

[0041] In some implementations, ring A is Where * indicates that the bond at that position is connected to L, and ** indicates that the bond at that position is connected to a structural segment. Connected.

[0042] In some implementations, L is selected from -(CRR'). q -、-(CRR') q -(CH=CH) i - or -(CRR') q -(C≡C) i - The definitions of R, R', q, or i are as described in this disclosure.

[0043] In some implementations, L is selected from -(CRR'). q - or -(CRR') q -(CH=CH) i - The definitions of R, R', q, or i are as described in this disclosure.

[0044] In some implementations, L is selected from a key, or -CH=CH-.

[0045] In some implementations, L stands for key.

[0046] In some implementations, R and R' are each independently selected from hydrogen, deuterium, halogen, -NH2, -OH, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 Heteroalkyl. Alternatively, in some embodiments, R and R' together with the linked carbon atom form C=O or cyclopropyl.

[0047] In some implementations, R and R' are each independently selected from hydrogen, F, Cl, -NH2, -OH, or methyl.

[0048] In some implementations, R and R' are each independently hydrogen.

[0049] In some implementations, ring B is selected from C. 5-10 cycloalkyl, C 5-10Cycloalkenyl, 5-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 5-10 cycloalkyl, C 5-10 Cycloalkenyl, 5-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 aryl groups may be selectively coated with 1, 2 or 3 R groups. b Instead, the R b The definition is as described in this disclosure.

[0050] In some embodiments, ring B is selected from phenyl, 5-6-membered or 9-10-membered heteroaryl groups, wherein the phenyl, 5-6-membered or 9-10-membered heteroaryl group is optionally independently surrounded by one or two R groups. b Instead, the R b The definition is as described in this disclosure.

[0051] In some embodiments, ring B is selected from phenyl or 5-6-membered heteroaryl, said phenyl or 5-6-membered heteroaryl optionally independently surrounded by one or two R atoms. b Instead, the R b The definition is as described in this disclosure.

[0052] In some embodiments, ring B is selected from 5-6-membered heteroaryl groups, said 5-6-membered heteroaryl group optionally surrounded by one or two R groups. b Instead, the R b The definition is as described in this disclosure.

[0053] In some embodiments, ring B is selected from pyrrole, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thiophenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl, and ring B is optionally surrounded by one or two R groups. b Instead, the R b The definition is as described in this disclosure.

[0054] In some embodiments, ring B is a thiazolyl group, which is optionally surrounded by one or two R groups. b Instead, the R b The definition is as described in this disclosure.

[0055] 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 selected from 5-membered heteroaryl. In some embodiments, ring B is thiazolyl.

[0056] In some implementation schemes, ring B is Here, # indicates that the key at that position is connected to L, and the ring B is arbitrarily connected by one or two Rs. b Instead, the R bThe definition is as described in this disclosure.

[0057] In some implementation schemes, ring B is Here, # indicates that the key at that position is connected to L.

[0058] In some implementation schemes, R a and R b Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-8 Alkyl, C 1-8 Heteroalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein C 1-8 Alkyl, C 1-8 Heteroalkyl, C 2-8 alkenyl or C 2-8 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, and -CN; the C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups are optionally and independently bound by one or more groups selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-4 Alkyl, C 1-4 Heteroalkyl, hydroxyl-substituted C 1-4 Alkyl, C 1-4 Halogenated alkyl or amino-substituted C 1-4 Alkyl substituents.

[0059] In some implementation schemes, R a Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-3 Alkyl, C 1-3 Heteroalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 1-3 Alkyl, C 1-3 Heteroalkyl, C 2-4 alkenyl or C 2-4 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, or -CN; the C 3-6 The cycloalkyl or 3-6 membered heterocyclic group is optionally and independently surrounded by one or more groups selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, C 1-3 Heteroalkyl or C 1-3 Substituents of haloalkyl groups.

[0060] In some implementation schemes, R a Each is independently selected from halogens, C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 2-4 alkenyl or C 2-4 alkynyl group, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 2-4 alkenyl or C 2-4 The alkynyl group may be independently substituted by one or more halogens.

[0061] In some implementation schemes, R a Each is independently selected from F, Cl, and C. 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C) 1-2 alkyl), -N(C) 1-2 Alkyl)2 or C 2-4 alkynyl group, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C) 1-2 alkyl), -N(C) 1-2 Alkyl)2 or C 2-4 The alkynyl group may be independently substituted by one or more halogens.

[0062] In some implementation schemes, R a Each is independently selected from F, Cl, and C. 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C) 1-2 alkyl), -N(C) 1-2 Alkyl)2 or C 2-4 Alkyne group.

[0063] In some implementation schemes, R a Each is independently selected from F, Cl, and C. 1-4 Alkyl, C 2-4 Alkyne group, -NH2, -OH, -SH or -CN.

[0064] In some implementation schemes, R a Each is independently selected from C 1-3 Alkyl or C 2-4 Alkyne group.

[0065] In some implementation schemes, R a Each is independently selected from ethyl or ethynyl groups.

[0066] In some implementation schemes, R a Each is independently selected from C 1-3 alkyl.

[0067] In some implementation schemes, R a Each is independently selected from ethyl.

[0068] In some implementation schemes, R b Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl or C 2-6 alkynyl group, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl or C 2-6 The alkynyl group may be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, or -CN.

[0069] In some implementation schemes, R b Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-4 Alkyl or C 1-4 Heteroalkyl, the C 1-4 Alkyl or C 1-4 The heteroalkyl group may be independently substituted by one or more substituents selected from F, Cl, -NH2, -OH, -SH or -CN.

[0070] In some implementation schemes, R b Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C) 1-2 alkyl) or -N(C) 1-2 Alkyl)2, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C) 1-2 alkyl) or -N(C) 1-2 Alkyl group 2 may be independently substituted by one, two or three F atoms.

[0071] In some implementation schemes, R b Each is independently selected from halogens, -NH2, -OH, -SH, -CN, or C. 1-3 alkyl.

[0072] In some implementation schemes, R b Each is independently selected from one or two of the following: -F, -Cl, -NH2, -OH, -SH, or -CN.

[0073] In some implementation schemes, R b Each is independently selected from F, Cl, or -OH.

[0074] In some implementations, structural fragments Selected from condition (b), R 1 Selected from C 2-4 alkenyl, C 2-4 alkynyl group, C 4-9 Cycloalkenyl or 5-9 membered heterocyclic alkenyl, wherein the C 2-4 alkenyl or C 2-4 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, -CN, or -COOH; the C 4-9 The cycloalkenyl or 5-9 membered heterocyclic alkenyl group is optionally and independently surrounded by one or more R groups. c replace.

[0075] In some implementations, structural fragments Selected from condition (b), R 1 Selected from C 4-9 Cycloalkenyl or 4-9 membered heterocyclic alkenyl, wherein the C 4-9 The cycloalkenyl or 5-9 membered heterocyclic alkenyl group is optionally and independently surrounded by one or more R groups. c replace.

[0076] In some implementations, structural fragments Selected from condition (b), R 1 Selected from C 4-7 Monocyclic cycloalkenyl, C 7-9 Bicyclic cycloalkenyl, 4-7 membered monocyclic heterocyclic alkenyl, or 7-9 membered bicyclic heterocyclic alkenyl, wherein C 4-7 Monocyclic cycloalkenyl, C 7-9 Bicyclic cycloalkenyl, 4-7 membered monocyclic heterocyclic alkenyl, or 7-9 membered bicyclic heterocyclic alkenyl can be independently separated by one or more R c replace.

[0077] In some implementations, structural fragments Selected from condition (b), R 1 Selected from C 4-9 Cycloalkenyl, the C 4-9 The cycloalkenyl group is optionally surrounded by one or two R groups. c replace.

[0078] In some implementations, structural fragments Selected from condition (b), R 1 Selected from C 4-7 Monocyclic cycloalkenyl, C 7-9 Bicyclic cycloalkenyl, the C 4-7Monocyclic cycloalkenyl, C 7-9 Bicyclic cycloalkenyl groups are optionally surrounded by one or two R groups. c replace.

[0079] In some implementations, structural fragments Selected from condition (b), R 1 Selected from C 4-7 Cycloalkenyl, the C 4-7 The cycloalkenyl group is optionally surrounded by one or two R groups. c replace.

[0080] In some implementations, structural fragments Selected from condition (b), R 1 Selected from 1, 2 or 3 Rs c The following groups may be substituted: cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, bicyclo[2.2.1]hept-2-enyl, or 2,3,3a,4,7,7a-hexahydro-1H-indenyl.

[0081] In some implementations, structural fragments Selected from condition (b), R 1 Selected from 1, 2 or 3 Rs c The following groups are substituted:

[0082] In some implementations, structural fragments Selected from condition (b), R 1 Selected from 1, 2 or 3 Rs c The following groups are substituted:

[0083] In some implementations, structural fragments Selected from condition (b), R 1 Selected from 1, 2 or 3 Rs c The following groups are substituted:

[0084] In some implementations, structural fragments Selected from condition (b), R 1 Selected from 1, 2 or 3 Rs c The following groups are substituted: In some implementations, structural fragments Selected from condition (b), R 1 Selected from 1, 2 or 3 Rs c The following groups are substituted:

[0085] In some implementations, structural fragments Selected from condition (b), R 1 Selected from 1, 2 or 3 Rs c The following groups are substituted:

[0086] In some implementations, structural fragments Selected from condition (b), R 1 Selected from 1, 2 or 3 Rs c The following groups are substituted:

[0087] In some implementations, structural fragments Selected from condition (b), R 1 Selected from In some implementations, structural fragments Selected from condition (b), R 1 Selected from

[0088] In some implementations, structural fragments Selected from condition (b), R 1 Selected from

[0089] In some implementations, structural fragments Selected from condition (b), R 1 Selected from

[0090] In some implementations, structural fragments Selected from condition (b), R 1 Selected from In some implementation schemes, R 1 Selected from

[0091] In some implementations, structural fragments Selected from condition (b), R 1 Selected from

[0092] In some implementations, structural fragments Selected from condition (b), R 1 Selected from

[0093] In some implementations, structural fragments Selected from condition (b), R 1 Selected from In some implementations, structural fragments Selected from condition (b), R 1 Selected from

[0094] In some implementations, structural fragments Selected from condition (b), R 1 Selected from

[0095] In some implementations, structural fragments Selected from condition (b), R 1 Selected from

[0096] In some implementations, structural fragments Selected from condition (b), R 1 Selected from

[0097] In some implementations, structural fragments Selected from condition (a), R 1 Selected from C 2-4 alkenyl, C 2-4 alkynyl group, C 4-9 Cycloalkenyl or 5-9 membered heterocyclic alkenyl, wherein the C 2-4 alkenyl or C 2-4 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, -CN, or -COOH; the C 4-9 Cycloalkenyl or 5-9 membered heterocyclic alkenyl groups are independently bounded by one or more R groups. c replace.

[0098] In some implementations, structural fragments Selected from condition (a), R 1 Selected from C 4-9 Cycloalkenyl or 4-9 membered heterocyclic alkenyl, wherein the C 4-9 Cycloalkenyl or 5-9 membered heterocyclic alkenyl groups are independently bounded by one or more R groups. c replace.

[0099] In some implementations, structural fragments Selected from condition (a), R 1 Selected from C 4-7 Monocyclic cycloalkenyl, C 7-9 Bicyclic cycloalkenyl, 4-7 membered monocyclic heterocyclic alkenyl, or 7-9 membered bicyclic heterocyclic alkenyl, wherein C 4-7 Monocyclic cycloalkenyl, C 7-9 Bicyclic cycloalkenyl, 4-7 membered monocyclic heterocyclic alkenyl, or 7-9 membered bicyclic heterocyclic alkenyl are independently bounded by one or more R c replace.

