Fused tricyclic compound and medical use thereof

IL330051APending Publication Date: 2026-08-01CHIA TAI TIANQING PHARMA GRP CO LTD

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Patent Information

Authority / Receiving Office: IL · IL
Patent Type: Applications
Current Assignee / Owner: CHIA TAI TIANQING PHARMA GRP CO LTD
Filing Date: 2024-12-18
Publication Date: 2026-08-01

AI Technical Summary

Technical Problem

The prior art is difficult to effectively treat cancers caused by mutations in Kras gene, especially the problem of continuous Ras activation caused by mutations in G12.

Method used

A triangular cyclic compound was developed to target Kras mutant proteins through specific structural modifications (such as selection and combination of groups such as X, L1, R1, L2, R2a, R2b, R3, R4, etc.) to inhibit the growth and division of cancer cells.

Benefits of technology

This compound can significantly inhibit the activity of Kras mutant protein, slow down the proliferation and progress of cancer cells, and provides a new anti-cancer treatment strategy.

✦ Generated by Eureka AI based on patent content.

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Abstract

The present application belongs to the field of medical chemistry, and relates to a fused tricyclic compound and the medical use thereof. The compound has a structure as represented by formula (I). Particularly, the present application further relates to a method for preparing the compound, a pharmaceutical composition of the compound and the use of the compound in the treatment of diseases.

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Description

Tricyclic compounds and their medical uses

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits to Chinese patent application No. 202311755340.0 filed with the State Intellectual Property Office of China on December 19, 2023, Chinese patent application No. 202410160703.4 filed with the State Intellectual Property Office of China on February 4, 2024, and Chinese patent application No. 202411837405.0 filed with the State Intellectual Property Office of China on December 12, 2024, and the contents disclosed in said applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to tricyclic compounds, preparation methods thereof, pharmaceutical compositions containing the compounds, and uses thereof in treating cancer. Background Art

[0004] The Ras gene is an important proto-oncogene, named after the rat sarcoma virus. The Ras protein it encodes is located on the inner side of the cell membrane. It can bind to GTP / GDP and hydrolyze GTP with the assistance of GTPase-activating protein (GAP). By converting between active (GTP-bound) and inactive (GDP-bound) conformations, the Ras protein controls the "on" and "off" of signal transmission processes such as growth factors and cytokines, playing an important role in life processes such as cell proliferation, differentiation, aging, and apoptosis (Bos JL et al., Cell, 2007, 129(5):865-877). The human Ras gene family has three members: Harvey rat sarcoma viral oncogene homolog (HRas), neuroblastoma rat sarcoma viral oncogene homolog (NRas) and Kirsten rat sarcoma viral oncogene homolog (Kras), among which Kras is mainly expressed in the intestine, lung and thymus (Rajalingam K et al., Biochim Biophys Acta, 2007, 1773(8):1177-1195).

[0005] Studies have shown that more than 30% of human tumors have Ras gene mutations, of which Kras mutations account for approximately 86% (Riely GJ et al., Proc Am Thorac Soc, 2009, 6(2):201-205). For Kras mutations, mutations at position 12 glycine (G12) account for approximately 80%, and G12D mutations (mutation of position 12 glycine to aspartic acid) are the main form of G12 mutations. (Prior IA et al., Cancer Res, 2012, 72(10):2457-2467). Mutations at G12 reduce the catalytic activity of GAP, ultimately promoting the continued activation of Ras, making it unable to effectively regulate cell signal transduction, thereby promoting the occurrence and development of tumors.

[0006] Currently, mutant Kras has become an attractive anti-cancer target.

[0007] Detailed Description of the Invention

[0008] The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0009] in,

[0010] X is selected from -N-, or optionally replaced by R x substituted -CH-;

[0011] R x Selected from deuterium, halogen, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino;

[0012] L 1 Selected from -O-, -S-, or optionally one or more R 1 Substituted groups: -NH-, C 1-5 Alkylene, C 1-4 Heteroalkylene, C 2-5 Alkenylene, or C 1-4 heteroalkenylene;

[0013] Each R 1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino;

[0014] L 2 is selected from a single bond, Ring B is selected from optionally substituted by one or more R B or R C Substituted: 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0015] Or, L 2 Selected from -C(R 2a R 2b )-, Ring B is selected from optionally substituted by one or more R B or R C Substituted: 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0016] R 2a is selected from H, deuterium, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl;

[0017] Each R 2a1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino;

[0018] R 2bSelected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino;

[0019] Or, R 2a and R 2b Together they form =O;

[0020] Each R B independently selected from deuterium, oxo, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino;

[0021] Ring A is selected from the group consisting of A or R C Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0022] Each R A independently selected from deuterium, oxo, halogen, -CN, -OH, -NH2, or optionally substituted by one or more R A1 Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0023] Each R A1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino;

[0024] Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted groups: -NH-, or -N(C 1-6 alkyl)-;

[0025] Each R z independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo C 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino;

[0026] R 3 selected from H, deuterium, or optionally substituted by one or more R 3a or R C Substituted with the following groups: C 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0027] Each R 3a independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 3b Substituted groups: =NH, =CH2, =N(C 1-6 alkyl), =CH(C 1-6 alkyl), =C(C 1-6 Alkyl)2, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, or di-C 1-6 Alkylamino;

[0028] Each R 3b independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, or di-C 1-4 Alkylamino;

[0029] Each R C Independently selected from -NR C1 C(O)R C2 、-NR C1 C(O)OR C2 、-NR C1 C(O)OC 1-6 Alkylene OC(O)R C2 、-NR C1 C(O)OC 1-6 Alkylene NR C1 C(O)R C2 、-NR C1 C(O)NR C1 R C2 、-NR C1 C(O)NR C1 C 1-6 Alkylene NR C1 C(O)R C2 、-NR C1 C(O)NR C1 C 1-6 Alkylene OC(O)R C2 、-OC(O)R C2 、-OC(O)OR C2 、-OC(O)OC 1-6 Alkylene OC(O)R C2 、-OC(O)OC 1-6 Alkylene NR C1 C(O)R C2 、-OC(O)NR C1 R C2 、-OC(O)NR C1 C 1-6 Alkylene OC(O)R C2 、-OC(O)NR C1 C 1-6 Alkylene NR C1 C(O)R C2 、-P(O)(ORC2 )2. -C 1-6 Alkylene P(O)(OR C2 )2. -C 1-6 Alkylene NR C1 P(O)(OR C2 )2. -C 1-6 Alkylene OP(O)(OR C2 )2、-NR C1 P(O)(OR C2 )2、-NR C1 C 1-6 Alkylene P(O)(OR C2 )2、-NR C1 C 1-6 Alkylene OP(O)(OR C2 )2、-NR C1 C 1-6 Alkylene NR C1 P(O)(OR C2 )2、-OP(O)(OR C2 )2. -OC 1-6 Alkylene P(O)(OR C2 )2. -OC 1-6 Alkylene OP(O)(OR C2 )2. -OC 1-6 Alkylene NR C1 P(O)(OR C2 )2、-P(O)HOR C2 、-C 1-6 Alkylene P(O)HOR C2 、-C 1-6 Alkylene NR C1 P(O)HOR C2 、-C 1-6 Alkylene OP(O)HOR C2 、-NR C1 P(O)HOR C2 、-NR C1 C 1-6 Alkylene P(O)HOR C2 、-NR C1 C 1-6 Alkylene OP(O)HOR C2 、-NR C1 C 1-6 Alkylene NR C1 P(O)HOR C2 、-OP(O)HOR C2 、-OC 1-6 Alkylene P(O)HOR C2 、-OC 1-6Alkylene OP(O)HOR C2 , or -OC 1-6 Alkylene NR C1 P(O)HOR C2 ;

[0030] R C1 Independently selected from H, or C 1-6 alkyl;

[0031] R C2 independently selected from H, or optionally substituted by one or more R C3 Substituted with the following groups: C 1-12 Alkyl, C 1-12 heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0032] Each R C3 independently selected from deuterium, oxo, halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, -P(O)(OH)2, -C 1-4 Alkylene P(O)(OH)2, -C 1-4 Alkylene OP(O)(OH)2, -C 1-4 Alkylene NR C1 P(O)(OH)2、-NR C1 P(O)(OH)2、-NR C1 C 1-4 Alkylene P(O)(OH)2, -NR C1 C 1-4 Alkylene OP(O)(OH)2, -NR C1 C 1-4 Alkylene NR C1 P(O)(OH)2, -OP(O)(OH)2, -OC 1-4 Alkylene P(O)(OH)2, -OC 1-4Alkylene OP(O)(OH)2, -OC 1-4 Alkylene NR C1 P(O)(OH)2, -P(O)HOH, -C 1-4 Alkylene P(O)HOH, -C 1-4 Alkylene OP(O)HOH, -C 1-4 Alkylene NR C1 P(O)HOH、-NR C1 P(O)HOH、-NR C1 C 1-4 Alkylene P(O)HOH, -NR C1 C 1-4 Alkylene OP(O)HOH, -NR C1 C 1-4 Alkylene NR C1 P(O)HOH、-OP(O)HOH、-OC 1-4 Alkylene P(O)HOH, -OC 1-4 Alkylene OP(O)HOH, -OC 1-4 Alkylene NR C1 P(O)HOH、-C(O)NR C1 C 1-6 Alkyl, -NR C1 C(O)C 1-6 Alkyl, -NR C1 C(O)OC 1-6 Alkyl, -NR C1 C(O)NR C1 C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, or -OC(O)NR C1 C 1-6 alkyl;

[0033] R 4 Selected from H, deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy;

[0034] Each R x , L 1 、R 1 、R 2a 、R 2a1 、R 2b 、R B 、R A 、R A1 、Rz 、R 3 、R 3a 、R 3b 、R C 、R C1 、R C2 、R C3 、R 4 each independently optionally substituted with one or more substituents;

[0035] Provided that the compound of formula (I) comprises at least one R C .

[0036] In some embodiments, L 2 is selected from a single bond, Ring B is selected from optionally substituted by one or more R B or R C Substituted: 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0037] R 3 selected from H, deuterium, or optionally substituted by one or more R 3a or R C Substituted with the following groups: C 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0038] Each R C Independently selected from -C 1-6 Alkylene OP(O)(OH)2, -NR C1 P(O)(OH)2, or -NR C1 C 1-6 Alkylene OP(O)(OH)2.

[0039] In some embodiments, L 2 Selected from -C(R 2a R 2b )-, Ring B is selected from optionally substituted by one or more R B or R C Substituted: 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0040] Ring A is selected from the group consisting of A or R CSubstituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0041] R 3 selected from H, deuterium, or optionally substituted by one or more R 3a or R C Substituted with the following groups: C 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0042] Each R C Independently selected from -NR C1 C(O)OR C2 、-NR C1 P(O)(OR C2 )2、-NR C1 P(O)HOR C2 、-NR C1 C 1-6 Alkylene OP(O)(OR C2 )2, or -C 1-6 Alkylene OP(O)(OR C2 )2;

[0043] R C1 Independently selected from H, or C 1-6 alkyl;

[0044] R C2 independently selected from one or more R C3 Substituted with the following groups: C 1-12 Alkyl, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0045] Each R C3 Independently selected from -NR C1 P(O)(OH)2、-NR C1 C 1-4 Alkylene OP(O)(OH)2, or -OC(O)C 1-6 alkyl.

[0046] In some embodiments, the R x Selected from deuterium, halogen, -OH, -NH2, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0047] In some embodiments, the R x Selected from deuterium, halogen, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, halo C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino.

[0048] In some embodiments, the R x Selected from deuterium, -F, -Cl, -Br, -I, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or halogenated C 1-3 Alkoxy.

[0049] In some embodiments, the R x is selected from deuterium, -F, -Cl, -Br, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, or trifluoromethoxy.

[0050] In some embodiments, X is selected from -N-, -CH-, -C(C 1-6 Alkyl)-, or -C(halogenated C 1-6 alkyl)-.

[0051] In some embodiments, X is selected from -N-, -CH-, -C(C 1-3 Alkyl)-, or -C(halogenated C 1-3 alkyl)-.

[0052] In some embodiments, X is selected from -N-.

[0053] In some embodiments, the L 1Selected from -O-, -S-, or optionally one or more R 1 Substituted groups: -NH-, C 2-4 Alkylene, C 1-3 Heteroalkylene, C 2-4 Alkenylene, or C 1-3 Heteroalkenylene.

[0054] In some embodiments, the L 1 Selected from -O-, or optionally one or more R 1 Substituted groups: -NH-, C 2-4 Alkylene, or C 1-3 Heteroalkylene.

[0055] In some embodiments, the L 1 Selected from -O-, or optionally one or more R 1 Substituted with the following groups: -NH-, -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2OCH2-, -CH2CH2O-, -O(CH2)3-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2CH2O-, -NHCH2-, -NHCH2CH2-, -CH2NHCH2-, -CH2CH2NH-, -NH(CH2)3-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, or -CH2CH2CH2NH-.

[0056] In some embodiments, the L 1 Selected from optionally one or more R 1 Substituted: -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -OCH2CH2-, -O(CH2)3-, -NHCH2-, -NHCH2CH2-, or -NH(CH2)3-.

[0057] In some embodiments, the L 1 Selected from optionally one or more R 1 Substituted groups include: -(CH2)3-, -OCH2CH2-, or -NHCH2CH2-.

[0058] In some embodiments, the L 1 Selected from optionally one or more R 1 Substituted -OCH2CH2-.

[0059] In some embodiments, when X is selected from -N-, said L 1Not selected from -O-, -S-, -NH-, or -N(C 1-6 alkyl)-.

[0060] In some embodiments, each of said R 1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0061] In some embodiments, each of said R 1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, halo C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino.

[0062] In some embodiments, each of said R 1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl or halogenated C 1-3 Alkoxy.

[0063] In some embodiments, each of said R 1 independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or halogenated C 1-3 Alkoxy.

[0064] In some embodiments, each of said R 1 Independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -CH2F, trifluoromethyl, or trifluoromethoxy.

[0065] In some embodiments, each of said R 1 Independently selected from C 1-3 Alkyl or fluorinated C 1-3 alkyl.

[0066] In some embodiments, each of said R 1 Independently selected from methyl, ethyl, isopropyl, trifluoromethyl, or -CH2F.

[0067] In some embodiments, the L 2 is selected from a single bond, Ring B is selected from optionally substituted by one or more R B or R C Substituted: 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0068] In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of optionally substituted with one or more R B or R C Substituted: 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0069] In some embodiments, the L 2 is selected from a single bond, Ring B is selected from optionally substituted by one or more R B or R C Substituted 5-10 membered heterocycloalkenyl.

[0070] In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of optionally substituted with one or more R B or R C Substituted: 3-6 membered cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl.

[0071] In some embodiments, the L 2 is selected from a single bond, Ring B is selected from optionally substituted by one or more R B or R CSubstituted: dihydroindolinyl, cyclopentapyridinyl, dihydropyrrolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or tetrahydronaphthyridinyl.

[0072] In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of optionally substituted with one or more R B or R C Substituted cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0073] In some embodiments, the L 2 is selected from a single bond, Ring B is selected from optionally substituted by one or more R B or R C Substituted cyclopentapyridinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl.

[0074] In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of optionally substituted with one or more R B or R C Substituted cyclopropane, cyclobutane, cyclopentane, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrazolyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0075] In some embodiments, the L 2 is selected from a single bond, Ring B is selected from optionally substituted by one or more R B or R C Substituted groups:

[0076] In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of optionally substituted with one or more R B or R C Substituted groups: Phenyl,

[0077] In some embodiments, the L2 is selected from a single bond, Ring B is selected from optionally substituted by one or more R B or R C Substituted tetrahydroisoquinolinyl.

[0078] In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of optionally substituted with one or more R B or R C Substituted groups include phenyl and 5-6 membered heteroaryl.

[0079] In some embodiments, the L 2 is selected from a single bond, Ring B is selected from optionally substituted by one or more R B or R C Substituted 5,6,7,8-tetrahydroisoquinolinyl.

[0080] In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of optionally substituted with one or more R B or R C Substituted groups: phenyl,

[0081] In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of optionally substituted with one or more R B or R C Substituted pyridyl.

[0082] In some embodiments, the L 2 is selected from a single bond, Ring B is selected from optionally substituted by one or more R B or R C Substituted groups:

[0083] In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of optionally substituted with one or more R B or R C Substituted groups:

[0084] In some embodiments, the ring B is optionally replaced by one or more R B In some embodiments, the ring B is not replaced by RC replace.

[0085] In some embodiments, the L 2 is selected from a single bond, Ring B is selected from optionally substituted by one or more R B Substituted groups: In some embodiments, the L 2 Selected from single bonds, Ring B is selected from

[0086] In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of optionally substituted with one or more R B Substituted groups: In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from

[0087] In some embodiments, the L 2 Selected from single bonds, Ring B is selected from

[0088] In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from cyclopropane, Cyclobutane, Cyclopentyl,

[0089] In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from cyclopropane, Cyclobutane, Cyclopentyl, In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from In some embodiments, the L2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from cyclopropane, Cyclobutane, Cyclopentyl, In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from In some embodiments, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from

[0090] In some embodiments, the R 2a is selected from H, deuterium, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a1 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, 3-8 membered cycloalkyl, or 4-8 membered heterocyclic group.

[0091] In some embodiments, the R 2a Selected from H, deuterium, or optionally one or more R 2a1 Substituted C 1-4 alkyl.

[0092] In some embodiments, the R 2a is selected from H, deuterium, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a1 Substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, 3-8 membered cycloalkyl, or 4-8 membered heterocycloalkyl.

