Phosphonic acid compound and use thereof

Abstract

The present application belongs to the field of medicinal chemistry, and relates to a phosphonic acid compound and the use thereof, wherein the compound has a structure as shown in formula (I'). Specifically, the present application further relates to a method for preparing the compound, a pharmaceutical composition thereof, and the use thereof in the treatment of diseases.

Description

Phosphonic acid compounds and uses thereof

[0001] Reference to Related Applications

[0002] This application claims priority to and the benefit of Chinese Patent Application No. 202410888099.7, filed July 3, 2024, Chinese Patent Application No. 202510325822.5, filed March 18, 2025, and Chinese Patent Application No. 202510864025.4, filed June 25, 2025, in the State Intellectual Property Office of the People’s Republic of China, the contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] The present disclosure relates to phosphonic acid compounds, methods of making the same, pharmaceutical compositions containing the same, and uses thereof in the treatment of diseases. BACKGROUND

[0004] STAT3 is a member of the STAT transcription factor family, which can transmit cytokine and growth factor signals from cell surface receptors to the nucleus, regulating important cellular processes such as cell cycle, cell survival, and immune response. Studies have shown that nearly 70% of malignant tumors have abnormal activation of STAT3, and the abnormal activation of STAT3 signal promotes the growth, survival, and metastasis of tumor cells, and inhibits the anti-tumor immune response. Blocking STAT3 has been shown to inhibit tumor growth, induce apoptosis, reverse acquired drug resistance, and stimulate immune response, with good tolerance in normal cells.

[0005] Therefore, STAT3 has become a highly concerned anti-tumor target. Currently, 8 STAT3 inhibitors have entered the clinical stage, but most of them have progressed slowly due to insufficient clinical performance.

[0006] DETAILED DESCRIPTION

[0007] The present disclosure relates to a compound of Formula (I’), or a pharmaceutically acceptable salt thereof,

[0008] wherein,

[0009] Ring A is selected from 3-6 membered cycloalkyl, 4-6 membered cycloalkenyl, or 4-6 membered heterocyclyl, optionally substituted with one or more R A substituents;

[0010] Ring B is selected from 4-12 membered heterocyclyl, optionally substituted with one or more R B substituents;

[0011] Ring C is selected from 4-12 membered heterocyclyl, optionally substituted with one or more R Csubstituted 4-12 membered heterocyclyl;

[0012] Ring D is selected from an optionally substituted D substituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0013] each R A , R B , R C , or R D is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1- 6alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylamino, halo diC 1-6 alkylamino, -C(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -NHC(O)C 1- 6alkyl, -N(C 1-6 alkyl)C(O)C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -SO2C 1-6 alkyl, -NHSO2C 1-6 alkyl, -N(C 1-6 alkyl)SO2C 1-6 alkyl, -SO2NHC 1-6 alkyl, -SO2N(C 1-6 alkyl)2, -C(O)-(3-6 membered cycloalkyl), -C(O)-(3-6 membered cycloalkenyl), or -C(O)-(4-6 membered heterocyclyl);

[0014] Q is selected from -O-, -S-, -S(O)-, -S(O)2-, -NR Q -, -C(O)-, or -C(R Q )2-;

[0015] each R Q is each independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino;

[0016] Y 1 Selected from OR P1 or N(R) P1 )2;

[0017] Y 2 Selected from OR P2 or N(R) P2 )2;

[0018] R P1 R P2 Each is independently selected from H, deuterium, or arbitrarily selected by one or more R. P3 Replacement C 1-6 Alkyl, or optionally with one or more R P4 The following groups may be substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0019] Or, R P1 R P2 The atoms connected to them together form an optional structure with one or more R P5 Substituted 4-12 membered heterocyclic groups;

[0020] Each R P3 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, or optionally influenced by one or more R. P3a The following groups are substituted: C 1-12 Alkoxy, C 1-12 Alkylamino, diC 1-12 Alkylamino, -C(O)C 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl group, -NHC(O)C 1-12 Alkyl, -N(C) 1-6 Alkyl)C(O)C 1-12 Alkyl group, -C(O)NHC 1- 12 Alkyl, -C(O)N(C) 1-12 alkyl)2、-NHC(O)NHC 1-12alkyl, -SO2C 1-12 alkyl, -S(O)C 1-12 alkyl, -NHSO2C 1-12 alkyl, -NHS(O)C 1-12 alkyl, -N(C 1-6 alkyl)SO2C 1-12 alkyl, -SO2NHC 1-12 alkyl, -S(O)NHC 1-12 alkyl, -SO2N(C 1-12 alkyl)2, S(O)N(C 1-12 alkyl)2, -SC(O)C 1-12 alkyl, -C(O)C 0-6 alkylene (4-6 membered heterocyclyl), -C(O)OC 0-6 alkylene (4-6 membered heterocyclyl), -OC(O)C 0-6 alkylene (4-6 membered heterocyclyl), -OC(O)OC 0-6 alkylene (4-6 membered heterocyclyl), -SC(O)C 0-6 alkylene (4-6 membered heterocyclyl), -C(O)C 0-6 alkylene (3-6 membered cycloalkyl), -C(O)OC 0-6 alkylene (3-6 membered cycloalkyl), -OC(O)C 0-6 alkylene (3-6 membered cycloalkyl), -OC(O)OC 0-6 alkylene (3-6 membered cycloalkyl), -SC(O)C 0-6 alkylene (3-6 membered cycloalkyl), -C(O)C 0-6 alkylene phenyl, -C(O)OC 0-6 alkylene phenyl, -SC(O)C 0-6 alkylene phenyl, -C(O)OC 0-6 alkylene (5-6 membered heteroaryl), or -SC(O)C 0-6 alkylene (5-6 membered heteroaryl);

[0021] each R P3a is independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-3 alkoxy C 1-3 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, halo C 1-6 alkyl, halo C 1- 6alkoxy, halo C 1-3 alkoxy C1-3 alkoxy, haloC 1-6 alkylamino, or halo-diC 1-6 alkylamino;

[0022] each R P4 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylamino, or halo-diC 1-6 alkylamino;

[0023] each R P5 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R P5a substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0024] each R P5a is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylamino, or halo-diC 1-6 alkylamino;

[0025] R 1 is selected from H, deuterium, or is optionally substituted with one or more R 1a substituted C 1-6 alkyl;

[0026] each R 1aeach independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -C(O)NH2, -SO2NH2, C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1- alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -OC(O)C

[0027] -L- is selected from -LNK 1 -Cy 1 -LNK 2 -Cy 2 -LNK 3 -;

[0028] LNK 1 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK1 alkylene, C 1-12 alkylene, C 2-12 alkylene, C 2-12 alkylene, C 1-12 heteroalkylene, C 1-12 heteroalkylene, C 2-12 heteroalkylene, C

[0029] LNK 2 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 alkylene, C 1-12 alkylene, C 2-12 alkylene, C2-12 Ethyne group, C 1-12 Heteroalkylene, C 1-12 Heteroeneyl, or C 2-12 Hetero-ynyl group;

[0030] LNK 3 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK3 The following groups are substituted: C 1-12 Alkylene, C 2-12 imidene group, C 2-12 Ethyne group, C 1-12 Heteroalkylene, C 1-12 Heteroeneyl, or C 2-12 Hetero-ynyl group;

[0031] Each R LNK1 R LNK2 、or R LNK3 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, or optionally influenced by one or more R. LNKa The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-4 Alkylene, 3-12 membered cycloalkenyl C 1-4 Alkylene, 4-12 membered heterocyclic C 1-4 Alkylene, 6-10 aryl C 1-4 alkylene or 5-10 heteroaryl C 1-4 Alkylene;

[0032] Each R LNKa Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino;

[0033] Cy 1 Selected from a single key, or optionally by one or more R keys Cy1substituted with one or more R

[0034] Cy 2 is selected from a single bond, or is optionally substituted with one or more R Cy2 substituted with one or more R

[0035] each R Cy1 or R Cy2 each is independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 1- 6alkylamino, or halo-di-C 1-6 alkylamino;

[0036] ULM is selected from

[0037] -L A - is selected from a single bond, -O-, -S-, -NR A1 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR LA1 -, -NR LA1 C(O)-, -NR LA1 C(O)NR LA1 -, -S(O)-, -S(O)2-, -S(O)2NR LA1 -, -NR LA1 S(O)2-, or is optionally substituted with one or more R LA2 substituted with one or more R

[0038] each R LA1 each is independently selected from H, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, or halo-C 1-6 alkyl;

[0039] each R LA2each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C1-6alkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkoxy, C1-6haloalkoxy, 1-6 C1-6alkylamino, di(C1-6alkyl)amino, 1-6 C1-6alkylamino, deuterated C1-6alkylamino, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkoxy, C1-6haloalkoxy, 1-6 C1-6alkylamino, or dihaloC1-6alkylamino, 1-6 C1-6alkylamino;

[0040] R 2 is selected from H, deuterium, or is optionally substituted with one or more R 2a substituted with one or more R 1-6 C1-6alkyl, 3-6 membered cycloalkyl, -3-6 membered cycloalkenyl, or 4-6 membered heterocyclyl;

[0041] each R 2a each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C1-6alkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkoxy, C1-6haloalkoxy, 1-6 C1-6alkylamino, di(C1-6alkyl)amino, 1-6 C1-6alkylamino, deuterated C1-6alkylamino, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkoxy, C1-6haloalkoxy, 1-6 C1-6alkylamino, or dihaloC1-6alkylamino, 1-6 C1-6alkylamino;

[0042] X 1 , X 2 , or X 3 each independently selected from a single bond, -O-, -S-, -S(O)-, -S(O)2-, -NR XA -, -C(O)-, or -C(R XA )2-;

[0043] each R XA each independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C1-6alkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkoxy, C1-6haloalkoxy, 1- C1-6alkylamino, di(C1-6alkyl)amino, 1-6 C1-6alkylamino, deuterated C1-6alkylamino, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkoxy, C1-6haloalkoxy, 1-6 C1-6alkylamino, or dihaloC1-6alkylamino, 1-6alkylamino, or hydroxyC 1-6 alkyl;

[0044] or, two R XA together form an optionally substituted group of 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl; XA1

[0045] each R XA1 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylamino, or halo diC 1-6 alkylamino;

[0046] Ring E is selected from 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0047] each R E is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is an optionally substituted group of C E1 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0048] each R E1 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylamino, or halo diC 1-6 alkylamino; ​

[0049] n is selected from 0, 1, 2, 3, 4, or 5;

[0050] Ring F is selected from 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-12 membered heteroaryl;

[0051] each R F is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R F1 substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, or diC 1-6 alkylamino;

[0052] each R F1 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylamino, or halogenated diC 1-6 alkylamino;

[0053] m is selected from 0, 1, 2, 3, 4, or 5;

[0054] the R A , R B , R C , R D , R Q , R P3 , R 1a , R LNKa , R Cy1 , R Cy2 , R LA1 , R LA2 , R 2a , R XA , R XA1 , R E1 , or R F1 are optionally substituted with one or more substituents.

[0055] The present disclosure relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof,

[0056] wherein,

[0057] Ring A is selected from optionally substituted with one or more R Asubstituted 3-6 membered cycloalkyl, 4-6 membered cycloalkenyl, or 4-6 membered heterocyclyl;

[0058] Ring B is selected from an optionally substituted B substituted 4-12 membered heterocyclyl;

[0059] Ring C is selected from an optionally substituted C substituted 4-12 membered heterocyclyl;

[0060] Ring D is selected from an optionally substituted D substituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0061] each R A , R B , R C , or R D is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1- 6alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylamino, halo diC 1-6 alkylamino, -C(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -NHC(O)C 1- 6alkyl, -N(C 1-6 alkyl)C(O)C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -SO2C 1-6 alkyl, -NHSO2C 1-6 alkyl, -N(C 1-6 alkyl)SO2C 1-6 alkyl, -SO2NHC 1-6 alkyl, or -SO2N(C 1-6 alkyl)2;

[0062] Q is selected from -O-, -S-, -S(O)-, -S(O)2-, -NR Q -, -C(O)-, or -C(R Q )2-;

[0063] Each R Q Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino;

[0064] R P1 R P2 Each is independently selected from H, deuterium, or arbitrarily selected by one or more R. P3 Replacement C 1-6 alkyl;

[0065] Each R P3 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, Halogenated diC 1-6 Alkylamino, -C(O)C 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl group, -NHC(O)C 1- 6-alkyl, -N(C) 1-6 Alkyl)C(O)C 1-6 Alkyl group, -C(O)NHC 1-6 Alkyl, -C(O)N(C) 1-6 alkyl)2、-NHC(O)NHC 1-6 Alkyl, -SO2C 1- 6-alkyl, -NHSO2C 1-6 Alkyl, -N(C) 1-6 Alkyl)SO2C 1-6 Alkyl group, -SO2NHC 1-6 Alkyl, or -SO2N(C 1-6 Alkyl)2;

[0066] R1 H, deuterium, or is optionally substituted with one or more R 1a substituted C 1-6 alkyl;

[0067] each R 1a is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -C(O)NH2, -SO2NH2, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, haloC 1-6 alkoxy, haloC 1-6 alkylamino, halo diC 1- 6alkylamino, -C(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -NHC(O)C 1-6 alkyl, -N(C 1-6 alkyl)C(O)C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -NHC(O)NHC 1-6 alkyl, -SO2C 1-6 alkyl, -NHSO2C 1-6 alkyl, -N(C 1-6 alkyl)SO2C 1-6 alkyl, -SO2NHC 1-6 alkyl, or -SO2N(C 1-6 alkyl)2;

[0068] -L- is selected from -LNK 1 -Cy 1 -LNK 2 -Cy 2 -LNK 3 -;

[0069] LNK 1 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK1 substituted C 1-12 alkylene, C 2-12 alkenylene, C 2-12 alkynylene, C 1-12 heteroalkylene, C 1-12 heteroalkenylene, or C 2-12 heteroalkynylene;

[0070] LNK 2 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R 1-12 alkylene, C 2-12 alkenylene, C 2-12 alkynylene, C 1-12 heteroalkylene, C 1-12 heteroalkenylene, or C 2-12 heteroalkynylene;