[0100] In some implementations, structural fragments Selected from condition (a), R 1 Selected from C 4-9 Cycloalkenyl, the C 4-9 The cycloalkenyl group is surrounded by one or two R groups. c replace.

[0101] In some implementations, structural fragments Selected from condition (a), R 1 Selected from C 4-7 Monocyclic cycloalkenyl, C 7-9 Bicyclic cycloalkenyl, the C 4-7 Monocyclic cycloalkenyl, C 7-9 The bicyclic cycloalkenyl group is independently bounded by one or two R groups. c replace.

[0102] In some implementations, structural fragments Selected from condition (a), R 1 Selected from C 4-7 Cycloalkenyl, the C 4-7 The cycloalkenyl group is surrounded by one or two R groups. c replace.

[0103] In some implementations, structural fragments Selected from condition (a), R 1 Selected from 1, 2 or 3 R c The following groups may be substituted: cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, bicyclo[2.2.1]hept-2-enyl, or 2,3,3a,4,7,7a-hexahydro-1H-indenyl.

[0104] In some implementations, structural fragments Selected from condition (a), R 1 Selected from 1, 2 or 3 R c The following groups are substituted:

[0105] In some implementations, structural fragments Selected from condition (a), R 1 Selected from 1, 2 or 3 R c The following groups are substituted:

[0106] In some implementations, structural fragments Selected from condition (a), R 1 Selected from 1, 2 or 3 R c The following groups are substituted:

[0107] In some implementations, structural fragments Selected from condition (a), R 1 Selected from 1, 2 or 3 R c The following groups are substituted: In some implementations, structural fragments Selected from condition (a), R 1 Selected from 1, 2 or 3 R c The following groups are substituted:

[0108] In some implementations, structural fragments Selected from condition (a), R 1 Selected from 1, 2 or 3 R c The following groups are substituted:

[0109] In some implementations, structural fragments Selected from condition (a), R 1 Selected from 1, 2 or 3 R c The following groups are substituted:

[0110] In some implementations, structural fragments Selected from condition (a), R 1 Selected from In some implementations, structural fragments Selected from condition (a), R 1 Selected from

[0111] In some implementations, structural fragments Selected from condition (a), R 1 Selected from

[0112] In some implementations, structural fragments Selected from condition (a), R 1 Selected from

[0113] In some implementations, structural fragments Selected from condition (a), R 1 Selected from

[0114] In some implementations, structural fragments Selected from condition (a), R 1 Selected from

[0115] In some implementations, structural fragments Selected from condition (a), R 1 Selected from

[0116] In some implementations, structural fragments Selected from condition (a), R 1 Selected from

[0117] In some implementations, structural fragments Selected from condition (b), each R c Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, -COOH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-10 Aryl, 5-14 membered heteroaryl, said C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 6-10 The aryl or 5-14-membered heteroaryl group is optionally and independently substituted by one or more substituents selected from halogens, -OH, -SH, -NH2, -CN, -NH(CH3) or -N(CH3)2, and the 3-14-membered cycloalkyl or 4-14-membered heterocyclic group is optionally and independently substituted by one or more substituents selected from halogens, =O, -NH2, -OH, -SH, -CN, -COOH, C1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2 substituents.

[0118] In some implementations, structural fragments Selected from condition (b), each R c Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-8 Cycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1- 6-alkyl)2, phenyl, naphthyl, 5-10 heteroaryl groups are optionally and independently substituted by one or two substituents selected from halogens, -OH or -NH2, wherein C 3-8 The cycloalkyl group or 4-10 membered heterocyclic group is optionally and independently surrounded by one or more groups selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NH(C) 1-3 alkyl) or -N(C) 1-3 Alkyl)2 substituents.

[0119] In some implementations, structural fragments Selected from condition (b), each R c Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group, 2-phenyl group, naphthyl group, 5-10-membered heteroaryl group, or 4-10-membered heterocyclic group, wherein the phenyl group, naphthyl group, 5-10-membered heteroaryl group, or 4-10-membered heterocyclic group is optionally surrounded by one or more groups selected from F, Cl, -OH, -SH, -NH2, -CN, C. 1-6 Alkyl, -OC1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2 substituents.

[0120] In some implementations, structural fragments Selected from condition (b), each R c Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl), 2-phenyl, naphthyl, 5-10 heteroaryl or 4-10 heterocyclic group.

[0121] In some implementations, structural fragments Selected from condition (b), each R c Each is independently selected from halogens, -OH, -NH2, -CN, -SH, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -O(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -SC 1-6 Alkyl, -NH(C) 1-6 Alkyl), phenyl, 5-6 membered heteroaryl, or containing 1-2 5-8 membered heterocyclic groups selected from N or O heteroatoms.

[0122] In some implementations, structural fragments Selected from condition (b), each R c Each is independently selected from F, Cl, -OH, -NH2, -CN, -SH, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -O(C) 1-4 alkyl), -N(C) 1-4 2. Alkyl group, phenyl group, 5-6 membered heteroaryl group containing 1-2 nitrogen atoms or 5-6 membered heterocyclic group containing 1-2 nitrogen atoms or nitrogen atoms, wherein the phenyl group, 5-6 membered heteroaryl group containing 1-2 nitrogen atoms or 5-6 membered heterocyclic group containing 1-2 nitrogen atoms or nitrogen atoms or nitrogen atoms is optionally surrounded by one or more atoms selected from F, Cl, -OH, -SH, -NH2, -CN, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH(C) 1-4 alkyl) or -N(C) 1-4Alkyl)2 substituents.

[0123] In some implementations, structural fragments Selected from condition (b), each R c Each is independently selected from F, Cl, -OH, -NH2, -CN, -SH, and C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, -O(C) 1-3 alkyl), -N(C) 1-3 Alkyl group, phenyl group, 5-6 membered heteroaryl group containing 1-2 N atoms or 5-6 membered heterocyclic group containing 1-2 N or O heteroatoms.

[0124] In some implementations, structural fragments Selected from condition (b), each R c Each is independently selected from F, Cl, -OH, -NH2, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -O(C) 1-3 alkyl), -N(C) 1-3 Alkyl group, phenyl group, 5-6 membered heteroaryl group containing 1-2 nitrogen atoms, or 5-6 membered heterocyclic group containing 1-2 nitrogen atoms selected from nitrogen or oxygen, wherein the 5-6 membered heteroaryl group containing 1-2 nitrogen atoms is optionally surrounded by one or more atoms selected from nitrogen, oxygen, carbon ... 1-4 Alkyl substituents.

[0125] In some implementations, structural fragments Selected from condition (b), each R c Each is independently selected from F, Cl, -OH, -NH2, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -O(C) 1-3 alkyl), -N(C) 1-3 Alkyl group, phenyl group, 5-6 membered heteroaryl group containing 1-2 N atoms or 5-6 membered heterocyclic group containing 1-2 N or O heteroatoms.

[0126] In some implementations, structural fragments Selected from condition (b), each R c Each is independently selected from F, Cl, -OH, -NH2, CF3, -OCH3, methyl, -N(CH3)2, phenyl, pyrazolyl or pyrrolidinyl.

[0127] In some implementations, structural fragments Selected from condition (b), each R c Each is independently selected from F, Cl, -OH, -NH2, CF3, -OCH3, C1-3 Alkyl, -N(C) 1-3 Alkyl)2, phenyl, pyrroleyl or optionally with one or two C 1-3 Alkyl-substituted pyrazolyl group.

[0128] In some implementations, structural fragments Selected from condition (b), each R c Each is independently selected from F, Cl, -OH, -NH2, CF3, -OCH3, methyl, -N(CH3)2, phenyl, pyrrolyl, or pyrazolyl group optionally substituted with one methyl group.

[0129] In some implementations, structural fragments Selected from condition (b), each R c Each is independently selected from F, Cl, -OH, -NH2, CF3, -OCH3, methyl, -N(CH3)2,

[0130] In some implementations, structural fragments Selected from condition (a), each R c Each is independently selected from C 3-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-10 Aryl, 5-14 membered heteroaryl, said C 6-10 The aryl or 5-14-membered heteroaryl group is optionally and independently substituted by one or more substituents selected from halogens, -OH, -SH, -NH2, -CN, -NH(CH3) or -N(CH3)2, and the 3-14-membered cycloalkyl or 4-14-membered heterocyclic group is optionally and independently substituted by one or more substituents selected from halogens, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2 substituents.

[0131] In some implementations, structural fragments Selected from condition (a), each R c Each is independently selected from C 3-8 Cycloalkyl, phenyl, naphthyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group, wherein the phenyl, naphthyl, or 5-10-membered heteroaryl group is optionally independently substituted by one or two substituents selected from halogens, -OH, or -NH2, wherein the C 3-8 The cycloalkyl group or 4-10 membered heterocyclic group is optionally and independently surrounded by one or more groups selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC1-3 Alkyl, -SC 1-3 Alkyl, -NH(C) 1-3 alkyl) or -N(C) 1-3 Alkyl)2 substituents.

[0132] In some implementations, structural fragments Selected from condition (a), each R c Each is independently selected from phenyl, naphthyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclic group.

[0133] In some implementations, structural fragments Selected from condition (a), each R c Each is independently selected from phenyl, 5-6-membered heteroaryl, or containing 1-2 5-8-membered heterocyclic groups selected from N or O heteroatoms.

[0134] In some implementations, structural fragments Selected from condition (a), each R c Each of the following groups is independently selected from phenyl, a 5-6 membered heteroaryl group containing 1-2 nitrogen atoms, or a 5-6 membered heterocyclic group containing 1-2 nitrogen atoms or nitrogen atoms (N or O). The phenyl, 5-6 membered heteroaryl group containing 1-2 nitrogen atoms, or 5-6 membered heterocyclic group containing 1-2 nitrogen atoms or nitrogen atoms (N or O) is optionally surrounded by one or more groups selected from F, Cl, -OH, -SH, -NH2, -CN, C. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -NH(C) 1-4 alkyl) or -N(C) 1-4 Alkyl)2 substituents.

[0135] In some implementations, structural fragments Selected from condition (a), each R c Each is independently selected from phenyl, 5-6 membered heteroaryl groups containing 1-2 N atoms, or 5-6 membered heterocyclic groups containing 1-2 N or O heteroatoms.

[0136] In some implementations, structural fragments Selected from condition (a), each R c Each of the following groups is independently selected from phenyl, a 5-6 membered heteroaryl group containing 1-2 nitrogen atoms, or a 5-6 membered heterocyclic group containing 1-2 nitrogen atoms selected from nitrogen or oxygen atoms, wherein the 5-6 membered heteroaryl group containing 1-2 nitrogen atoms is optionally surrounded by one or more atoms selected from F, Cl, OH, NH2, CN, or C. 1-4 Alkyl substituents.

[0137] In some implementations, structural fragments Selected from condition (a), each R c Each is independently selected from phenyl, pyrazolyl, or pyrrolidinyl.

[0138] In some implementations, structural fragments Selected from condition (a), each R c Each is independently selected from phenyl, pyrroleyl, or optionally surrounded by one or two C atoms. 1-3 Alkyl-substituted pyrazolyl group.

[0139] In some implementations, structural fragments Selected from condition (a), each R c Each is independently selected from phenyl, pyrrolidinyl, or pyrazolyl groups optionally substituted with one methyl group.

[0140] In some implementations, structural fragments Selected from condition (a), each R c Each independently selected

[0141] In some implementation schemes, X 3 Let N be the number of elements in the array.