[0093] In some embodiments, the R 2a is selected from H, deuterium, -F, -Cl, -Br, -I, -OH, -NH2, -CN, or optionally substituted by one or more R 2a1Substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl.

[0094] In some embodiments, the R 2a is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, or optionally substituted by one or more R 2a1 Substituted groups include methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, ethylamino, dimethylamino, cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.

[0095] In some embodiments, the R 2a is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, or optionally substituted by one or more R 2a1 Substituted groups include methyl, methoxy, methylthio, methylamino, dimethylamino, cyclopropane, or azetidinyl.

[0096] In some embodiments, the R 2a is selected from H, deuterium, -F, -Cl, -Br, methyl, trifluoromethyl, methoxy, trifluoromethoxy, methylamino, dimethylamino, or cyclopropane.

[0097] In some embodiments, each of said R 2a1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0098] In some embodiments, each of said R 2a1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, halo C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino.

[0099] In some embodiments, each of said R 2a1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl or halogenated C 1-3 Alkoxy.

[0100] In some embodiments, each of said R 2a1 are independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

[0101] In some embodiments, the R 2b independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0102] In some embodiments, the R 2b independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, halo C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino.

[0103] In some embodiments, the R 2b independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl or halogenated C 1-3 Alkoxy.

[0104] In some embodiments, the R 2b independently selected from H, deuterium, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or halogenated C 1-3 Alkoxy.

[0105] In some embodiments, the R 2b Independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -CH2F, trifluoromethyl, or trifluoromethoxy.

[0106] In some embodiments, the R 2b Independently selected from H, deuterium, -F, -Cl, methyl, -CH2F, or trifluoromethyl.

[0107] In some embodiments, the R 2a is selected from methyl, said R 2b In some embodiments, the R 2a is selected from methyl, said R 2b Selected from H.

[0108] In some embodiments, each of said R B independently selected from deuterium, oxo, halogen, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0109] In some embodiments, each of said R B independently selected from deuterium, oxo, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, halo C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino.

[0110] In some embodiments, each of said R B Independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, ethylamino, dimethylamino, fluoromethyl, fluoromethoxy, fluoromethylamino, or fluorodimethylamino.

[0111] In some embodiments, each of said R B Independently selected from deuterium, oxo, -F, -Cl, -Br, -CN, -OH, -NH2, methyl, methoxy, methylthio, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

[0112] In some embodiments, each of said R B Independently selected from -F, -Cl, -OH, -NH2, methyl, methylamino, or dimethylamino.

[0113] In some embodiments, the R B Selected from -F, -Cl, or -NH2.

[0114] In some embodiments, the ring A is selected from the group consisting of A or R C Substituted: 3-6 membered cycloalkyl, 5-10 membered cycloalkenyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0115] In some embodiments, the ring A is selected from the group consisting of A or R C Substituted: benzo 4-6 membered cycloalkenyl, benzo 4-6 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0116] In some embodiments, the ring A is selected from the group consisting of A or RC Substituted phenyl, naphthyl, benzocyclohexenyl, benzocyclopentenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzopyrimidinyl, benzothienyl, pyridopyrazolyl, or pyridopyrrolyl.

[0117] In some embodiments, the ring A is selected from the group consisting of A or R C Substituted phenyl, naphthyl, pyrazolyl, pyridyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzothienyl, pyridopyrazolyl, or pyridopyrrolyl.

[0118] In some embodiments, the ring A is selected from the group consisting of A or R C Substituted groups:

[0119] In some embodiments, the ring A is selected from the group consisting of A or R C Substituted: phenyl, naphthyl, or benzothienyl.

[0120] In some embodiments, the ring A is selected from the group consisting of A or R C Substituted groups: In some embodiments, the ring A is selected from the group consisting of A or R C Replaced In some embodiments, the ring A is selected from the group consisting of A or R C Replaced In some embodiments, the ring A is selected from the group consisting of A or R C Replaced

[0121] In some embodiments, the ring A is optionally replaced by one or more R A In some embodiments, the ring A is not replaced by R C replace.

[0122] In some embodiments, the ring A is selected from the group consisting ofA Substituted groups: In some embodiments, the ring A is selected from

[0123] In some embodiments, the ring A is selected from

[0124] In some embodiments, the ring A is selected from In some embodiments, the ring A is selected from In some embodiments, the ring A is selected from In some embodiments, the ring A is selected from

[0125] In some embodiments, each of said R A independently selected from deuterium, oxo, halogen, -CN, -OH, -NH2, or optionally substituted by one or more R A1 Substituted with the following groups: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 alkylamino, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0126] In some embodiments, each of said R A independently selected from deuterium, oxo, halogen, -CN, -OH, -NH2, or optionally substituted by one or more R A1 Substituted with the following groups: C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 alkylamino, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0127] In some embodiments, each of said RA independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -CN, -OH, -NH2, or optionally substituted by one or more R A1 Substituted groups include methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, methylthio, methylamino, dimethylamino, 3-6 membered cycloalkyl, or 4-7 membered heterocycloalkyl.

[0128] In some embodiments, each of said R A independently selected from deuterium, -F, -Cl, -Br, -CN, -OH, -NH2, or optionally substituted by one or more R A1 Substituted groups include methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, methylthio, methylamino, dimethylamino, cyclopropane, cyclobutane, oxetanyl, or azetidinyl.

[0129] In some embodiments, each of said R A independently selected from deuterium, -F, -Cl, -Br, -CN, -OH, -NH2, or optionally substituted by one or more R A1 Substituted groups include methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, methylthio, methylamino, dimethylamino, or cyclopropane.

[0130] In some embodiments, each of said R A independently selected from deuterium, -F, -Cl, -Br, -CN, -OH, -NH2, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, trifluoromethyl, hydroxymethylene, methoxy, trifluoromethoxy, methylamino, dimethylamino, methylthio, trifluoromethylthio, or cyclopropane optionally substituted with -F, -Cl, -Br, or methyl.

[0131] In some embodiments, each of said R A Independently selected from deuterium, -F, -Cl, -CN, -OH, -NH2, methyl, ethyl, isopropyl, ethynyl, propynyl, trifluoromethyl, methoxy, trifluoromethoxy, dimethylamino, methylthio, or cyclopropane substituted with methyl.

[0132] In some embodiments, each of said R A Independently selected from deuterium, -F, -Cl, -CN, -OH, -NH2, methyl, ethyl, ethynyl, or trifluoromethyl.

[0133] In some embodiments, each of said R A1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, halo C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino.

[0134] In some embodiments, each of said R A1 Independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, methylthio, methylamino, dimethylamino, diethylamino, fluoromethyl, or fluoromethoxy.

[0135] In some embodiments, each of said R A1 Independently selected from deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, methylthio, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

[0136] In some embodiments, each of said R A1 Independently selected from -F, -Cl, -Br, or methyl.

[0137] In some embodiments, Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted groups: -NH-, or -N(C 1-6 alkyl)-.

[0138] In some embodiments, Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-4 alkyl)-.

[0139] In some embodiments, Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-3 alkyl)-.

[0140] In some embodiments, Z is selected from a single bond, -O-, -NH-, or -N(CH3)-.

[0141] In some embodiments, said Z is selected from -O-.

[0142] In some embodiments, each of said R z independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0143] In some embodiments, each of said R z independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, halo C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino.

[0144] In some embodiments, each of said R z independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl or halogenated C 1-3 Alkoxy.

[0145] In some embodiments, each of said R z Independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

[0146] In some embodiments, the heterocyclyl is selected from heterocycloalkyl. In some embodiments, the heterocyclyl is selected from partially unsaturated heterocyclyl.

[0147] In some embodiments, the 3-12 membered heterocyclyl is selected from 3-12 membered heterocyclyl or benzo 4-6 membered heterocyclyl. 1-6 Alkylene is selected from 3-12 membered heterocycloalkyl C 1-6 Alkylene or benzo 4-6 membered heterocyclic group C 1-6 Alkylene.

[0148] In some embodiments, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a or R C Substituted with the following groups: C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl C 1-4 Alkylene, 3-10 membered heterocyclic group C 1-4 Alkylene, 6-10 membered aryl C 1-4 Alkylene, or 5-10 membered heteroaryl C 1-4 Alkylene.

[0149] In some embodiments, the 3-10 membered heterocyclyl is selected from 3-10 membered heterocyclyl or benzo 4-6 membered heterocyclyl. 1-4 Alkylene is selected from 3-10 membered heterocycloalkyl C 1-4 Alkylene or benzo 4-6 membered heterocyclic group C 1-4 Alkylene.

[0150] In some embodiments, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a or R C Substituted with the following groups: C 1-4 Alkyl, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-10 membered cycloalkyl C 1-3 Alkylene, 4-10 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0151] In some embodiments, the 4-10 membered heterocyclyl is selected from 4-10 membered heterocyclyl or benzo 4-6 membered heterocyclyl. 1-3 Alkylene is selected from 4-10 membered heterocycloalkyl C 1-3 Alkylene or benzo 4-6 membered heterocyclic group C 1-3 Alkylene.

[0152] In some embodiments, the R 3 Selected from optionally one or more R 3a or R C Substituted 3-10 membered heterocyclic group or 3-10 membered heterocyclic group C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a or RC In some embodiments, the R 3 Selected from optionally one or more R 3a or R C Substituted 4-10-membered, 4-9-membered, 4-8-membered, or 5-9-membered heterocyclic group C 1-3 Alkylene.

[0153] In some embodiments, the R 3 Selected from optionally one or more R 3a or R C Substituted 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a or R C In some embodiments, the R 3 Selected from optionally one or more R 3a or R C Substituted 4-10-membered, 4-9-membered, 4-8-membered, or 5-9-membered heterocycloalkyl C 1-3 Alkylene.

[0154] In some embodiments, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a or R C Substituted with the following groups: C 1-4 Alkyl, 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl C 1-3 Alkylene, 4-10 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0155] In some embodiments, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a or R C Substituted with the following groups: C 1-4 Alkyl, 3-8 membered cycloalkyl, 4-10 membered heterocyclic group, 5-6 membered heteroaryl, 3-8 membered cycloalkyl C 1-3 Alkylene, 4-10 membered heterocyclic group C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0156] In some embodiments, the R 3selected from H, deuterium, or optionally substituted by one or more R 3a or R C Substituted with the following groups: C 1-4 Alkyl, 4-10 membered heterocyclic group, 3-8 membered cycloalkyl C 1-3 Alkylene, 4-10 membered heterocyclic group C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0157] In some embodiments, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a or R C Substituted with the following groups: C 1-4 Alkyl, 4-10 membered heterocycloalkyl, 3-8 membered cycloalkyl C 1-3 Alkylene, 4-10 membered heterocycloalkyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0158] In some embodiments, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a or R C Substituted groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, piperazinyl, hexahydro-1H-pyrrolazinyl, 5-azaspiro[2.4]heptyl, tetrahydro-1'H,3'H-pyrrolo[cyclopropane-1,2'-pyrrolidine], cyclopropyl C 1-3 Alkylene, cyclobutyl C 1-3 Alkylene, cyclopentyl C 1-3 Alkylene, cyclohexyl C 1-3 Alkylene, azetidinyl C 1-3 Alkylene, tetrahydropyrrolyl C 1-3 Alkylene, morpholinyl C 1-3 Alkylene, piperidinyl C 1-3 Alkylene, piperazinyl C 1-3 Alkylene, hexahydro-1H-pyrrolizinyl C 1-3 Alkylene, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl C 1-3 Alkylene, 5-azaspiro[2.4]heptyl C 1-3 Alkylene, tetrahydro-1'H,3'H-pyrrolo[cyclopropane-1,2'-pyrrolidine]C 1-3 Alkylene, or imidazolyl C 1-3 Alkylene.

[0159] In some embodiments, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a or R C Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclohexyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, cyclopropyl C 1-3 Alkylene, cyclobutyl C 1-3 Alkylene, cyclopentyl C 1-3 Alkylene, azetidinyl C 1-3 Alkylene, tetrahydropyrrolyl C 1-3 Alkylene, morpholinyl C 1-3 Alkylene, piperidinyl C 1-3 Alkylene, piperazinyl C 1-3 Alkylene, hexahydro-1H-pyrrolizinyl C 1-3 Alkylene, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl C 1-3 Alkylene, 5-azaspiro[2.4]heptyl C 1-3 Alkylene, tetrahydro-1'H,3'H-pyrrolo[cyclopropane-1,2'-pyrrolidine]C 1-3 Alkylene, or imidazolyl C 1-3 Alkylene.

[0160] In some embodiments, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a or R C Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,

[0161] In some embodiments, the R 3 Selected from optionally one or more R 3a or R C Substituted hexahydro-1H-pyrrolizinyl C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a or R C Replaced In some embodiments, the R 3 Selected from optionally one or more R 3a Replaced In some embodiments, the R 3 Selected from optionally one or more R 3a Replaced In some embodiments, the R3 Selected from optionally one or more R 3a Replaced In some embodiments, the R 3 Selected from In some embodiments, the R 3 Selected from

[0162] In some embodiments, the R 3 Selected from optionally one or more R 3a or R C Substituted tetrahydropyrrolyl C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a or R C Replaced In some embodiments, the R 3 Selected from optionally one or more R 3a Replaced In some embodiments, the R 3 Selected from optionally one or more R 3a Replaced In some embodiments, the R 3 Selected from optionally one or more R 3a Replaced In some embodiments, the R 3 Selected from optionally one or more R 3a Replaced In some embodiments, the R 3 Selected from In some embodiments, the R 3 Selected from

[0163] In some embodiments, the R 3 Optionally, one or more R 3a In some embodiments, the R 3 Not R C replace.

[0164] In some embodiments, the R 3 Selected from H, deuterium, methyl,

[0165] In some embodiments, the R 3 Selected from In some embodiments, the R 3 Selected from In some embodiments, the R 3 Selected from In some embodiments, the R 3 Selected from In some embodiments, the R 3 Selected from In some embodiments, the R 3 Selected from

[0166] In some embodiments, each of said R 3a The substituted positions are independently selected from R 3 In some embodiments, each of R 3a The substituted position is R 3 In some embodiments, each of the R 3a The substituted position is R 3 The alkylene portion.

[0167] In some embodiments, each of said R 3a independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 3b Substituted groups: =NH, =CH2, =N(C 1-4 alkyl), =CH(C 1-4 alkyl), =C(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, or di-C 1-4 Alkylamino.

[0168] In some embodiments, each of said R 3a independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH2, -CN, or optionally substituted by one or more R 3b Substituted groups include: =NH, =CH2, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, ethylamino, or dimethylamino.

[0169] In some embodiments, each of said R 3a Independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, =CH2, =CHF, =CF2, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, trifluoromethoxy, or dimethylaminomethylene.

[0170] In some embodiments, each of said R 3b independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, or di-C 1-3 Alkylamino.

[0171] In some embodiments, each of said R 3b are independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH2, -CN, methoxy, ethoxy, methylthio, methylamino, ethylamino, dimethylamino, or diethylamino.

[0172] In some embodiments, each of said R 3b Independently selected from -F, -Cl, -NH2, methyl, methoxy, methylamino, or dimethylamino.

[0173] In some embodiments, Ring B is optionally replaced by one or more R C and optionally substituted by one or more R B Ring A is optionally substituted with one or more R C and optionally substituted by one or more R A Replacement; R 3 Optionally, one or more R C and optionally substituted by one or more R 3a In some embodiments, Ring B is optionally replaced by one R C and optionally substituted by one or more R B Ring A is optionally substituted with one R C and optionally substituted by one or more R A Replacement; R 3 Optionally replaced by an R C and optionally substituted by one or more R 3a replace.

[0174] In some embodiments, Ring B is replaced by one or more R C and optionally substituted by one or more R B In some embodiments, Ring B is replaced by one R Cand optionally substituted by one or more R B replace.

[0175] In some embodiments, Ring B is replaced by one or more R C and optionally substituted by one or more R B Ring A is not replaced by R C and optionally substituted by one or more R A Replacement; R 3 Not R C and optionally substituted by one or more R 3a In some embodiments, Ring B is replaced by one R C and optionally substituted by one or more R B Ring A is not replaced by R C and optionally substituted by one or more R A Replacement; R 3 Not R C and optionally substituted by one or more R 3a replace.

[0176] In some embodiments, Ring A is replaced by one or more R C and optionally substituted by one or more R A In some embodiments, Ring A is replaced by one R C and optionally substituted by one or more R A replace.

[0177] In some embodiments, Ring A is replaced by one or more R C and optionally substituted by one or more R A Ring B is not replaced by R C and optionally substituted by one or more R B Replacement; R 3 Not R C and optionally substituted by one or more R 3a In some embodiments, Ring A is replaced by one R C and optionally substituted by one or more R A Ring B is not replaced by R C and optionally substituted by one or more R B Replacement; R 3 Not R C and optionally substituted by one or more R 3a replace.

[0178] In some embodiments, R 3 By one or more R C and optionally substituted by one or more R3a In some embodiments, R 3 By an R C and optionally substituted by one or more R 3a replace.

[0179] In some embodiments, R 3 By one or more R C and optionally substituted by one or more R 3a Ring A is not replaced by R C and optionally substituted by one or more R A Ring B is not replaced by R C and optionally substituted by one or more R B In some embodiments, R 3 By an R C and optionally substituted by one or more R 3a Ring A is not replaced by R C and optionally substituted by one or more R A Ring B is not replaced by R C and optionally substituted by one or more R B replace.

[0180] In some embodiments, the compound of formula (I) comprises one, two, three, four, five, or six R C .

[0181] In some embodiments, the compound of formula (I) comprises one or two R C .

[0182] In some embodiments, the compound of formula (I) has one and only one R C .