[0071] LNK 3 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R 1-12 alkylene, C 2-12 alkenylene, C 2-12 alkynylene, C 1-12 heteroalkylene, C 1-12 heteroalkenylene, or C 2-12 heteroalkynylene;

[0072] each R LNK1 , R LNK2 , or R LNK3 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R LNKa is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-4 alkylene, 3-12 membered cycloalkenyl C 1-4 alkylene, 4-12 membered heterocyclyl C 1-4 alkylene, 6-10 membered aryl C 1-4 alkylene, or 5-10 membered heteroaryl C 1-4 alkylene;

[0073] each R LNKa is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C1-6 alkylamino, or halodicyano; 1-6 alkylamino;

[0074] Cy 1 is selected from a single bond, or a group optionally substituted with one or more R Cy1 substituted with 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0075] Cy 2 is selected from a single bond, or a group optionally substituted with one or more R Cy2 substituted with 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0076] each R Cy1 or R Cy2 are each independently selected from the group consisting of deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, dicyano; 1-6 alkylamino, dicyano; 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1- 6alkylamino, or halodicyano; 1-6 alkylamino;

[0077] ULM is selected from

[0078] -L A - is selected from a single bond, -O-, -S-, -NR A1 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR LA1 -, -NR LA1 C(O)-, -NR LA1 C(O)NR LA1 -, -S(O)-, -S(O)2-, -S(O)2NR LA1 -, -NR LA1 S(O)2-, or a group optionally substituted with one or more R LA2 substituted with 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0079] each R LA1 are each independently selected from the group consisting of H, deuterium, C 1-6 alkyl, dideuterated C1-6 alkyl, or haloalkyl; 1-6 alkyl;

[0080] each R LA2 is each independently selected from the group consisting of deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, haloalkyl; 1-6 alkyl, haloalkyl; 1-6 alkoxy, haloalkyl; 1-6 alkylamino, or halo-di-C 1-6 alkylamino;

[0081] R 2 is selected from H, deuterium, or is optionally substituted C 2a ; substituted with one or more R 1-6 alkyl;

[0082] each R 2a is each independently selected from the group consisting of deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, haloalkyl; 1-6 alkyl, haloalkyl; 1-6 alkoxy, haloalkyl; 1-6 alkylamino, or halo-di-C 1-6 alkylamino;

[0083] X 1 , X 2 , or X 3 are each independently selected from a single bond, -O-, -S-, -S(O)-, -S(O)2-, -NR XA -, -C(O)-, or -C(R XA )2-;

[0084] each R XA is each independently selected from the group consisting of H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1- alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, haloalkyl; 1-6 alkyl, haloalkyl; 1-6Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino;

[0085] Or, two Rs XA Together they form an optional combination of one or more R XA1 The following groups are substituted: 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl;

[0086] Each R XA1 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino;

[0087] The ring E is selected from 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0088] Each R E Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, or optionally influenced by one or more R. E1 The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0089] Each R E1 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6alkylamino, or diC

[0090] n is selected from 0, 1, 2, 3, 4, or 5;

[0091] Ring F is selected from 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-12 membered heteroaryl;

[0092] each R F is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R F1 substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, or diC 1-6 alkylamino, or diC

[0093] each R F1 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylamino, or halogenated diC 1-6 alkylamino, or diC

[0094] m is selected from 0, 1, 2, 3, 4, or 5;

[0095] the R A , R B , R C , R D , R Q , R P3 , R 1a , R LNKa , R Cy1 , R Cy2 , R LA1 , R LA2 , R 2a , R XA , R XA1 , R E1 , or R F1 are optionally substituted with one or more substituents.

[0096] In some embodiments, the R A , R B , R C , R D , R Q , R P3R 1a R LNKa R Cy1 R Cy2 R LA1 R LA2 R 2a R XA R XA1 R E1 R F1 optionally substituted with one or more substituents selected from the group consisting of deuterium, oxo, halogen, -OH, -NH2, -CN, thiol, nitro, nitroso, azido, sulfoxide group, sulfone group, sulfonamide group, carboxyl, aldehyde group, imine group, C 1-12 alkyl, halo-C 1-12 alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3-12 membered cycloalkenyl, halo-3-12 membered cycloalkenyl, C 2-12 alkynyl, halo-C 2-12 alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C 1-12 heteroalkyl, halo-C 1- 12 heteroalkyl, C 1-12 alkoxy, C 1-12 alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered aryl C 1- 12 alkylene, 6-10 membered aryl C 1-12 alkylene, 6-10 membered aryl C 1-12 alkylene, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered heterocyclyl C 1-12 alkylene, C 1-12 acyl, C 1-12 acyloxy, carbamate group, C 1-12 amide group, urea group, epoxy group, C 2-12 ester group, oxo, and thioxo, etc., said substituents are optionally substituted with one or more substituents selected from the group consisting of deuterium atom, oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C1-12 alkoxy, haloC 1-12 alkoxy, C 1-12 alkylamino, diC 1-12 alkylamino, haloC 1-12 alkylamino, halo diC 1-12 alkylamino, carboxy, -C(O)O-C 1-12 alkyl, -OC(O)-C 1-12 alkyl, -C(O)NH2, -C(O)NH-C 1-12 alkyl, -C(O)N(C 1-12 alkyl)2, -NHC(O)-C 1-12 alkyl, -C(O)-C 1-12 alkyl, -S(O)-C 1-12 alkyl, -S(O)2-C 1-12 alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 alkyl, -S(O)2N(C 1-12 alkyl)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkylC 1-12 alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclylC 1-12 alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 alkylene or 6-10 membered aryloxy.

[0097] In some embodiments, the R A , R B , R C , R D , R Q , R P3 , R 1a , R LNKa , R Cy1 , R Cy2 , R LA1 , R LA2 , R 2a , R XA , R XA1 , R E1 , or R F1 is optionally substituted with one or more substituents selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3alkyl, or haloC 1-3 alkoxy.

[0098] Ring A described herein shares one ring atom with ring B.

[0099] In some embodiments, a "heterocycloalkyl" described herein is selected from a 4-12 membered, 4-10 membered, 6-9 membered, or 4-7 membered heterocycloalkyl.

[0100] In some embodiments, ring A is selected from a group consisting of a 3-6 membered cycloalkyl or a 4-6 membered heterocycloalkyl optionally substituted with one or more R A substituted with one or more R

[0101] In some embodiments, ring A is selected from a group consisting of a cyclopropyl, a cyclobutyl, a cyclopentyl, a cyclohexyl, an azetidinyl, an oxetanyl, a tetrahydrofuranyl, a tetrahydropyrrolyl, a piperidinyl, a morpholinyl, or a piperazinyl optionally substituted with one or more R A substituted with one or more R

[0102] In some embodiments, ring A is selected from a group consisting of a cyclopropyl or a cyclobutyl optionally substituted with one or more R A substituted with one or more R

[0103] In some embodiments, ring A is selected from a cyclopropyl optionally substituted with one or more R A substituted with one or more R

[0104] In some embodiments, a "4-12 membered heterocycloalkyl" described herein is selected from a 4-12 membered, 4-10 membered, 6-9 membered, or 4-7 membered heterocycloalkyl. In some embodiments, a "4-12 membered heterocycloalkyl" described herein is selected from a 4-12 membered, 4-10 membered, 6-9 membered, or 4-7 membered heterocycloalkyl.

[0105] In some embodiments, ring B is selected from a 4-10 membered heterocycloalkyl optionally substituted with one or more R B substituted with one or more R

[0106] In some embodiments, ring B is selected from a 6-9 membered heterocycloalkyl optionally substituted with one or more R B substituted with one or more R

[0107] In some embodiments, ring B is selected from a group consisting of a 6 membered, a 7 membered, an 8 membered, or a 9 membered heterocycloalkyl optionally substituted with one or more R B substituted with one or more R

[0108] In some embodiments, ring B is selected from a group consisting of a piperidinyl, a piperazinyl, an azepanyl, a diazepanyl, an azocanyl, a diazocanyl, an azonanyl, or a diazonanyl optionally substituted with one or more R B substituted with one or more R

[0109] In some embodiments, Ring B is selected from 4-10 membered heterocyclyl optionally substituted with one or more R B substituted with one or more R

[0110] In some embodiments, Ring C is selected from 4-10 membered heterocyclyl optionally substituted with one or more R C substituted with one or more R

[0111] In some embodiments, Ring C is selected from 4-10 membered heterocyclyl optionally substituted with one or more R C substituted with one or more R

[0112] In some embodiments, Ring C is selected from 4-10 membered heterocyclyl optionally substituted with one or more R C substituted with one or more R

[0113] In some embodiments, Ring C is selected from 4-10 membered heterocyclyl optionally substituted with one or more R C substituted with one or more R

[0114] In some embodiments, Ring C is selected from 4-10 membered heterocyclyl optionally substituted with one or more R C substituted with one or more R

[0115] In some embodiments, structural unit is selected from

[0116] In some embodiments, structural unit is selected from

[0117] In some embodiments, structural unit is selected from In some embodiments, structural unit is selected from

[0118] In some embodiments, structural unit is selected from

[0119] In some embodiments, Ring D is selected from 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl optionally substituted with one or more R D substituted with one or more R

[0120] In some embodiments, Ring D is selected from 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl optionally substituted with one or more R Dsubstituted 5-10 membered cycloalkyl, 5-10 membered cycloalkenyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0121] In some embodiments, ring D is selected from optionally substituted D substituted phenyl, naphthyl, benzo 5-6 membered heteroaryl, or 5-6 membered heteroaryl and 5-6 membered heteroaryl.

[0122] In some embodiments, ring D is selected from optionally substituted D substituted naphthyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, benzothiazolyl, benzopyridinyl, or benzopyrimidinyl.

[0123] In some embodiments, ring D is selected from optionally substituted D substituted wherein U is O, S, or NH.

[0124] In some embodiments, ring D is selected from optionally substituted D substituted

[0125] In some embodiments, ring D is selected from optionally substituted D substituted wherein is connected to Q.

[0126] In some embodiments, each R A , R B , R C , or R D is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, halogenated diC 1-4 alkylamino, -C(O)C 1-4 alkyl, -OC(O)C 1-4 alkyl, -C(O)OC 1- 4alkyl, -NHC(O)C 1-4 alkyl, -N(C 1-4 alkyl)C(O)C 1-4alkyl, -C(O)NHC 1-4 alkyl, -C(O)N(C 1-4 alkyl)2, -SO2C 1-4 alkyl, -NHSO2C 1-4 alkyl, -N(C 1-4 alkyl)SO2C 1-4 alkyl, -SO2NHC 1-4 alkyl, -SO2N(C 1-4 alkyl)2, -C(O)-(3-6 membered cycloalkyl), -C(O)-(3-6 membered cycloalkenyl), -C(O)-(4-6 membered heterocycloalkyl), -C(O)-(3-5 membered cycloalkyl), -C(O)-(3-5 membered cycloalkenyl), or -C(O)-(4-5 membered heterocycloalkyl).

[0127] In some embodiments, each R A , R B , R C , or R D is independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, haloC 1-4 alkyl, haloC 1-4 alkoxy, haloC 1-4 alkylamino, halo diC 1-4 alkylamino, -C(O)C 1-4 alkyl, -OC(O)C 1-4 alkyl, -C(O)OC 1- alkyl, -NHC(O)C 1-4 alkyl, -N(C 1-4 alkyl)C(O)C 1-4 alkyl, -C(O)NHC 1-4 alkyl, -C(O)N(C 1-4 alkyl)2, -SO2C 1-4 alkyl, -NHSO2C 1-4 alkyl, -N(C 1-4 alkyl)SO2C 1-4 alkyl, -SO2NHC 1-4 alkyl, or -SO2N(C 1-4 alkyl)2. In some embodiments, each R A , R B , R C , or R Deach independently selected from -C(O)-(3-6 membered cycloalkyl), -C(O)-(3-6 membered cycloalkenyl), or -C(O)-(4-6 membered heterocycloalkyl). In some embodiments, each R A , R B , R C , or R D is independently selected from -C(O)-(3-5 membered cycloalkyl), -C(O)-(3-5 membered cycloalkenyl), or -C(O)-(4-5 membered heterocycloalkyl).

[0128] In some embodiments, each R A , R B , R C , or R D is independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, halogenated C 1-3 alkylamino, halogenated diC 1-3 alkylamino, -C(O)C 1-3 alkyl, -OC(O)C 1-3 alkyl, -C(O)OC 1- 3alkyl, -NHC(O)C 1-3 alkyl, -N(C 1-3 alkyl)C(O)C 1-3 alkyl, -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl)2, -SO2C 1-3 alkyl, -NHSO2C 1-3 alkyl, -N(C 1-3 alkyl)SO2C 1-3 alkyl, -SO2NHC 1-3 alkyl, -SO2N(C 1-3 alkyl)2,

[0129] In some embodiments, each R A , R B , R C , or R D is independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 alkyl, C 1-3 alkoxy, C1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylamino, halo diC 1-3 alkylamino, -C(O)C 1-3 alkyl, -OC(O)C 1-3 alkyl, -C(O)OC 1- 3alkyl, -NHC(O)C 1-3 alkyl, -N(C 1-3 alkyl)C(O)C 1-3 alkyl, -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl)2, -SO2C 1-3 alkyl, -NHSO2C 1-3 alkyl, -N(C 1-3 alkyl)SO2C 1-3 alkyl, -SO2NHC 1-3 alkyl, or -SO2N(C 1-3 alkyl)2. In some embodiments, each R A , R B , R C , or R D is each independently selected from

[0130] In some embodiments, each R A , R B , R C , or R D is each independently selected from deuterium, oxo, thioxo, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, di(trifluoromethyl)amino, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -NHC(O)CH3, -N(CH3)C(O)CH3, -C(O)NHCH3, -C(O)N(CH3)2, -SO2CH3, -NHSO2CH3, -N(CH3)SO2CH3, -SO2NHCH3, -SO2N(CH3)2, monofluoroethyl, difluoroethyl, trifluoroethyl, or

[0131] In some embodiments, each R A , R B , R C , or R D is each independently selected from deuterium, oxo, thioxo, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, di(trifluoromethyl)amino, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -NHC(O)CH3, -N(CH3)C(O)CH3, -C(O)NHCH3, -C(O)N(CH3)2, -SO2CH3, -NHSO2CH3, -N(CH3)SO2CH3, -SO2NHCH3, or -SO2N(CH3)2. In some embodiments, each R A , R B , R C , or R D is each independently selected from monofluoroethyl, difluoroethyl, trifluoroethyl, or

[0132] In some embodiments, each R A , R B , R C , or R D is independently selected from deuterium, oxo, -F, -Cl, methyl, methoxy, -C(O)CH3, ethyl,

[0133] In some embodiments, each R A , R B , R C , or R D is independently selected from deuterium, oxo, -F, -Cl, methyl, methoxy, or -C(O)CH3. In some embodiments, each R A , R B , R C , or R D is independently selected from ethyl,

[0134] In some embodiments, each R A or R C is independently selected from deuterium, oxo, -F, -Cl, methyl, or methoxy.