[0142] In some implementations, the structural fragment in condition (a) Selected from

[0143] In some implementations, the structural fragment in condition (b) Selected from

[0144] In some implementations, each R 2 Each is independently selected from halogens, -NH2, -OH, -SH, -CN, -C(O)NH(C) 1-3 Alkyl), -C(O)N(C 1-3 Alkyl)2、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -N(C) 1-3 Alkyl)C(O)(C 1-3 Alkyl), -NHS(O)2(C 1-3 Alkyl), -S(O)2NH(C 1-3 Alkyl), -S(O)2N(C 1-3 Alkyl)2、-P(O)(C 1-3 Alkyl)2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-10cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, -CN, or -COOH, wherein the C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups are optionally and independently bounded by one or more R groups. d replace.

[0145] In some implementations, each R 2 Each is independently selected from F, Cl, -NH2, -OH, -SH, -CN, and C. 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-8 cycloalkyl, C 5-8 Cycloalkenyl, 5-14 membered heterocyclic groups, C 6-10 Aryl or 5-6 heteroaryl, wherein C 1-4 Alkyl or C 1-4 The heteroalkyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, -CN, or -COOH, wherein the C 3-8 cycloalkyl, C 5-8 Cycloalkenyl, 5-14 membered heterocyclic groups, C 6-10 Aryl or 5-6 heteroaryl groups are optionally and independently bounded by one or more R groups. d replace.

[0146] In some implementations, each R 2 Each is independently selected from C 3-8 cycloalkyl, C 5-8 Cycloalkenyl or 5-8 membered heterocyclic groups, wherein the C 3-8 cycloalkyl, C 5-8 The cycloalkenyl or 5-8 membered heterocyclic group is optionally and independently surrounded by one or more R groups. d replace.

[0147] In some implementations, each R 2 Each is independently selected from 5-8 membered heterocyclic groups, wherein the 5-8 membered heterocyclic group is optionally converted by one or more R d replace.

[0148] In some implementations, each R 2Each is independently selected from 5-8 membered heterocyclic groups containing one or two N or O atoms, wherein the 5-8 membered heterocyclic group is optionally selected by one or more of R atoms. d replace.

[0149] In some implementations, each R 2 Each is independently selected from 5-8 membered heterocyclic alkyl groups, wherein the 5-8 membered heterocyclic alkyl group is optionally surrounded by one or more R d replace.

[0150] In some implementations, each R 2 Each is independently selected from 5-6 membered heterocyclic alkyl groups containing one or two heteroatoms selected from N or O, wherein the 5-6 membered heterocyclic alkyl group is optionally surrounded by one or more R atoms. d replace.

[0151] In some implementations, each R 2 Each is independently selected from 5-6 membered heterocyclic alkyl groups containing one or two N atoms, wherein the 5-6 membered heterocyclic alkyl group is optionally surrounded by one or two R atoms. d replace.

[0152] In some implementations, each R 2 Each is independently selected from piperidinyl or piperazine, wherein the piperidinyl or piperazine is optionally independently surrounded by one or two R groups. d replace.

[0153] In some implementations, each R 2 Each is independently selected from piperazine groups, wherein the piperazine group is optionally independently surrounded by one or two R groups. d replace.

[0154] In some implementations, each R d Each is independently selected from halogens, -OH, -NH2, and C. 1-3 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-6 membered heterocyclic group, wherein C 1-3 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NH(C) 1-3 alkyl) or -N(C) 1-3 The alkyl group, 2-phenyl group, or 5-6-membered heteroaryl group may be independently substituted by one or two substituents selected from halogens, -OH, or -NH2, wherein the C 3-6The cycloalkyl or 4-6 membered heterocyclic group is optionally and independently surrounded by one or more groups selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NH(C) 1-3 alkyl) or -N(C) 1-3 Alkyl)2 substituents.

[0155] In some implementations, each R d Each is independently selected from halogens, -OH, -NH2, and C. 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-6 membered heterocyclic group, wherein C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C) 1- 3-alkyl), -N(C) 1-3 Alkyl)2, C 3-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl or 4-6-membered heterocyclic groups may be independently substituted by one or two substituents selected from halogens, -OH or -NH2.

[0156] In some implementations, each R d Each is independently selected from halogens, -OH, -NH2, and C. 1-3 Alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclic group may be independently substituted by one or two substituents selected from halogens, -OH or -NH2.

[0157] In some implementations, each R d Each is independently selected from C 1-3 Alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclic group may be independently substituted by one or two substituents selected from halogens, -OH or -NH2.

[0158] In some implementations, each R d Each is independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl.

[0159] In some implementations, each Rd Each is independently selected from C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0160] In some implementations, each R d Each is independently selected from methyl or cyclopropyl.

[0161] In some implementations, each R 2 Each is independently piperazine group, which may optionally be substituted with methyl or cyclopropyl groups.

[0162] In some implementations, each R 2 Each independently selected

[0163] In some implementations, each R 2 Each independently

[0164] In some implementations, m is selected from 0, 1, or 2.

[0165] In some implementations, m is selected from 0 or 1.

[0166] In some implementations, m is 1.

[0167] In some implementations, i is 1.

[0168] In some implementations, q is selected from 0, 1, or 2.

[0169] In some implementations, q is selected from 0 or 1. In some implementations, q is 0.

[0170] In some implementation schemes, R 3 Selected from hydrogen, halogens, -NH2, -OH, -SH, -CN, C 1-4 Alkyl or C 1-4 Heteroalkyl, the C 1-4 Alkyl or C 1-4 The heteroalkyl group may be independently substituted by one, two or three substituents selected from halogens, -NH2, -OH, -SH or -CN.

[0171] In some implementation schemes, R 3 Selected from F, Cl, -NH2, -OH, -CN, C 1-3 Alkyl or C 1-3 Heteroalkyl, the C 1-3 Alkyl or C 1- The 3 heteroalkyl groups may be independently substituted by one or two F atoms.

[0172] In some implementation schemes, R 3 Selected from C1-3 Heteroalkyl. In some embodiments, R 3 Selected from C3 heteroalkyl groups.

[0173] In some implementation schemes, R 3 Selected from -OC 1-3 Alkyl-substituted C 1-3 alkyl.

[0174] In some implementation schemes, R 3 for

[0175] In some implementation schemes, R 3 for

[0176] In some implementations, structural fragments Selected from

[0177] In some implementations, structural fragments Selected from

[0178] In some embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof described in this disclosure are selected from the compounds of formula (IX), formula (I-1), formula (I-1A), formula (I-2), formula (I-2A), formula (I-2A-1), formula (I-2A-2), formula (I-3), formula (I-3A), formula (I-4), formula (I-4A), formula (I-4A-1), formula (I-5), formula (I-5A), or formula (I-5A-1), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0179] Wherein, p is selected from 0, 1, 2 or 3;

[0180] The value of j is selected from 1, 2, 3, or 4;

[0181] Rings A, B, L, and R 1 R 2 R 3 R a R c X 3 m and structural fragments The definition is as described in this disclosure.

[0182] In some implementations, p is selected from 0 or 1. In some implementations, p is 1.

[0183] In some implementations, j is selected from 1, 2, or 3. In some implementations, j is selected from 2 or 3.

[0184] In some implementation schemes, R, R', R a R b R c R d R 1 R 2 and R 3 One or more of them contain deuterium.

[0185] In the specific implementation scheme and / or claims regarding any particular X 3 Ring A, L, Ring B, R 1 R 2 R 3 R a R b R c R d Where the range of substituents R and R' is disclosed, it should be understood that one or more substituents may be deleted from that range, and the remaining range of substituents should also be considered as an embodiment of this disclosure.

[0186] This disclosure provides the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0187] This disclosure provides the following compounds or pharmaceutically acceptable salts thereof.

[0188] On the other hand, this disclosure relates to the above-mentioned compounds in crystalline or amorphous form, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0189] On the other hand, this disclosure provides pharmaceutical compositions comprising the compounds described above, their stereoisomers, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions of this disclosure further include pharmaceutically acceptable excipients.

[0190] In some embodiments, the pharmaceutical composition contains 0.01 mg to 1000 mg (in the free form of the compound) of the above-mentioned compound or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, the pharmaceutical composition contains a single dose (based on the compound, its stereoisomers or pharmaceutically acceptable salts thereof) of 0.01 mg to 1000 mg (based on the free form of the compound).

[0192] In some embodiments, the 0.01 mg to 1000 mg is further selected from 0.1 mg to 1000 mg, 1 mg to 1000 mg, 10 mg to 1000 mg, 20 mg to 1000 mg, 30 mg to 1000 mg, or 31 mg to 1000 mg.

[0193] In some embodiments, the pharmaceutical composition contains, in the form of, 0.01 to 95% wt or 0.4 to 95% wt of the above-mentioned compound or a pharmaceutically acceptable salt thereof, in the free form of the compound.

[0194] In some embodiments, the 0.01–95% wt is further selected from 0.1–95% wt, 0.4–95% wt, or 1–95% wt.

[0195] In some embodiments, the pharmaceutical composition wherein the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the above-mentioned compound or a pharmaceutically acceptable salt thereof in crystalline or amorphous form.

[0196] In some embodiments, the target of administration of the pharmaceutical composition is selected from mammals, such as humans.

[0197] In some embodiments, the pharmaceutical composition is selected from solid pharmaceutical compositions, semi-solid pharmaceutical compositions, liquid pharmaceutical compositions, or gaseous pharmaceutical compositions.

[0198] In some embodiments, the pharmaceutical composition is selected from solid pharmaceutical compositions.

[0199] In some embodiments, the pharmaceutical composition is selected from liquid pharmaceutical compositions.

[0200] In some embodiments, the pharmaceutical composition is selected from pharmaceutical compositions in oral or injectable form.

[0201] In some embodiments, the pharmaceutical composition is selected from pharmaceutical compositions in oral form.

[0202] In some embodiments, the pharmaceutical composition is selected from injectable pharmaceutical compositions.

[0203] In some embodiments, the pharmaceutical composition is selected from oral solid pharmaceutical compositions.

[0204] In some embodiments, the pharmaceutical composition is selected from liquid pharmaceutical compositions for injection.

[0205] In some embodiments, the pharmaceutical compositions disclosed herein also include pharmaceutically acceptable excipients.

[0206] On the other hand, this disclosure provides a method for preventing or treating diseases related to Ras protein in mammals, the method comprising administering to a mammal, preferably a human, a therapeutically effective amount of the above-mentioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0207] On the other hand, this disclosure provides the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of diseases related to Ras protein.

[0208] On the other hand, this disclosure provides the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the prevention or treatment of diseases related to Ras protein.

[0209] On the other hand, this disclosure provides the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the prevention or treatment of diseases related to Ras protein.

[0210] Furthermore, the compound or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, may optionally be used in combination with one or more other drugs.

[0211] Furthermore, this disclosure relates to the use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention or treatment of diseases related to Ras protein, in combination with one or more other drugs.

[0212] Furthermore, this disclosure relates to the use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in combination with one or more other drugs, in the preparation of a medicament for the prevention or treatment of diseases related to Ras protein.

[0213] Furthermore, this disclosure relates to the use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more other pharmaceuticals in the preparation of a medicament for the prevention or treatment of diseases related to Ras protein.

[0214] Furthermore, this disclosure relates to the use of the aforementioned compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases related to Ras protein, wherein the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof are used in combination with one or more other medicaments.

[0215] In another aspect, this disclosure relates to the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases related to Ras protein, wherein the prevention or treatment includes use in combination with one or more other medicaments.

[0216] In some implementations, the Ras protein-related diseases are selected from cancer.

[0217] In some implementations, the Ras protein-associated disease is selected from pancreatic cancer.

[0218] The compounds disclosed herein, or the compounds described herein, include compounds of general formulas, specific compounds, or compounds of embodiments.