[0183] In some embodiments, each of said R C Independently selected from -NR C1 C(O)R C2 、-NR C1 C(O)OR C2 、-NR C1 C(O)OC 1-4 Alkylene OC(O)R C2 、-NR C1 C(O)OC 1-4 Alkylene NR C1 C(O)R C2 、-NR C1 C(O)NR C1 R C2 、-NR C1 C(O)NR C1 C1-4 Alkylene NR C1 C(O)R C2 、-NR C1 C(O)NR C1 C 1-4 Alkylene OC(O)R C2 、-OC(O)R C2 、-OC(O)OR C2 、-OC(O)OC 1-4 Alkylene OC(O)R C2 、-OC(O)OC 1-4 Alkylene NR C1 C(O)R C2 、-OC(O)NR C1 R C2 、-OC(O)NR C1 C 1-4 Alkylene OC(O)R C2 、-OC(O)NR C1 C 1-4 Alkylene NR C1 C(O)R C2 、-P(O)(OR C2 )2. -C 1-4 Alkylene P(O)(OR C2 )2. -C 1-4 Alkylene NR C1 P(O)(OR C2 )2. -C 1-4 Alkylene OP(O)(OR C2 )2、-NR C1 P(O)(OR C2 )2、-NR C1 C 1-4 Alkylene P(O)(OR C2 )2、-NR C1 C 1-4 Alkylene OP(O)(OR C2 )2、-NR C1 C 1-4 Alkylene NR C1 P(O)(OR C2 )2、-OP(O)(OR C2 )2. -OC 1-4 Alkylene P(O)(OR C2 )2. -OC 1-4 Alkylene OP(O)(OR C2 )2. -OC 1-4 Alkylene NR C1 P(O)(OR C2 )2、-P(O)HORC2 、-C 1-4 Alkylene P(O)HOR C2 、-C 1-4 Alkylene NR C1 P(O)HOR C2 、-C 1-4 Alkylene OP(O)HOR C2 、-NR C1 P(O)HOR C2 、-NR C1 C 1-4 Alkylene P(O)HOR C2 、-NR C1 C 1-4 Alkylene OP(O)HOR C2 、-NR C1 C 1-4 Alkylene NR C1 P(O)HOR C2 、-OP(O)HOR C2 、-OC 1-4 Alkylene P(O)HOR C2 、-OC 1-4 Alkylene OP(O)HOR C2 , or -OC 1-4 Alkylene NR C1 P(O)HOR C2 .

[0184] In some embodiments, each of said R C Independently selected from -NR C1 C(O)R C2 、-NR C1 C(O)OR C2 、-NR C1 C(O)OC 1-3 Alkylene OC(O)R C2 、-NR C1 C(O)OC 1-3 Alkylene NR C1 C(O)R C2 、-NR C1 C(O)NR C1 R C2 、-NR C1 C(O)NR C1 C 1-3 Alkylene NR C1 C(O)R C2 、-NR C1 C(O)NR C1 C 1-3 Alkylene OC(O)R C2 、-OC(O)RC2 、-OC(O)OR C2 、-OC(O)OC 1-3 Alkylene OC(O)R C2 、-OC(O)OC 1-3 Alkylene NR C1 C(O)R C2 、-OC(O)NR C1 R C2 、-OC(O)NR C1 C 1-3 Alkylene OC(O)R C2 、-OC(O)NR C1 C 1-3 Alkylene NR C1 C(O)R C2 、-P(O)(OR C2 )2. -C 1-3 Alkylene P(O)(OR C2 )2. -C 1-3 Alkylene NR C1 P(O)(OR C2 )2. -C 1-3 Alkylene OP(O)(OR C2 )2、-NR C1 P(O)(OR C2 )2、-NR C1 C 1-3 Alkylene P(O)(OR C2 )2、-NR C1 C 1-3 Alkylene OP(O)(OR C2 )2、-NR C1 C 1-3 Alkylene NR C1 P(O)(OR C2 )2、-OP(O)(OR C2 )2. -OC 1-3 Alkylene P(O)(OR C2 )2. -OC 1-3 Alkylene OP(O)(OR C2 )2. -OC 1-3 Alkylene NR C1 P(O)(OR C2 )2、-P(O)HOR C2 、-C 1-3 Alkylene P(O)HOR C2 、-C 1-3 Alkylene NR C1 P(O)HOR C2 、-C 1-3 Alkylene OP(O)HORC2 、-NR C1 P(O)HOR C2 、-NR C1 C 1-3 Alkylene P(O)HOR C2 、-NR C1 C 1-3 Alkylene OP(O)HOR C2 、-NR C1 C 1-3 Alkylene NR C1 P(O)HOR C2 、-OP(O)HOR C2 、-OC 1-3 Alkylene P(O)HOR C2 、-OC 1-3 Alkylene OP(O)HOR C2 , or -OC 1-3 Alkylene NR C1 P(O)HOR C2 .

[0185] In some embodiments, each of said R C Independently selected from -NR C1 C(O)R C2 、-NR C1 C(O)OR C2 、-NR C1 C(O)OC 1-3 Alkylene OC(O)R C2 、-NR C1 C(O)OC 1-3 Alkylene NR C1 C(O)R C2 、-OC(O)R C2 、-OC(O)OR C2 、-OC(O)OC 1-3 Alkylene OC(O)R C2 、-OC(O)OC 1-3 Alkylene NR C1 C(O)R C2 、-OC(O)NR C1 R C2 、-OC(O)NR C1 C 1-3 Alkylene OC(O)R C2 、-OC(O)NR C1 C 1-3 Alkylene NR C1 C(O)R C2 、-C 1-3 Alkylene NR C1 P(O)(ORC2 )2. -C 1-3 Alkylene OP(O)(OR C2 )2、-NR C1 P(O)(OR C2 )2、-NR C1 C 1-3 Alkylene OP(O)(OR C2 )2、-NR C1 C 1-3 Alkylene NR C1 P(O)(OR C2 )2、-OP(O)(OR C2 )2. -OC 1-3 Alkylene OP(O)(OR C2 )2. -OC 1-3 Alkylene NR C1 P(O)(OR C2 )2. -C 1-3 Alkylene NR C1 P(O)HOR C2 、-C 1-3 Alkylene OP(O)HOR C2 、-NR C1 P(O)HOR C2 、-NR C1 C 1-3 Alkylene OP(O)HOR C2 、-NR C1 C 1-3 Alkylene NR C1 P(O)HOR C2 、-OP(O)HOR C2 、-OC 1-3 Alkylene OP(O)HOR C2 , or -OC 1-3 Alkylene NR C1 P(O)HOR C2 .

[0186] In some embodiments, each of said R C Independently selected from -NR C1 C(O)R C2 、-NR C1 C(O)OR C2 、-NR C1 C(O)OC 1-3 Alkylene OC(O)R C2 、-OC(O)R C2 、-OC(O)OR C2 、-OC(O)OC 1-3 Alkylene OC(O)R C2、-OC(O)NR C1 R C2 、-OC(O)NR C1 C 1-3 Alkylene OC(O)R C2 、-OC(O)NR C1 C 1-3 Alkylene NR C1 C(O)R C2 、-C 1-3 Alkylene NR C1 P(O)(OR C2 )2. -C 1-3 Alkylene OP(O)(OR C2 )2、-NR C1 P(O)(OR C2 )2、-NR C1 C 1-3 Alkylene OP(O)(OR C2 )2、-NR C1 C 1-3 Alkylene NR C1 P(O)(OR C2 )2、-OP(O)(OR C2 )2. -OC 1-3 Alkylene OP(O)(OR C2 )2. -OC 1-3 Alkylene NR C1 P(O)(OR C2 )2. -C 1-3 Alkylene NR C1 P(O)HOR C2 、-C 1-3 Alkylene OP(O)HOR C2 、-NR C1 P(O)HOR C2 、-NR C1 C 1-3 Alkylene OP(O)HOR C2 、-NR C1 C 1-3 Alkylene NR C1 P(O)HOR C2 、-OP(O)HOR C2 、-OC 1-3 Alkylene OP(O)HOR C2 , or -OC 1-3 Alkylene NR C1 P(O)HOR C2 .

[0187] In some embodiments, each of said R C Independently selected from -NRC1 C(O)R C2 、-NR C1 C(O)OR C2 、-OC(O)R C2 、-OC(O)OR C2 、-OC(O)OC 1-3 Alkylene OC(O)R C2 、-OC(O)NR C1 R C2 、-C 1-3 Alkylene OP(O)(OR C2 )2、-NR C1 P(O)(OR C2 )2、-NR C1 C 1-3 Alkylene OP(O)(OR C2 )2、-OP(O)(OR C2 )2. -OC 1-3 Alkylene OP(O)(OR C2 )2, or -NR C1 P(O)HOR C2 .

[0188] In some embodiments, each of said R C Independently selected from -NR C1 C(O)OR C2 、-C 1-2 Alkylene OP(O)(OR C2 )2、-NR C1 P(O)(OR C2 )2、-NR C1 C 1-2 Alkylene OP(O)(OR C2 )2, or -NR C1 P(O)HOR C2 .

[0189] In some embodiments, each of said R C Independently selected from -NR C1 C(O)OR C2 、-C 1-2 Alkylene OP(O)(OH)2, -NR C1 P(O)(OH)2、-NR C1 P(O)(OR C2 )2、-NR C1 C 1-2 Alkylene OP(O)(OH)2, or -NR C1 P(O)HOR C2 .

[0190] In some embodiments, each of said R C Independently selected from -NR C1 C(O)OR C2 、-P(O)(OR C2 )2. -C 1-4 Alkylene P(O)(OR C2 )2. -C 1-4 Alkylene NR C1 P(O)(OR C2 )2. -C 1-4 Alkylene OP(O)(OR C2 )2、-NR C1 P(O)(OR C2 )2、-NR C1 C 1-4 Alkylene P(O)(OR C2 )2、-NR C1 C 1-4 Alkylene OP(O)(OR C2 )2、-NR C1 C 1-4 Alkylene NR C1 P(O)(OR C2 )2、-OP(O)(OR C2 )2. -OC 1-4 Alkylene P(O)(OR C2 )2. -OC 1-4 Alkylene OP(O)(OR C2 )2. -OC 1-4 Alkylene NR C1 P(O)(OR C2 )2、-P(O)HOR C2 、-C 1-4 Alkylene P(O)HOR C2 、-C 1-4 Alkylene NR C1 P(O)HOR C2 、-C 1-4 Alkylene OP(O)HOR C2 、-NR C1 P(O)HOR C2 、-NR C1 C 1-4 Alkylene P(O)HOR C2 、-NR C1 C 1-4 Alkylene OP(O)HOR C2 、-NR C1 C 1-4 Alkylene NR C1 P(O)HOR C2 、-OP(O)HORC2 、-OC 1-4 Alkylene P(O)HOR C2 、-OC 1-4 Alkylene OP(O)HOR C2 , or -OC 1-4 Alkylene NR C1 P(O)HOR C2 .

[0191] In some embodiments, each of said R C Independently selected from -NR C1 C(O)OR C2 、-P(O)(OR C2 )2. -C 1-3 Alkylene P(O)(OR C2 )2. -C 1-3 Alkylene NR C1 P(O)(OR C2 )2. -C 1-3 Alkylene OP(O)(OR C2 )2、-NR C1 P(O)(OR C2 )2、-NR C1 C 1-3 Alkylene P(O)(OR C2 )2、-NR C1 C 1-3 Alkylene OP(O)(OR C2 )2、-NR C1 C 1-3 Alkylene NR C1 P(O)(OR C2 )2、-OP(O)(OR C2 )2. -OC 1-3 Alkylene P(O)(OR C2 )2. -OC 1-3 Alkylene OP(O)(OR C2 )2. -OC 1-3 Alkylene NR C1 P(O)(OR C2 )2、-P(O)HOR C2 、-C 1-3 Alkylene P(O)HOR C2 、-C 1-3 Alkylene NR C1 P(O)HOR C2 、-C 1-3 Alkylene OP(O)HOR C2 、-NR C1 P(O)HOR C2 、-NRC1 C 1-3 Alkylene P(O)HOR C2 、-NR C1 C 1-3 Alkylene OP(O)HOR C2 、-NR C1 C 1-3 Alkylene NR C1 P(O)HOR C2 、-OP(O)HOR C2 、-OC 1-3 Alkylene P(O)HOR C2 、-OC 1-3 Alkylene OP(O)HOR C2 , or -OC 1-3 Alkylene NR C1 P(O)HOR C2 .

[0192] In some embodiments, each of said R C Independently selected from -NR C1 C(O)OR C2 、-C 1-3 Alkylene NR C1 P(O)(OR C2 )2. -C 1-3 Alkylene OP(O)(OR C2 )2、-NR C1 P(O)(OR C2 )2、-NR C1 C 1-3 Alkylene OP(O)(OR C2 )2、-NR C1 C 1-3 Alkylene NR C1 P(O)(OR C2 )2、-OP(O)(OR C2 )2. -OC 1-3 Alkylene OP(O)(OR C2 )2. -OC 1-3 Alkylene NR C1 P(O)(OR C2 )2. -C 1-3 Alkylene NR C1 P(O)HOR C2 、-C 1-3 Alkylene OP(O)HOR C2 、-NR C1 P(O)HOR C2 、-NR C1 C 1-3 Alkylene OP(O)HOR C2、-NR C1 C 1-3 Alkylene NR C1 P(O)HOR C2 、-OP(O)HOR C2 、-OC 1-3 Alkylene OP(O)HOR C2 , or -OC 1-3 Alkylene NR C1 P(O)HOR C2 .

[0193] In some embodiments, each of said R C Independently selected from -NR C1 C(O)OR C2 、-C 1-3 Alkylene NR C1 P(O)(OH)2、-C 1-3 Alkylene NR C1 P(O)(OR C2 )2. -C 1-3 Alkylene OP(O)(OH)2, -C 1-3 Alkylene OP(O)(OR C2 )2、-NR C1 P(O)(OH)2、-NR C1 P(O)(OR C2 )2、-NR C1 C 1-3 Alkylene OP(O)(OH)2, -NR C1 C 1-3 Alkylene OP(O)(OR C2 )2、-NR C1 C 1-3 Alkylene NR C1 P(O)(OH)2、-NR C1 C 1-3 Alkylene NR C1 P(O)(OR C2 )2、-OP(O)(OH)2、-OP(O)(OR C2 )2. -OC 1-3 Alkylene OP(O)(OH)2, -OC 1-3 Alkylene OP(O)(OR C2 )2. -OC 1-3 Alkylene NR C1 P(O)(OH)2、-OC 1-3 Alkylene NR C1 P(O)(OR C2 )2. -C 1-3 Alkylene NR C1P(O)HOH、-C 1-3 Alkylene NR C1 P(O)HOR C2 、-C 1-3 Alkylene OP(O)HOH, -C 1-3 Alkylene OP(O)HOR C2 、-NR C1 P(O)HOH、-NR C1 P(O)HOR C2 、-NR C1 C 1-3 Alkylene OP(O)HOH, -NR C1 C 1-3 Alkylene OP(O)HOR C2 、-NR C1 C 1-3 Alkylene NR C1 P(O)HOH、-NR C1 C 1-3 Alkylene NR C1 P(O)HOR C2 、-OP(O)HOH、-OP(O)HOR C2 、-OC 1-3 Alkylene OP(O)HOH, -OC 1-3 Alkylene OP(O)HOR C2 、-OC 1-3 Alkylene NR C1 P(O)HOH, or -OC 1-3 Alkylene NR C1 P(O)HOR C2 .

[0194] In some embodiments, each of said R C Independently selected from -NR C1 C(O)OR C2 、-C 1-2 Alkylene NR C1 P(O)(OH)2、-C 1-2 Alkylene OP(O)(OH)2, -NR C1 P(O)(OH)2、-NR C1 P(O)(OR C2 )2、-NR C1 C 1-2 Alkylene OP(O)(OH)2, -NR C1 C 1-2 Alkylene NR C1 P(O)(OH)2, -OP(O)(OH)2, -OP(O)(OR C2 )2. -OC 1-2Alkylene OP(O)(OH)2, -OC 1-2 Alkylene NR C1 P(O)(OH)2、-C 1-2 Alkylene NR C1 P(O)HOH、-C 1-2 Alkylene OP(O)HOH, -NR C1 P(O)HOH、-NR C1 P(O)HOR C2 、-NR C1 C 1-3 Alkylene OP(O)HOH, -NR C1 C 1-3 Alkylene NR C1 P(O)HOH, -OP(O)HOH, -OP(O)HOR C2 、-OC 1-3 Alkylene OP(O)HOH, or -OC 1-3 Alkylene NR C1 P(O)HOH.

[0195] In some embodiments, each of said R C Independently selected from

[0196] In some embodiments, each of said R C Independently selected from In some embodiments, each of said R C Independently selected from In some embodiments, each of said R C Independently selected from In some embodiments, each of said R C Independently selected from In some embodiments, each of said R C Independently selected from In some embodiments, each of said R C Independently selected from

[0197] In some embodiments, the R C1 Independently selected from H, or C 1-4 alkyl.

[0198] In some embodiments, the R C1 Independently selected from H, or C 1-3 alkyl.

[0199] In some embodiments, the R C1 Independently selected from H, methyl, ethyl, or isopropyl.

[0200] In some embodiments, the R C1 Independently selected from H or methyl.

[0201] In some embodiments, the R C1 Independently selected from H.

[0202] In some embodiments, the R C2 independently selected from H, or optionally substituted by one or more R C3 Substituted with the following groups: C 1-10 Alkyl, C 1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkylC 1-6 Alkylene, 3-10 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 Alkylene.