[0135] In some embodiments, each R Bindependently selected from deuterium, oxo, -F, -CI, methyl, methoxy, or -C(0)CH3. In some embodiments, each R

[0136] In some embodiments, each R B is independently selected from deuterium, oxo, -F, -CI, methyl, methoxy, or -C(0)CH3. In some embodiments, each R B is independently selected from deuterium, oxo, -F, -CI, methyl, methoxy, or -C(0)CH3. In some embodiments, each R

[0137] In some embodiments, each R D is independently selected from deuterium, -F, -CI, methyl, or methoxy.

[0138] In some embodiments, ring A is selected from cyclopropyl or cyclobutyl.

[0139] In some embodiments, ring B is selected from the following groups optionally substituted with oxo, -C(0)CH3, methyl, ethyl, substituted with azacyclooctane or diazacyclooctane.

[0140] In some embodiments, ring B is selected from the following groups optionally substituted with oxo, -C(0)CH3, methyl, ethyl, substituted with azacyclooctane or diazacyclooctane.

[0141] In some embodiments, ring C is selected from tetrahydropyrrolyl.

[0142] In some embodiments, structural unit is selected from

[0143] In some embodiments, structural unit is selected from In some embodiments, structural unit is selected from

[0144] In some embodiments, structural unit is selected from

[0145] In some embodiments, structural unit is selected from In some embodiments, structural unit is selected from

[0146] In some embodiments, the structural unit is selected from

[0147] In some embodiments, the structural unit is selected from In some embodiments, the structural unit is selected from

[0148] In some embodiments, ring D is selected from wherein U is O, S, or NH.

[0149] In some embodiments, ring D is selected from

[0150] In some embodiments, ring D is selected from wherein, is connected to Q.

[0151] In some embodiments, Q is selected from -C(O)- or -C(R Q )2-.

[0152] In some embodiments, each R Q is each independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, or halogenated diC 1-4 alkylamino.

[0153] In some embodiments, each R Q is each independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, halogenated C 1-3 alkylamino, or halogenated diC 1-3 alkylamino.

[0154] In some embodiments, each RQ Each is independently selected from H, deuterium, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuterylmethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0155] In some implementations, each R Q Each is independently selected from H, deuterium, halogen, -OH, -NH2, or C. 1-4 alkyl.

[0156] In some implementations, each R Q Each is independently selected from H, deuterium, -F, -Cl, or methyl.

[0157] In some implementations, Q is selected from -C(O)-, -CH2-, -CHF-, or -CF2-.

[0158] In some implementations, Q is selected from -C(O)- or -CF2-.

[0159] In some implementation schemes, Y 1 Selected from OR P1 .

[0160] In some implementation schemes, Y 1 Selected from N(R) P1 )2.

[0161] In some implementation schemes, Y 1 Selected from NHR P1 .

[0162] In some implementation schemes, Y 2 Selected from OR P2 .

[0163] In some implementation schemes, Y 2 Selected from N(R) P2 )2.

[0164] In some implementation schemes, Y 2 Selected from NHR P2 .

[0165] In some implementation schemes, Y 1 Selected from OR P1 Y 2 Selected from OR P2 .

[0166] In some implementation schemes, Y1 Selected from OR P1 Y 2 Selected from NHR P2 .

[0167] In some implementation schemes, R P1 R P2 Each is independently selected from H, deuterium, or arbitrarily selected by one or more R. P3 Replacement C 1-4 Alkyl, or optionally with one or more R P4 The following groups are substituted: 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; or, R P1 R P2 The atoms connected to them together form an optional structure with one or more R P5 Substituted 4-10 membered heterocyclic groups.

[0168] In some implementation schemes, R P1 R P2 Each is independently selected from H, deuterium, or arbitrarily selected by one or more R. P3 Replacement C 1-4 Alkyl group. In some embodiments, R P1 R P2 Each is independently selected from one or more R options. P4 The following groups are substituted: 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; or, R P1 R P2 The atoms connected to them together form an optional structure with one or more R P5 Substituted 4-10 membered heterocyclic groups.

[0169] In some implementation schemes, R P1 R P2 Each is independently selected from H, deuterium, or arbitrarily selected by one or more R. P3 Replacement C 1-4 Alkyl, or optionally with one or more R P4 The following groups may be substituted: 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, naphthyl, or 5-6 membered heteroaryl; or, R P1 R P2 The atoms connected to them together form an optional structure with one or more R P5 Substituted 4-6 membered heterocyclic groups.

[0170] In some implementation schemes, R P1 R P2 Each is independently selected from H, deuterium, or arbitrarily selected by one or more R.P3 Replacement C 1-3 Alkyl, or optionally with one or more R P4 The following groups are substituted: phenyl, naphthyl, or 5-6 membered heteroaryl; or, R P1 R P2 The atoms connected to them together form an optional structure with one or more R P5 Substituted 4-6 membered heterocyclic alkyl groups.

[0171] In some implementation schemes, R P1 R P2 Each is independently selected from H, deuterium, or arbitrarily selected by one or more R. P3 Replacement C 1-3 Alkyl group. In some embodiments, R P1 R P2 Each is independently selected from one or more R options. P4 The following groups are substituted: phenyl, naphthyl, or 5-6 membered heteroaryl; or, R P1 R P2 The atoms connected to them together form an optional structure with one or more R P5 Substituted 4-6 membered heterocyclic alkyl groups.

[0172] In some implementation schemes, R P1 R P2 Each is independently selected from H, deuterium, or arbitrarily selected by one or more R. P3 The following groups are substituted: methyl, ethyl, n-propyl or isopropyl, or optionally replaced by one or more R groups. P4 The following groups are substituted: phenyl or naphthyl; or, R P1 R P2 The atoms connected to them together form an optional structure with one or more R P5 The following groups are substituted:

[0173] In some implementation schemes, R P1 R P2 Each is independently selected from H, deuterium, or arbitrarily selected by one or more R. P3 The following groups are substituted: methyl or ethyl. In some embodiments, R P1 R P2 Each is independently selected from one or more R options. P3 The following groups are substituted: n-propyl or isopropyl, or optionally replaced by one or more R groups. P4 The following groups are substituted: phenyl or naphthyl; or, R P1 R P2 The atoms connected to them together form an optional structure with one or more R P5 The following groups are substituted:

[0174] In some embodiments, R P1 , R P2 each independently is selected from H, deuterium, or is an optionally substituted group: phenyl, naphthyl, or heteroaryl having 1 to 4 heteroatoms selected from O, S, and N; P3 In some embodiments, R P1 , R P2 , together with the atom to which they are attached, form an optionally substituted group: P5 In some embodiments, R

[0175] In some embodiments, R P1 is selected from H, deuterium, or is an optionally substituted group: phenyl or naphthyl, R P4 is selected from H, deuterium, or is an optionally substituted group: methyl, ethyl, n-propyl, or i-propyl; or, R P2 , R P3 , together with the atom to which they are attached, form an optionally substituted group: P1 In some embodiments, R P2 , R P5 , together with the atom to which they are attached, form an optionally substituted group:

[0176] In some embodiments, each R P3 each independently is selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is an optionally substituted group: C P3a alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, -C(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -NHC(O)C 1-6 alkyl, -N(C 1-4 alkyl)C(O)C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -NHC(O)NHC 1-6 alkyl, -SO2C 1-6 alkyl, -NHSO2C 1-6 alkyl, -N(C 1-4 alkyl)SO2C 1-6 alkyl, -SO2NHC 1-6 alkyl, -SO2N(C1-6 alkyl)2, -SC(O)C 1-6 alkyl, -C(O)C 0-4 alkylene (4-6 membered heterocyclyl), -C(O)OC 0-4 alkylene (4-6 membered heterocyclyl), -OC(O)C 0-4 alkylene (4-6 membered heterocyclyl), -OC(O)OC 0-4 alkylene (4-6 membered heterocyclyl), -SC(O)C 0-4 alkylene (4-6 membered heterocyclyl), -C(O)C 0-4 alkylene (3-6 membered cycloalkyl), -C(O)OC 0-4 alkylene (3-6 membered cycloalkyl), -OC(O)C 0-4 alkylene (3-6 membered cycloalkyl), -OC(O)OC 0-4 alkylene (3-6 membered cycloalkyl), -SC(O)C 0-4 alkylene (3-6 membered cycloalkyl), -C(O)C 0-4 alkylene phenyl, -C(O)OC 0-4 alkylene phenyl, -SC(O)C 0-4 alkylene phenyl, -C(O)OC 0-4 alkylene (5-6 membered heteroaryl), or -SC(O)C 0-4 alkylene (5-6 membered heteroaryl).

[0177] In some embodiments, each R P3 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R P3a substituted C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, -C(O)C 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -NHC(O)C 1-6 alkyl, -N(C 1-2 alkyl)C(O)C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -NHC(O)NHC 1-6 alkyl, -SO2C 1-6 alkyl, -NHSO2C 1-6 alkyl, -N(C 1-2 alkyl)SO2C1-6 Alkyl group, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)2、-SC(O)C 1-6 Alkyl, -C(O)C 0-2 Alkylene (4-6 membered heterocyclic alkyl), -C(O)OC 0-2 Alkylene (4-6 membered heterocyclic alkyl), -OC(O)C 0-2 Alkylene (4-6 membered heterocyclic alkyl), -OC(O)OC 0-2 Alkylene (4-6 membered heterocyclic alkyl), -SC(O)C 0-2 Alkylene (4-6 membered heterocyclic alkyl), -C(O)C 0-2 Alkylene (3-6 membered cycloalkyl), -C(O)OC 0-2 Alkylene (3-6 membered cycloalkyl), -OC(O)C 0-2 Alkylene (3-6 membered cycloalkyl), -OC(O)OC 0-2 Alkylene (3-6 membered cycloalkyl), -SC(O)C 0-2 Alkylene (3-6 membered cycloalkyl), -C(O)C 0-2 alkylene phenyl, -C(O)OC 0-2 alkylenephenyl, -SC(O)C 0-2 alkylene phenyl, -C(O)OC 0-2 Alkylene (5-6 membered heteroaryl), or -SC(O)C 0-2 Alkylene (5-6 membered heteroaryl).

[0178] In some implementations, each R P3 Each is independently selected from deuterium, halogens, -OH, -SH, -NH2, -CN, -NO2, or optionally by one or more R P3a The following groups are substituted: C 1-4 Alkyl groups, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SC(O)C 1-6 Alkyl, -OC(O)OC 0-2 Alkylene (4-6 membered heterocyclic alkyl), -C(O)OC 0-2 alkylenephenyl, or -SC(O)C 0-2 Alkylphenylene.

[0179] In some implementations, each R P3 Each is independently selected from deuterium, -F, -Cl, -OH, or optionally influenced by one or more R groups. P3a The following groups are substituted: methoxy, ethoxy,

[0180] In some embodiments, each R P3a each is independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-2 alkoxy, C 1-2 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, haloC 1- 4alkyl, haloC 1-4 alkoxy, haloC 1-2 alkoxy, C 1-2 alkoxy, haloC 1-4 alkylamino, or halo diC 1-4 alkylamino.

[0181] In some embodiments, each R P3a each is independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 alkyl, C 1-3 alkoxy, methoxyC 1-2 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, halomethoxyC 1-2 alkoxy, haloC 1-3 alkylamino, or halo diC 1-3 alkylamino.

[0182] In some embodiments, each R P3a each is independently selected from deuterium, oxo, thioxo, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methoxymethoxy, methoxyethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethoxyethoxy, difluoromethoxyethoxy, trifluoromethoxyethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0183] In some embodiments, each R P3aEach is independently selected from deuterium, -F, -Cl, methoxy, or methoxyethoxy.

[0184] In some implementations, each R P3 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -NO2, -CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino, Halogenated diC 1-4 Alkylamino, -C(O)C 1-4 Alkyl, -OC(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -OC(O)OC 1- 4-alkyl, -NHC(O)C 1-4 Alkyl, -N(C) 1-4 Alkyl)C(O)C 1-4 Alkyl group, -C(O)NHC 1-4 Alkyl, -C(O)N(C) 1-4 alkyl)2、-NHC(O)NHC 1- 4-alkyl, -SO2C 1-4 Alkyl, -NHSO2C 1-4 Alkyl, -N(C) 1-4 Alkyl)SO2C 1-4 Alkyl group, -SO2NHC 1-4 Alkyl, or -SO2N(C 1-4 Alkyl)2.

[0185] In some implementations, each R P3 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -NO2, -CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, deuterated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino, Halogenated diC 1-3 Alkylamino, -C(O)C 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3alkyl, -OC(O)OC 1- 3alkyl, -NHC(O)C 1-3 alkyl, -N(C 1-3 alkyl)C(O)C 1-3 alkyl, -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl)2, -NHC(O)NHC 1- 3alkyl, -SO2C 1-3 alkyl, -NHSO2C 1-3 alkyl, -N(C 1-3 alkyl)SO2C 1-3 alkyl, -SO2NHC 1-3 alkyl, or -SO2N(C 1-3 alkyl)2.