[0219] The compounds disclosed herein include compounds of formula (I), (IX), (I-1), (I-1A), (I-2), (I-2A), (I-2A-1), (I-2A-2), (I-3), (I-3A), (I-4), (I-4A), (I-4A-1), (I-5), (I-5A), (I-5A-1), or specific compounds or compounds of the examples.

[0220] Technical effect

[0221] The disclosed compounds, their pharmaceutically acceptable salts, or pharmaceutical compositions thereof exhibit good Ras protein inhibitory activity, as well as good AsPc-1 and Capan-1 cell proliferation inhibitory activity. They are also metabolically stable in liver microsomes in vitro, and possess good in vivo pharmacodynamics and pharmacokinetic properties.

[0222] definition

[0223] Unless otherwise stated, the following terms as used in this disclosure have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0224] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0225] The terms “optional” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group being “optionally” substituted with a halogen means that the ethyl group can be unsubstituted (-CH2CH3), monosubstituted (e.g., -CH2CH2F), polysubstituted (e.g., -CHFCH2F, -CH2CHF2, etc.), or fully substituted (-CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0226] C in this article m-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms; "C 1-3 "" means that the group can have 1 carbon atom, 2 carbon atoms or 3 carbon atoms.

[0227] In this article, "one or more" refers to an integer from one to ten. For example, "one or more" means one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" means one, two, three, four, five, or six; or, "one or more" means one, two, or three.

[0228] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.

[0229] When a substituent is cross-bonded between two atoms on a ring, it can bond with any atom on that ring. For example, structural units. This indicates that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0230] Groups or structural moiety in this application, such as -NH-(CRR') q -、-O-(CRR') q -、-S-(CRR') q -、-(CRR') q -(CH=CH) i -、-NH-(CH=CH) i -、-O-(CH=CH) i -、-S-(CH=CH) i -、-(CRR') q -(C≡C)i -、-NH-(C≡C) i -、-O-(C≡C) i -or-S-(C≡C) i - and its specific options, which can optionally be read from left to right, are respectively connected to the group or part of the left and right groups in the general formula, as in -(CRR'). q -(CH=CH) i In the middle, following the reading order from left to right, -(CRR') q - Connect to ring A on the left side of the general formula, -(CH=CH) i - Connects to ring B on the right. Optionally, such as the groups or structural portions described above, a right-to-left reading order can also be used, specifically as -(CRR'). q -(CH=CH) i In the middle, following the reading order from right to left, -(CH=CH) i - Connects to ring A on the left, -(CRR') q - Connect to ring B on the right side of the general formula.

[0231] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0232] The term "hydroxyl group" refers to the -OH group.

[0233] The term "amino" refers to the -NH2 group.

[0234] The term "nitro" refers to the -NO2 group.

[0235] The term "cyano" refers to the -CN group.

[0236] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1 The alkyl group. This alkyl group can be straight-chain or branched. For example, the term "C 1-6 "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 groups has the same definition as above.

[0237] The term "heteroalkyl" refers to a straight-chain or branched alkyl group composed of a certain number of carbon atoms and at least one skeletal chain heteroatom or heteroatomic group, preferably having 1 to 14 carbon atoms in the chain, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms. The heteroatoms are preferably 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 heteroatomic group is preferably -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. Numerical range (e.g., C 1-6 A heteroalkyl group (C3) refers to the number of carbon atoms in a chain, in this example meaning 1-6 carbon atoms. For example, the -CH2OCH2CH3 group is called a C3 heteroalkyl group. Heteroatoms or heterogroups can be located at any internal position of the heteroalkyl group, including positions where the alkyl group is attached to the rest of the molecule. In said heteroalkyl groups, the portion directly attached to the parent structure can optionally be a carbon atom, a heteroatom, or a heterogroup. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, alkyl sulfides, tertiary amine alkyl groups, or secondary aminoalkyl groups, including alkoxy, alkylthio, and alkylamino groups; unless otherwise specified, C3... 1-6 Heteroalkyl groups include C1, C2, C3, C4, C5, and C6 heteroalkyl groups, such as C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino.

[0238] The term "bicyclic" refers to a cyclic group containing two rings, which can be fully saturated, partially saturated, or aromatic. The bicyclic group may consist entirely of carbon atoms or contain one or more heteroatoms selected from N, O, S, or P, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom may also be optionally quaternized. The bicyclic group can be a fused ring, a bridged ring, or a spirocyclic ring.

[0239] The term "tricyclic" refers to a cyclic group containing three rings, which can be fully saturated, partially saturated, or aromatic. The tricyclic group may consist entirely of carbon atoms or contain one or more heteroatoms selected from N, O, S, or P, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom may also be optionally quaternized. Any two rings in the tricyclic group can be fused rings, bridged rings, or spirocyclic rings.

[0240] The term "cycloalkyl" refers to a fully saturated carbon ring. Unless otherwise indicated, the carbon ring is typically a 3- to 14-membered ring. Unless otherwise indicated, the cycloalkyl group can be monocyclic, bicyclic, or tricyclic. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0241] The term "heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated) and can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 20-membered, 3- to 14-membered, 3- to 12-membered, or 3- to 10-membered ring (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered), 4- to 8-membered, 5- to 8-membered, or 5- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclic groups include, but are not limited to, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, pyrrolylyl, N-methylpyrrolylyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolylyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophene, etc.

[0242] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbon ring that can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 16-membered, 3- to 14-membered, 3- to 12-membered, 3- to 10-membered, or 3- to 8-membered ring (specifically, for example, 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered rings). Unless otherwise indicated, the cycloalkenyl group can be monocyclic, bicyclic, or tricyclic. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and cycloheptadienyl. wait.

[0243] The term "heterocyclic alkenyl" includes cycloalkenyl groups in which one or more carbon atoms are replaced by heteroatoms, specifically, for example, cycloalkenyl groups in which at most three carbon atoms, at most two carbon atoms, or in one embodiment, one carbon atom is independently replaced by N, O, or S (O), provided that at least one cycloalkenyl carbon-carbon double bond is retained. Heterocyclic alkenyl groups can be cyclic groups existing as monocyclic, bridged, or spirocyclic groups, and can be 3 to 16-membered rings (e.g., 3 to 12-membered, 5 to 8-membered rings, specifically 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered rings). Examples of heterocyclic alkenyl groups include, but are not limited to, dihydropyridyl, dihydropyrrole, tetrahydropyridyl, tetrahydroazapyrrolyl, or azaspirooctene.

[0244] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic ring having a conjugated π-electron system. Unless otherwise indicated, aryl groups 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, anthracene, and 1,2,3,4-tetrahydronaphthalene, preferably phenyl. In some embodiments, the aryl group may be a phenyl group fused with a heterocyclic group or 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 aryl group is a benzene ring. Non-limiting examples of aryl groups include, but are not limited to, […]. wait.

[0245] The term "heteroaryl" refers to a monocyclic or polycyclic system containing at least one element selected from N, O, or S(O). n P(O) n An aromatic ring having at least one heteroaryl ring, wherein n is 0, 1, or 2 ring atoms, the remaining ring atoms are carbon, and n is a ring of at least one heteroaryl ring. Unless otherwise indicated, the heteroaryl group may be monocyclic, bicyclic, or tricyclic. Unless otherwise indicated, the heteroaryl group may have a single 5- to 8-membered ring, or multiple fused rings comprising 6 to 14, particularly 6 to 10, ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, isoindoleyl, etc. In some embodiments, the heteroaryl group may be a 5- or 6-membered heteroaryl group fused with an aryl, heteroaryl, heterocyclic, cycloalkyl, or cycloalkenyl group to form two or more rings (e.g., two, three, four rings, etc.). The heteroaryl ring in the heteroaryl group is directly connected to the parent structure. Non-limiting embodiments of the heteroaryl group include, but are not limited to, those mentioned above. wait.

[0246] Unless otherwise specified, the term "heteroatom" means heteroatom or heterogroup (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing such heteroatoms, such as heteroatoms including but not limited to oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), and boron (B), and specific heteroatoms or heterogroups such as: -O-, -S-, -N=, =O, =S, -P(=O)-, -P(=O)2-, -P(=O)O-, -P(=O)2O-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, and optionally substituted -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- or -S(=O)N(H)-. Preferably, the term "heterogeneous" means that the heteroatom or heteroatomic group (i.e., a group containing a heteroatom) is selected from oxygen, nitrogen, or sulfur.

[0247] The term "treatment" means administering the compounds or preparations described in this disclosure to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0248] (i) Suppress the disease or disease state, that is, curb its development;

[0249] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0250] The term "therapeutic effective amount" means the amount of the disclosed compound used to treat (i) the specific disease, condition, or disorder described herein, (ii) reduce, improve, or eliminate one or more symptoms of the specific disease, condition, or disorder described herein, or (iii) prevent or delay the onset of one or more symptoms of the specific disease, condition, or disorder described herein. The amount of the disclosed compound constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by someone skilled in the art based on their own knowledge and the content of this disclosure.

[0251] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0252] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0253] The term "pharmaceutical composition" refers to a mixture of one or more compounds disclosed herein, their stereoisomers, or salts thereof, with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the disclosed compounds to an organism.

[0254] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties 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.

[0255] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0256] Unless otherwise specified, singular terms encompass plural terms, and plural terms encompass singular terms. Unless otherwise specified, the words "a" or "an" mean "at least one" or "at least one". Unless otherwise specified, the use of "or" means "and / or".

[0257] The compounds disclosed herein can exist in specific geometric or stereoisomer forms (including transisomers). This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure.

[0258] Unless otherwise stated, "(D)" or "(+)" indicates right-handed rotation, "(L)" or "(-)" indicates left-handed rotation, and "(DL)" or "(±)" indicates racemic rotation.

[0259] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid.

[0260] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide a 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 salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0261] This disclosure also includes compounds of this disclosure that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this 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.

[0262] Certain isotope-labeled compounds of this disclosure (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (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 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this disclosure can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0263] In addition, heavier isotopes (such as deuterium) are used. 2 H or D) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases, wherein the deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium, and complete deuterium substitution means that all hydrogens on the group are substituted by deuterium, for example, methyl (-CH3) completely substituted by deuterium is -CD3.

[0264] The compounds disclosed herein may exist in their tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low-barrier transitions. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer may be an imidazole moiety, in which a proton can migrate between two ring nitrogens. The compounds disclosed herein are generally present in solid form, and may be crystalline or amorphous. The crystalline form of the compounds disclosed herein can be prepared using methods well known in the art, such as recrystallization. The amorphous form of the compounds disclosed herein can be prepared using methods well known in the art, such as spray drying.

[0265] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds of the disclosed invention with suitable pharmaceutically acceptable excipients.

[0266] Typical routes of administration of the disclosed compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, include, but are not limited to, oral, topical, inhalation, parenteral, intranasal, intraocular, intramuscular, subcutaneous, and intravenous administration.

[0267] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0268] In all methods of administration of the compound (I) disclosed herein, the daily dose is from 0.001 to 2000 mg / kg body weight, in single or separate doses.

[0269] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0270] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. To obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction processes based on existing embodiments. An important consideration in synthetic route planning in this art is selecting suitable protecting groups for reactive functional groups (such as amino groups in this disclosure).

[0271] In some embodiments, the compounds disclosed herein can be prepared by those skilled in the art of organic synthesis by referring to the following routes:

[0272] Preparation route 1:

[0273] Preparation route 2:

[0274] Preparation route 3:

[0275] Wherein, BPin is selected from borate groups or pinacol borate ester groups; Pg is selected from hydroxyl protecting groups, preferably acetyl groups; X is selected from halogens, preferably Br; ring A, ring B, L, R 1 R 2 R 3 X 3 and structural fragments The definition is as described in this disclosure.