[0203] In some embodiments, the R C2 independently selected from H, or optionally substituted by one or more R C3 Substituted with the following groups: C 1-8 Alkyl, C 1-8 heteroalkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkylC 1-4 Alkylene, 3-8 membered heterocyclic group C 1-4 Alkylene, 6-10 membered aryl C 1-4 Alkylene, or 5-10 membered heteroaryl C 1-4 Alkylene.

[0204] In some embodiments, the R C2 independently selected from H, or optionally substituted by one or more R C3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 heteroalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-3 Alkylene, 3-6 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3Alkylene.

[0205] In some embodiments, the R C2 The “heteroalkyl” portion is selected from alkoxy, alkylamino, dialkylamino, alkoxyalkylene, alkylaminoalkylene, dialkylaminoalkylene, alkoxyalkyleneoxy, alkoxyalkyleneamino, alkylaminoalkyleneoxy, alkylaminoalkyleneamino, dialkylaminoalkyleneoxy, or dialkylaminoalkyleneamino.

[0206] In some embodiments, the R C2 independently selected from H, or optionally substituted by one or more R C3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-3 Alkylamino, C 1-3 Alkoxy C 1-3 Alkylene, C 1-3 Alkylamino C 1-3 Alkylene, di-C 1-2 Alkylamino C 1-2 Alkylene, C 1-3 Alkoxy C 1-3 Alkyleneoxy, C 1-3 Alkoxy C 1-3 Alkyleneamino, C 1-3 Alkylamino C 1-3 Alkyleneoxy, C 1-3 Alkylamino C 1-3 Alkyleneamino, di-C 1-2 Alkylamino C 1-2 Alkyleneoxy, di-C 1-2 Alkylamino C 1-2 Alkyleneamino, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-3 Alkylene, 3-6 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0207] In some embodiments, the R C2 independently selected from H, or optionally substituted by one or more R C3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-3 Alkylamino, C 1-4 Alkoxy C 1-2 Alkylene, C 1-4Alkylamino C 1-2 Alkylene, di-C 1-2 Alkylamino C 1-2 Alkylene, C 1-4 Alkoxy C 1-2 Alkyleneoxy, C 1-4 Alkoxy C 1-2 Alkyleneamino, C 1-4 Alkylamino C 1-2 Alkyleneoxy, C 1-4 Alkylamino C 1-2 Alkyleneamino, di-C 1-2 Alkylamino C 1-2 Alkyleneoxy, di-C 1-2 Alkylamino C 1-2 Alkyleneamino, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-3 Alkylene, 3-6 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0208] In some embodiments, the R C2 independently selected from H, or optionally substituted by one or more R C3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-3 Alkylamino, C 1-5 Alkoxymethylene, C 1-5 Alkylaminomethylene, di-C 1-2 Alkylaminomethylene, C 1-5 Alkoxymethyleneoxy, C 1-5 Alkoxymethyleneamino, C 1-5 Alkylaminomethyleneoxy, C 1-5 Alkylaminomethyleneamino, di-C 1-2 Alkylaminomethyleneoxy, di-C 1-2 Alkylaminomethyleneamino, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-3 Alkylene, 3-6 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0209] In some embodiments, the R C2 independently selected from H, or optionally substituted by one or more R C3 Substituted with the following groups: C1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-3 Alkylene, 4-6 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0210] In some embodiments, the R C2 independently selected from H, or optionally substituted by one or more R C3 Substituted groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, dioxolyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, cyclopropyl, C 1-3 Alkylene, cyclobutyl C 1-3 Alkylene, cyclopentyl C 1-3 Alkylene, cyclohexyl C 1-3 Alkylene, azetidinyl C 1-3 Alkylene, oxetane C 1-3 Alkylene, pyrrolidyl C 1-3 Alkylene, tetrahydrofuranyl C 1-3 Alkylene, piperidinyl C 1-3 Alkylene, tetrahydropyranyl C 1-3 Alkylene, piperazinyl C 1-3 Alkylene, morpholinyl C 1-3 Alkylene, dioxolyl C 1-3 Alkylene, phenyl C 1-3 Alkylene, pyrrolyl C 1-3 Alkylene, pyrazolyl C 1-3 Alkylene, imidazolyl C 1-3 Alkylene, pyridyl C 1-3 Alkylene, pyridazinyl C 1-3 Alkylene, pyrimidinyl C 1-3 Alkylene, or pyrazinyl C 1-3 Alkylene.

[0211] In some embodiments, the R C2 independently selected from H, or optionally substituted by one or more R C3 Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, phenyl, cyclopentyl C 1-3 Alkylene, tetrahydropyranyl C 1-3 Alkylene, dioxolyl C 1-3Alkylene or phenyl C 1-3 Alkylene.

[0212] In some embodiments, the R C2 independently selected from H, or optionally substituted by one or more R C3 Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, phenyl, cyclopentylmethylene, benzyl, or phenylethylene.

[0213] In some embodiments, the R C2 Independently selected from n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, Cyclopentyl, phenyl, cyclopentylmethylene, H, methyl, ethyl,

[0214] In some embodiments, each of said R C3 independently selected from deuterium, oxo, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, halo C 1-3 Alkylamino, halogenated di-C 1-3 Alkylamino, -P(O)(OH)2, -C 1-3 Alkylene P(O)(OH)2, -C 1-3 Alkylene OP(O)(OH)2, -C 1-3 Alkylene NR C1 P(O)(OH)2、-NR C1 P(O)(OH)2、-NR C1 C 1-3 Alkylene P(O)(OH)2, -NR C1 C 1-3 Alkylene OP(O)(OH)2, -NR C1 C 1-3 Alkylene NR C1 P(O)(OH)2, -OP(O)(OH)2, -OC 1-3 Alkylene P(O)(OH)2, -OC 1-3Alkylene OP(O)(OH)2, -OC 1-3 Alkylene NR C1 P(O)(OH)2, -P(O)HOH, -C 1-3 Alkylene P(O)HOH, -C 1-3 Alkylene OP(O)HOH, -C 1-3 Alkylene NR C1 P(O)HOH、-NR C1 P(O)HOH、-NR C1 C 1-3 Alkylene P(O)HOH, -NR C1 C 1-3 Alkylene OP(O)HOH, -NR C1 C 1-3 Alkylene NR C1 P(O)HOH、-OP(O)HOH、-OC 1-3 Alkylene P(O)HOH, -OC 1-3 Alkylene OP(O)HOH, -OC 1-3 Alkylene NR C1 P(O)HOH、-C(O)NR C1 C 1-4 Alkyl, -NR C1 C(O)C 1-4 Alkyl, -NR C1 C(O)OC 1-4 Alkyl, -NR C1 C(O)NR C1 C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -OC(O)C 1-4 Alkyl, -OC(O)OC 1-4 Alkyl, or -OC(O)NR C1 C 1-4 alkyl.

[0215] In some embodiments, each of said R C3 independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -CN, -NH2, methyl, ethyl, isopropyl, methoxy, methylthio, methylamino, dimethylamino, diethylamino, fluoromethyl, fluoromethoxy, -C 1-2 Alkylene OP(O)(OH)2, -C 1-2 Alkylene NR C1 P(O)(OH)2、-NR C1 P(O)(OH)2、-NR C1 C 1-2 Alkylene OP(O)(OH)2, -NR C1 C1-2 Alkylene NR C1 P(O)(OH)2, -OP(O)(OH)2, -OC 1-2 Alkylene OP(O)(OH)2, -OC 1-2 Alkylene NR C1 P(O)(OH)2、-C 1-2 Alkylene OP(O)HOH, -C 1-2 Alkylene NR C1 P(O)HOH、-NR C1 P(O)HOH、-NR C1 C 1-2 Alkylene OP(O)HOH, -NR C1 C 1-2 Alkylene NR C1 P(O)HOH、-OP(O)HOH、-OC 1-2 Alkylene OP(O)HOH, -OC 1-2 Alkylene NR C1 P(O)HOH、-C(O)NR C1 C 1-4 Alkyl, -NR C1 C(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, or -OC(O)C 1-4 alkyl.

[0216] In some embodiments, each of said R C3 independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, methyl, methoxy, methylthio, methylamino, dimethylamino, trifluoromethyl, trifluoromethoxy, -NHP(O)(OH)2, -NHC 1-2 Alkylene OP(O)(OH)2, -NHC 1-2 Alkylene NHP(O)(OH)2, -OP(O)(OH)2, -OC 1-2 Alkylene OP(O)(OH)2, -OC 1-2 Alkylene NHP(O)(OH)2, -NHP(O)HOH, -NHC 1-2 Alkylene OP(O)HOH, -NHC 1-2 Alkylene NHP(O)HOH, -OP(O)HOH, -OC 1-2 Alkylene OP(O)HOH, -OC 1-2 Alkylene NHP(O)HOH, -C(O)NR C1 C 1-4 Alkyl, -NR C1 C(O)C 1-4 Alkyl, -C(O)OC1-4 Alkyl, or -OC(O)C 1-4 alkyl.

[0217] In some embodiments, each of said R C3 independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, methyl, methoxy, methylthio, methylamino, dimethylamino, trifluoromethyl, trifluoromethoxy, -NHP(O)(OH)2, -NHC 1-2 Alkylene OP(O)(OH)2, -NHC 1-2 Alkylene NHP(O)(OH)2, -OP(O)(OH)2, -OC 1-2 Alkylene OP(O)(OH)2, -OC 1-2 Alkylene NHP(O)(OH)2, -NR C1 C(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, or -OC(O)C 1-4 alkyl.

[0218] In some embodiments, each of said R C3 are independently selected from deuterium, oxo, -F, -Cl, -OH, -NH2, methyl,

[0219] In some embodiments, the R 4 Selected from H, deuterium, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 Halogenated alkoxy.

[0220] In some embodiments, the R 4 Selected from H, deuterium, halogen, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 Halogenated alkoxy.

[0221] In some embodiments, the R 4 is selected from H, deuterium, -F, -Cl, -Br, -I, -CN, methyl, methoxy, difluoromethyl, trifluoromethyl, or trifluoromethoxy.

[0222] In some embodiments, the R 4 is selected from H, deuterium, -F, or -Cl.

[0223] In some embodiments, the compound of formula (I) is selected from onium ion compounds. In some embodiments, the compound of formula (I) is selected from mono-onium ion compounds. In some embodiments, the compound of formula (I) is selected from di-onium ion compounds. In some embodiments, the compound of formula (I) is selected from nitrogen onium ion compounds. In some embodiments, the compound of formula (I) is selected from onium ion compounds formed in the ring A portion. In some embodiments, the compound of formula (I) is selected from onium ion compounds formed in the ring B portion. In some embodiments, the compound of formula (I) is selected from 3 Partially formed onium ion compound.

[0224] In some embodiments, the compound of formula (I) is selected from onium ion compounds, wherein each R C Independently selected from -C 1-6 Alkylene P(O)(OR C2 )2. -C 1-6 Alkylene NR C1 P(O)(OR C2 )2. -C 1-6 Alkylene OP(O)(OR C2 )2. -C 1-6 Alkylene P(O)HOR C2 、-C 1-6 Alkylene NR C1 P(O)HOR C2 , or -C 1-6 Alkylene OP(O)HOR C2 .

[0225] In some embodiments, the compound of formula (I) is selected from onium ion compounds, wherein each R C Independently selected from -C 1-4 Alkylene P(O)(OR C2 )2. -C 1-4 Alkylene NR C1 P(O)(OR C2 )2. -C 1-4 Alkylene OP(O)(OR C2 )2. -C 1-4 Alkylene P(O)HOR C2 、-C 1-4 Alkylene NR C1 P(O)HOR C2 , or -C 1-4 Alkylene OP(O)HOR C2 .

[0226] In some embodiments, the compound of formula (I) is selected from onium ion compounds, wherein each R C Independently selected from -C 1-2Alkylene P(O)(OH)2, -C 1-2 Alkylene NHP(O)(OH)2, or -C 1-2 Alkylene OP(O)(OH)2.

[0227] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from an onium ion compound or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the compound of formula (I) is selected from onium ion compounds, and the pharmaceutically acceptable salt of the compound of formula (I) is selected from internal salts.

[0229] In some embodiments, the compound of formula (I) is selected from an onium ion compound, and the pharmaceutically acceptable salt of the compound of formula (I) is selected from a hydrochloride salt.

[0230] In some embodiments, the compound of formula (I) is selected from an onium ion compound, and the pharmaceutically acceptable salt of the compound of formula (I) is selected from a monohydrochloride salt.

[0231] In some embodiments, the C 1-12 Selected from C 1-10 、C 1-8 、C 1-6 、C 1-4 、C 1-3 , or C 1-2 .

[0232] In some embodiments, the C 1-6 Alkyl is selected from C 1-4 Alkyl, C 1-3 Alkyl, or C 1-2 alkyl.

[0233] In some embodiments, the C 1-6 Alkylene is selected from C 1-4 Alkylene, C 1-3 Alkylene, or C 1-2 Alkylene.

[0234] In some embodiments, the halogen is selected from -F, -Cl, -Br, or -I.

[0235] In some embodiments, the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.

[0236] In some embodiments, the 3-12-membered is selected from 3-10-membered, 3-8-membered, 3-6-membered, 4-10-membered, 4-9-membered, 4-8-membered, 4-7-membered, 4-6-membered, 5-10-membered, 5-8-membered, or 5-6-membered.

[0237] In some embodiments, the heteroalkylene group contains 1 or 2 heteroatoms selected from N, O, or S.

[0238] In some embodiments, the heteroalkylene group contains 1 or 2 heteroatoms selected from N or O.

[0239] In some embodiments, the heteroalkylene group contains 1 N atom and 1 O atom.

[0240] In some embodiments, the heteroalkylene group contains 1 N atom.

[0241] In some embodiments, the heteroalkylene group contains 1 O atom.

[0242] In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.

[0243] In some embodiments, the heterocycloalkyl group contains 1 N atom.

[0244] In some embodiments, the heterocycloalkyl group contains 1 O atom.

[0245] In some embodiments, the heterocycloalkyl group contains 1 N atom and 1 O atom.

[0246] In some embodiments, the heterocyclyl or heteroaryl group contains 1 or 2 heteroatoms selected from N, O, or S.

[0247] In some embodiments, the heterocyclyl or heteroaryl group contains 1 or 2 N atoms.

[0248] In some embodiments, the heterocyclyl or heteroaryl group contains 1 N atom and 1 O atom.

[0249] In some embodiments, the heterocyclyl or heteroaryl contains 1 N atom and 1 S atom.

[0250] In some embodiments, the heterocyclyl or heterocycloalkyl group includes a monocyclic, spirocyclic, fused, or bridged ring. In some embodiments, the heterocyclyl or heterocycloalkyl group includes a monocyclic, fused, or spirocyclic ring.

[0251] In some embodiments, "one or more" in the present disclosure may refer to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" refers to one, two, three, four, five, or six; or, "one or more" refers to one, two, three, or four; or, "one or more" refers to one, two, or three; or, "one or more" refers to one, or two.

[0252] The present disclosure relates to compounds of formula (II), (III), (III-1), (III-1a), (IV-1), (IV-2), (IV-3) or pharmaceutically acceptable salts thereof,

[0253] Among them, L 1 、R 1 、R 2a 、R 2b 、R 3 、R 4 、R A 、R B 、R C , Z, Ring A, Ring B are as defined above; n is selected from 0, 1, 2, 3, 4 or 5; p is selected from 0, 1, 2, 3, 4 or 5; q is selected from 0, 1, 2, 3, 4 or 5; m is selected from 0, 1, 2, 3, 4 or 5.

[0254] In some embodiments, n is selected from 0, 1, 2, or 3.

[0255] In some embodiments, m is selected from 0, 1, 2, or 3.

[0256] In some embodiments, p is selected from 0, 1, 2, or 3.

[0257] In some embodiments, q is selected from 0, 1, 2, or 3.

[0258] In some embodiments, the present disclosure relates to a compound of formula (A), (A-1), (B), (B-1), (C), (D), (E), (E-1), (F), (F-1), (G), (H), or a pharmaceutically acceptable salt thereof,

[0259] Among them, L 1 , L 2 , X, R 3a 、R 2a 、R 2b 、R 3 、R 4 、R B 、R C 、R 1 , Z, Ring A, and Ring B are as defined above; n is selected from 0, 1, 2, 3, 4, or 5; m is selected from 0, 1, 2, 3, 4, or 5; and p is selected from 0, 1, 2, 3, 4, or 5.

[0260] In some embodiments, R C Selected from -C 1-6 Alkylene P(O)(OR C2 )2. -C 1-6 Alkylene NR C1P(O)(OR C2 )2. -C 1-6 Alkylene OP(O)(OR C2 )2. -C 1-6 Alkylene P(O)HOR C2 、-C 1-6 Alkylene NR C1 P(O)HOR C2 , or -C 1-6 Alkylene OP(O)HOR C2 .

[0261] In some embodiments, R C Selected from -C 1-4 Alkylene P(O)(OR C2 )2. -C 1-4 Alkylene NR C1 P(O)(OR C2 )2. -C 1-4 Alkylene OP(O)(OR C2 )2. -C 1-4 Alkylene P(O)HOR C2 、-C 1-4 Alkylene NR C1 P(O)HOR C2 , or -C 1-4 Alkylene OP(O)HOR C2 .

[0262] In some embodiments, R C Selected from -C 1-2 Alkylene P(O)(OH)2, -C 1-2 Alkylene NHP(O)(OH)2, or -C 1-2 Alkylene OP(O)(OH)2.

[0263] In some embodiments, n is selected from 0, 1, 2, or 3.

[0264] In some embodiments, m is selected from 0, 1, 2, or 3.

[0265] In some embodiments, p is selected from 0, 1, 2, or 3.