[0186] In some embodiments, R P3 each instance of R is independently selected from deuterium, oxo, thioxo, -F, -Cl, -Br, -OH, -SH, -NH2, -NO2, -CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, di(trifluoromethyl)amino, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -OC(O)OCH3, -NHC(O)CH3, -N(CH3)C(O)CH3, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)NHCH3, -SO2CH3, -NHSO2CH3, -N(CH3)SO2CH3, -SO2NHCH3, -SO2N(CH3)2,

[0187] In some embodiments, R P3Each is independently selected from deuterium, oxo, thio, -F, -Cl, -Br, -OH, -SH, -NH2, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuterylmethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, di(trifluoromethyl) Amino group, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -OC(O)OCH3, -NHC(O)CH3, -N(CH3)C(O)CH3, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)NHCH3, -SO2CH3, -NHSO2CH3, -N(CH3)SO2CH3, -SO2NHCH3, or -SO2N(CH3)2. In some embodiments, each R P3 Each independently selected

[0188] In some implementations, each R P3 Each is independently selected from deuterium, oxo, -F, -Cl, methoxy, -OC(O)CH3, -C(O)OCH3, -OC(O)OCH3, -NHC(O)CH3, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)NHCH3,

[0189] In some implementations, each R P3 Each is independently selected from deuterium, oxo, -F, -Cl, methoxy, -OC(O)CH3, -C(O)OCH3, -OC(O)OCH3, -NHC(O)CH3, -C(O)NHCH3, -C(O)N(CH3)2, or -NHC(O)NHCH3. In some embodiments, each R P3 Each independently selected

[0190] In some implementations, each R P4 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4haloalkyl, haloalkoxy, alkylamino, dialkylamino, or dihaloalkylamino. 1-4 haloalkyl, haloalkoxy, alkylamino, dialkylamino, or dihaloalkylamino. 1-4 alkylamino, dialkylamino, or dihaloalkylamino.

[0191] In some embodiments, each R P4 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino. 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, dialkylamino, or dihaloalkylamino. 1-3 alkylamino, dialkylamino, or dihaloalkylamino. 1-3 alkyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, dialkylamino, or dihaloalkylamino. 1-3 alkylamino, dialkylamino, or dihaloalkylamino.

[0192] In some embodiments, each R P4 is each independently selected from deuterium, oxo, thioxo, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0193] In some embodiments, each R P4 is each independently selected from deuterium, -F, -Cl, or methyl.

[0194] In some embodiments, each R P5 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R P5a alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, dialkylamino, or dihaloalkylamino. 1-4 alkylamino, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0195] In some embodiments, each R P5 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R P5a alkyl, C 1-3 alkyl, C 1-3Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 4-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl.

[0196] In some implementations, each R P5 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, or optionally influenced by one or more R. P5a The following groups are substituted: C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl.

[0197] In some implementations, each R P5 Each is independently selected from deuterium, oxo, thio, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, or optionally influenced by one or more R groups. P5a The following groups may be substituted: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0198] In some implementations, each R P5 Each is independently selected from deuterium, oxo, -F, -Cl, or optionally by one or more R. P5a The following groups can be substituted: methyl, methoxy, or phenyl.

[0199] In some implementations, each R P5a Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino or halogenated diC 1-4 Alkylamino.

[0200] In some embodiments, each R P5a each is independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C1-C6alkyl, 1-3 C1-C6alkyl, C1-C6haloalkyl, 1-3 C1-C6alkoxy, C1-C6haloalkoxy, 1-3 C1-C6alkylamino, di-C1-C6alkylamino, 1-3 C1-C6alkylamino, deuterated C1-C6alkylamino, 1-3 C1-C6alkyl, C1-C6haloalkyl, 1-3 C1-C6alkyl, C1-C6haloalkyl, 1-3 C1-C6alkoxy, C1-C6haloalkoxy, 1-3 C1-C6alkylamino, or di-C1-C6haloalkylamino, 1-3 C1-C6alkylamino.

[0201] In some embodiments, each R P5a each is independently selected from deuterium, oxo, thioxo, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0202] In some embodiments, each R P5a each is independently selected from deuterium, -F, -Cl, or methyl.

[0203] In some embodiments, each R P5 is independently selected from deuterium, -F, -Cl, methyl, trifluoromethyl,

[0204] In some embodiments, R P1 , R P2 each is independently selected from H, deuterium, methyl, ethyl, or R P1 , R P2 together with the atom to which they are attached form

[0205] In some embodiments, R P1 , R P2 each is independently selected from H, deuterium, methyl, or ethyl. In some embodiments, R P1 , R P2 each is independently selected from or R P1 , RP2 Together with the atoms they are connected to form

[0206] In some implementation schemes, structural units Selected from

[0207] In some implementation schemes, structural units Selected from

[0208] In some implementation schemes, structural units Selected from

[0209] In some implementation schemes, R 1 Selected from H, deuterium, or arbitrarily selected by one or more R 1a Replacement C 1-4 alkyl.

[0210] In some implementation schemes, R 1 Selected from H, deuterium, or arbitrarily selected by one or more R 1a Replacement C 1-3 alkyl.

[0211] In some implementation schemes, R 1 Selected from H, deuterium, or arbitrarily selected by one or more R 1a The following groups can be substituted: methyl, ethyl, or n-propyl.

[0212] In some implementation schemes, R 1 Selected from H, deuterium, or arbitrarily selected by one or more R 1a Substituted ethyl group.

[0213] In some implementation schemes, R 1 Selected from H, deuterium, or arbitrarily selected by one or more R 1a The following groups are substituted:

[0214] In some implementations, each R 1a Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -C(O)NH2, -SO2NH2, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, halogenated C 1-4 Alkoxy, halogenated C 1-4alkylamino, halo 1-4 alkylamino, -C(O)C 1-4 alkyl, -OC(O)C 1-4 alkyl, -C(O)OC 1-4 alkyl, -OC(O)OC 1-4 alkyl, -NHC(O)C 1-4 alkyl, -N(C 1-4 alkyl)C(O)C 1-4 alkyl, -C(O)NHC 1-4 alkyl, -C(O)N(C 1-4 alkyl)2, -NHC(O)NHC 1-4 alkyl, -SO2C 1-4 alkyl, -NHSO2C 1-4 alkyl, -N(C 1-4 alkyl)SO2C 1-4 alkyl, -SO2NHC 1-4 alkyl, or -SO2N(C 1-4 alkyl)2.

[0215] In some embodiments, each R 1a is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -C(O)NH2, -SO2NH2, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, haloC 1-3 alkoxy, haloC 1- 3alkylamino, halo diC 1-3 alkylamino, -C(O)C 1-3 alkyl, -OC(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, -OC(O)OC 1-3 alkyl, -NHC(O)C 1-3 alkyl, -N(C 1-3 alkyl)C(O)C 1-3 alkyl, -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl)2, -NHC(O)NHC 1-3 alkyl, -SO2C 1-3 alkyl, -NHSO2C 1-3 alkyl, -N(C 1-3 alkyl)SO2C 1-3 alkyl, -SO2NHC 1-3 alkyl, or -SO2N(C 1-3 alkyl)2.

[0216] In some embodiments, each R 1a is each independently selected from deuterium, oxo, thioxo, -F, -CI, -Br, -OH, -SH, -NH2, -CN, -N02, -COOH, -C(O)NH2, -SO2NH2, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, di(trifluoromethyl)amino, -C(O)CH3, -OC(O)CH3, -C(O)OCH3, -OC(O)OCH3, -NHC(O)CH3, -N(CH3)C(O)CH3, -C(O)NHCH3, -C(O)N(CH3)2, -NHC(O)NHCH3, -SO2CH3, -NHSO2CH3, -N(CH3)SO2CH3, -SO2NHCH3, or -SO2N(CH3)2.

[0217] In some embodiments, each R 1a is each independently selected from deuterium, oxo, -F, -CI, -OH, -NH2, -CN, -COOH, -C(O)NH2, or -SO2NH2.

[0218] In some embodiments, R 1 is selected from

[0219] In some embodiments, LNK 1 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK1 C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 heteroalkylene, C 1-6 heteroalkenylene, or C 2-6 heteroalkynylene.

[0220] In some embodiments, LNK 1 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK1 C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, C 1-4 heteroalkylene, C 1-4 heteroalkenylene, or C 2-4 heteroalkynylene.

[0221] In some embodiments, LNK1 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK1 The following groups are substituted: C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 2-3 Heteroeneyl, or C 2-3 Hetero-ynyl group.

[0222] In some implementation schemes, LNK 1 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK1 The following groups are substituted: -CH2-, -CH2CH2-, -CH=CH-, -CH2CH=CH-, -CH=CHCH2-, -C≡C-, -CH2C≡C-, -C≡CCH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -CH2OCH2CH2-, -CH2CH2OCH2-, -OCH2CH2CH2-, -CH2CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH 2-, -CH2CH2NH-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, -NHCH2CH2CH2-, -CH2CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH= CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2CH≡CH-, -CH≡CHCH2O-, -NHCH2CH≡CH-, or -CH≡CHCH2NH-.

[0223] In some implementation schemes, LNK 1 Selected from single keys, -O-, or optionally by one or more R keys. LNK1 The following groups can be substituted: -CH2O- or -CH2NHCH2CH2-.

[0224] In some implementation schemes, LNK 2 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK2 The following groups are substituted: C 1-8 Alkylene, C 2-8 imidene group, C 2-8 Ethyne group, C 1-8 Heteroalkylene, C 1-8 Heteroeneyl, or C2-8 Hetero-ynyl group.

[0225] In some implementation schemes, LNK 2 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK2 The following groups are substituted: C 2-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 2-6 Heteroalkylene, C 2-6 Heteroeneyl, or C 2-6 Hetero-ynyl group.

[0226] In some implementation schemes, LNK 2 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK2 The following groups are substituted: C 3-5 Alkylene, C 3-5 imidene group, C 3-5 Ethyne group, C 2-5 Heteroalkylene, C 2-5 Heteroeneyl, or C 2-5 Hetero-ynyl group.

[0227] In some implementation schemes, LNK 2 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK2-CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH=CH-, -CH=CHCH2-, -CH2CH=CHCH2-, -CH2CH2CH=CH-, -CH=CHCH2CH2-, -CH2CºC-, -CºCCH2-, -CH2CºCCH2-, -CH2CH2CºC-, -CºCCH2CH2-, -CH2CH2CH2CºC-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -CH2OCH2CH2-, -CH2CH2OCH2-, -OCH2CH2CH2-, -CH2CH2CH2O-, -CH2CH2CH2CH2O-, -CH2NHCH2-, -NHCH2CH2-, -CH2CH2NH-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, -NHCH2CH2CH2-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2CHºC-, -CHºCCH2O-, -NHCH2CHºC-, or -CHºCCH2NH-.

[0228] In some embodiments, LNK is 2 is selected from a single bond, -O-, or is optionally substituted with one or more R LNK2 -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CºC-, or -CH2CH2CH2O-.

[0229] In some embodiments, LNK is 3 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 heteroalkylene, C 1-6 heteroalkenylene, or C 2-6 heteroalkynylene.

[0230] In some embodiments, LNK is 3 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3The following groups are substituted: C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 1-4 Heteroalkylene, C 1-4 Heteroeneyl, or C 2-4 Hetero-ynyl group.

[0231] In some implementation schemes, LNK 3 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK3 The following groups are substituted: C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 2-3 Heteroeneyl, or C 2-3 Hetero-ynyl group.

[0232] In some implementation schemes, LNK 3 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK3 The following groups are substituted: -CH2-, -CH2CH2-, -CH=CH-, -CH2CH=CH-, -CH=CHCH2-, -C≡C-, -CH2C≡C-, -C≡CCH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -CH2OCH2CH2-, -CH2CH2OCH2-, -OCH2CH2CH2-, -CH2CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH 2-, -CH2CH2NH-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, -NHCH2CH2CH2-, -CH2CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH= CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2CH≡CH-, -CH≡CHCH2O-, -NHCH2CH≡CH-, or -CH≡CHCH2NH-.

[0233] In some implementation schemes, LNK 3 Selected from single keys, -O-, or optionally by one or more R keys. LNK3 The following groups can be substituted: -CH2-, -CH2CH2-, -C≡C-, -CH2C≡C-, or -CH2O-.

[0234] In some embodiments, the 4-12 membered heterocyclyl is selected from 4-12 membered, 4-10 membered, or 4-6 membered heterocycloalkenyl. In some embodiments, the 4-12 membered heterocyclyl is selected from 4-12 membered, 4-10 membered, or 4-6 membered heterocycloalkyl.

[0235] In some embodiments, each R LNK1 , R LNK2 , or R LNK3 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R LNKa In some embodiments, each R 1-4 is each independently selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkylC 1-4 alkylene, 3-10 membered cycloalkenylC 1-4 alkylene, 4-10 membered heterocyclylC 1-4 alkylene, 6-10 membered arylC 1-4 alkylene, or 5-10 membered heteroarylC LNK1 alkylene.

[0236] In some embodiments, each R LNK2 , R LNK3 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R LNKa In some embodiments, each R 1-3 is each independently selected from C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkylC 1-3 alkylene, 3-6 membered cycloalkenylC 1-3 alkylene, 4-6 membered heterocyclylC 1-3 alkylene, phenylC 1-3 alkylene, or 5-6 membered heteroarylC LNK1 alkylene.

[0237] In some embodiments, each R LNK2 , R LNK3each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R LNKa substituted C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, or di-C 1-3 alkylamino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-2 alkylene, 4-6 membered heterocycloalkyl C 1-2 alkylene, phenyl C 1-2 alkylene, or 5-6 membered heteroaryl C 1-2 alkylene.

[0238] In some embodiments, each R LNK1 , R LNK2 , or R LNK3 each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R LNKa substituted C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, or di-C 1-3 alkylamino, 3-6 membered cycloalkyl, phenyl, 3-6 membered cycloalkyl C 1-2 alkylene, or phenyl C 1-2 alkylene.

[0239] In some embodiments, ULM is selected from each R LNK1 each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R LNKa substituted C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, or di-C 1-3 alkylamino.

[0240] In some embodiments, ULM is selected from each R LNK1 each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R LNKa substituted C 1-3 alkyl, C 1-3 alkoxy, C 1- alkylamino, or di-C 1-3alkyl, C 1-2 alkylene, or phenyl C 1-2 alkylene.