[0276] The following abbreviations are used in this disclosure:

[0277] 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(diphenylphosphine)-9,9-dimethyloxanthracene; t-BuOK represents potassium tert-butoxide; Pd(dppf)Cl2 .CH2Cl2 represents [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex; DIPEA represents N,N-diisopropylethylamine; HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; HOAT represents N-hydroxy-7-azobenzotriazole; MeCN represents acetonitrile; Pd(dtbpf)Cl2 represents [1,1'-bis(di-tert-butylphosphine)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; MeOH represents methanol; NaBH4 represents sodium borohydride; CF3TMS represents trifluoromethyltrimethylsilane; TBAF represents tetrabutylammonium fluoride. Detailed Implementation

[0278] Intermediate Example 1: Preparation of Intermediate A

[0279] Step 1:

[0280] Compound A-0 (50 g) and imidazole (32 g) were dissolved in dichloromethane (1 L), cooled to 0 °C, and TBDPSCl (120 mL) was added dropwise. The mixture was stirred at room temperature until the reaction was complete. The reaction was then quenched with 2N hydrochloric acid (1.2 L), 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 dryness to obtain compound A-1 (154 g).

[0281] Step Two:

[0282] Compound A-1 (154 g) was dissolved in toluene (500 mL), and thionyl chloride (40 mL) and DMF (1-3 drops) were added. The mixture was stirred at 80 °C until the reaction was complete. After the reaction solution was evaporated to dryness under reduced pressure, crude compound A-2 (162 g) was obtained. This crude compound A-2 was used directly in the next step without purification.

[0283] Step 3:

[0284] The crude compound A-2 obtained in the previous step (162 g) was dissolved in dichloromethane (360 mL), cooled to 0°C in an ice bath, and anhydrous tin tetrachloride (117 g) in dichloromethane solution (400 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at 0°C for 0.5 h, and then 5-bromoindole (75 g) in dichloromethane solution (120 mL) was added dropwise. The mixture was stirred for 45 min in an ice-water bath and then transferred to room temperature for further stirring. After the reaction was complete, the solvent in the reaction solution was evaporated under reduced pressure, and ethyl acetate (500 mL) was added and stirred until dissolved. The mixture was washed three times with saturated brine (300 mL * 3), and the aqueous layers were combined. The mixture was extracted twice with ethyl acetate (200 mL * 2), and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was slurried three times at room temperature with PE:EA = 2:1 (300 mL * 3), filtered, and evaporated to dryness to obtain compound A-3 (189 g).

[0285] Step Four:

[0286] Compound A-3 (189 g) was dissolved in THF (372 mL), and the mixture was cooled and stirred in an ice-water bath. Sodium borohydride (52.4 g) was added in six batches, and the reaction was stirred at 60-65 °C after the addition was complete. When the reaction was complete, methanol (200-300 mL) was added dropwise to quench the reaction, followed by water (200 mL). The mixture was allowed to stand and filtered. The filter cake was washed with EA (20 mL). The filtrate was concentrated under reduced pressure, and EA (500 mL) was added. After stirring and filtering to remove insoluble matter, 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).

[0287] Step 5:

[0288] Compound A-4 (122 g) and triethylamine (179 mL) were dissolved in DCM (1 L). The mixture was cooled in an ice-water bath for 1 h, then acetic anhydride (66.1 g) was added, and the reaction was carried out for 1 h. DMAP (4.1 g) was then added, and the reaction was carried out for 0.5 h. The ice bath was removed, and the mixture 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 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). The mixture was 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).

[0289] Step Six:

[0290] Compound A-5 (10 g) was dissolved in THF (200 mL). Sodium bicarbonate (3.1 g), silver trifluoromethanesulfonate (9.5 g), and I₂ (7.8 g) were added under ice bath conditions, and the reaction was stirred at 0 °C. After the reaction was complete, purified water (100 mL) was added to quench the reaction mixture. Extraction was performed twice with EA (300 mL * 2). The organic phases were combined and washed successively with sodium sulfite solution (200 mL) and sodium chloride solution (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain intermediate A (11.34 g). LC-MS: m / z: 449.9 (MH) - .

[0291] Intermediate Example 2: Preparation of a mixture of intermediates B and B-4

[0292] Step 1:

[0293] Compound B-0 (80 g), pinacol diboronate (141 g), dtbpy (14.9 g), and (1,5-cyclooctadiene)methoxyiridium(I) dimer (7.5 g) were dissolved in THF (400 mL). After purging with nitrogen three times, the mixture was stirred at 75 °C. Once the reaction was complete, the reaction solution was cooled to room temperature, and sodium carbonate (40 g) and sodium hydroxide (10 g) were added to water (600 mL) to dissolve them completely, yielding an alkaline aqueous solution. Ethyl acetate (200 mL) 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 (800 mL), cooled in an ice bath, and the pH was adjusted to 6 with a 6N dilute hydrochloric acid aqueous solution. A solid precipitated, and the solid was filtered to obtain compound B-1 (62 g).

[0294] LC-MS: m / z: 260; 262.1 (M+H) + .

[0295] Step Two:

[0296] Compound B-1 (16.3 g) and NIS (35.27 g) were added to acetonitrile (300 mL) and stirred at 80 °C. After the reaction was complete, the reaction solution was cooled to room temperature. The reaction solution was washed twice with saturated sodium thiosulfate aqueous solution (300 mL * 2), 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).

[0297] LC-MS:m / z:341.91; 343.92(M+H) + .

[0298] Step 3:

[0299] Compound B-2 (9.88 g), benzyl-1-piperazine carbonate (15.73 g), XantPhos (1.68 g), Pd2(dba)3 (530.74 mg), and t-BuOK (4.88 g) were dissolved in toluene (200 mL), purged three times with argon, 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, and the mixture was extracted with EA (200 mL x 2), washed with saturated brine (200 mL x 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).

[0300] LC-MS: m / z:434.21; 436.19(M+H) + .

[0301] Step Four:

[0302] Compound B-3 (9.9 g), pinacol diboronate (8.68 g), potassium acetate (5.59 g), and Pd(dppf)Cl2 were added. . CH2Cl2 (1.86 g) was dissolved in toluene (120 mL), purged three times with argon, 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 prepared into sand. The sand was separated by neutral alumina packed column chromatography to obtain a mixture of intermediates B and B-4 (13.6 g).

[0303] Intermediate B-4: LC-MS: m / z: 400.29 (M+H) + .

[0304] Intermediate Example 3: Preparation of Intermediate C

[0305] Step 1:

[0306] Compound C-0 (27 g) and potassium carbonate (22.5 g) were dissolved in THF (400 mL), and after stirring, a tetrahydrofuran solution of iodomethane (12.7 g) was added dropwise. The mixture was stirred at room temperature. After the reaction was complete, the reaction solution was directly filtered, the filter cake was washed, the filtrate was collected, concentrated, and purified by silica gel column chromatography to obtain compound C-1 (23 g).

[0307] Step Two:

[0308] Compound C-1 (23 g) was dissolved in dichloromethane (230 mL), and trifluoroacetic acid (115 mL) was added. The mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to evaporate the solvent. The residue was dried twice with toluene to obtain compound C-2 (25 g).

[0309] LC-MS: m / z: 145 (M+H) + .

[0310] Step 3:

[0311] Compound SZ (10 g) and lithium hydroxide monohydrate (366.45 mg) were dissolved in tetrahydrofuran (50 mL) and water (25 mL), and the mixture was stirred at 40 °C. 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 2N dilute hydrochloric acid aqueous solution. The mixture was extracted and separated. The aqueous phase was extracted again with DCM (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound C-3 (13.8 g).

[0312] Step Four:

[0313] DIPEA (20 g) was added to a dichloromethane (50 mL) solution of compound C-2 (21.94 g), and the resulting mixture was kept for later use. Compound C-3 (13.8 g) was dissolved in DCM (200 mL), cooled in an ice bath, and then the aforementioned mixture, HATU (19.33 g), HOAT (2.67 g), and DIPEA (30.79 g) were added. The mixture was stirred and reacted at 0-5 °C. After the reaction was complete, water (500 mL) and DCM (200 mL) were added, and the mixture was stirred and separated. The organic phase was washed with 10% saline (500 mL), dried, filtered, and concentrated. The residue was separated by silica gel column chromatography (eluent: PE:EA = 2:1) to obtain intermediate C (16.2 g).

[0314] LC-MS: m / z: 477.1 (M+H) + .

[0315] Intermediate Example 4: Preparation of Intermediate D

[0316] Step 1:

[0317] A mixture of intermediates B and B-4 (8.38 g), intermediate A (6.3 g), K₂CO₃ (3.86 g), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (2.53 g) were dissolved in a mixed solvent of toluene, 1,4-dioxane, and water (v / v / v = 3 / 1 / 1, total 250 mL). The mixture was purged with nitrogen three times and stirred at 70 °C. After the reaction was complete, water (150 mL) and ethyl acetate (150 mL * 2) were added to the reaction solution for extraction twice. The organic phase was then 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).

[0318] LC-MS: m / z: 677.2 (M+H) + .

[0319] Step Two:

[0320] Compound D-1 (5.28 g) was dissolved in DMF (50 mL) by stirring. Cesium carbonate (7.61 g) was added, and 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. The organic phase was then washed with 10% saline solution (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product D-2 (7 g).

[0321] LC-MS: m / z: 705.3 (M+H) + .

[0322] Step 3:

[0323] The crude D-2 product (7g) obtained in the previous step was dissolved in methanol (50mL), and LiOH (1.36g) and K3PO4 (2.1g) were added. The mixture was stirred at 40℃. After the reaction was complete, the presence of the blocked isomer was monitored under liquid chromatography-mass spectrometry (LC-MS / MS) conditions (column: Waters ACQUITY CSH C18; mobile phase A: 0.1% formic acid (FA) / H2O; mobile phase B: MeCN; gradient elution from 0 to 7 min (15%-95%-5%-15%)). The retention times of the first and last peaks were 4.23 min and 4.40 min, respectively. The reaction solution was cooled to room temperature, and the mixture was directly prepared and separated by silica gel column chromatography (eluent: PE:EA = 1:2) to obtain two blocked isomers of D-3, including the first peak compound D-3B (2.37g) and the last peak compound D-3A (2.53g).

[0324] LC-MS: m / z: 663.4 (M+H) + .

[0325] Step Four:

[0326] Compound D-3A (2.5 g), pinacol diborate (1.43 g), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (408.9 mg), and potassium acetate (736.96 mg) were dissolved in toluene (50 mL), purged three times with nitrogen, and stirred at 90 °C. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated, and purified to form sand. The sand was then separated by silica gel column chromatography (eluent: PE:EA = 1:1.5) to obtain 2.18 g of compound D-4A.

[0327] LC-MS: m / z 711.5 (M+H) + .

[0328] Step 5:

[0329] Compound D-4A (1.5 g), intermediate C (875.84 mg), and Pd(dtbpf)Cl2 (137.51 mg) were added. 、 K3PO4 (1.11 g) was dissolved in 25 mL of a mixed solvent of toluene / dioxane / water (v / v / v = 3 / 1 / 1), purged three times with nitrogen, and stirred at 70 °C. After the reaction was complete, the reaction solution was cooled, concentrated, and precipitated into sand. Compound D-5A (1.67 g) was obtained by silica gel column chromatography (eluent: PE:EA = 1:10).

[0330] LC-MS: m / z 981.64 (M+H) + .