[0266] In some embodiments, the compounds of the present disclosure do not include the following compounds, or pharmaceutically acceptable salts thereof:

[0267] In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0268] The present disclosure also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0269] The present disclosure also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0270] The present disclosure also relates to the following compounds or pharmaceutically acceptable salts thereof:

[0271] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0272] In another aspect, the present disclosure relates to a method for treating a disease in a mammal, comprising administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure to a mammal, preferably a human, in need of such treatment.

[0273] In another aspect, the present disclosure relates to use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure in preparing a medicament for treating a disease.

[0274] In another aspect, the present disclosure relates to use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure in treating a disease.

[0275] In another aspect, the present disclosure relates to a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in treating a disease.

[0276] In some embodiments of the present disclosure, the disease is preferably a Kras-related disease.

[0277] In some embodiments of the present disclosure, the Kras-related disease is preferably a Kras-mutated cancer.

[0278] In some embodiments of the present disclosure, the Kras-associated disease is selected from cancer (eg, pancreatic cancer, non-small cell lung cancer, colon cancer, or multiple myeloma).

[0279] In some embodiments of the present disclosure, the Kras-related disease is preferably Kras G12D Related diseases.

[0280] In some embodiments of the present disclosure, the Kras G12D Related diseases are preferably Kras G12D Mutated cancer.

[0281] In some embodiments of the present disclosure, the Kras G12D The related disease is selected from cancer (eg pancreatic cancer).

[0282] In some embodiments of the present disclosure, the Kras-related disease is preferably Kras G12V Related diseases.

[0283] In some embodiments of the present disclosure, the Kras G12V Related diseases are preferably Kras G12V Mutated cancer.

[0284] In some embodiments of the present disclosure, the Kras G12V The related disease is selected from cancer (eg pancreatic cancer).

[0285] In some embodiments of the present disclosure, the Kras-related disease is preferably Kras G12C Related diseases.

[0286] In some embodiments of the present disclosure, the Kras G12C Related diseases are preferably Kras G12C Mutated cancer.

[0287] In some embodiments of the present disclosure, the Kras G12C The relevant disease is selected from cancer (eg non-small cell lung cancer).

[0288] In some embodiments of the present disclosure, the Kras-related disease is preferably Kras G12A Related diseases.

[0289] In some embodiments of the present disclosure, the KrasG12A Related diseases are preferably Kras G12A Mutated cancer.

[0290] In some embodiments of the present disclosure, the Kras G12A The related disease is selected from cancer (eg, multiple myeloma).

[0291] In some embodiments of the present disclosure, the Kras-related disease is preferably Kras G13D Related diseases.

[0292] In some embodiments of the present disclosure, the Kras G13D Related diseases are preferably Kras G13D Mutated cancer.

[0293] In some embodiments of the present disclosure, the Kras G13D The related disease is selected from cancer (eg colon cancer).

[0294] Technical Effects

[0295] The compounds disclosed herein or their pharmaceutically acceptable salts, including the example compounds, have high Kras inhibitory activity (e.g., Kras G12D and / or Kras G12V The compounds of the present invention have good stability, bioavailability and / or other pharmacokinetic parameters in vitro liver microsome stability and in vivo pharmacokinetics (e.g., mouse and / or rat and / or dog) studies. The compounds of the present invention or their pharmaceutically acceptable salts, including the example compounds, have good safety, such as a large safety window.

[0296] definition

[0297] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0298] The term "substituted" refers to the replacement of any one or more hydrogen atoms or any one or more lone pairs of electrons on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0299] Non-limiting examples of “substituents” as described herein include hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, carboxaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkyl, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group and ester group, etc., wherein the group is optionally Substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0300] The term "substituted" means that a specific atom or group can be replaced by a specified other atom or group. For example, one, two, or three -CH2- in -CH2CH2CH2- can be replaced by O, S, or NH to obtain -O-CH2-CH2-, -O-CH2-, -CH2-O-CH2-, -CH2-O-, -CH2-CH2-O-, -O-, etc.

[0301] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0302] Herein, "or" and "alternatively" can be used interchangeably with "and / or".

[0303] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0304] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0305] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0306] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a covalent bond, it means that the structure is actually AZ.

[0307] When the listed linking groups do not specify their connection direction, the connection direction is arbitrary. For example, in ALZ, the linking group L is -MW-, which means that the structure can be AMWZ or AWMZ.

[0308] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0309] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0310] The term "hydroxy" refers to an -OH group.

[0311] The term "cyano" refers to a -CN group.

[0312] The term "mercapto" refers to a -SH group.

[0313] The term "amino" refers to a -NH2 group.

[0314] The term "nitro" refers to a -NO2 group.

[0315] The term "alkylene" refers to a group of the formula C n H 2n A saturated straight or branched chain divalent hydrocarbon group typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, the term "C 1-6 "Alkylene" refers to an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or -CH2CH(CH3)-), butylene (-CH2CH2CH2CH2-, -CH2CH(CH3)CH2- or -CH2CH2CH(CH3)-), and the like. The alkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0316] The term "heteroalkylene" refers to an alkylene group in which one or more carbon atoms (and hydrogen atoms attached thereto) are each independently replaced by the same or different heteroatom groups. Unless otherwise indicated, the heteroalkylene group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6"Heteroalkylene" refers to a heteroalkylene group containing 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkylene group (e.g., internal or terminal), including the position that connects the alkylene group to the rest of the molecule. Typically, when more than one heteroatom group is present, the heteroatoms are not adjacent to each other. Non-limiting examples of heteroalkylene include, but are not limited to, -OCH2-, -OCH2CH2-, -OCH2CH2CH2-, -CH2OCH2-, -OCH2O-, -OCH2CH2O-, -OCH2OCH2CH2-, -SCH2-, -SCH2CH2-, -SCH2CH2CH2-, -CH2SCH2-, -SCH2S-, -SCH2CH2S-, -SC H2SCH2CH2-, -NHCH2-, -NHCH2CH2-, -NHCH2CH2CH2-, -CH2NHCH2-, -N(CH3)CH2-, -CH2N(CH3)-, -OCH2NH-, -OCH2CH2NH-, -OCH2NHCH2CH2-, -OCH2N(CH3)CH2-, etc. The heteroalkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

[0317] The term "alkyl" refers to a group of the formula C n H 2n+1 The saturated hydrocarbon group typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. The alkyl group can be straight or branched and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms. For example, the term "C 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). The alkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy. Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.

[0318] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and hydrogen atoms attached thereto) are each independently replaced by the same or different heteroatom groups. Unless otherwise indicated, the heteroalkyl group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6 "Heteroalkyl" refers to a heteroalkyl group containing from 1 to 6 carbon atoms and from 1 to 3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkyl group (e.g., internal or terminal), including the position at which the heteroalkyl group is attached to the rest of the molecule. Typically, when more than one heteroatom group is present, the heteroatom groups are not adjacent to each other. Exemplary heteroalkyl groups include, but are not limited to, alkoxy, alkoxyalkylene, alkylamino, alkylaminoalkylene, dialkylamino, dialkylaminoalkylene, and the like. The heteroalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0319] The term "alkoxy" refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0320] The term "alkylamino" refers to an -NH-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0321] The term "dialkylamino" refers to -N(alkyl)2, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0322] The term "alkylsulfonyl" refers to an -SO2-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0323] The term "alkylthio" refers to an -S-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0324] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like. The alkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0325] The term "alkenylene" refers to a divalent form of an alkenyl group. The alkenylene group typically has 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkenylene groups include, but are not limited to, vinylene, 1-propenylene, 2-propenylene, 1-butenylene, isobutenylene, 1,3-butadienylene, etc. The alkenylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0326] The term "heteroalkenyl" refers to an alkenyl group in which one or more carbon atoms (and their associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. Unless otherwise indicated, the heteroalkenyl group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. For example, the term "C 1-4 "Heteroalkenyl" refers to a heteroalkenyl group containing 1 to 4 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkenyl group (e.g., internal or terminal), including the position at which the heteroalkenyl group is attached to the rest of the molecule. Typically, when more than one heteroatom group is present, the heteroatom groups are not adjacent to each other. Exemplary heteroalkenyl groups include, but are not limited to, CH2=N-, alkenyl-O-, alkenyl-NH-, alkenyl-S-, alkenyl-O-alkylene-, alkyl-O-alkenylene-, alkenyl-NH-alkylene-, alkyl-NH-alkenylene-, alkenyl-S-alkylene-, alkyl-S-alkenylene-, Alkenyl-CH=N-, alkenyl-N=CH-, alkyl-CH=N-alkenylene-, alkenyl-CH=N-alkylene-, or alkyl-NH-alkenylene-O-. In some embodiments, the double bond in the heteroalkenyl group is a carbon-carbon double bond. The heteroalkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0327] The term "heteroalkenylene" refers to the divalent form of heteroalkenyl. Unless otherwise indicated, the heteroalkenylene contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. For example, the term "C 1-4 “Heteroalkenylene” refers to a heteroalkenylene group containing 1 to 4 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkenylene group (e.g., internal or terminal), including the position at which the heteroalkenylene group is attached to the remainder of the molecule. Typically, when more than one heteroatom group is present, the heteroatom groups are not adjacent to each other. Exemplary heteroalkenylene groups include, but are not limited to, -alkenylene-O-, -alkenylene-NH-, -alkenylene-S-, -alkenylene-O-alkylene-, -alkylene-O-alkenylene-, -alkenylene-NH-alkylene-, -alkylene-NH-alkenylene-, -alkenylene-S-alkylene-, -alkylene-S-alkenylene -, -alkenylene-CH=N-, -alkenylene-N=CH-, -alkylene-CH=N-alkenylene-, -alkenylene-CH=N-alkylene-, or -alkylene-NH-alkenylene-O-. In some embodiments, the double bond in the heteroalkenylene is a carbon-carbon double bond. The heteroalkenylene is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0328] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡CC≡CH), and the like. The alkynyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0329] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc. The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0330] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic ring with at least one double bond and which can exist as a monocycle, bridged ring or spirocycle. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10 ring, a 4 to 8 ring, a 5 to 8 ring or a 5 to 6 ring. Non-limiting examples of cycloalkenyl include but are not limited to cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl etc. The cycloalkenyl is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl,-C (O) O-alkyl,-OC (O)-alkyl,-C (O) NH ,-C (O) NH-alkyl,-C (O) N (alkyl) ,-NHC (O)- Alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0331] Term " heterocyclic radical " refers to fully saturated or partially undersaturated (but not fully unsaturated heteroaromatic) and can be with monocycle, bridged ring, and ring or spirocyclic non-aromatic ring.Unless otherwise indicated, the heterocycle is generally 3 to 12 yuan, 3 to 10 yuan, 4 to 8 yuan, 5 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulphur, oxygen, nitrogen, phosphorus, silicon and / or boron.The limiting examples of heterocyclic radical include but are not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N- methylpyrrolidinyl, dihydropyrrolyl, piperidyl, piperazinyl, pyrazolidinyl, 4H- pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc. The heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)- Alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0332] The term "heterocyclenyl" refers to a non-aromatic ring that is partially unsaturated (but not completely unsaturated heteroaromatic) and can exist as a monocycle, a bridged ring, a ring or a spirocycle. Unless otherwise indicated, the heterocyclenyl is typically 3 to 12, 3 to 10, 4 to 8, 5 to 8, 5 to 6, 3 to 7 or 4 to 6 rings containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron. Non-limiting examples of heterocyclenyl include but are not limited to dihydrofuranyl, dihydropyrrolidinyl, dihydrothienyl, dihydroindole, tetrahydroquinolinyl (such as 1,2,3,4-tetrahydroquinolinyl), tetrahydroisoquinolinyl (such as 5,6,7,8-tetrahydroisoquinolinyl,) etc. The heterocycloalkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O) -alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0333] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3-12-membered, 3-10-membered, 4-8-membered, 5-8-membered, 5-6-membered, 3-7-membered, or 4-6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridinyl groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. The heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O) -alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0334] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0335] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, typically having 5 to 14, 5 to 12, 5 to 10, 5 to 8, 5 to 7, or 5 to 6 rings. Preferred heteroaryls have a single 4 to 8-membered ring, especially a 5 to 6-membered ring, or a plurality of fused rings containing 5 to 14, especially 5 to 10, ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc. The heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0336] The group -L in the present disclosure 1- adopts the reading order from left to right or from right to left, for example, the reading order from left to right corresponds to the connection of the lower group and the right group connected to the group in the general formula, for example, when -L 1 When - is -OCH2CH2-, the structure The corresponding

[0337] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0338] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0339] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0340] The term "preventing" or "preventing" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0341] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0342] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0343] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0344] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0345] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0346] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0347] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0348] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes of the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0349] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

[0350] The compounds of the present disclosure may have one or more atropisomers. Unless otherwise specified, atropisomers refer to optically active isomers resulting from the obstruction of free rotation between single bonds. The compounds of the present disclosure containing a chiral axis can be isolated in racemic form. When the energy barrier for free rotation between single bonds of the compounds of the present disclosure containing a chiral axis is sufficiently high, the atropisomers can be isolated in optically pure form.

[0351] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0352] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0353] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0354] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, gels, slurries, suspensions, and the like for oral administration to a patient.

[0355] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0356] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0357] In all administration methods of the compounds of formula I described herein, the daily dosage is 0.01 to 200 mg / kg body weight. The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0358] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0359] The compounds of formula (I) disclosed herein, such as compounds of formula (III), can be prepared by those skilled in the art of organic synthesis via route 1, wherein n, R 1 、R 2a 、R 2b 、R 3 、R 4 , Z, Ring A and Ring B are as defined above.

[0360] The compounds of formula (I) disclosed herein, such as compounds of formula (F), can be prepared by those skilled in the art of organic synthesis via route 2 or route 3, wherein n, m, R 1 , L 2 、R 3a 、R C 、R 4 , Z, Ring A and Ring B are as defined above.

[0361] Each product obtained by the reaction in the above-mentioned route can be obtained by conventional separation techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. The starting materials can be synthesized by themselves or purchased from commercial institutions (such as, but not limited to, Adrich or Sigma). These raw materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described in this disclosure can be obtained as single isomers or mixtures of isomers using synthetic methods.

[0362] This disclosure uses the following abbreviations:

[0363] DMF stands for N,N-dimethylformamide; PMB stands for p-methoxybenzyl; TIPS stands for triisopropylsilyl; MOM stands for methoxymethyl; DIPEA stands for diisopropylethylamine; and DMSO stands for dimethyl sulfoxide.

[0364] Commercially available compounds were referred to by their supplier catalog names.

[0365] For the sake of clarity, the present invention is further illustrated by examples, but the examples are not intended to limit the scope of the present disclosure. The present disclosure has been described in detail herein and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications will be made to the embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0366] All reagents used in this disclosure were commercially available and used without further purification. Example

[0367] Example 1 and Example 2

[0368] Step 1:

[0369] 1a (7.25 g) and p-methoxybenzyl chloride (26.3 g) were dispersed in DMF (80 mL). Sodium hydroxide (60%, 5.9 g) was added with stirring at room temperature and the reaction was continued with stirring for 2 h. After the reaction was complete, ammonium chloride solution (20 mL) was added to quench the reaction. Water (100 mL) and ethyl acetate (150 mL) were added and stirred to separate the liquids. The aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined and washed with 5% brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was present. Compound 1b was purified by column chromatography (ethyl acetate:petroleum ether = 1:100 to 1:10) to obtain compound 1b. LC-MS: m / z = 413.16 [M+H] + .

[0370] Step 2:

[0371] 1b (1.25 g), bis(diphenylphosphine palladium dichloride) (0.21 g), and tributyl(1-ethoxyethylene)tin (3.1 mL) were dispersed in DMF (10 mL) under nitrogen atmosphere and stirred at 80°C for 8 h. After the reaction was complete, the reaction solution was cooled to room temperature, the pH was adjusted to acidic with dilute hydrochloric acid, and water (100 mL) and ethyl acetate (100 mL) were added. The mixture was stirred and separated, and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined and washed once with 10% sodium bicarbonate solution (100 mL) and once with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was present. Compound 1c was purified by column chromatography (ethyl acetate:petroleum ether = 1:50 to 1:5) to obtain compound 1c. LC-MS: m / z = 377.26 [M+H] + .

[0372] Step 3:

[0373] 1c (1.4 g), L-aminopropanol (0.84 g), and tetraisopropyl titanate (4.5 g) were dispersed in methanol (28 mL) and heated to 80°C with stirring for 16 h. The reaction mixture was cooled to 0°C, sodium borohydride (280 mg) was added, and the mixture was stirred at room temperature for 4 h. After the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated until no liquid was present. Compound 1d was purified by column chromatography (methanol:dichloromethane = 1:200 to 1:10) to obtain compound 1d. LC-MS: m / z = 436.40 [M+H] + .

[0374] Step 4:

[0375] Disperse 1e (5 g) in acetonitrile (100 mL), then add DIPEA (13.8 g) and phosphorus oxychloride (8.19 g) sequentially. Heat to 80°C under nitrogen and stir for 2 h. After completion, cool the reaction mixture to room temperature, pour into ice water (500 mL), stir and crystallize for 30 min, and filter. The filter cake is dried under vacuum at 55°C for 6 h to yield compound 1f.

[0376] Step 5:

[0377] Disperse 1f (1.4 g), 1d (700 mg), and DIPEA (630 mg) in tetrahydrofuran (45 mL) and stir overnight. The reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether = 1:20 to 1:5) to obtain compound 1g. LC-MS: m / z = 697.31 [M+H] + .