[0241] each R LNK1 , R LNK2 , or R LNK3 is each independently selected from deuterium, oxo, thioxo, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R LNKa substituents: methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclopropylmethylidene, cyclobutylmethylidene, cyclopentylmethylidene, cyclohexylmethylidene, or benzyl.

[0242] each R LNK1 , R LNK2 , or R LNK3 is each independently selected from deuterium, oxo, -F, -Cl, or is optionally substituted with one or more R LNKa substituents: methyl, i-propyl, cyclohexyl, or benzyl.

[0243] each R LNKa is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, deuterated C 1-4 alkyl, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, halo-C 1-4 alkylamino, or halo-di-C 1-4 alkylamino.

[0244] each R LNKa is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, di-C 1-3 alkylamino, deuterated C 1-3 alkyl, halo-C 1-3 alkyl, halo-C 1-3 alkoxy, halo-C 1-3 alkylamino, or halo-di-C 1-3 alkylamino.

[0245] In some embodiments, each R LNKa is each independently selected from deuterium, oxo, thioxo, -F, -CI, -Br, -OH, -SH, -NH2, -CN, -N02, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0246] In some embodiments, each R LNKa is each independently selected from deuterium, oxo, -F, -CI, or methyl.

[0247] In some embodiments, each R LNK1 is independently selected from deuterium, oxo, -F, -CI, methyl, i-propyl, cyclohexyl,

[0248] In some embodiments, each R LNK2 or R LNK3 is each independently selected from deuterium, oxo, -F, -CI, or methyl.

[0249] In some embodiments, LNK 1 is selected from a single bond, -CH2O-, -C(0)0-, -CH2NHCH2CH2-, -C(0)NHCH2C(0)-,

[0250] In some embodiments, LNK 1 is selected from -CH2O-.

[0251] In some embodiments, LNK 2 is selected from a single bond, -0-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CºC-, or -CH2CH2CH2O-.

[0252] In some embodiments, LNK 2 is selected from -CH2CH2CH2-, -CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2-.

[0253] In some embodiments, LNK 3 is selected from a single bond, -0-, -CH2-, -CH2CH2-, -CºC-, -CH2CºC-, or -CH2O-.

[0254] In some embodiments, LNK 3 is selected from a single bond.

[0255] In some embodiments, 4-12 membered heterocyclyl is selected from 4-12 membered, 4-10 membered, or 4-6 membered heterocycloalkenyl. In some embodiments, the 4-12 membered heterocyclyl is selected from 4-12 membered, 4-10 membered, or 4-6 membered heterocycloalkyl.

[0256] In some embodiments, Cy 1 is selected from a single bond, or is optionally substituted with one or more R Cy1 substituted with 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0257] In some embodiments, Cy 1 is selected from a single bond, or is optionally substituted with one or more R Cy1 substituted with 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0258] In some embodiments, Cy 1 is selected from a single bond, or is optionally substituted with one or more R Cy1 substituted with 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl.

[0259] In some embodiments, Cy 1 is selected from a single bond, or is optionally substituted with one or more R Cy1 substituted with cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0260] In some embodiments, Cy 1 is selected from a single bond, or is optionally substituted with one or more R Cy1 substituted with piperidinyl or phenyl.

[0261] In some embodiments, Cy 1 is selected from a single bond, or is optionally substituted with one or more R Cy1 substituted with:

[0262] In some embodiments, Cy 1 is selected from optionally substituted with one or more R Cy1 substituted with:

[0263] In some implementations, Cy 1 Selected from

[0264] In some implementations, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups may be substituted: 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0265] In some implementations, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups may be substituted: 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 4-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl.

[0266] In some implementations, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups may be substituted: 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl.

[0267] In some implementations, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0268] In some implementations, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups can be substituted: piperidinyl or phenyl.

[0269] In some implementations, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups are substituted:

[0270] In some implementations, each R Cy1 or R Cy2 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, haloC 1-4 alkyl, haloC 1-4 alkoxy, haloC 1-4 alkylamino, or halo diC 1-4 alkylamino.

[0271] In some embodiments, each R Cy1 or R Cy2 each is independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino. 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylamino, or halo diC 1-3 alkylamino.

[0272] In some embodiments, each R Cy1 or R Cy2 each is independently selected from deuterium, oxo, thioxo, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0273] In some embodiments, each R Cy1 or R Cy2 each is independently selected from deuterium, -F, -Cl, or methyl.

[0274] In some embodiments, Cy 1 is selected from a single bond,

[0275] In some embodiments, Cy 2 is selected from a single bond.

[0276] In some embodiments, -L- is selected from -LNK 1 -Cy 1 -LNK 2 -.

[0277] In some embodiments, -L- is selected from f is 1, 2, or 3 (preferably f is 1 or 2).

[0278] In some embodiments, -L- is selected from wherein each of k1, k2 is independently selected from 0, 1, 2, or 3.

[0279] In some embodiments, -L- is selected from when f is 1, 2, or 3, ULM is selected from

[0280] In some embodiments, -L- is selected from when f is 1, 2, or 3, ULM is selected from

[0281] In some embodiments, -L- is selected from wherein each R Cy1 is independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-6 alkyl, or halogenated C 1-6 alkyl (preferably, each R Cy1 is independently selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, or i-propyl), k1 is 0, 1, 2, or 3 (preferably k1 is 1 or 2), f is 1, 2, or 3 (preferably f is 1 or 2), g is 1, 2, 3, 4, 5, or 6 (preferably g is 3, 4, or 5), and h is 0 or 1.

[0282] In some embodiments, -L- is selected from

[0283] In some embodiments, -L- is selected from

[0284] In some embodiments, ULM is selected from

[0285] In some embodiments, -L A - is selected from a single bond, -O-, -S-, -NR A1 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR LA1 -, -NR LA1 C(O)-, -NR LA1 C(O)NR LA1 -, -S(O)-, -S(O)2-, -S(O)2NR LA1 -, -NR LA1 S(O)2-, or is optionally substituted with one or more R LA2substituted with one or more R

[0286] In some embodiments, -L A - is selected from a single bond, -O-, -S-, -NR A1 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR LA1 -, -NR LA1 C(O)-, -NR LA1 C(O)NR LA1 -, -S(O)-, -S(O)2-, -S(O)2NR LA1 -, -NR LA1 S(O)2-, or is optionally substituted with one or more R LA2 substituted with one or more R

[0287] In some embodiments, -L A - is selected from a single bond, -O-, -S-, -NR A1 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR LA1 -, -NR LA1 C(O)-, -NR LA1 C(O)NR LA1 -, -S(O)-, -S(O)2-, -S(O)2NR LA1 -, -NR LA1 S(O)2-, or is optionally substituted with one or more R LA2 substituted with one or more R

[0288] In some embodiments, -L A - is selected from a single bond, -C(O)O-, -OC(O)-, -C(O)NR LA1 -, -NR LA1 C(O)-, -S(O)2NR LA1 -, -NR LA1 S(O)2-, or is optionally substituted with one or more RLA2 substituted pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, or isothiazolyl.

[0289] In some embodiments, -L A - selected from -C(O)NR LA1 - or optionally substituted by one or more R LA2 substituted 1,2,3-triazolyl.

[0290] In some embodiments, each R LA1 is each independently selected from H, deuterium, C 1-4 alkyl, deuterated C 1-4 alkyl, or halogenated C 1-4 alkyl.

[0291] In some embodiments, each R LA1 is each independently selected from H, deuterium, C 1-3 alkyl, deuterated C 1-3 alkyl, or halogenated C 1-3 alkyl.

[0292] In some embodiments, each R LA1 is each independently selected from H, deuterium, or methyl.

[0293] In some embodiments, each R LA2 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, or halogenated diC 1-4 alkylamino.

[0294] In some embodiments, each R LA2 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, halogenated C 1-3alkylamino, or halodicylo 1-3 alkylamino.

[0295] In some embodiments, each R LA2 is each independently selected from deuterium, oxo, thioxo, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0296] In some embodiments, each R LA2 is each independently selected from deuterium, -F, -Cl, or methyl.

[0297] In some embodiments, -L A is selected from a single bond, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH-, -NHS(O)2-, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, or isothiazolyl.

[0298] In some embodiments, -L A is selected from a single bond, -C(O)NH-,

[0299] In some embodiments, -L A is selected from a single bond, -C(O)NH-, In some embodiments, -L A is selected from

[0300] In some embodiments, R 2 is selected from H, deuterium, or is a group C 2a substituted with one or more R 1-6 alkyl, 3-6 membered cycloalkyl, -3-6 membered cycloalkenyl, or 4-6 membered heterocycloalkyl.

[0301] In some embodiments, R 2 is selected from H, deuterium, or is a group C 2a substituted with one or more R 1-4 alkyl or 3-6 membered cycloalkyl.

[0302] In some embodiments, R 2H, deuterium, or is optionally substituted with one or more R 2a substituted C 1-4 alkyl. In some embodiments, R 2 is selected from optionally substituted methyl, ethyl, n-propyl, i-propyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 2a substituted 3-6 membered cycloalkyl.

[0303] In some embodiments, R 2 H, deuterium, or is optionally substituted with one or more R 2a substituted methyl, ethyl, n-propyl, i-propyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0304] In some embodiments, R 2 H, deuterium, or is optionally substituted with one or more R 2a substituted methyl, ethyl, n-propyl, i-propyl, or t-butyl. In some embodiments, R 2 is selected from optionally substituted methyl, ethyl, n-propyl, i-propyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 2a substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0305] In some embodiments, each R 2a is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, or halogenated di-C 1-4 alkylamino.

[0306] In some embodiments, each R 2a is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, di-C 1-3 alkylamino, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, halogenated C 1-3 alkylamino, or halogenated di-C 1-3 alkylamino.

[0307] In some embodiments, each R 2aeach independently selected from deuterium, oxo, thioxo, -F, -CI, -Br, -OH, -SH, -NH2, -CN, -N02, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0308] In some embodiments, each R 2a each independently selected from deuterium, -F, -CI, or methoxy.

[0309] In some embodiments, R 2 is selected from i-propyl, t-butyl, or cyclohexyl.

[0310] In some embodiments, R 2 is selected from i-propyl or t-butyl. In some embodiments, R 2 is selected from cyclohexyl.

[0311] In some embodiments, X 1 , X 2 , or X 3 each independently is selected from a single bond, -O-, -NR XA -, -C(O)-, or -C(R XA )2-.

[0312] In some embodiments, X 1 , X 2 , or X 3 each independently is selected from -C(O)- or -C(R XA )2-.

[0313] In some embodiments, each R XA each independently is selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -N02, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, halogenated diC 1-4 alkylamino, or hydroxyC 1-4 alkyl; or, two R XA together form a 3-5 membered cycloalkyl or 4-5 membered heterocycloalkyl group optionally substituted with one or more R XA1 .

[0314] In some implementations, each R XA Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino or halogenated diC 1-4 Alkylamino; or, two Rs XA Together they form an optional combination of one or more R XA1 The substituted groups are 3-5 membered cycloalkyl or 4-5 membered heterocycloalkyl. In some embodiments, each R XA Each is independently selected from hydroxyl C 1-4 alkyl.

[0315] In some implementations, each R XA Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, deuterated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino, Halogenated diC 1-3 alkylamino or hydroxy C 1-3 Alkyl; or, two Rs XA Together they form an optional combination of one or more R XA1 The following groups are substituted: 3-4 membered cycloalkyl or 4-membered heterocycloalkyl.

[0316] In some implementations, each R XA Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, deuterated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino or halogenated diC 1-3 Alkylamino; or, two RsXA Together they form an optional combination of one or more R XA1 The substituted groups are: 3-4 membered cycloalkyl or 4-membered heterocycloalkyl. In some embodiments, each R XA Each is independently selected from hydroxyl C 1-3 alkyl.

[0317] In some implementations, each R XA Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuterylmethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, di(trifluoromethyl)amino, or hydroxymethyl; or, two R XA Together they form an optional combination of one or more R XA1 The following groups can be substituted: cyclopropyl, cyclobutyl, aziridine, or oxacyclobutyl.

[0318] In some implementations, each R XA Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideutermethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino; or, two R XA Together they form an optional combination of one or more R XA1 The substituted groups include cyclopropyl, cyclobutyl, aziridine, or oxacyclobutyl. In some embodiments, each R... XA Each is independently selected from hydroxymethyl.

[0319] In some implementations, each R XA Each is independently selected from H, deuterium, methyl, trideuterium, monofluoromethyl, difluoromethyl, trifluoromethyl, or hydroxymethyl; or, two Rs XA Together they form an optional combination of one or more R XA1 Substituted cyclopropyl group.

[0320] In some implementations, each R XA Each is independently selected from H, deuterium, methyl, trideuterium, monofluoromethyl, difluoromethyl, or trifluoromethyl; or, two Rs XA Together they form an optional combination of one or more R XA1substituted cyclopropyl. In some embodiments, each R XA each independently selected from hydroxymethyl.

[0321] In some embodiments, each R XA1 each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, or halogenated di-C 1-4 alkylamino.

[0322] In some embodiments, each R XA1 each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, di-C 1-3 alkylamino, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, halogenated C 1-3 alkylamino, or halogenated di-C 1-3 alkylamino.

[0323] In some embodiments, each R XA1 each independently selected from deuterium, oxo, thioxo, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0324] In some embodiments, each R XA1 each independently selected from deuterium, oxo, -F, -Cl, or methyl.

[0325] In some embodiments, R XA each independently selected from H, deuterium, methyl, or hydroxymethyl; or, two R XA together form a cyclopropyl.

[0326] In some embodiments, RXA each independently selected from H, deuterium, or methyl; or, two R XA together form a cyclopropyl group. In some embodiments, R XA each independently selected from hydroxymethyl.

[0327] In some embodiments, X 1 , X 2 , or X 3 each independently selected from -C(O)-, -CH2-, -C(CH3)2-,

[0328] In some embodiments, X 1 , X 2 , or X 3 each independently selected from -C(O)-, -CH2-, -C(CH3)2-, or In some embodiments, X 1 , X 2 , or X 3 each independently selected from

[0329] In some embodiments, X 1 or X 2 is selected from -C(O)-.