[0331] Step Six:

[0332] Compound D-5A (1.25 g) and LiOH (175.72 mg) were dissolved in 17.5 mL of a mixed solvent of THF and H₂O (v / v = 2 / 1), and the mixture was stirred at 35 °C. After the reaction was complete, 80 mL each of water and DCM were added to the system. The pH of the system was adjusted to 5-6 with a 2N dilute hydrochloric acid aqueous solution. The mixture was then extracted and separated. The aqueous phase was extracted again with DCM (80 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product D-6A (1.3 g), which was used directly in the next step.

[0333] LC-MS: m / z 967.9 (M+H) + .

[0334] Step Seven:

[0335] Crude D-6A (1.3 g) was dissolved in DCM (150 mL), and EDCI (7.72 g), DIPEA (4.91 g), and HOBT (185 mg) were added. The mixture was stirred at room temperature. After the reaction was complete, water (300 mL) and DCM (200 mL) were added, followed by extraction and washing. The organic phase was then washed with water (300 mL) and saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was then subjected to silica gel column chromatography (eluent: DCM:MeOH = 50:1) to give compound D-7A (350 mg).

[0336] LC-MS: m / z 949.8 (M+H) + .

[0337] Step 8:

[0338] Compound D-7A (350 mg) was dissolved in methanol (10 mL), and 10% Pd / C (100 mg) was added. The mixture was first purged with nitrogen, then purged three times with hydrogen balloons, and stirred at 50 °C. After the reaction was complete, the reaction solution was cooled, and the Pd / C powder was removed by filtration. The filtrate was concentrated under reduced pressure to obtain crude D-8A, which was used directly in the next step.

[0339] LC-MS: m / z 815.4 (M+H) + .

[0340] Step Nine:

[0341] 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, and 107.76 mg of 37% formaldehyde aqueous solution was added dropwise. Sodium cyanoborohydride (68.27 mg) was added, and the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and water (50 mL) and DCM (80 mL) were added for extraction. The organic phase was then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain crude D-9A (336 mg).

[0342] LC-MS: m / z 829.4 (M+H) + .

[0343] Step 10:

[0344] The crude D-9A obtained in the previous step (336 mg) 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 (4 M, 2 mL) was added dropwise. After the addition was complete, the mixture was stirred at room temperature. The reaction was completed, and the solvent was removed from the reaction solution under reduced pressure to obtain intermediate D (356 mg).

[0345] LC-MS: m / z 729.4 (M+H) + .

[0346] Example 7

[0347] Step 1:

[0348] Pinarol 1-ethoxycarbonylcyclohexyl-3-ene-4-boronic acid (500 mg), bromobenzene (336 mg), Pd(dppf)Cl2 (130 mg), and K2CO3 solution (492 mg K2CO3 dissolved in 5 mL water) were mixed. 15 mL of 1,4-dioxane was added, and the mixture was purged with nitrogen three times. The reaction was then carried out in an oil bath at 90 °C. After the reaction was complete, the mixture was cooled to room temperature, extracted with 20 mL of ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated by column chromatography to obtain intermediate 7-1 (400 mg).

[0349] Step Two:

[0350] Intermediate 7-1 (400 mg), LiOH . H2O (200 mg) and KOH (200 mg) were dissolved in THF / H2O (10 / 10 mL), and the mixture was stirred overnight at room temperature. After the reaction was complete, the pH of the system was adjusted to 4-5 with 2 M HCl, and the mixture was filtered to obtain intermediate 7-2 (250 mg).

[0351] Step 3:

[0352] Intermediate D (80 mg) was dissolved in DMF (5 mL), and intermediate 7-2 (28 mg), DIPEA (28.38 mg), and HATU (62.62 mg) were added. The mixture was stirred in an ice bath. After the reaction was complete, purified water (15 mL) was added, and the mixture was extracted twice with DCM (15 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 7 (38 mg) was obtained by preparative liquid chromatography.

[0353] LC-MS: m / z 913.6 (M+H) + .

[0354] Example 9

[0355] Step 1:

[0356] A mixture of 1-ethoxycarbonylcyclohexyl-3-ene-4-boronic acid pinacol ester (500 mg), 5-iodopyrazole (380 mg), Pd(dppf)Cl2 (130 mg), and K2CO3 solution (492 mg dissolved in 5 mL of water) was added, followed by the addition of 1,4-dioxane (15 mL). After purging with nitrogen three times, the mixture was reacted in an oil bath at 75 °C. Once the reaction was complete, the mixture was cooled to room temperature and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was then separated by column chromatography to obtain intermediate 9-1 (200 mg).

[0357] Step Two:

[0358] Intermediate 9-1 (200 mg), LiOH·H2O (100 mg), and KOH (100 mg) were dissolved in THF / H2O (10 / 10 mL) and reacted with stirring at room temperature. After the reaction was complete, the pH of the system was adjusted to 4-5 with 2 M HCl, and ethyl acetate (20 mL) was added for extraction. After drying the organic phase, the mixture was filtered, and the filtrate was concentrated and separated by column chromatography to obtain intermediate 9-2 (100 mg).

[0359] Step 3:

[0360] Intermediate D (58 mg) was dissolved in DMF (5 mL), and intermediate 9-2 (20 mg), DIPEA (20.68 mg), and HATU (45.6 mg) were added. The mixture was stirred in an ice bath. After the reaction was complete, purified water (15 mL) was added, and the mixture was extracted twice with DCM (15 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (YMC TA C18, specification 30 * 250 mm, 10 μm, mobile phase: A: 0.1% acetic acid, B: acetonitrile; gradient: 20%-60%-B 0-60 min, wavelength 254 nm, v = 30 mL / min, RT 29 min and RT 35 min) to separate compounds 9-A (6 mg) and 9-B (4 mg).

[0361] 9-A LC-MS: m / z 903.6 (M+H) + .

[0362] 9-B LC-MS: m / z 903.6 (M+H) + .

[0363] Example 14

[0364] Step 1:

[0365] A mixture of 1-ethoxycarbonylcyclohexyl-3-ene-4-boronic acid pinacol ester (700 mg), 5-iodo-1-methyl-1H-pyrazole (470 mg), Pd(dppf)Cl2 (130 mg), and K2CO3 solution (492 mg dissolved in 5 mL of water) was added, followed by the addition of 1,4-dioxane (15 mL). After purging with nitrogen three times, the reaction was carried out in an oil bath at 75 °C. Once the reaction was complete, the reaction solution was cooled to room temperature, extracted with ethyl acetate (20 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated by column chromatography to obtain intermediate 14-1 (410 mg).

[0366] Step Two:

[0367] Intermediate 14-1 (410 mg), LiOH·H2O (200 mg), and KOH (200 mg) were dissolved in a THF / H2O mixed solution (15 mL / 15 mL), and the mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 4-5 with 2 M HCl, and ethyl acetate (20 mL) was added for extraction. The organic phase was dried, filtered, and the filtrate was concentrated and separated by column chromatography to obtain intermediate 14-2 (220 mg).

[0368] Step 3:

[0369] Intermediate D (58 mg) was dissolved in DMF (5 mL), and intermediate 14-2 (20 mg), DIPEA (20.68 mg), and HATU (45.6 mg) were added. The mixture was stirred in an ice bath. After the reaction was complete, purified water (15 mL) was added to the reaction solution, and the mixture was extracted twice with DCM (15 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography to obtain 14-2 (30 mg).

[0370] LC-MS: m / z = 917.49 [M+H] + .

[0371] Example 15

[0372] Step 1:

[0373] Pinarol 1-ethoxycarbonylcyclohexyl-3-ene-4-boronic acid (741 mg), 3-iodo-1-methyl-1H-pyrazole (500 mg), Pd(dppf)Cl2 (175 mg), and K2CO3 solution (662 mg dissolved in 5 mL of water) were mixed, and 15 mL of 1,4-dioxane was added. After purging with nitrogen three times, the mixture was reacted in an oil bath at 75 °C for 4 h. After the reaction was complete, the reaction solution was cooled to room temperature, extracted with 20 mL of ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated by column chromatography to obtain intermediate 15-1 (500 mg).

[0374] Step Two:

[0375] Intermediate 15-1 (500 mg), LiOH·H2O (300 mg), and KOH (300 mg) were dissolved in a THF / H2O mixed solution (15 mL / 15 mL), and the mixture was stirred overnight at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 4-5 with 2 M HCl, and ethyl acetate was added for extraction. After drying the organic phase, the mixture was filtered, and the filtrate was concentrated. The concentrate was then separated by column chromatography to obtain intermediate 15-2 (300 mg).

[0376] Step 3:

[0377] Intermediate D (111 mg) was dissolved in DMF (5 mL), and intermediate 15-2 (30 mg), DIPEA (56.2 mg), and HATU (82.7 mg) were added. The mixture was stirred in an ice bath. After the reaction was complete, purified water (15 mL) was added to the reaction solution, and the mixture was extracted twice with DCM (15 mL * 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated by preparative liquid chromatography to obtain Example 15 (40 mg).

[0378] LC-MS: m / z = 917.49 [M+H] + .

[0379] Examples 17-A and 17-B

[0380] Step 1:

[0381] 15-2 (3g) and (R)-4-benzyl-2-oxazolidinone (3.4g) were dissolved in anhydrous DCM (100mL), and triethylamine (3.9g) and 4-dimethylaminopyridine (156mg) were added. The mixture was cooled to 0℃ in an ice bath, and 2-chloro-1-methylpyridine oxide (5.5g) was added in portions. After the addition was complete, the mixture was stirred at room temperature for 2h. After the reaction was complete, 100mL of water was added to quench the reaction, and the mixture was extracted twice with DCM (50mL*2). The mixture was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to prepare slag. The slag was crudely separated by column chromatography (PE / EA 2 / 1) to obtain the racemic 17-1. The racemic 17-1 was then finely separated by column chromatography (PE / EA 6 / 1~3 / 1), and the upper and lower points were collected to obtain 17-1A (1.5g) and 17-1B (1.7g) in sequence.

[0382] Step Two:

[0383] Dissolve 17-1A (1.5g) in THF (20mL), cool to 0℃ in an ice bath, add 30% hydrogen peroxide (1.4g), and then add LiOH. . H2O (345 mg) was dissolved in a 20 mL solution of purified water. After the addition was complete, the mixture was heated to room temperature and stirred until the reaction was complete. The reaction solution was then cooled in an ice bath, and a 5 mL solution of sodium thiosulfate was added dropwise to the system. The mixture was stirred for 30 min, separated, and the organic phase was concentrated to dryness and combined with the aqueous phase. EA (10 mL * 2) was added for extraction. The pH of the aqueous phase was adjusted to 5–6 with a 1 N HCl aqueous solution, and a white solid precipitated. The solid was filtered and concentrated to dryness to obtain 17-2A (560 mg).

[0384] Replace 17-1A with 17-1B and prepare 17-2B (620mg) using the same method.

[0385] Step 3:

[0386] Intermediate D (100 mg) was dissolved in DMF (5 mL), and 17-2A (27 mg) was added. The mixture was cooled to 0 °C in an ice bath, and DIPEA (42 mg), HATU (74.2 mg), and HOAT (3.54 mg) were added. The mixture was stirred at 0 °C until the reaction was complete. Purified water (15 mL) was added to the reaction solution, and the mixture was extracted twice with DCM (20 mL * 2). The solution was washed twice with saturated brine, dried over anhydrous sodium sulfate for 2 h, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by preparative column chromatography to obtain compound 17-A (40 mg).

[0387] LC-MS: m / z = 917.49 [M+H] + .

[0388] Intermediate D (100 mg) was dissolved in DMF (10 mL), and 17-2B (27 mg) was added. The mixture was cooled to 0 °C in an ice bath, and DIPEA (42 mg), HATU (74.2 mg), and HOAT (3.54 mg) were added. The mixture was stirred at 0 °C until the reaction was complete. Purified water (15 mL) was added to the reaction solution, and the mixture was extracted twice with DCM (20 mL * 2). The solution was washed twice with saturated brine, dried over anhydrous sodium sulfate for 2 h, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by preparative column chromatography to obtain compound 17-B (38 mg).