[0378] Step 6:

[0379] 1g (1.5g) and cesium fluoride (3.3g) were dispersed in DMF (150mL), heated to 60°C, and stirred for 2h. After the reaction was complete, the reaction solution was concentrated until no liquid flowed out. The residue was dissolved in ethyl acetate (100mL), and water (100mL) was added and stirred to separate the liquids. The aqueous phase was extracted with ethyl acetate (100mL*2). The organic phases were combined, washed with 10% brine (100mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid flowed out. Preparative SFC (YMC-SA 10μm 30*150 column; ethanol-CO2 (50%-50%, 0-15min isocratic elution)) gave 1A (Rt 10min, LC-MS: m / z=661.33[M+H] + ) and 2A (Rt 12min, LC-MS: m / z=661.33[M+H] + ).

[0380] Step 7:

[0381] Disperse 1A (6.3 g) in dichloromethane (252 mL), cool to 0-5°C, add m-chloroperbenzoic acid (75%, 8.2 g), and stir for 1 h. After the reaction is complete, add 10% sodium thiosulfate solution (100 mL) to the reaction solution, extract with dichloromethane (100 mL x 2). Combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid remains to obtain compound 1B. LC-MS: m / z = 693.28 [M+H] + .

[0382] Referring to the synthesis method of compound 1B, compound 2A was used instead of compound 1A to synthesize compound 2B. LC-MS: m / z = 693.28 [M+H] + .

[0383] Step 8:

[0384] 1B (6.3 g) and 1h (4.34 g) were dispersed in tetrahydrofuran (12 mL), cooled to 0°C, and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1N, 13.6 mL) was added dropwise. The mixture was stirred for 1 h. After the reaction was complete, saturated ammonium chloride solution (50 mL) was added to the reaction system to quench the reaction. Water (50 mL) and ethyl acetate (100 mL) were added, stirred, and separated. The mixture was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, washed with 5% brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was present. Compound 1C was purified by column chromatography (methanol:dichloromethane = 1:200 to 1:30) to obtain compound 1C. LC-MS: m / z = 772.38 [M+H] + .

[0385] Referring to the synthesis method of compound 1C, compound 2B was used instead of compound 1B to synthesize compound 2C. LC-MS: m / z = 772.33 [M+H] + .

[0386] Step 9:

[0387] Disperse 1C (8.8 g) in trifluoroacetic acid (88 mL), cool to 0°C, add methanesulfonic acid (13.2 mL) dropwise, and stir at room temperature for 2 h. After the reaction is complete, the reaction solution is concentrated under reduced pressure until no liquid flows out. The residue is dissolved in dichloromethane (200 mL), and the pH of the system is adjusted to alkaline with saturated sodium bicarbonate solution under ice. Water (100 mL) and dichloromethane (100 mL) are added, stirred, and separated. Extraction is performed with dichloromethane (100 mL x 2). The organic phases are combined, washed with 10% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid flows out. Purification by column chromatography (methanol:dichloromethane = 1:200 to 1:10) yields compound 1D. LC-MS: m / z = 532.21 [M+H] + .

[0388] Referring to the synthesis method of compound 1D, compound 2C was used instead of compound 1C to synthesize compound 2D. LC-MS: m / z = 532.20 [M+H] + .

[0389] Step 10:

[0390] 1D (1.06 g), 1i (1.36 g), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (230 mg), potassium phosphate (1.3 g), and water (4.3 mL) were dispersed in 1,4-dioxane (21.3 mL) under nitrogen protection. The temperature was raised to 90°C and stirred for 1 h. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (methanol:dichloromethane = 1:200 to 1:10) to obtain compound 1E. LC-MS: m / z = 822.52 [M+H] + .

[0391] Referring to the synthesis method of compound 1E, compound 2D was used instead of compound 1D to synthesize compound 2E. LC-MS: m / z = 822.52 [M+H] + .

[0392] Step 11:

[0393] 1E (4.17 g) and cesium fluoride (7.71 g) were dispersed in DMF (40 mL) and stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure until no liquid outflowed. The residue was dissolved in dichloromethane (100 mL) and water (100 mL) was added and stirred to separate the liquids. The aqueous phase was extracted with dichloromethane (60 mL*2). The organic phases were combined and washed with 10% brine (100 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The product was purified by column chromatography (methanol:dichloromethane = 1:100 to 1:10) to obtain compound 1F. LC-MS: m / z = 666.31 [M+H] + .

[0394] Referring to the synthesis method of compound 1F, compound 2E was used instead of compound 1E to synthesize compound 2F. LC-MS: m / z = 666.30 [M+H] + .

[0395] Step 12:

[0396] 1F (270 mg), sodium iodide (900 mg), potassium carbonate (830 mg), and di-tert-butyl chloromethyl phosphate (1040 mg) were dispersed in acetonitrile (50 mL) and stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was purified by column chromatography (methanol:dichloromethane = 1:100 to 1:4) to obtain compound 1G. LC-MS: m / z = 832.43 [M] + .

[0397] Referring to the synthesis method of compound 1G, compound 2F was used instead of compound 1F to synthesize compound 2G. LC-MS: m / z = 832.41 [M] + .

[0398] Step 13:

[0399] Disperse 1G (200 mg) in dichloromethane (10 mL) and add a 1,4-dioxane solution of hydrogen chloride (4 N, 1 mL) dropwise to the reaction system. Stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction mixture under reduced pressure until no liquid remains, yielding compound 1H. LC-MS: m / z = 776.26 [M] + .

[0400] Referring to the synthesis method of compound 1H, compound 2G was used instead of compound 1G to synthesize compound 2H. LC-MS: m / z = 776.26 [M] + .

[0401] Step 14:

[0402] Compound 1H was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (5%-75% / 0-70 min gradient elution)) to obtain compound 1. LC-MS: m / z = 776.35 [M+H] + ; 1 H-NMR(500MHz,CD3OD)δ8.19-8.07(m,2H),8.06-7.97(m,1H),7.86(d,J=7.5Hz,1H),7.76-7.57 (m,2H),7.52-7.39(m,1H),6.89-6.72(m,2H),5.64(J=55.0Hz,1H),5.29-5.12(m,2H),5.07-4.9 4(m,2H),4.76-4.48(m,2H),4.45-4.33(m,1H),4.32-4.00(m,3H),3.92-3.78(m,1H),3.68(s,0. 4H),3.44(s,0.6H),3.12-2.90(m,1H),2.74-2.31(m,5H),1.85-1.64(m,3H),0.88-0.70(m,3H).

[0403] Referring to the purification method of compound 1, compound 2H was used instead of compound 1H to purify compound 2. LC-MS: m / z=776.35 [M+H] + .

[0404] Example 3 and Example 4

[0405] Referring to the preparation process of compound 1 in Example 1, in step 10, 2-(7,8-difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used to replace compound 1i to prepare compound 3. LC-MS: m / z=770.41 [M+H] + .

[0406] Referring to the preparation process of compound 2 in Example 2, in step 10, 2-(7,8-difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used to replace compound 1i to prepare compound 4. LC-MS: m / z = 770.43 [M+H] + .

[0407] Example 5 and Example 6

[0408] Referring to the preparation process of compound 1 in Example 1, in step 10, 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used to replace compound 1i to prepare compound 5. LC-MS: m / z=768.20 [M+H] + .

[0409] Referring to the preparation process of compound 2 in Example 2, in step 10, 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used to replace compound 1i to prepare compound 6. LC-MS: m / z=768.18 [M+H] + .

[0410] Example 7 and Example 8

[0411] Referring to the preparation process of compound 1 in Example 1, in step 10, ((6-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane was used to replace compound 1i to prepare compound 7. LC-MS: m / z = 776.26 [M+H] + .

[0412] Referring to the preparation process of compound 2 in Example 2, in step 10, ((6-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane was used to replace compound 1i to prepare compound 8. LC-MS: m / z = 776.26 [M+H]+ .

[0413] Example 9 and Example 10

[0414] Step 1:

[0415] 1D (0.5 g), sodium iodide (2.1 g), potassium carbonate (1.95 g), and di-tert-butyl chloromethyl phosphate (2.45 g) were dispersed in acetonitrile (25 mL) and stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was purified by column chromatography (methanol:dichloromethane = 1:100 to 1:3) to obtain compound 9A. LC-MS: m / z = 698.25 [M] + .

[0416] Referring to the synthesis method of compound 9A, compound 2D was used instead of compound 1D to synthesize compound 10A. LC-MS: m / z = 698.24 [M] + .

[0417] Step 2:

[0418] 9A (315 mg), 9a (315 mg), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (52 mg), potassium phosphate (290 mg), and water (6 mL) were dispersed in 1,4-dioxane (30 mL) under nitrogen protection. The temperature was raised to 90°C and stirred for 2 h. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (methanol:dichloromethane = 1:200 to 1:10) to obtain compound 9B. LC-MS: m / z = 857.35 [M] + .

[0419] Referring to the synthesis method of compound 9B, compound 10A was used instead of compound 9A to synthesize compound 10B. LC-MS: m / z = 857.35 [M] + .

[0420] Step 3:

[0421] Disperse 9B (290 mg) in dichloromethane (8 mL) and add a 4N 1,4-dioxane solution (0.8 mL) dropwise to the reaction system. Stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction mixture under reduced pressure until no liquid remains, yielding compound 9C. LC-MS: m / z = 801.23 [M] + .

[0422] Referring to the synthesis method of compound 9C, compound 10B was used instead of compound 9B to synthesize compound 10C. LC-MS: m / z = 801.27 [M] + .

[0423] Step 4:

[0424] Compound 9C was purified by preparative liquid chromatography (YMC AQ C18 10 μm 50*250 column; acetonitrile-0.1% formic acid aqueous solution (15%-75% / 0-60 min gradient elution)) to give compound 9. LC-MS: m / z = 801.23 [M+H] + ; 1 H-NMR(500MHz,CD3OD)δ8.29(d,J=7.0Hz,1H),8.00(d,J=6.0Hz,1H),7.08(t,J=7.0Hz,1H), 6.92(s,1H),6.80(brs,1H),6.64-6.33(m,1H),5.66(dt,J=5.0Hz,50.0Hz,1H),5.35-5.24(m ,1H),5.23-5.13(m,1H),5.02-4.92(m,2H),4.76-4.65(m,1H),4.50-4.10(m,5H),3.98-3.8 4(m,1H),3.14-2.96(m,1H),2.78-2.30(m,5H),1.77(d,J=6.5Hz,3H),0.83(d,J=7.0Hz,3H).

[0425] Referring to the purification method of compound 9, compound 10C was used instead of compound 9C to purify compound 10. LC-MS: m / z=801.27 [M+H] + .

[0426] Example 11 and Example 12

[0427] Referring to the preparation process of compound 9 in Example 9, in step 2, 2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline was used to replace compound 9a to prepare compound 11. LC-MS: m / z = 799.33 [M+H] + ).

[0428] Referring to the preparation process of compound 10 in Example 10, in step 2, 2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline was used to replace compound 9a to prepare compound 12. LC-MS: m / z = 799.34 [M+H] + ).

[0429] Example 13

[0430] 1 (50 mg) and 10% palladium on carbon (20 mg) were dispersed in methanol (10 mL), replaced with hydrogen, and stirred at room temperature overnight under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% formic acid aqueous solution (20%-80% / 0-60 min gradient elution)) to obtain compound 13. LC-MS: m / z = 780.33 [M+H] + .

[0431] Example 14

[0432] Referring to the preparation process of compound 1 in Example 1, in step 10, triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane was used to replace compound 1i to prepare compound 14. LC-MS: m / z = 758.28 [M+H] + .

[0433] Example 15

[0434] Referring to the preparation process of compound 1 in Example 1, in step 10, ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane was used to replace compound 1i to prepare compound 15. LC-MS: m / z = 792.33 [M+H] + .

[0435] Example 16

[0436] Referring to the preparation process of compound 1 in Example 1, in step 8, N-methyl-L-prolinol was used to replace compound 1h to prepare compound 16. LC-MS: m / z=732.28 [M+H] + .

[0437] Example 17

[0438] Referring to the preparation process of compound 1 in Example 1, in step 8, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methane-d2-ol was substituted for compound 1h to prepare compound 17. LC-MS: m / z = 778.36 [M+H] + .

[0439] Example 18

[0440] Step 1:

[0441] Disperse 1E (330 mg) and triethylamine (6 mL) in dichloromethane (40 mL), cool to 0°C, add phosphorus oxychloride (180 mg) dropwise, and stir at room temperature for 1 h. Add water (10 mL) to the reaction mixture, stir, and separate. The organic phase is washed with saturated ammonium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid remains to obtain compound 18a. LC-MS: m / z = 902.53 [M+H] + .

[0442] Step 2:

[0443] 18a (200 mg) and cesium fluoride (500 mg) were dispersed in DMF (2.5 mL) and stirred at room temperature for 1 h. Water (15 mL) and dichloromethane (25 mL) were added to the reaction solution, stirred, and the mixture separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated until no liquid outflowed and purified by preparative liquid chromatography (YMC TA C18, 10 μm, 30×250 column; acetonitrile-0.1% aqueous ammonia solution (10%-70% / 0-50 min gradient elution)) to obtain compound 18. LC-MS: m / z = 746.37 [M+H] + .

[0444] Example 19

[0445] Referring to the preparation process of compound 1F in Example 1, in step 8, N-methyl-L-prolinol was used to replace compound 1h to prepare compound 19a. LC-MS: m / z = 622.40 [M+H] + .

[0446] Referring to the preparation method of compound 18a in Example 18, 1E was replaced with 19a to prepare compound 19. LC-MS: m / z=702.22 [M+H] + .

[0447] Example 20

[0448] Referring to the preparation process of compound 1E in Example 1, in step 10, 9a was substituted for compound 1i to prepare compound 20a. LC-MS: m / z = 691.23 [M+H] + .

[0449] Referring to the preparation method of compound 18a in Example 18, 1E was replaced with 20a to prepare compound 20. LC-MS: m / z=771.24 [M+H] + .

[0450] Example 21

[0451] Step 1:

[0452] Referring to the preparation method of compound 9B in Example 9, 9a was replaced with 21a to prepare compound 21b. LC-MS: m / z = 1003.46 [M] + .

[0453] Step 2:

[0454] Referring to the preparation method of compound 1F in Example 1, 1E was replaced with 21b to prepare compound 21c. LC-MS: m / z = 847.33 [M] + .

[0455] Step 3:

[0456] Referring to the preparation method of compound 1H in Example 1, 1G was replaced with 21c to prepare compound 21d. LC-MS: m / z = 791.30 [M] + .

[0457] Step 4:

[0458] Compound 21d was purified by preparative liquid chromatography (YMC AQ C18 10 μm 30*250 column; methanol-0.1% acetic acid aqueous solution (10%-10%-15%-55% / 0-4-5-85 min gradient elution)) to give compound 21. LC-MS: m / z = 791.30 [M+H] + .

[0459] Example 22

[0460] Step 1:

[0461] Disperse 1E (300 mg) and triethylamine (364 mg) in dichloromethane (30 mL), cool to 0°C, and add diisopropyl chlorophosphate (732 mg) dropwise. Bring to room temperature and stir overnight. Add water (10 mL) to the reaction mixture, stir, and separate. The organic phase is washed with saturated ammonium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid remains to obtain compound 22a. LC-MS: m / z = 986.56 [M+H] + .

[0462] Step 2:

[0463] 22a (400 mg) and cesium fluoride (920 mg) were dispersed in DMF (20 mL) and stirred at room temperature for 4 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, stirred, and the mixture separated. The aqueous phase was extracted with ethyl acetate (50 mL). The organic phases were combined, washed with 10% brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until no liquid was present. Compound 22 was then purified by preparative liquid chromatography (YMC TA C18 10 μm 50 x 250 column; methanol-0.1% ammonia aqueous solution (30%-90%-100% / 0-60-70 min gradient elution)). LC-MS: m / z = 830.48 [M+H] + .

[0464] Experimental Example 1: Nucleotide Exchange Experimental Method

[0465] 1. Reagents: His-KRAS G12D (1-169); SOS1 cat (564-1049); GDP (purchased from Sigma); Anti-6HIS-Cryptate (purchased from Cisbio); EDA-GTP-DY-647P1 (purchased from Jena Bioscience)

[0466] 2. Prepare buffer solution:

[0467] 1) Assay buffer: HEPES pH 7.4, NaCl, MgCl2, DTT, BSA, Igepal;

[0468] 2) KRAS G12D working solution: Prepare KRAS G12D working solution containing 100 nM His-KRAS G12D and 2 nM Anti-6HIS-Cryptate in assay buffer;

[0469] 3) SOS1 cat Working solution: Prepared with assay buffer containing 20 nM SOS1 catand 200 nM EDA-GTP-DY-647P1 SOS1 cat Working fluid;

[0470] 4) Blank control working solution: Prepare a blank control solution containing 2 nM Anti-6HIS-Cryptate using assay buffer.

[0471] 3. Testing process:

[0472] The entire experimental process was completed at room temperature. Using a black bottom transparent 384-well plate, 5 μL of KRAS G12D working solution was added to each well of the experimental group and the negative group. At the same time, 5 μL of blank control working solution was added to each well of the blank group and incubated at room temperature for 10 minutes. Then, an ultra-micropipette was used to add a compound with a starting concentration of 100 μM and 8 concentration gradients of continuous 1:2 dilution to the experimental group and incubated at room temperature for 30 minutes. Finally, 5 μL of SOS1 was added to each well. cat The working solution was incubated at room temperature for 15 minutes, and the signal values at 665 nm / 620 nm were measured using a PerkinElmer Envision HTS multi-label reader. The inhibition rate was calculated as: inhibition rate (%) = (average value of negative control group - average value of experimental group) / (average value of negative control group - average value of blank group) × 100%. The logarithm of compound concentration was used as the horizontal axis, and the inhibition rate was used as the vertical axis. A four-parameter logistic model was used to fit the curve and calculate the IC 50 value.