[0330] In some embodiments, X 3 is selected from -CH2-,

[0331] In some embodiments, X 3 is selected from -CH2-, In some embodiments, X 3 is selected from

[0332] In some embodiments, the 4-12 membered heterocyclyl is selected from 4-12 membered, 4-10 membered, or 4-8 membered heterocycloalkenyl. In some embodiments, the 4-12 membered heterocyclyl is selected from 4-12 membered, 4-10 membered, or 4-8 membered heterocycloalkyl.

[0333] In some embodiments, ring E is selected from 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0334] In some embodiments, ring E is selected from 5-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 4-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0335] In some embodiments, Ring E is selected from phenyl or 5-6 membered heteroaryl.

[0336] In some embodiments, Ring E is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0337] In some embodiments, Ring E is selected from phenyl.

[0338] In some embodiments, n is selected from 0, 1, 2, or 3.

[0339] In some embodiments, n is selected from 0, 1, or 2.

[0340] In some embodiments, n is selected from 0 or 1.

[0341] In some embodiments, structural unit is selected from

[0342] In some embodiments, each R E is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R E1 groups: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0343] In some embodiments, each R E is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R E1 groups: C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0344] In some embodiments, each R Eeach independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R E1 substituted alkyl, C 1-3 substituted alkyl, C 2-3 substituted alkenyl, C 2-3 substituted alkynyl, C 1-3 substituted alkoxy, C 1-3 substituted alkylamino, di-C 1-3 substituted alkylamino, phenyl, or 5-6 membered heteroaryl.

[0345] In some embodiments, each R E each independently selected from deuterium, oxo, thioxo, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R E1 substituted methyl, ethynyl,

[0346] In some embodiments, R E each independently selected from deuterium, -F, -Cl, or is optionally substituted with one or more R E1 substituted methyl, ethynyl,

[0347] In some embodiments, R E each independently selected from deuterium, -F, -Cl, or is optionally substituted with one or more R E1 substituted methyl, ethynyl, or In some embodiments, R E each independently selected from deuterium, -F, -Cl, or is optionally substituted with one or more R E1 substituted

[0348] In some embodiments, each R E1 each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 substituted alkyl, C 1-4 substituted alkoxy, C 1-4 substituted alkylamino, di-C 1-4 substituted alkylamino, deuterated C 1-4 substituted alkyl, halogenated C 1-4 substituted alkyl, halogenated C 1-4 substituted alkoxy, halogenated C 1-4 substituted alkylamino, or halogenated di-C1-4 alkylamino.

[0349] In some embodiments, each R E1 each is independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino. 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylamino, or halo diC 1-3 alkylamino.

[0350] In some embodiments, each R E1 each is independently selected from deuterium, oxo, thioxo, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0351] In some embodiments, each R E1 each is independently selected from deuterium, -F, -Cl, methyl, or ethyl.

[0352] In some embodiments, each R E1 each is independently selected from deuterium, -F, -Cl, or methyl. In some embodiments, each R E1 each is independently selected from ethyl.

[0353] In some embodiments, each R E each is independently selected from ethynyl,

[0354] In some embodiments, each R E each is independently selected from ethynyl or In some embodiments, each R E each is independently selected from

[0355] In some embodiments, Formula (A) is selected from

[0356] In some embodiments, Formula (A) is selected from In some embodiments, Formula (A) is selected from

[0357] In some embodiments, ULM is selected from

[0358] In some embodiments, Ring F is selected from 9-12 membered heterocyclyl, 6-10 membered aryl, or 9-12 membered heteroaryl.

[0359] In some embodiments, Ring F is selected from benzo 5-6 membered heterocyclenyl, naphthyl, or benzo 5-6 membered heteroaryl.

[0360] In some embodiments, Ring F is selected from dihydrobenzimidazolyl, dihydroindolyl, dihydroisoindolyl, naphthyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzothiophenyl, benzothiazolyl, benzisothiazolyl, benzopyridinyl, or benzopyrimidinyl.

[0361] In some embodiments, Ring F is selected from

[0362] In some embodiments, Ring F is selected from wherein, is attached to .

[0363] In some embodiments, R F is substituted at the 5-6 membered heteroaryl portion of the “benzo 5-6 membered heteroaryl”.

[0364] In some embodiments, R F is substituted at the 5-6 membered heteroaryl portion of the “benzo 5-6 membered heteroaryl”.

[0365] In some embodiments, each R F is independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R F1 is independently selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, or diC 1-4 alkylamino.

[0366] In some embodiments, each R F is independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 alkyl, C 1-3 alkoxy, C1-3 alkylamino, or diC 1-3 alkylamino.

[0367] In some embodiments, each R F is each independently selected from deuterium, oxo, thioxo, -F, -CI, -Br, -OH, -SH, -NH2, -CN, -NO2, or is optionally substituted with one or more R F1 substituted with one or more R

[0368] In some embodiments, each R F1 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, haloC 1-4 alkyl, haloC 1-4 alkoxy, haloC 1-4 alkylamino, or halo diC 1-4 alkylamino.

[0369] In some embodiments, each R F1 is each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylamino, or halo diC 1-3 alkylamino.

[0370] In some embodiments, each R F1 is each independently selected from deuterium, oxo, thioxo, -F, -CI, -Br, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0371] In some embodiments, each RF1 each independently selected from deuterium, -F, -Cl, or methyl.

[0372] In some embodiments, each R F each independently selected from deuterium, oxo, thioxo, -F, -Cl, -Br, -OH, -SH, -NH2, -CN, -NO2, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, or diethylamino, trifluoromethyl, monofluoromethyl, difluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0373] In some embodiments, each R F each independently selected from deuterium, oxo, -F, -Cl, or methyl.

[0374] In some embodiments, m is selected from 0, 1, 2, or 3.

[0375] In some embodiments, m is selected from 0, 1, or 2.

[0376] In some embodiments, m is selected from 1, or 2.

[0377] In some embodiments, ring F is selected from wherein, is connected to .

[0378] In some embodiments, formula (B) is selected from

[0379] In some embodiments, ULM is selected from

[0380] In some embodiments, ULM is selected from In some embodiments, ULM is selected from

[0381] In some embodiments, -L-ULM is selected from

[0382] In some embodiments, -L-ULM is selected from

[0383] In some embodiments, -L-ULM is selected from

[0384] In some embodiments, the heterocyclyl of the present disclosure is selected from heterocycloalkyl. In some embodiments, the heterocyclyl of the present disclosure is selected from heterocycloalkenyl.

[0385] In some embodiments, the 3-12 membered of the present disclosure is selected from 3-10 membered, 3-8 membered, 3-6 membered, 4-7 membered, 4-6 membered, 5-8 membered, 5-7 membered, or 5-6 membered.

[0386] In some embodiments, the C of the present disclosure is selected from C 1-12 selected from C 1-10 , C 1-8 , or C 1-6 . In some embodiments, the C 1-6 selected from C 1- 5, C 1-4 , C 1-3 , or C 1-2 .

[0387] In some embodiments, the C of the present disclosure is selected from C 1-6 alkyl is selected from C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl.

[0388] In some embodiments, the C of the present disclosure is selected from C 1-12 alkylene is selected from C 1-10 alkylene, C 1-8 alkylene, or C 1-6 alkylene. In some embodiments, the C 1-6 alkylene is selected from C 1-5 alkylene, C 1-4 alkylene, C 1-3 alkylene, or C 1-2 alkylene.

[0389] In some embodiments, the C of the present disclosure is selected from C 2-12 alkenylene is selected from C 2-10 alkenylene, C 2-8 alkenylene, or C 2-6 alkenylene. In some embodiments, the C 2-6 alkenylene is selected from C 2-5 alkenylene, C 2-4 alkenylene, or C 2-3 alkenylene.

[0390] In some embodiments, the C 2-12 alkynylene is selected from C 2-10 alkynylene, C 2-8 alkynylene, or C 2-6 alkynylene. In some embodiments, the C 2-6 alkynylene is selected from C 2-5 alkynylene, C 2-4 alkynylene, or C 2-3 alkynylene.

[0391] In some embodiments, the C 1-12 heteroalkylene is selected from C 1-10 heteroalkylene, C 1-8 heteroalkylene, C 1-6 heteroalkylene, or C 1-2 heteroalkylene. In some embodiments, the C 1-6 heteroalkylene is selected from C 1-5 heteroalkylene, C 1-4 heteroalkylene, C 1-3 heteroalkylene, or C 1-2 heteroalkylene.

[0392] In some embodiments, the C 1-12 heteroalkenylene is selected from C 1-10 heteroalkenylene, C 1-8 heteroalkenylene, or C 1-6 heteroalkenylene. In some embodiments, the C 1-6 heteroalkenylene is selected from C 1-5 heteroalkenylene, C 1-4 heteroalkenylene, C 1-3 heteroalkenylene, C 2-5 heteroalkenylene, C 2-4 heteroalkenylene, or C 2-3 heteroalkenylene.

[0393] In some embodiments, the C 2-12 heteroalkynylene is selected from C 2-10 heteroalkynylene, C 2-8 heteroalkynylene, or C 2-6 heteroalkynylene. In some embodiments, the C 2-6 heteroalkynylene is selected from C 2-5 heteroalkynylene, C 2-4 heteroalkynylene, or C 2-3 heteroalkynylene.

[0394] In some embodiments, the halogen of the present disclosure is selected from F, Cl, Br, or I.

[0395] In some embodiments, the halo of the present disclosure is selected from fluoro, chloro, or bromo. In some embodiments, the halo of the present disclosure is selected from fluoro or chloro. In some embodiments, the halo of the present disclosure is fluoro.

[0396] In some embodiments, "one or more" of the present disclosure can refer to an integer from one to less than 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.

[0397] In some embodiments, the heterocycloalkenyl or heterocycloalkyl of the present disclosure, wherein the heteroatom is selected from N, NH, O, or S. In some embodiments, the heterocycloalkenyl or heterocycloalkyl of the present disclosure, wherein the heteroatom is selected from N, O, or S. In some embodiments, the heteroaryl of the present disclosure, wherein the heteroatom is selected from N, O, S. In some embodiments, the heteroalkylene of the present disclosure, wherein the heteroatom is selected from N, NH, O, S, S(O), or S(O)2. In some embodiments, the heteroalkenylene of the present disclosure, wherein the heteroatom is selected from N, NH, O, S, S(O), or S(O)2. In some embodiments, the heteroalkynylene of the present disclosure, wherein the heteroatom is selected from N, NH, O, S, S(O), or S(O)2.

[0398] In some embodiments, the heterocycloalkenyl, heterocycloalkyl, heteroalkylene, or heteroaryl of the present disclosure, wherein the number of heteroatoms is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the heterocycloalkenyl, heterocycloalkyl, heteroalkylene, or heteroaryl of the present disclosure, wherein the number of heteroatoms is selected from 1, 2, 3, or 4. In some embodiments, the heterocycloalkenyl, heterocycloalkyl, heteroalkylene, or heteroaryl of the present disclosure, wherein the number of heteroatoms is selected from 1, 2, or 3.

[0399] In some embodiments, the heterocyclyl, heterocycloalkyl, or heteroaryl of the present disclosure contains 1 or 2 heteroatoms selected from N, O, S, P, or Si.

[0400] In some embodiments, the heterocyclyl, heterocycloalkyl, or heteroaryl of the present disclosure contains 1 or 2 heteroatoms selected from N, O, S, or P.

[0401] In some embodiments, the heterocyclyl, heterocycloalkyl, or heteroaryl of the present disclosure contains 1 or 2 heteroatoms selected from N, O, or S.

[0402] In some embodiments, the heterocyclyl, heterocycloalkyl, or heteroaryl of the present disclosure contains 1, 2, or 3 N atoms.

[0403] In some embodiments, the heterocyclyl, heterocycloalkyl, or heteroaryl of the present disclosure contains 1 O atom.

[0404] In some embodiments, the heterocyclyl, heterocycloalkyl, or heteroaryl of the present disclosure contains 1 N atom and 1 O atom.

[0405] In some embodiments, the heterocyclyl, heterocycloalkyl, or heteroaryl of the present disclosure contains 1 N atom and 1 S atom.

[0406] In some embodiments, the heterocyclyl, heterocycloalkyl of the present disclosure contains 1 N atom, 1 O atom, and 1 P atom.

[0407] In some embodiments, the heterocyclyl, heterocycloalkyl of the present disclosure contains 2 O atoms and 1 P atom.

[0408] In some embodiments, the heterocyclyl, heterocycloalkyl of the present disclosure contains 2 N atoms and 1 P atom.

[0409] In some embodiments, the heterocyclyl or heterocycloalkyl of the present disclosure comprises a monocyclic, spirocyclic, fused, or bridged ring. In some embodiments, the heterocycloalkyl of the present disclosure comprises a monocyclic or spirocyclic ring. In some embodiments, the heterocyclyl or heterocycloalkyl of the present disclosure comprises a monocyclic or bridged ring.

[0410] The present disclosure relates to a compound of Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0411] wherein,

[0412] Ring A, R B , R C , Ring D, Q, R P1 , R P2 , R 1 , -L-, and ULM are as defined by the present disclosure;

[0413] Z is selected from NH or CH2;

[0414] b1or b2are each independently selected from 0, 1, 2, or 3, and b1+ b2≤ 3;

[0415] c1is selected from 0, 1, 2, or 3;

[0416] p is selected from 0, 1, 2, 3, or 4;

[0417] q is selected from 0, 1, or 2.

[0418] In some embodiments, Z is selected from NH.

[0419] In some embodiments, each of b1or b2is independently selected from 0, 1, or 2, and b1+b2≤ 3.

[0420] In some embodiments, each of b1or b2is independently selected from 0 or 1.

[0421] In some embodiments, each of b1or b2is independently selected from 0 or 1.

[0422] In some embodiments, each of b1or b2is independently selected from 0 or 1.

[0423] In some embodiments, each of b1or b2is independently selected from 0 or 1.

[0424] In some embodiments, each of b1or b2is independently selected from 0 or 1.

[0425] In some embodiments, each of b1or b2is independently selected from 0 or 1.

[0426] In some embodiments, each of b1or b2is independently selected from 0 or 1.

[0427] The present disclosure relates to a compound of Formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0428] wherein,

[0429] Ring A, R B , R C , Ring D, Q, Y 1 , Y 2 , R 1 , -L-, ULM, Z, b1, b2, c1, p, and q are as defined in the present disclosure.