[0389] LC-MS: m / z = 917.49 [M+H] + .

[0390] Experimental Example 1: Assay of AsPc-1 Cell Proliferation Inhibition Activity

[0391] Collect AsPc-1 cells in good growth condition into centrifuge tubes and adjust the cell density to 3 × 10⁻⁶. 4 The compound was seeded at a concentration of 100 μL / well in 96-well plates, and simultaneously added using a nanoparticle pipette to achieve a final concentration of 5000 nM - 0.31 nM. Two replicates were performed, and a control was also included. After culturing for 72 hours in a cell incubator, the assay reagent CCK-8 (manufacturer: Tongren Chemical, 10 μL / well) was added. After incubation for 3 hours in a cell incubator, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The experimental results are shown in Table 1.

[0392] Experimental Example 2: Assay of Capan-1 Cell Proliferation Inhibition Activity

[0393] Capan-1 cells in good growth condition were collected into centrifuge tubes, and the cell density was adjusted to 1.5 × 10⁻⁶. 4 Compounds were seeded at a concentration of 100 μL / well in 96-well plates using a nanoparticle pipette to achieve a final concentration of 20000 nM - 9.1 nM. Two replicates were performed, and a control was also included. After culturing for 5 days, the assay reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation for 4 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The experimental results are shown in Table 1.

[0394] Table 1 Results of cell proliferation inhibition assays for each compound

[0395] The experimental results show that the compound disclosed herein has good inhibitory activity against the proliferation of AsPc-1 and Capan-1 cells.

[0396] Experimental Example 3: In vitro stability of liver microsomes

[0397] Liver microsomal incubation samples (species: human and mouse) were prepared as follows: mixed PBS buffer (pH=7.4), liver microsomal solution (0.5 mg / mL), test compound, and NADPH+MgCl2 solution were incubated at 37°C and 300 rpm for 1 hour. Samples at 0 hours were prepared as follows: mixed PBS buffer (pH=7.4), liver microsomal solution (0.5 mg / mL), and test compound. The samples were precipitated with acetonitrile solution containing internal standard to prepare the supernatant, which was then diluted for LC / MS / MS analysis.

[0398] The experimental results show that the compound disclosed herein is metabolically stable in liver microsomes in vitro, and the residual amount in mouse liver microsomes (T=60min) (0.5mg / mL) can be >30%.

[0399] Example 4: Pharmacokinetic Evaluation in Mice

[0400] ICR mice, weighing 20-24g, were acclimatized for 3-5 days and then randomly divided into groups of 9 mice each. The compound disclosed was administered by gavage at a dose of 10mg / kg.

[0401] The test animals (ICR mice) were fasted for 12 hours before administration and given food 4 hours after administration. They had free access to water before, during, and after the experiment.

[0402] Following oral administration, blood was collected from each mouse at 3–4 time points at 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, and 10 h, with 3 mice at each time point. Approximately 0.1 mL of blood was collected from the orbital cavity. After anticoagulation with EDTA-K2, the plasma was transferred to a centrifuge at 4000 rpm for 10 min at 4°C within 30 min to separate the plasma. All collected plasma was immediately stored at -20°C for analysis.

[0403] Take 20 μL of the plasma sample and standard curve sample, add 400 μL of acetonitrile solution containing internal standard (20 ng / mL), vortex to mix for 10 min, centrifuge at 13000 rpm for 10 min, take 50 μL of the supernatant, dilute with 100 μL of ultrapure water, mix well, and take 0.5 μL for LC / MS / MS determination, record the chromatogram. Pharmacokinetic parameters are obtained by fitting a non-compartmental model.

[0404] The experimental results show that the disclosed compound has good in vivo pharmacokinetic properties in mice.

[0405] Example 5: Pharmacokinetic Evaluation in Rats

[0406] SD rats, weighing 180–220 g, were randomly divided into 3 groups of 3 rats each after 3–5 days of acclimatization. The compound disclosed was administered by gavage at a dose of 10 mg / kg.

[0407] The test animals (SD rats) were fasted for 12 hours before administration and given food 4 hours after administration. They had free access to water before, during, and after the experiment.

[0408] Following oral administration, approximately 0.2 mL of blood was collected from the orbital cavity at 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h. After EDTA-K2 anticoagulation, the plasma was transferred to a centrifuge at 4000 rpm for 10 min at 4°C within 30 min to separate the plasma. All collected plasma was immediately stored at -20°C for analysis.

[0409] Take 50 μL of the plasma sample and standard curve sample, add 300 μL of acetonitrile solution containing internal standard (diazepam 20 mg / mL), vortex to mix for 5 min, centrifuge at 13000 rpm for 10 min, take 75 μL of the supernatant, dilute with 75 μL of ultrapure water, mix well, and take 2 μL for LC / MS / MS determination, record the chromatogram. Pharmacokinetic parameters are obtained by fitting a non-compartmental model.

[0410] The experimental results show that the disclosed compound has good in vivo pharmacokinetic properties in rats.

[0411] Example 6: Pharmacokinetic Evaluation in Dogs

[0412] Beagles weighing 10-12 kg were randomly divided into groups of 6 after acclimatization for 3-5 days and administered the compound disclosed herein by gavage at a dose of 2 mg / kg per dog.

[0413] Blood was collected at 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, 30 h, and 48 h, and plasma samples were prepared from veins in the forelimbs.

[0414] Take 30 μL of the plasma sample to be tested and the standard sample, add methanol solution containing internal standard, and obtain supernatant by protein precipitation. After dilution, use it for LC / MS / MS determination.

[0415] Pharmacokinetic parameters were obtained by fitting a non-compartmental model.

[0416] The experimental results show that the disclosed compound has good in vivo pharmacokinetic properties in dogs.

Claims

1. A compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, in, Ring A is selected from C 6-10 aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclic, wherein C 6-10 Aryl, 5-14-membered heteroaryl, or 5-14-membered heterocyclic group may be independently bonded by one, two, or three R groups. a replace; L is selected from -(CRR') q -, -NH-(CRR') q -, -O-(CRR') q -, -S-(CRR') q -, -(CRR') q -(CH=CH) i -, -NH-(CH=CH) i -, -O-(CH=CH) i -, -S-(CH=CH) i -, -(CRR') q -(C≡C) i -, -NH-(C≡C) i -, -O-(C≡C) i - or -S-(C≡C) i -; R and R' are each independently selected from hydrogen, deuterium, halogen, -NH2, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 The cycloalkyl or 3-6 membered heterocyclic group is optionally and independently substituted by one or more substituents selected from halogens, =O, -NH2, -OH, -SH, or -CN; or, R and R' together with the attached carbon atom form C=O, ... 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 The cycloalkyl or 3-6 membered heterocyclic group may be independently substituted by one or more substituents selected from halogen, =O, -NH2, -OH, -SH or -CN; Ring B is selected from C 3-14 cycloalkyl, C 3-14 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-14 heteroaryl, wherein C 3-14 cycloalkyl, C 3-14 Cycloalkenyl, 3-14 membered heterocyclic groups, C 6-10 Aryl or 5-14 heteroaryl groups are optionally and independently bound by one, two, or three R groups. b replace; R a and R b Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein C 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 alkenyl or C 2-12 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, and -CN; the C 3-8 Cycloalkyl, 3-8-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups are optionally and independently bound by one or more groups selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, hydroxyl-substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or amino-substituted C 1-6 Alkyl substituents; Each R 2 Each is independently selected from halogens, -NH2, -OH, -SH, -CN, and -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 group, -NHS(O)2C 1-6 Alkyl group, -S(O)2NHC 1-6 Alkyl group, -S(O)2N(C) 1- 6-alkyl)2、-P(O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 cycloalkyl, C 4-14 Cycloalkenyl, 4-14 membered heterocyclic groups, C 6-10 Aryl or 5-14 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, -CN, and -COOH, wherein the C 3-14 cycloalkyl, C 4-14 Cycloalkenyl, 4-14 membered heterocyclic groups, C 6-10 Aryl or 5-14 heteroaryl groups are optionally and independently constituting one or more R groups. d replace; Each R d Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, -COOH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1- 6-alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-10 Aryl, 5-14 membered heteroaryl, said C 1- 6-alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 The alkyl group (2) is optionally and independently substituted by one or more substituents selected from halogens, -OH, -SH, -NH2, -CN, -NH(CH3)2, or -N(CH3)2, wherein the C 6-10 The aryl or 5-14 heteroaryl group is optionally and independently bound by one or more elements selected from halogen, -OH, -SH, -NH2, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 The alkyl group is substituted with a substituent of (2), wherein the 3-14 membered cycloalkyl group or the 4-14 membered heterocyclic group is optionally independently replaced by one or more substituents selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Substitution of alkyl group 2; X 3 Selected from CH or N; m is selected from 0, 1, 2, 3 or 4; i is selected from 1 or 2; q is selected from 0, 1, 2, or 3; R 3 Selected from hydrogen, halogens, -NH2, -OH, -SH, -CN, C 1-6 Alkyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group may be independently substituted by one, two or three substituents selected from halogens, -NH2, -OH, -SH or -CN; Structural fragments Choose from either (a) or (b) below: (a) Structural fragments Selected from R 1 Selected from C 2-6 alkenyl, C 2-6 alkynyl group, C 4-14 Cycloalkenyl or 5-14 membered heterocyclic alkenyl, wherein the C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, -CN, or -COOH, wherein the C 4-14 Cycloalkenyl or 5-14 membered heterocyclic alkenyl groups are independently bounded by one or more R groups. c replace; Each R c Each is independently selected from C 3-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-10 Aryl, 5-14 membered heteroaryl, said C 6-10 The aryl or 5-14 heteroaryl group is optionally and independently bound by one or more elements selected from halogen, -OH, -SH, -NH2, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1- 6-alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 The alkyl group is substituted with a substituent of (2), wherein the 3-14 membered cycloalkyl group or the 4-14 membered heterocyclic group is optionally independently replaced by one or more substituents selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1- 6-alkyl) or -N(C 1-6 Substitution of alkyl group 2; (b) Structural Fragments Selected from R 1 Selected from C 2-6 alkenyl, C 2-6 alkynyl group, C 4-14 Cycloalkenyl or 5-14 membered heterocyclic alkenyl, wherein the C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, -CN, or -COOH, wherein the C 4-14 The cycloalkenyl or 5-14 membered heterocyclic alkenyl group is optionally and independently surrounded by one or more R groups. c replace; Each R c Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, -COOH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1- 6-alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-10 Aryl, 5-14 membered heteroaryl, said C 1- 6-alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 The alkyl group (2) is optionally and independently substituted by one or more substituents selected from halogens, -OH, -SH, -NH2, -CN, -NH(CH3)2, or -N(CH3)2, wherein the C 6-10 The aryl or 5-14 heteroaryl group is optionally and independently bound by one or more elements selected from halogen, -OH, -SH, -NH2, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 The alkyl group is substituted with a substituent of (2), wherein the 3-14 membered cycloalkyl group or the 4-14 membered heterocyclic group is optionally independently replaced by one or more substituents selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2 substituents.