[0473] Test Example 2: AsPc-1 cell proliferation inhibitory activity assay

[0474] Take AsPc-1 cells that are in good growth state, collect them into a centrifuge tube, and adjust the cell density to 3×10 4 Cells were inoculated at 100 μL / well in a 96-well plate. Compounds were added using a nanoliter pipette to a final concentration of 5000 nM to 0.31 nM in duplicate wells. A control was also set up. After 72 hours of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 3 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 .

[0475] Test Example 3: Capan-1 cell proliferation inhibitory activity assay

[0476] Take Capan-1 cells that are in good growth condition, collect them into a centrifuge tube, and adjust the cell density to 1.5×10 4Cells were plated at 100 μL / mL in a 96-well plate (100 μL / well). Compounds were added using a nanoliter pipette to a final concentration of 20,000 nM to 9.1 nM in duplicate wells. A control was also set up. After 5 days of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 4 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 .

[0477] Test Example 4: Determination of NCI-H358 Cell Proliferation Inhibitory Activity

[0478] Take NCI-H358 cells that are in good growth condition, collect them into a centrifuge tube, and adjust the cell density to 3×10 4 Cells were inoculated at 100 μL / well in a 96-well plate. Compounds were added using a nanoliter pipette to a final concentration of 10,000 nM to 4.6 nM in duplicate wells. A control was also set up. Cells were cultured in a cell culture incubator for 72 hours. The detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 3 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 .

[0479] Test Example 5: HCT-116 cell proliferation inhibitory activity assay

[0480] Take HCT-116 cells that are in good growth condition, collect them into a centrifuge tube, and adjust the cell density to 1×10 4 Cells were inoculated at 100 μL / well in a 96-well plate. Compounds were added using a nanoliter pipette to a final concentration of 20,000 nM to 9.1 nM in duplicate wells. A control was also set up. After 5 days of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After 2 hours of incubation in a cell culture incubator, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 .

[0481] Test Example 6: RPMI-8226 Cell Proliferation Inhibitory Activity Assay

[0482] Take RPMI-8226 cells that are in good growth condition, collect them into a centrifuge tube, and adjust the cell density to 3×10 4Cells were plated at 100 μL / well and inoculated onto a 96-well plate (100 μL / well). Compounds were added using a nanoliter pipette to a final concentration of 10,000 nM to 4.6 nM, with two replicates. A control was also set up. Cells were cultured in a cell culture incubator for 72 hours before the addition of CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well). After incubation in a cell culture incubator for 4 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 .

[0483] Test Example 7: Determination of NCI-H1975 Cell Proliferation Inhibitory Activity

[0484] Take NCI-H1975 cells that are in good growth condition, collect them into a centrifuge tube, and adjust the cell density to 1×10 4 Cells were inoculated at 100 μL / well in a 96-well plate. Compounds were added using a nanoliter pipette to a final concentration of 20,000 nM to 9.1 nM in duplicate wells. A control was also set up. After 5 days of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After 2 hours of incubation in a cell culture incubator, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 .

[0485] The test results of some compounds disclosed in the present invention are shown in Table 1.

[0486] Table 1 Test results of some compounds Note: A stands for IC 50 ≤100nM; B represents 100nM<IC 50 ≤500nM; C represents 500nM<IC 50 ≤999nM; ——represents IC 50 Value not detected.

[0487] Test Example 8: In vitro liver microsome stability

[0488] Liver microsomal incubation samples (species: human, monkey, rat, and mouse) were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), test compound, and NADPH + MgCl₂ solution at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and test compound. The sample was added to acetonitrile containing an internal standard for protein precipitation, and the supernatant was prepared and diluted for LC / MS / MS analysis. The results are shown in Table 2.

[0489] Table 2. In vitro liver microsome metabolic stability results

[0490] Experimental Example 9: Pharmacokinetic Evaluation in Mice

[0491] ICR mice weighing 20-24 g were acclimated for 3-5 days and then randomly divided into groups of 9 mice each. The experimental compound was orally administered at a dose of 35 mg / kg.

[0492] The test animals (ICR mice) were fasted for 12 h before administration and given food 4 h after administration. They had free access to water before, during and after the experiment.

[0493] After oral administration, blood samples were collected from the eye sockets of three mice at three to four time points: 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, and 10 h after oral administration. Blood samples were collected from three mice at each time point. Approximately 0.1 mL of blood was collected from the eye sockets. After anticoagulation with EDTA-K2, the blood was transferred to 4°C and centrifuged at 4000 rpm for 10 min within 30 min to separate plasma. All collected plasma was immediately stored at -20°C until testing.

[0494] Pipette 20 μL of the plasma sample to be tested and the standard sample, add 400 μL of acetonitrile solution containing the internal standard (20 ng / mL), shake and mix for 10 minutes, centrifuge at 13000 rpm for 10 minutes, take 50 μL of the supernatant, add 100 μL of ultrapure water to dilute, mix, and take 0.5 μL for LC / MS / MS determination, and record the chromatogram.

[0495] Experimental results: The compounds of the present application, such as Example Compounds 1, 3, 5, 9, 17, and 18, have good oral pharmacokinetic parameters (including Tmax, Cmax, AUC, etc.) in mice.

[0496] Test Example 10: Pharmacokinetic evaluation in rats

[0497] SD rats weighing 210-230 g were randomly divided into groups after acclimation for 3-5 days, with 3 rats in each group, and were orally administered with the solution of Example at a dose of 35 mg / kg.

[0498] Blood was collected from the eye sockets at the time points of 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, and 32 h to prepare the plasma samples to be tested.

[0499] 50 μL of plasma sample to be tested and standard curve sample were taken, and acetonitrile solution containing internal standard was added to obtain protein precipitation to obtain supernatant, which was diluted and used for LC / MS / MS determination, and non-compartmental model fitting was adopted.

[0500] Test Example 11: Pharmacokinetic Evaluation in Dogs

[0501] Beagle dogs weighing 10-12 kg were randomly divided into groups of 3 after acclimation for 3-5 days and were orally administered with the solution of Example at a dose of 17.5 mg / kg.

[0502] Blood was collected from the forelimb vein at the time points of 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, 32 h, and 48 h to prepare the plasma samples to be tested.

[0503] 50 μL of plasma sample to be tested and standard curve sample were taken, and acetonitrile solution containing internal standard was added to obtain protein precipitation to obtain supernatant, which was diluted and used for LC / MS / MS determination, and non-compartmental model fitting was adopted.

[0504] Experimental Example 12: Pharmacodynamic Evaluation of AsPc-1 Cell Subcutaneous Transplanted Tumor Model in NOD-SCID Mice

[0505] SPF female NOD-SCID mice (source: Jiangsu Huachuang Xinnuo Pharmaceutical Technology Co., Ltd.) were inoculated subcutaneously in the right axilla with 1×107 AsPc-1 cells per mouse. When the average tumor volume reached approximately 200 mm3, the animals were divided into groups.

[0506] The day of grouping was designated Day 0. Starting from Day 1, drugs were administered intraperitoneally once daily. Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. General performance of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[0507] The detection indicators and calculation formulas are as follows:

[0508] Tumor volume, TV (mm3) = 1 / 2 × (a × b2); where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0509] Relative tumor volume, RTV=TVt / TV0; TV0 is the tumor volume on day 0, and TVt is the tumor volume at each measurement.

[0510] Relative tumor growth rate, T / C (%) = TRTV / CRTV × 100%; where TRTV is the RTV of the treatment group; CRTV is the RTV of the vehicle control group.

[0511] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0512] Body weight change rate, WCR (%) = (Wtt-Wt0) / Wt0×100%; wherein Wt0 is the weight of the mouse on day 0, and Wtt is the weight of the mouse at each measurement.

[0513] Experimental Example 13: Efficacy evaluation of NCI-H358 cell CB17-SCID mouse subcutaneous transplant tumor model

[0514] NCI-H358 cells were subcutaneously inoculated in the right axilla of SPF female CB17-SCID mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) at a concentration of 5 × 10 6 (1:1 mixed with Matrigel inoculation). When the average tumor volume reaches 200mm 3 When about 30 seconds, divide the animals into groups.

[0515] The day of grouping was designated Day 0. Starting from Day 0, mice were gavaged once daily (1-10 mg / kg). Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. General performance of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[0516] The detection indicators and calculation formulas are as follows:

[0517] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2 ), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0518] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[0519] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[0520] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0521] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wt t is the weight of the mice at each measurement.

[0522] Experimental results: Two weeks after administration, some compounds of the present application, including the example compounds, showed excellent pharmacodynamic indicators in the NCI-H358 cell CB17-SCID mouse subcutaneous transplant tumor model, including but not limited to tumor growth inhibition rate (for example, tumor growth inhibition rate greater than 80% or greater than 90%).

[0523] Experimental Example 14: Evaluation of drug efficacy in a Capan-1 cell subcutaneous transplant tumor model in nude mice

[0524] Capan-1 cells were subcutaneously inoculated in the right axilla of SPF female nude mice (source: Changzhou Cavens Laboratory Animal Co., Ltd.) at a concentration of 2 × 10 6 When the average tumor volume reaches 200-250mm 3 When about 30 seconds, divide the animals into groups.

[0525] The day of grouping was designated Day 0. Starting from Day 0, mice were gavaged once daily (20-60 mg / kg). Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. General performance of the mice was observed and recorded daily. Tumors were removed, weighed, and photographed at the end of the experiment.

[0526] The detection indicators and calculation formulas are as follows:

[0527] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2 ), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0528] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[0529] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[0530] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0531] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wt t is the weight of the mice at each measurement.

[0532] Experimental results: 37 days after administration, some compounds of the present application, including the example compounds, showed excellent pharmacodynamic indicators in the Capan-1 cell nude mouse subcutaneous transplant tumor model, including but not limited to tumor growth inhibition rate (for example, tumor growth inhibition rate greater than 80% or greater than 90%).

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, X is selected from -N-, or optionally R x substituted -CH-; R x Selected from deuterium, halogen, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino; L 1 is selected from -O-, -S-, or optionally one or more R 1 Substituted with the following groups: -NH-, C 1-5 Alkylene, C 1-4 Heteroalkylene, C 2-5 Alkenylene, or C 1-4 heteroalkenylene; Each R 1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino; L 2 is selected from a single bond, Ring B is selected from optionally substituted with one or more R B or R C Substituted: 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Or, L 2 Selected from -C(R 2a R 2b )-, Ring B is selected from optionally substituted with one or more R B or R C Substituted: 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; R 2a is selected from H, deuterium, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl; Each R 2a1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino; R 2b Selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino; Or, R 2a and R 2b Together they form = O; Each R B independently selected from deuterium, oxo, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino; Ring A is selected from optionally substituted with one or more R A or R C Substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Each R A independently selected from deuterium, oxo, halogen, -CN, -OH, -NH2, or optionally substituted by one or more R A1 Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Each R A1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino; Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted with the following groups: -NH-, or -N(C 1-6 alkyl)-; Each R z independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 1-6 Alkylamino, or halogenated di-C 1-6 Alkylamino; R 3 is selected from H, deuterium, or optionally one or more R 3a or R C Substituted with the following groups: C 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 Alkylene; Each R 3a independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 3b Substituted with the following groups: =NH, =CH2, =N(C 1-6 alkyl), =CH(C 1-6 alkyl), =C(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, or di-C 1-6 Alkylamino; Each R 3b independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, or di-C 1-4 Alkylamino; Each R C Independently selected from -NR C1 C(O)R C2 、-NR C1 C(O)OR C2 、-NR C1 C(O)OC 1-6 Alkylene OC(O)R C2 、-NR C1 C(O)OC 1-6 Alkylene NR C1 C(O)R C2 、-NR C1 C(O)NR C1 R C2 、-NR C1 C(O)NR C1 C 1-6 Alkylene NR C1 C(O)R C2 、-NR C1 C(O)NR C1 C 1-6 Alkylene OC(O)R C2 、-OC(O)R C2 、-OC(O)OR C2 、-OC(O)OC 1-6 Alkylene OC(O)R C2 、-OC(O)OC 1-6 Alkylene NR C1 C(O)R C2 、-OC(O)NR C1 R C2 、-OC(O)NR C1 C 1-6 Alkylene OC(O)R C2 、-OC(O)NR C1 C 1-6 Alkylene NR C1 C(O)R C2 、-P(O)(OR C2 2. -C 1-6 Alkylene P(O)(OR C2 2. -C 1-6 Alkylene NR C1 P(O)(OR C2 2. -C 1-6 Alkylene OP(O)(OR C2 )2.-NR C1 P(O)(OR C2 )2.-NR C1 C 1-6 Alkylene P(O)(OR C2 )2.-NR C1 C 1-6 Alkylene OP(O)(OR C2 )2.-NR C1 C 1-6 Alkylene NR C1 P(O)(OR C2 )2.-OP(O)(OR C2 )2. -OC 1-6 Alkylene P(O)(OR C2 )2. -OC 1-6 Alkylene OP(O)(OR C2 )2. -OC 1-6 Alkylene NR C1 P(O)(OR C2 )2. -P(O)HOR C2 , -C 1-6 Alkylene P(O)HOR C2 , -C 1-6 Alkylene NR C1 P(O)HOR C2 , -C 1-6 Alkylene OP(O)HOR C2 、-NR C1 P(O)HOR C2 、-NR C1 C 1-6 Alkylene P(O)HOR C2 、-NR C1 C 1-6 Alkylene OP(O)HOR C2 、-NR C1 C 1-6 Alkylene NR C1 P(O)HOR C2 、-OP(O)HOR C2 、-OC 1-6 Alkylene P(O)HOR C2 、-OC 1-6 Alkylene OP(O)HOR C2 , or -OC 1-6 Alkylene NR C1 P(O)HOR C2 ; R C1 Independently selected from H, or C 1-6 alkyl; R C2 independently selected from H, or optionally one or more R C3 Substituted with the following groups: C 1-12 Alkyl, C 1-12 heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 Alkylene; Each R C3 independently selected from deuterium, oxo, halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 1-4 Alkylamino, halogenated di-C 1-4 Alkylamino, -P(O)(OH)2, -C 1-4 Alkylene P(O)(OH)2, -C 1-4 Alkylene OP(O)(OH)2, -C 1-4 Alkylene NR C1 P(O)(OH)2、-NR C1 P(O)(OH)2、-NR C1 C 1-4 Alkylene P(O)(OH)2, -NR C1 C 1-4 Alkylene OP(O)(OH)2, -NR C1 C 1-4 Alkylene NR C1 P(O)(OH)2, -OP(O)(OH)2, -OC 1-4 Alkylene P(O)(OH)2, -OC 1-4 Alkylene OP(O)(OH)2, -OC 1-4 Alkylene NR C1 P(O)(OH)2, -P(O)HOH, -C 1-4 Alkylene P(O)HOH, -C 1-4 Alkylene OP(O)HOH, -C 1-4 Alkylene NR C1 P(O)HOH、-NR C1 P(O)HOH、-NR C1 C 1-4 Alkylene P(O)HOH, -NR C1 C 1-4 Alkylene OP(O)HOH, -NR C1 C 1-4 Alkylene NR C1 P(O)HOH、-OP(O)HOH、-OC 1-4 Alkylene P(O)HOH, -OC 1-4 Alkylene OP(O)HOH, -OC 1-4 Alkylene NR C1 P(O)HOH、-C(O)NR C1 C 1-6 Alkyl, -NR C1 C(O)C 1-6 Alkyl, -NR C1 C(O)OC 1-6 Alkyl, -NR C1 C(O)NR C1 C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, or -OC(O)NR C1 C 1-6 alkyl; R 4 Selected from H, deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; Each R x , L 1 , R 1 , R 2a , R 2a1 , R 2b , R B , R A , R A1 , R z , R 3 , R 3a , R 3b , R C , R C1 , R C2 , R C3 , R 4 each independently optionally substituted with one or more substituents; Provided that the compound of formula (I) comprises at least one R C .