[0430] The present disclosure relates to a compound of Formula (II-1), Formula (II-1'), Formula (II-2), Formula (II-2'), Formula (III-1), Formula (III-1'), Formula (III-2), Formula (III-2'), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0431] wherein, Ring A, R B , R C , p, q, Ring D, Q, R P1 , R P2 , Y 1 , Y 2 , R 1 , -L-, and ULM are as defined in the present disclosure.

[0432] The present disclosure relates to a compound of Formula (IV), Formula (IV-1), or Formula (IV-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0433] wherein R B , p, ring D, Q, Y 1 , Y 2 , R 1 , -L-, and ULM are as defined in the disclosure, U is O, S, or NH.

[0434] In some embodiments, the disclosure relates to a compound of Formula (V), Formula (V-1), Formula (V-2), or Formula (V-3), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0435] wherein ring A, R B , p, ring D, Q, Y 1 , Y 2 , -L-, -L A -, R 2 , X 1 , X 2 , X 3 , ring E, R E , n, R Cy1 , and R E1 are as defined in the disclosure, k1 is 0, 1, 2, or 3 (preferably k1 is 1 or 2), f is 1, 2, or 3 (preferably f is 1 or 2, for example f is 1), g is 1, 2, 3, 4, 5, or 6 (preferably g is 3, 4, or 5), h is 0 or 1, ring G is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N or O or S (preferably a 5 membered heteroaryl containing 1-2 heteroatoms selected from N or O or S), and n1 is selected from 0, 1, or 2 (preferably n1 is selected from 0 or 1).

[0436] In some embodiments, the disclosure relates to a compound of Formula (VI), Formula (VI-1), or Formula (VI-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0437] wherein R B , p, ring D, Q, R P1 , R P2 , -L-, -L A -, R 2 , X 1 , X 2 , X 3 , ring E, R E , n, R Cy1 , and R E1As defined by the present disclosure, U is O, S, or NH, k1 is 0, 1, 2, or 3 (preferably k1 is 1 or 2), f is 1, 2, or 3 (preferably f is 1 or 2, for example f is 1), g is 1, 2, 3, 4, 5, or 6 (preferably g is 3, 4, or 5), h is 0 or 1, ring G is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N or O or S (preferably a 5 membered heteroaryl containing 1-2 heteroatoms selected from N or O or S), and n1 is selected from 0, 1, or 2 (preferably n1 is selected from 0 or 1).

[0438] In some embodiments, in each of the compounds described herein, stereoisomer thereof, or pharmaceutically acceptable salt thereof, R B is selected from deuterium, -C(O)CH3, 1-6 alkyl, C 1-6 haloalkyl, -C(O)-(3-5 membered cycloalkyl) (preferably R 1-6 alkyl, -C(O)-(3-5 membered cycloalkyl) (preferably R B is selected from deuterium, -F, -Cl, -Br, methyl, methoxy, -C(O)CH3, );

[0439] p is 0 or 1;

[0440] U is O, S, or NH (preferably U is S or NH);

[0441] Q is selected from -C(O)- or -C(R Q )2-; Q each R 1-4 is independently selected from H, deuterium, halogen, -OH, -NH2, C Q alkyl (preferably, each R P1 is independently fluorine, chlorine, bromine, or iodine);

[0442] R P2 is independently selected from H, deuterium, or C 1-3 alkyl (preferably R P1 , R P2 is independently H or deuterium);

[0443] -L- is selected from wherein each R Cy1 is independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-6 alkyl, or haloC 1-6 alkyl (preferably, each R Cy1 is independently selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, or i-propyl), k1 is 0, 1, 2, or 3 (preferably k1 is 1 or 2), f is 1, 2, or 3 (preferably f is 1 or 2), g is 1, 2, 3, 4, 5, or 6 (preferably g is 3, 4, or 5), and h is 0 or 1;

[0444] -L A - selected from -C(O)NR LA1 -, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, or isothiazolyl, wherein R LA1 each is independently selected from H, deuterium, C 1-4 alkyl, deuterated C 1-4 alkyl, or halogenated C 1-4 alkyl (preferably, -L A - selected from -C(O)NH-, );

[0445] R 2 is selected from C 1-6 alkyl or 3-6 membered cycloalkyl (preferably R 2 is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl);

[0446] X 1 is selected from -C(O)- or -C(R XA )2-, each R XA is independently selected from -OH, or -SH, preferably X 1 is -C(O)-;

[0447] X 2 is selected from -C(O)- or -C(R XA )2-, each R XA is independently selected from -OH, or -SH, preferably X 2 is -C(O)-;

[0448] X 3 is selected from -C(R XA )2-, each R XA is independently selected from H, deuterium, C 1-4 alkyl, C 1-4 alkylamino, or hydroxy C 1-4 alkyl, or, two R XA together form a 3-5 membered cycloalkyl or 4-5 membered heterocycloalkyl; preferably X 3 is selected from -CH2-,

[0449] Ring G is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N or O or S (preferably a 5 membered heteroaryl containing 1-2 heteroatoms selected from N or O or S);

[0450] R E1 is selected from deuterium, halogen, -OH, -NH2, C1-6 alkyl, or haloC 1-6 alkyl; preferably R E1 selected from fluorine, chlorine, bromine, C 1-6 alkyl (e.g. C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl), or haloC 1-6 alkyl (e.g. haloC 1-5 alkyl, haloC 1-4 alkyl, haloC 1-3 alkyl), n1 is selected from 0, 1, or 2 (preferably n1 is selected from 0 or 1).

[0451] R is absent, as described herein, when p is 0. B absent, structural unit represents

[0452] R is absent, as described herein, when p is 0. B absent, structural unit represents

[0453] The compounds of formula (I) or (I’) of the present disclosure include stereoisomers thereof.

[0454] In some embodiments, the present disclosure includes the above-defined variables and embodiments thereof, and any combination thereof.

[0455] The present disclosure also relates to the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0456] The present disclosure also relates to the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0457] On the other hand, this disclosure relates to pharmaceutical compositions comprising compounds of this disclosure (including their stereoisomers) or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions of this disclosure further include pharmaceutically acceptable excipients.

[0458] On the other hand, this disclosure relates to methods of treating mammalian diseases, including administering to a mammal, preferably a human, a therapeutically effective amount of a compound of this disclosure (including its stereoisomers) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

[0459] On the other hand, this disclosure relates to the use of the compounds of this disclosure (including their stereoisomers) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of this disclosure, in the preparation of medicaments for treating diseases.

[0460] On the other hand, this disclosure relates to the use of the compounds of this disclosure (including their stereoisomers) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of this disclosure, in the treatment of diseases.

[0461] On the other hand, this disclosure relates to compounds of this disclosure (including stereoisomers thereof) or pharmaceutically acceptable salts thereof for the treatment of diseases, or pharmaceutical compositions of this disclosure.

[0462] In some embodiments of this disclosure, the disease is selected from STAT3-related diseases.

[0463] In some embodiments of this disclosure, the STAT3-related diseases are selected from cancer.

[0464] In some embodiments of this disclosure, the cancer is selected from hematologic malignancies and solid tumors. In some embodiments of this disclosure, the hematologic malignancy is a lymphoma (e.g., anaplastic large cell lymphoma).

[0465] In some embodiments of this disclosure, the lymphoma is selected from peripheral T-cell lymphomas (e.g., anaplastic large cell lymphoma).

[0466] On the other hand, this disclosure relates to the use of the compounds of this disclosure (including their stereoisomers) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of this disclosure, in the preparation of STAT3 protein degrading agents. Alternatively, this disclosure relates to the use of the compounds of this disclosure (including their stereoisomers) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of this disclosure, as STAT3 protein degrading agents. Alternatively, this disclosure relates to a method for degrading STAT3 proteins in mammals, comprising administering a therapeutically effective amount of the compounds of this disclosure (including their stereoisomers) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of this disclosure, to a mammal, preferably a human, requiring such treatment.

[0467] Technical effect

[0468] The compounds of the present disclosure can have high STAT3 protein degradation ability and cell proliferation inhibition activity (e.g., SU-DHL-1 cells), can have good in vitro liver microsomal stability, and can exhibit good drugability in in vitro and in vivo pharmacokinetic, bioavailability, and / or pharmacodynamic studies.

[0469] Definitions

[0470] Unless otherwise indicated, the following terms used in the present disclosure have the following meanings. A particular term should not be construed as indefinite or unclear in the absence of a specific definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0471] The term "substituted" means that any one or more hydrogen atoms on a particular atom is / are replaced with a substituent, as long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

[0472] "substituents" described herein include all substituents mentioned herein in context, for example including those defined by the terms "alkyl", "alkylene", "heteroalkyl", "alkoxy", "alkylamino", "dialkylamino", "alkylthio", "alkenyl", "alkynyl", "cycloalkyl", "cycloalkenyl", "heterocyclyl", "heterocycloalkyl", "aryl", "heteroaryl", and the like related groups, and corresponding non-limiting or exemplary groups, some non-limiting examples of which include deuterium atom, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido group, sulfoxide group, sulfone group, sulfonamide group, carboxyl, carboxaldehyde group, imine group, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, aralkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroaralkoxy, heteroaralkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, ureido, epoxy group, and ester group, and the like, optionally substituted with one or more substituents selected from 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)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.

[0473] In some embodiments herein, the substituents are selected from deuterium atom, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido group, sulfoxide group, sulfone group, sulfonamide group, carboxyl, aldehyde group, imine group, C 1-12 alkyl, halo-C 1-12 alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3-12 membered cycloalkenyl, halo-3-12 membered cycloalkenyl, C 2-12 alkynyl, halo-C 2-12alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C 1-12 heteroalkyl, halo-C 1-12 heteroalkyl, C 1-12 alkoxy, C 1-12 alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered aryl C 1-12 alkylene, 6-10 membered aryl C 1- 12 alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered heterocyclyl C 1-12 alkoxy, 3-12 membered heterocyclyl C 1-12 alkylthio, C 1-12 acyl, C 1-12 acyloxy, carbamate, C 1-12 amide, ureido, epoxy, C 2-12 ester, oxo, and thioxo, said substituent optionally substituted with one or more substituents selected from: deuterium atom, oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, halo-C 1-12 alkoxy, C 1-12 alkylamino, di-C 1-12 alkylamino, halo-C 1- 12 alkylamino, halo-di-C 1-12 alkylamino, carboxyl, -C(O)O-C 1-12 alkyl, -OC(O)-C 1-12 alkyl, -C(O)NH2, -C(O)NH-C 1-12 alkyl, -C(O)N(C 1-12 alkyl)2, -NHC(O)-C 1-12 alkyl, -C(O)-C 1-12 alkyl, -S(O)-C 1-12 alkyl, -S(O)2-C 1-12 alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 alkyl, -S(O)2N(C 1-12alkyl)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 alkylene, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 alkylene, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 alkylene, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 alkylene, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C

[0474] The term "substituted" or "substitution" means that a particular atom or group of atoms can be replaced or replaced by a specified other atom or group of atoms. For example, 1 or 2 or 3 -CH2- in -CH2CH2CH2- can be replaced by O, S, NH to give -O-CH2-CH2-, -O-CH2-, -CH2-O-CH2-, -CH2-O-, -CH2-CH2-O-, -O-, etc.

[0475] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that the ethyl group can 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 is introduced that is not physically or synthetically possible.

[0476] C in this document m-n is that the moiety has an integer number of carbon atoms in the 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.

[0477] When any variable (e.g., R) occurs more than one time in a compound; each definition is independent. Thus, for example, if a group is substituted with 2 occurrences of R, then each R is selected independently of the other.

[0478] When the number of occurrences of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0479] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected, such as L represents a covalent bond in A-L-Z means that the structure is actually A-Z.

[0480] When the recited linking group is not indicated as to its direction of attachment, its direction of attachment is arbitrary, such as in A-L-Z, where the linking group L is -M-W-, this structure can be either A-M-W-Z or A-W-M-Z.

[0481] When a bond to a substituent intersects with a bond to a ring atom, the substituent can be bonded to either ring atom. For example, the structural unit represents that it can be substituted at any one of the positions on the cyclohexyl or cyclohexadiene ring.

[0482] The term "halo" or "halogen" means fluoro, chloro, bromo, and iodo.

[0483] The term "hydroxy" means an -OH group.

[0484] The term "cyano" means a -CN group.

[0485] The term "mercapto" means an -SH group.

[0486] The term "amino" means an -NH2 group.

[0487] The term "nitro" means an -NO2 group.

[0488] The term "alkylene" means a saturated straight or branched chain divalent hydrocarbon radical of the general formula C n H 2n having typically 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" means an alkylene group having 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.

[0489] The term "alkyl" means a saturated hydrocarbon radical of the general formula C n H 2n+1 having typically 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, typically having 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"Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like).

[0490] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and the hydrogen atoms attached thereto) are each independently replaced with the same or different heteroatom group. Unless otherwise indicated, the heteroalkyl groups contain 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, S(O), S(O)2, P, P(O), B, N, or NH, and typically have 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 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position in the heteroalkyl group (e.g., internal or terminal positions), including the position that connects the heteroalkyl group to the rest of the molecule. Typically, where more than one heteroatom group is present, the heteroatom groups are not adjacent to one another. Exemplary heteroalkyl groups include, but are not limited to, alkoxy, alkoxyalkylene, alkylamino, alkylaminoalkylene, dialkylamino, dialkylaminoalkylene, and the like.

[0491] The term "heteroalkylene" refers to an alkylene group in which one or more carbon atoms (and the hydrogen atoms attached thereto) are each independently replaced with the same or different heteroatom group. Unless otherwise indicated, the heteroalkylene groups contain 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, S(O), S(O)2, P, P(O), B, N, or NH, and typically have 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 in the heteroalkylene group (e.g., internal or terminal positions), including the position that connects the heteroalkyl group to the rest of the molecule. Typically, where more than one heteroatom group is present, the heteroatom groups are not adjacent to one another.

[0492] 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.

[0493] 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.

[0494] 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.

[0495] The term "alkylthio" refers to -S-alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.

[0496] The term "alkenyl" refers to a straight or branched chain, unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon and hydrogen atoms, 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.