2. The compound of formula (I) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Ring A is selected from C 6-10 Aryl or 5-13 heteroaryl, wherein C 6-10 Aryl or 5-13 heteroaryl groups are optionally and independently bound by one, two, or three R groups. a replace; Alternatively, ring A is selected from 5-6 membered monocyclic heteroaryl or 9-13 membered bicyclic or tricyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl or 9-13 membered bicyclic or tricyclic heteroaryl contains 1, 2 or 3 N atoms, and the 5-6 membered monocyclic heteroaryl or 9-13 membered bicyclic or tricyclic heteroaryl is optionally independently bounded by 1 or 2 R atoms. a replace; Alternatively, ring A is selected from 9-membered or 12-membered heteroaryl groups, wherein the 9-membered or 12-membered heteroaryl group is optionally independently constituted by one or two R groups. a replace; Alternatively, ring A is selected from pyrrole, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thiophenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoyindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, indolyl, The ring A is optionally bounded by one or two Rs. a replace.

3. The compound of formula (I) as described in claim 1 or 2, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, L is selected from -(CRR') q -、-(CRR') q -(CH=CH) i - or -(CRR') q -(C≡C) i -; Alternatively, L can be selected from a bond, or -CH=CH-; Optionally, R and R' are each independently selected from hydrogen, deuterium, halogen, -NH2, -OH, C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 Heteroalkyl; Alternatively, R and R' together with the attached carbon atom form C=O or cyclopropyl; Alternatively, R and R' can be independently selected from hydrogen, F, Cl, -NH2, -OH, or methyl.

4. The compound of formula (I) as described in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Ring B is selected from C 5-10 cycloalkyl, C 5-10 Cycloalkenyl, 5-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 5-10 cycloalkyl, C 5-10 Cycloalkenyl, 5-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 aryl groups may be selectively coated with 1, 2 or 3 R groups. b replace; Alternatively, ring B is selected from phenyl or 5-6-membered heteroaryl, wherein the phenyl or 5-6-membered heteroaryl is optionally independently surrounded by one or two R atoms. b replace; Alternatively, ring B is selected from 5-6-membered heteroaryl groups, wherein the 5-6-membered heteroaryl group is optionally surrounded by one or two R groups. b replace.

5. The compound of formula (I) as described in any one of claims 1-4, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R a and R b Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-8 Alkyl, C 1-8 Heteroalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein C 1-8 Alkyl, C 1-8 Heteroalkyl, C 2-8 alkenyl or C 2-8 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, and -CN; the C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups are optionally and independently bound by one or more groups selected from halogen, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-4 Alkyl, C 1-4 Heteroalkyl, hydroxyl-substituted C 1-4 Alkyl, C 1-4 Halogenated alkyl or amino-substituted C 1-4 Alkyl substituents; Optional, R a Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-3 Alkyl, C 1-3 Heteroalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 1-3 Alkyl, C 1-3 Heteroalkyl, C 2-4 alkenyl or C 2-4 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, or -CN; the C 3-6 The cycloalkyl or 3-6 membered heterocyclic group is optionally and independently surrounded by one or more groups selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, C 1-3 Heteroalkyl or C 1-3 Substituents of haloalkyl groups; Or, R a Each is independently selected from F, Cl, and C. 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C) 1-2 alkyl), -N(C) 1-2 Alkyl)2 or C 2-4 alkynyl group; Or, R a Each is independently selected from C 1-3 alkyl; Optional, R b Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl or C 2-6 alkynyl group, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl or C 2-6 The alkynyl group may be optionally and independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH or -CN; Or, R b Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C) 1-2 alkyl) or -N(C) 1-2 Alkyl)2, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NH(C) 1-2 alkyl) or -N(C) 1-2 Alkyl)2 optionally independently by 1 One, two, or three F atoms are substituted; Or, R b Each is independently selected from F, Cl, or -OH.

6. The compound of formula (I) as described in any one of claims 1-5, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Structural fragments Selected from condition (b), R 1 Selected from C 2-4 alkenyl, C 2-4 alkynyl group, C 4-9 Cycloalkenyl or 5-9 membered heterocyclic alkenyl, wherein the C 2-4 alkenyl or C 2-4 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, -CN, or -COOH; the C 4-9 The cycloalkenyl or 5-9 membered heterocyclic alkenyl group is optionally and independently surrounded by one or more R groups. c replace; Or, structural fragments Selected from condition (b), R 1 Selected from C 4-9 Cycloalkenyl or 4-9 membered heterocyclic alkenyl, wherein the C 4-9 The cycloalkenyl or 5-9 membered heterocyclic alkenyl group is optionally and independently surrounded by one or more R groups. c replace; Or, structural fragments Selected from condition (b), R 1 Selected from C 4-9 Cycloalkenyl, the C 4-9 The cycloalkenyl group is optionally surrounded by one or two R groups. c replace; Or, structural fragments Selected from condition (b), R 1 Selected from 1, 2 or 3 Rs c The following groups may be substituted: cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, bicyclo[2.2.1]hept-2-enyl, or 2,3,3a,4,7,7a-hexahydro-1H-indenyl; Or, structural fragments Selected from condition (b), R 1 Selected from 1, 2 or 3 Rs c The following groups are substituted: Or, structural fragments Selected from condition (a), R 1 Selected from C 2-4 alkenyl, C 2-4 alkynyl group, C 4-9 Cycloalkenyl or 5-9 membered heterocyclic alkenyl, wherein the C 2-4 alkenyl or C 2-4 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, -CN, or -COOH; the C 4-9 Cycloalkenyl or 5-9 membered heterocyclic alkenyl groups are independently bounded by one or more R groups. c replace; Or, structural fragments Selected from condition (a), R 1 Selected from C 4-9 Cycloalkenyl, the C 4-9 The cycloalkenyl group is surrounded by one or two R groups. c replace; Or, structural fragments Selected from condition (a), R 1 Selected from 1, 2 or 3 R c The following groups are substituted:

7. The compound of formula (I) as described in any one of claims 1-6, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Each R 2 Each is independently selected from halogens, -NH2, -OH, -SH, -CN, -C(O)NH(C) 1-3 Alkyl), -C(O)N(C 1-3 Alkyl)2、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -N(C) 1-3 Alkyl)C(O)(C 1-3 Alkyl), -NHS(O)2(C 1-3 Alkyl), -S(O)2NH(C 1-3 Alkyl), -S(O)2N(C 1-3 Alkyl)2、-P(O)(C 1-3 Alkyl)2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be independently substituted by one or more substituents selected from halogens, -NH2, -OH, -SH, -CN, or -COOH, wherein the C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups are optionally and independently bounded by one or more R groups. d replace; Or, each R 2 Each is independently selected from C 3-8 cycloalkyl, C 5-8 Cycloalkenyl or 5-8 membered heterocyclic groups, wherein the C 3-8 cycloalkyl, C 5-8 The cycloalkenyl or 5-8 membered heterocyclic group is optionally and independently surrounded by one or more R groups. d replace; Or, each R 2 Each is independently selected from piperidinyl or piperazine, wherein the piperidinyl or piperazine is optionally independently surrounded by one or two R groups. d replace.

8. The compound of formula (I) as described in any one of claims 1-7, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Structural fragments Selected from condition (b), each R c Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, -COOH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-10 Aryl, 5-14 membered heteroaryl, said C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 6-10 The aryl or 5-14-membered heteroaryl group is optionally and independently substituted by one or more substituents selected from halogens, -OH, -SH, -NH2, -CN, -NH(CH3) or -N(CH3)2, and the 3-14-membered cycloalkyl or 4-14-membered heterocyclic group is optionally and independently substituted by one or more substituents selected from halogens, =O, -NH2, -OH, -SH, -CN, -COOH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Substitution of alkyl group 2; Or, structural fragments Selected from condition (b), each R c Each is independently selected from halogens, =O, -NH2, -OH, -SH, -CN, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group, 2-phenyl group, naphthyl group, 5-10-membered heteroaryl group, or 4-10-membered heterocyclic group, wherein the phenyl group, naphthyl group, 5-10-membered heteroaryl group, or 4-10-membered heterocyclic group is optionally surrounded by one or more groups selected from F, Cl, -OH, -SH, -NH2, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH(C) 1- 6-alkyl) or -N(C 1-6 Substitution of alkyl group 2; Or, structural fragments Selected from condition (b), each R c Each is independently selected from F, Cl, -OH, -NH2, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -O(C) 1-3 alkyl), -N(C) 1-3 Alkyl group, phenyl group, 5-6 membered heteroaryl group containing 1-2 nitrogen atoms, or 5-6 membered heterocyclic group containing 1-2 nitrogen atoms selected from nitrogen or oxygen, wherein the 5-6 membered heteroaryl group containing 1-2 nitrogen atoms is optionally surrounded by one or more atoms selected from nitrogen, oxygen, carbon ... 1-4 Alkyl substituents; Or, structural fragments Selected from condition (b), each R c Each is independently selected from F, Cl, -OH, -NH2, CF3, -OCH3, C 1-3 Alkyl, -N(C) 1-3 Alkyl)2, phenyl, pyrroleyl or optionally with one or two C 1-3 Alkyl-substituted pyrazolyl group; Or, structural fragments Selected from condition (a), each R c Each is independently selected from C 3-8 Cycloalkyl, phenyl, naphthyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group, wherein the phenyl, naphthyl, or 5-10-membered heteroaryl group is optionally independently substituted by one or two substituents selected from halogens, -OH, or -NH2, wherein the C 3-8 The cycloalkyl group or 4-10 membered heterocyclic group is optionally and independently surrounded by one or more groups selected from halogen, =O, -NH2, -OH, -SH, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NH(C) 1-3 alkyl) or -N(C) 1-3 Substitution of alkyl group 2; Or, structural fragments Selected from condition (a), each R c Each is independently selected from phenyl, 5-6-membered heteroaryl, or 5-8-membered heterocyclic groups containing 1-2 heteroatoms selected from N or O; Or, structural fragments Selected from condition (a), each R c Each is independently selected from phenyl, 5-6 membered heteroaryl groups containing 1-2 N atoms, or 5-6 membered heterocyclic groups containing 1-2 N or O heteroatoms; Or, structural fragments Selected from condition (a), each R c Each is independently selected from phenyl, pyrroleyl, or optionally surrounded by one or two C atoms. 1-3 Alkyl-substituted pyrazolyl group.

9. The compound of formula (I) as described in any one of claims 1-8, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Each R d Each is independently selected from halogens, -OH, -NH2, and C. 1-3 Alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclic group may be independently substituted by one or two substituents selected from halogens, -OH or -NH2; Or, each R d Each is independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl.

10. The compound of formula (I) as claimed in any one of claims 1-9, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 3 Selected from hydrogen, halogens, -NH2, -OH, -SH, -CN, C 1-4 Alkyl or C 1-4 Heteroalkyl, the C 1-4 Alkyl or C 1-4 The heteroalkyl group may be independently substituted by one, two or three substituents selected from halogens, -NH2, -OH, -SH or -CN; Alternatively, F, Cl, -NH2, -OH, -CN, C 1-3 Alkyl or C 1-3 Heteroalkyl, the C 1-3 Alkyl or C 1-3 The heteroalkyl group may be independently substituted by one or two F atoms; Or, R 3 Selected from -OC 1-3 Alkyl-substituted C 1-3 alkyl.

11. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

12. A compound or a pharmaceutically acceptable salt thereof, selected from the following compounds or pharmaceutically acceptable salts thereof:

13. A pharmaceutical composition comprising the compound of any one of claims 1-11, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the compound of claim 12 or a pharmaceutically acceptable salt thereof; optionally, the pharmaceutical composition is selected from solid pharmaceutical compositions, semi-solid pharmaceutical compositions, liquid pharmaceutical compositions, or gaseous pharmaceutical compositions.

14. Use of the compound of any one of claims 1-11, its stereoisomers or pharmaceutically acceptable salts thereof, or the compound of claim 12 or its pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 13 in the preparation of a treatment for a disease associated with Ras protein; optionally, the disease associated with Ras protein is selected from cancer.

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