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: X is selected from -N-, -CH-, -C(C 1-6 Alkyl)-, or -C(halogenated C 1-6 alkyl)-; Alternatively, X is selected from -N-, -CH-, -C(C 1-3 Alkyl)-, or -C(halogenated C 1-3 alkyl)-; Alternatively, X is selected from -N-.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: The L 1 is selected from -O-, -S-, or optionally one or more R 1 Substituted with the following groups: -NH-, C 2-4 Alkylene, C 1-3 Heteroalkylene, C 2-4 Alkenylene, or C 1-3 heteroalkenylene; Alternatively, the L 1 -O-, or optionally one or more R 1 Substituted with the following groups: -NH-, C 2-4 Alkylene, or C 1-3 heteroalkylene; Alternatively, the L 1 -O-, or optionally one or more R 1 Substituted with the following groups: -NH-, -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2OCH2-, -CH2CH2O-, -O(CH2)3-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2CH2O-, -NHCH2-, -NHCH2CH2-, -CH2NHCH2-, -CH2CH2NH-, -NH(CH2)3-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, or -CH2CH2CH2NH-; Alternatively, the L 1 Selected from optionally one or more R 1 Substituted with the following groups: -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -OCH2CH2-, -O(CH2)3-, -NHCH2-, -NHCH2CH2-, or -NH(CH2)3-; Alternatively, the L 1 Selected from optionally one or more R 1 Substituted with the following groups: -(CH2)3-, -OCH2CH2-, or -NHCH2CH2-; Alternatively, the L 1 Selected from optionally one or more R 1 Substituted -OCH2CH2-.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: Each R 1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino; Alternatively, each R 1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, halo 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino; Alternatively, each R 1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl or halogenated C 1-3 Alkoxy; Alternatively, each R 1 independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or halogenated C 1-3 Alkoxy; Alternatively, each R 1 independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -CH2F, trifluoromethyl, or trifluoromethoxy; Alternatively, each R 1 Independently selected from C 1-3 Alkyl or fluorinated C 1-3 alkyl; Alternatively, each R 1 Independently selected from methyl, ethyl, isopropyl, trifluoromethyl, or -CH2F.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: The L 2 is selected from a single bond, Ring B is selected from optionally substituted with one or more R B or R C Substituted: 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Alternatively, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of B or R C Substituted: 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Alternatively, the L 2 is selected from a single bond, Ring B is selected from optionally substituted with one or more R B or R C Substituted 5-10 membered heterocycloalkenyl; Alternatively, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of B or R C Substituted: 3-6 membered cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; Alternatively, the L 2 is selected from a single bond, Ring B is selected from optionally substituted with one or more R B or R C Substituted: dihydroindolinyl, cyclopentapyridinyl, dihydropyrrolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or tetrahydronaphthyridinyl; Alternatively, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of B or R C substituted cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; Alternatively, the L 2 is selected from a single bond, Ring B is selected from optionally substituted with one or more R B or R C Substituted cyclopentapyridyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl; Alternatively, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of B or R C Substituted cyclopropane, cyclobutane, cyclopentane, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrazolyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; Alternatively, the L 2 is selected from a single bond, Ring B is selected from optionally substituted with one or more R B or R C Substituted with the following groups: Alternatively, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from the group consisting of B or R C Substituted with the following groups: Phenyl, Alternatively, the L 2 Selected from single bonds, Ring B is selected from Alternatively, the L 2 Selected from -C(R 2a R 2b )-, wherein the ring B is selected from cyclopropane, Cyclobutane, Cyclopentyl, 6. A compound of formula (IA) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: The ring A is selected from the group consisting of A or R C Substituted: 3-6 membered cycloalkyl, 5-10 membered cycloalkenyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Alternatively, the ring A is selected from optionally one or more R A or R C Substituted: benzo 4-6 membered cycloalkenyl, benzo 4-6 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Alternatively, the ring A is selected from optionally one or more R A or R C substituted phenyl, naphthyl, benzocyclohexenyl, benzocyclopentenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzopyrimidinyl, benzothienyl, pyridopyrazolyl, or pyridopyrrolyl; Alternatively, the ring A is selected from optionally one or more R A or R C Substituted phenyl, naphthyl, pyrazolyl, pyridyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzothienyl, pyridopyrazolyl, or pyridopyrrolyl; Alternatively, the ring A is selected from optionally one or more R A or R C Substituted with the following groups: Alternatively, the ring A is selected from 7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: The Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted with the following groups: -NH-, or -N(C 1-6 alkyl)-; Alternatively, Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-4 alkyl)-; Alternatively, Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-3 alkyl)-; Alternatively, Z is selected from a single bond, -O-, -NH-, or -N(CH3)-; Alternatively, said Z is selected from -O-.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: The R 3 is selected from H, deuterium, or optionally one or more R 3a or R C Substituted with the following groups: C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl 1-4 Alkylene, 3-10 membered heterocyclic group C 1-4 Alkylene, 6-10 membered aryl C 1-4 Alkylene, or 5-10 membered heteroaryl C 1-4 Alkylene; Alternatively, the R 3 is selected from H, deuterium, or optionally one or more R 3a or R C Substituted with the following groups: C 1-4 Alkyl, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-10 membered cycloalkyl 1-3 Alkylene, 4-10 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene; Alternatively, the R 3 is selected from H, deuterium, or optionally one or more R 3a or R C Substituted with the following groups: C 1-4 Alkyl, 3-8 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl C 1-3 Alkylene, 4-10 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene; Alternatively, the R 3 is selected from H, deuterium, or optionally one or more R 3a or R C Substituted with the following groups: C 1-4 Alkyl, 3-8 membered cycloalkyl, 4-10 membered heterocyclyl, 5-6 membered heteroaryl, 3-8 membered cycloalkylC 1-3 Alkylene, 4-10 membered heterocyclic group C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene; Alternatively, the R 3 is selected from H, deuterium, or optionally one or more R 3a or R C Substituted with the following groups: C 1-4 Alkyl, 4-10 membered heterocyclic group, 3-8 membered cycloalkyl group C 1-3 Alkylene, 4-10 membered heterocyclic group C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene; Alternatively, the R 3 is selected from H, deuterium, or optionally one or more R 3a or R C Substituted with the following groups: C 1-4 Alkyl, 4-10 membered heterocycloalkyl, 3-8 membered cycloalkyl C 1-3 Alkylene, 4-10 membered heterocycloalkyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene; Alternatively, the R 3 is selected from H, deuterium, or optionally one or more R 3a or R C Substituted groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, piperazinyl, hexahydro-1H-pyrrolazinyl, 5-azaspiro[2.4]heptyl, tetrahydro-1'H,3'H-pyrrolo[cyclopropane-1,2'-pyrrolidine], cyclopropyl C 1-3 Alkylene, cyclobutyl C 1-3 Alkylene, cyclopentyl C 1-3 Alkylene, cyclohexyl C 1-3 Alkylene, azetidinyl C 1-3 Alkylene, tetrahydropyrrolyl C 1-3 Alkylene, morpholinyl C 1-3 Alkylene, piperidinyl C 1-3 Alkylene, piperazine C 1-3 Alkylene, hexahydro-1H-pyrrolizinyl C 1-3 Alkylene, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl C 1-3 Alkylene, 5-azaspiro[2.4]heptyl C 1-3 Alkylene, tetrahydro-1'H,3'H-pyrrolo[cyclopropane-1,2'-pyrrolidine]C 1-3 Alkylene or imidazolyl C 1-3 Alkylene; Alternatively, the R 3 is selected from H, deuterium, or optionally one or more R 3a or R C Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclohexyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, cyclopropyl 1-3 Alkylene, cyclobutyl C 1-3 Alkylene, cyclopentyl C 1-3 Alkylene, azetidinyl C 1-3 Alkylene, tetrahydropyrrolyl C 1-3 Alkylene, morpholinyl C 1-3 Alkylene, piperidinyl C 1-3 Alkylene, piperazine C 1-3 Alkylene, hexahydro-1H-pyrrolizinyl C 1-3 Alkylene, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl C 1-3 Alkylene, 5-azaspiro[2.4]heptyl C 1-3 Alkylene, tetrahydro-1'H,3'H-pyrrolo[cyclopropane-1,2'-pyrrolidine]C 1-3 Alkylene or imidazolyl C 1-3 Alkylene; Alternatively, the R 3 is selected from H, deuterium, or optionally one or more R 3a or R C Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Alternatively, the R 3 Selected from H, deuterium, methyl, 9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: Each R C Independently selected from -NR C1 C(O)R C2 、-NR C1 C(O)OR C2 、-NR C1 C(O)OC 1-4 Alkylene OC(O)R C2 、-NR C1 C(O)OC 1-4 Alkylene NR C1 C(O)R C2 、-NR C1 C(O)NR C1 R C2 、-NR C1 C(O)NR C1 C 1-4 Alkylene NR C1 C(O)R C2 、-NR C1 C(O)NR C1 C 1-4 Alkylene OC(O)R C2 、-OC(O)R C2 、-OC(O)OR C2 、-OC(O)OC 1-4 Alkylene OC(O)R C2 、-OC(O)OC 1-4 Alkylene NR C1 C(O)R C2 、-OC(O)NR C1 R C2 、-OC(O)NR C1 C 1-4 Alkylene OC(O)R C2 、-OC(O)NR C1 C 1-4 Alkylene NR C1 C(O)R C2 、-P(O)(OR C2 2. -C 1-4 Alkylene P(O)(OR C2 2. -C 1-4 Alkylene NR C1 P(O)(OR C2 2. -C 1-4 Alkylene OP(O)(OR C2 )2.-NR C1 P(O)(OR C2 )2.-NR C1 C 1-4 Alkylene P(O)(OR C2 )2.-NR C1 C 1-4 Alkylene OP(O)(OR C2 )2.-NR C1 C 1-4 Alkylene NR C1 P(O)(OR C2 )2.-OP(O)(OR C2 )2. -OC 1-4 Alkylene P(O)(OR C2 )2. -OC 1-4 Alkylene OP(O)(OR C2 )2. -OC 1-4 Alkylene NR C1 P(O)(OR C2 )2. -P(O)HOR C2 , -C 1-4 Alkylene P(O)HOR C2 , -C 1-4 Alkylene NR C1 P(O)HOR C2 , -C 1-4 Alkylene OP(O)HOR C2 、-NR C1 P(O)HOR C2 、-NR C1 C 1-4 Alkylene P(O)HOR C2 、-NR C1 C 1-4 Alkylene OP(O)HOR C2 、-NR C1 C 1-4 Alkylene NR C1 P(O)HOR C2 、-OP(O)HOR C2 、-OC 1-4 Alkylene P(O)HOR C2 、-OC 1-4 Alkylene OP(O)HOR C2 , or -OC 1-4 Alkylene NR C1 P(O)HOR C2 ; Alternatively, each R C Independently selected from -NR C1 C(O)R C2 、-NR C1 C(O)OR C2 、-NR C1 C(O)OC 1-3 Alkylene OC(O)R C2 、-NR C1 C(O)OC 1-3 Alkylene NR C1 C(O)R C2 、-NR C1 C(O)NR C1 R C2 、-NR C1 C(O)NR C1 C 1-3 Alkylene NR C1 C(O)R C2 、-NR C1 C(O)NR C1 C 1-3 Alkylene OC(O)R C2 、-OC(O)R C2 、-OC(O)OR C2 、-OC(O)OC 1-3 Alkylene OC(O)R C2 、-OC(O)OC 1-3 Alkylene NR C1 C(O)R C2 、-OC(O)NR C1 R C2 、-OC(O)NR C1 C 1-3 Alkylene OC(O)R C2 、-OC(O)NR C1 C 1-3 Alkylene NR C1 C(O)R C2 、-P(O)(OR C2 2. -C 1-3 Alkylene P(O)(OR C2 2. -C 1-3 Alkylene NR C1 P(O)(OR C2 2. -C 1-3 Alkylene OP(O)(OR C2 )2.-NR C1 P(O)(OR C2 )2.-NR C1 C 1-3 Alkylene P(O)(OR C2 )2.-NR C1 C 1-3 Alkylene OP(O)(OR C2 )2.-NR C1 C 1-3 Alkylene NR C1 P(O)(OR C2 )2.-OP(O)(OR C2 )2. -OC 1-3 Alkylene P(O)(OR C2 )2. -OC 1-3 Alkylene OP(O)(OR C2 )2. -OC 1-3 Alkylene NR C1 P(O)(OR C2 )2. -P(O)HOR C2 , -C 1-3 Alkylene P(O)HOR C2 , -C 1-3 Alkylene NR C1 P(O)HOR C2 , -C 1-3 Alkylene OP(O)HOR C2 、-NR C1 P(O)HOR C2 、-NR C1 C 1-3 Alkylene P(O)HOR C2 、-NR C1 C 1-3 Alkylene OP(O)HOR C2 、-NR C1 C 1-3 Alkylene NR C1 P(O)HOR C2 、-OP(O)HOR C2 、-OC 1-3 Alkylene P(O)HOR C2 、-OC 1-3 Alkylene OP(O)HOR C2 , or -OC 1-3 Alkylene NR C1 P(O)HOR C2 ; Alternatively, each R C Independently selected from -NR C1 C(O)R C2 、-NR C1 C(O)OR C2 、-NR C1 C(O)OC 1-3 Alkylene OC(O)R C2 、-NR C1 C(O)OC 1-3 Alkylene NR C1 C(O)R C2 、-OC(O)R C2 、-OC(O)OR C2 、-OC(O)OC 1-3 Alkylene OC(O)R C2 、-OC(O)OC 1-3 Alkylene NR C1 C(O)R C2 、-OC(O)NR C1 R C2 、-OC(O)NR C1 C 1-3 Alkylene OC(O)R C2 、-OC(O)NR C1 C 1-3 Alkylene NR C1 C(O)R C2 , -C 1-3 Alkylene NR C1 P(O)(OR C2 2. -C 1-3 Alkylene OP(O)(OR C2 )2.-NR C1 P(O)(OR C2 )2.-NR C1 C 1-3 Alkylene OP(O)(OR C2 )2.-NR C1 C 1-3 Alkylene NR C1 P(O)(OR C2 )2.-OP(O)(OR C2 )2. -OC 1-3 Alkylene OP(O)(OR C2 )2. -OC 1-3 Alkylene NR C1 P(O)(OR C2 2. -C 1-3 Alkylene NR C1 P(O)HOR C2 , -C 1-3 Alkylene OP(O)HOR C2 、-NR C1 P(O)HOR C2 、-NR C1 C 1-3 Alkylene OP(O)HOR C2 、-NR C1 C 1-3 Alkylene NR C1 P(O)HOR C2 、-OP(O)HOR C2 、-OC 1-3 Alkylene OP(O)HOR C2 , or -OC 1-3 Alkylene NR C1 P(O)HOR C2 ; Alternatively, each R C Independently selected from -NR C1 C(O)R C2 、-NR C1 C(O)OR C2 、-NR C1 C(O)OC 1-3 Alkylene OC(O)R C2 、-OC(O)R C2 、-OC(O)OR C2 、-OC(O)OC 1-3 Alkylene OC(O)R C2 、-OC(O)NR C1 R C2 、-OC(O)NR C1 C 1-3 Alkylene OC(O)R C2 、-OC(O)NR C1 C 1-3 Alkylene NR C1 C(O)R C2 , -C 1-3 Alkylene NR C1 P(O)(OR C2 2. -C 1-3 Alkylene OP(O)(OR C2 )2.-NR C1 P(O)(OR C2 )2.-NR C1 C 1-3 Alkylene OP(O)(OR C2 )2.-NR C1 C 1-3 Alkylene NR C1 P(O)(OR C2 )2.-OP(O)(OR C2 )2. -OC 1-3 Alkylene OP(O)(OR C2 )2. -OC 1-3 Alkylene NR C1 P(O)(OR C2 2. -C 1-3 Alkylene NR C1 P(O)HOR C2 , -C 1-3 Alkylene OP(O)HOR C2 、-NR C1 P(O)HOR C2 、-NR C1 C 1-3 Alkylene OP(O)HOR C2 、-NR C1 C 1-3 Alkylene NR C1 P(O)HOR C2 、-OP(O)HOR C2 、-OC 1-3 Alkylene OP(O)HOR C2 , or -OC 1-3 Alkylene NR C1 P(O)HOR C2 ; Alternatively, each R C Independently selected from -NR C1 C(O)R C2 、-NR C1 C(O)OR C2 、-OC(O)R C2 、-OC(O)OR C2 、-OC(O)OC 1-3 Alkylene OC(O)R C2 、-OC(O)NR C1 R C2 , -C 1-3 Alkylene OP(O)(OR C2 )2.-NR C1 P(O)(OR C2 )2.-NR C1 C 1-3 Alkylene OP(O)(OR C2 )2.-OP(O)(OR C2 )2. -OC 1-3 Alkylene OP(O)(OR C2 )2, or -NR C1 P(O)HOR C2 ; Alternatively, each R C Independently selected from -NR C1 C(O)OR C2 , -C 1-2 Alkylene OP(O)(OR C2 )2.-NR C1 P(O)(OR C2 )2.-NR C1 C 1-2 Alkylene OP(O)(OR C2 )2, or -NR C1 P(O)HOR C2 ; Alternatively, each R C Independently selected from -NR C1 C(O)OR C2 , -C 1-2 Alkylene OP(O)(OH)2, -NR C1 P(O)(OH)2、-NR C1 P(O)(OR C2 )2.-NR C1 C 1-2 Alkylene OP(O)(OH)2, or -NR C1 P(O)HOR C2 ; Alternatively, each R C Independently selected from 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: R 4 Selected from H, deuterium, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy; Or, R 4 Selected from H, deuterium, halogen, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 Haloalkoxy; Or, R 4 is selected from H, deuterium, -F, -Cl, -Br, -I, -CN, methyl, methoxy, difluoromethyl, trifluoromethyl, or trifluoromethoxy; Or, R 4 is selected from H, deuterium, -F, or -Cl.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which is selected from a compound of formula (II), (III), (III-1), (III-1a), (IV-1), (IV-2), (IV-3) or a pharmaceutically acceptable salt thereof, in, L 1 , R 1 , R 2a , R 2b , R 3 , R 4 , R A , R B , R C , Z, ring A, and ring B are as defined in claim 1; n is selected from 0, 1, 2, 3, 4 or 5; p is selected from 0, 1, 2, 3, 4 or 5; q is selected from 0, 1, 2, 3, 4 or 5; m is selected from 0, 1, 2, 3, 4 or 5.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, selected from compounds of formula (A), (A-1), (B), (B-1), (C), (D), (E), (E-1), (F), (F-1), (G), (H) or a pharmaceutically acceptable salt thereof, in, L 1 , L 2 ,X,R 3a , R 2a , R 2b , R 3 , R 4 , R B , R C , R 1 , Z, ring A, and ring B are as defined in claim 1; n is selected from 0, 1, 2, 3, 4 or 5; m is selected from 0, 1, 2, 3, 4 or 5; p is selected from 0, 1, 2, 3, 4 or 5.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, which is selected from the following compounds or pharmaceutically acceptable salts thereof: Alternatively, it is selected from the following compounds or pharmaceutically acceptable salts thereof: Alternatively, it is selected from the following compounds or pharmaceutically acceptable salts thereof:

14. A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13; optionally, further comprising a pharmaceutically acceptable excipient.

15. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating a disease.