[0497] The term "alkenylene" refers to the 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 include, but are not limited to, ethenylene, 1- propenylene, 2-propenylene, 1-butenylene, isobutenylene, 1,3-butadienylene, and the like.

[0498] The term "heteroalkenyl" refers to an alkenyl group in which one or more of the carbon atoms (and their incident hydrogen atoms) are each independently replaced with the same or different heteroatom group. Unless otherwise indicated, the heteroalkenyl group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, S(O), S(O)2, P, P(O), B, N, or NH, typically having 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 to 3 heteroatom groups. The heteroatom groups can be placed in any position of the heteroalkenyl group (e.g., internal or terminal positions), including the position that connects the heteroalkenyl group to the rest of the molecule. Typically, where more than one heteroatom group is present, the heteroatom groups are not adjacent to one another. 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.

[0499] The term "heteroalkenylene" refers to the divalent version of a heteroalkenyl group. Unless otherwise indicated, the heteroalkenylene group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, S(O), S(0)2, P, P(O), B, N, or NH, typically having 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 1-6 heteroalkenylene" refers to a heteroalkenylene group containing 1 to 6 carbon atoms and 1 to 3 heteroatom groups. The heteroatom groups can be positioned at any position of the heteroalkenylene group (e.g., internal or terminal positions), including the position(s) at which the heteroalkenylene group is attached to the remainder of the molecule. Typically, where more than one heteroatom group is present, the heteroatom groups are not adjacent to one another. 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(s) in the heteroalkenylene group is a carbon-carbon double bond.

[0500] The term "alkynyl" refers to a straight-chain or branched-chain, unsaturated aliphatic hydrocarbon group 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 groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡C-C≡CH), and the like.

[0501] The term "alkynylene" refers to the divalent version of an alkynyl group. The alkynylene 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 alkynylene groups include, but are not limited to, ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene, isobutynylene, and the like.

[0502] The term "heteroalkynyl" refers to an alkynyl group in which one or more of the carbon atoms (and their incident hydrogens) are each independently replaced with the same or different heteroatom group. Unless otherwise indicated, the heteroalkynyl group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, S(O), S(O)2, P, P(O), B, N, or NH, and typically has 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. For example, the term "C 2-6 heteroalkynyl" refers to a heteroalkynyl group containing 2 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed in any position of the heteroalkynyl group (e.g., internal or terminal positions), including the position that connects the heteroalkynyl group to the rest of the molecule. Typically, where more than one heteroatom group is present, the heteroatom groups are not adjacent to one another. Exemplary heteroalkynyl groups include, but are not limited to, alkynyl-O-, alkynyl-NH-, alkynyl-S-, alkynyl-O-alkylene-, alkyl-O-alkynylene-, alkynyl-NH-alkylene-, alkyl-NH-alkynylene-, alkynyl-S-alkylene-, or alkyl-S-alkynylene-. In some embodiments, the triple bond in the heteroalkynyl group is a carbon-carbon triple bond.

[0503] The term "heteroalkynyl" refers to an alkynyl group in which one or more of the carbon atoms (and their incident hydrogens) are each independently replaced with the same or different heteroatom group. Unless otherwise indicated, the heteroalkynyl group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, S(O), S(O)2, P, P(O), B, N, or NH, and typically has 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. For example, the term "C 2-6 heteroalkynyl" refers to a heteroalkynyl group containing 2 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed in any position of the heteroalkynyl group (e.g., internal or terminal positions), including the position that connects the heteroalkynyl group to the rest of the molecule. Typically, where more than one heteroatom group is present, the heteroatom groups are not adjacent to one another. Exemplary heteroalkynyl groups include, but are not limited to, alkynyl-O-, alkynyl-NH-, alkynyl-S-, alkynyl-O-alkylene-, alkyl-O-alkynylene-, alkynyl-NH-alkylene-, alkyl-NH-alkynylene-, alkynyl-S-alkylene-, or alkyl-S-alkynylene-. In some embodiments, the triple bond in the heteroalkynyl group is a carbon-carbon triple bond.

[0504] The term "cycloalkyl" refers to a carbon ring that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon 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 groups include, but are not limited to, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

[0505] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and has at least one double bond and 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 cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

[0506] The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not a fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 4- to 12-membered, 4- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 4- to 7-membered, or 4- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms). A sulfur or phosphorus atom in the heterocyclyl group is optionally oxidized. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like.

[0507] The term "heterocycloalkenyl" refers to a non-aromatic ring that is partially unsaturated (but not a fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 4- to 12-membered, 4- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 4- to 7-membered, or 4- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms). A sulfur or phosphorus atom in the heterocycloalkenyl group is optionally oxidized. Non-limiting examples of heterocycloalkenyl groups include, but are not limited to, dihydrofuranyl, dihydrothienyl, dihydropyrrolyl, dihydrooxazolyl, dihydrothiazolyl, dihydrooxazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydronitrogen hetero azepinyl, azepinyl,

[0508] 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 typically has 3 to 12 members, 3 to 10 members, 4 to 8 members, 5 to 8 members, 5 to 6 members, 3 to 7 members, or 4 to 6 members, ring atoms, of which 1 to 3 are independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron, preferably 1 or 2 heteroatoms. The sulfur or phosphorus atom in the heterocycloalkyl group is optionally oxidized. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thiiranyl, aziridinyl, non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxinanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl.

[0509] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic ring system that is aromatic. For example, aryl groups 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, anthracenyl, and the like.

[0510] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, typically having 5 to 14 members, 5 to 12 members, 5 to 10 members, 5 to 8 members, 5 to 7 members, or 5 to 6 members. Preferred heteroaryls have a single 4 to 8 member ring, especially 5 to 6 member rings, or multiple fused rings comprising 5 to 14, especially 5 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiophenyl, indolyl, isoindolyl, and the like.

[0511] Unless otherwise specified, the term "deuterated C 1-6 alkyl" refers to any number and position of H atoms in the above "C 1-6 alkyl" groups replaced by deuterium atoms. The C 1-6 deuterated alkyl group can be a C 1-5 , C 1-4 , C 1-3 , or C 1-2 deuterated alkyl group. Examples of deuterated alkyl groups include, but are not limited to, -CH2D, -CHD2, -CD3, etc.

[0512] It will be appreciated that the groups -L-, LNK 1 , LNK 2 , LNK 3 , -L A - are read in the order from left to right, corresponding to the left and right groups to which the group is attached in the general formula. For example, when -L- is , the structure is

[0513] The term "treatment" means the administration of a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0514] (i) inhibiting the disease or condition, i.e., arresting its development;

[0515] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0516] The term "prevention" means the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition, but has not yet been diagnosed as having it.

[0517] The term "therapeutically effective amount" means the amount of a compound of the present disclosure that will elicit the pharmacological and / or physiological effects for which it is administered, i.e., (i) treat or prevent a particular disease, condition, or disorder, (ii) alleviate, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that will constitute a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner as an initial consideration.

[0518] 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 humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0519] 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.

[0520] The term "pharmaceutical composition" means a mixture of one or more compounds of the present disclosure or salts thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism. Pharmaceutical compositions of the present disclosure can be prepared as pharmaceutical compositions with a single dose of 0.001 mg - 2000 mg.

[0521] The term "pharmaceutically acceptable excipient" means an excipient that is not biologically or otherwise undesirable, i.e., the excipient can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The presence of an excipient in a pharmaceutical composition is termed herein a "pharmaceutically acceptable amount" of the excipient.

[0522] The words "comprise" or "comprising" and variations such as "comprises" or "comprising", when used in this document, will be understood to imply the inclusion of a stated step or integer or group of steps or integers but not to the exclusion of any other step or integer or group of steps or integers.

[0523] The compounds and intermediates of the present disclosure can also exist in different tautomeric forms and all such forms are embraced within the scope of the present disclosure. The term "tautomer" or "tautomeric forms" refers to different energy structures that are interconvertible via a low energy barrier. For example, prototropic tautomers (also known as proton transfer tautomers) include interconversions via the migration of a proton, such as keto-enol and imine-enamine isomerization. A specific example of prototropic tautomers is the imidazole moiety, wherein a proton can migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0524] The present disclosure also includes isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, 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 36Cl, and the like. For example, it is understood that compounds of the disclosure wherein one or more hydrogen atoms are replaced by deuterium atoms, are within the scope of the compounds of the disclosure.

[0525] Certain isotopically-labeled compounds of the disclosure (for example, those 3 H and 14 C-labeled) are useful in compound and / or substrate tissue distribution analysis. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F are useful in positron emission tomography (PET) studies for measurement of substrate occupancy. Isotopically-labeled compounds of the disclosure can generally be prepared by

[0526] Furthermore, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and hence can be preferred in some circumstances. Deuterium substitution can be in the part or parts of the compounds that

[0527] The compounds of the disclosure can be asymmetric, for example, having one or more stereocenters. Unless otherwise indicated, all stereoisomers, including enantiomers and diastereomers, are included within the scope of the disclosure. Compounds of the disclosure containing an asymmetric carbon atom can be isolated in optically active or racemic forms. An optically active form can be obtained, for example, by resolution of a racemic mixture or by synthesis from an optically active starting material or reagent.

[0528] In the present application, a wavy line indicates one of the absolute configurations (e.g. ) of a stereocenter, specifically, indicates ) or one of the relative configurations (e.g. indicates When the compounds described herein contain olefinic double bonds, other centers of geometric asymmetry, unless otherwise indicated, they include E, Z geometric isomers. Likewise, all tautomeric forms of the compounds are included within the scope of the disclosure.

[0529] The compounds of the present disclosure can have one or more atropisomers, which refer to optically active isomers that result from the restriction of free rotation about single bonds, unless otherwise indicated. Compounds of the present disclosure containing a chiral axis can be isolated in racemic form. When the energy barrier to free rotation of the single bonds of the compounds of the present disclosure containing a chiral axis is sufficiently high, their atropisomers can be isolated in optically active form.

[0530] The pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with suitable pharmaceutically acceptable excipients.

[0531] The pharmaceutical compositions of the present disclosure can be manufactured by methods well known in the art, such as the conventional methods of blending, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying or the like.

[0532] In all of the methods of administration of the compounds described herein, the dosage administered daily is from 0.001 to 2000 mg / kg body weight, and the compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the embodiments with other chemical synthetic methods, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

[0533] The chemical reactions of the specific embodiments of the present disclosure are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical changes being effected. In the synthetic schemes and examples that follow, all substituents unless otherwise indicated, are as previously defined. Modifications can be made to the reaction conditions and the reaction orders described in the specific embodiments of the present disclosure, as is understood to those skilled in the art. For example, the reaction order can be reversed, or two consecutive reactions can be carried out simultaneously. Also, the protecting group index helps the skilled artisan to follow the synthetic routes described herein.

[0534] The compounds of formula (I) of the present disclosure can be prepared by a person skilled in the art of organic synthesis by Route 1:

[0535] Route 1

[0536] Compound a is converted to compound b by an amino deprotection reaction, then to compound d by an acid amine condensation reaction with compound c, and then to compound e by an amino deprotection reaction. Compound e is then reacted with compound f to give the compounds of general formula (I).

[0537] The compounds of formula (I’) of the present disclosure can be prepared by a person skilled in the art of organic synthesis by Route 1:

[0538] Route 2

[0539] Compound a undergoes an amino deprotection reaction to yield compound b, which then undergoes an acid-amine condensation reaction with compound c to yield compound d. Compound d then undergoes an amino deprotection reaction to yield compound e. Compound e and compound f' undergo an addition-elimination reaction to yield compound (I').

[0540] Each product obtained from the reactions described above can be obtained using conventional separation techniques, including but not limited to filtration, distillation, crystallization, and chromatographic separation. Starting materials can be synthesized in-house or purchased from commercial sources (e.g., but not limited to Adrich or Sigma). These materials can be characterized using conventional methods, such as physical constants and spectral data. The compounds described in this disclosure can be synthesized to obtain single isomers or mixtures of isomers.

[0541] The following abbreviations are used in this disclosure: Cbz represents benzyloxycarbonyl; Boc represents tert-butyloxycarbonyl; Et represents ethyl; DMSO represents dimethyl sulfoxide; Ir[dF(CF3)ppy]2(dtbbpy)PF6 represents [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridineN1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridylN]phenyl-C]iridium(III) hexafluorophosphate; DMF represents N,N-dimethylformamide; Ms represents methanesulfonyl; SFC represents supercritical fluid chromatography. Example

[0542] For clarity, the invention is further illustrated by embodiments, but these embodiments are not intended to limit the scope of this disclosure. This disclosure has been described in detail herein, and specific embodiments thereof have been disclosed. Various changes and modifications to the embodiments of this disclosure will be apparent to those skilled in the art without departing from the spirit and scope of this disclosure.

[0543] All reagents used in this disclosure are commercially available and can be used without further purification. Commercially available compounds are listed under supplier catalog names.

[0544] Example 1

[0545] Step 1:

[0546] Dichlorosulfoxide (1.0 M in dichloromethane, 8.5 mL) was dispersed in 15 mL of acetonitrile, the reaction solution was cooled to -40 °C under nitrogen protection, and a solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-hydroxypropanoate (1.00 g) in 30 mL of acetonitrile was added dropwise within 30 min, the reaction was allowed to warm to 25 °C slowly, and the reaction was allowed to react at 25 °C for 12 h. The reaction was quenched with 50 g of ice water, extracted with ethyl acetate (60 mL*3) for 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 1-1, which was directly used in the next step.

[0547] Step 2:

[0548] Intermediate 1-1 (1.16 g) and ruthenium chloride trihydrate (35.2 mg) were dispersed in 15 mL of acetonitrile and 15 mL of water, and sodium periodate (1.45 g) was added at 0 °C. The reaction was allowed to react at 0 °C for 3 h. The reaction was extracted with ethyl acetate (50 mL*2) for 2 times, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) gave intermediate 1-2 (1.09 g). 1 H NMR (500 MHz, CDCl3) δ 7.47-7.31 (m, 5H), 5.35 (s, 2H), 4.81-4.61 (m, 3H), 1.43 (s, 9H). LC-MS: m / z 356.2 (M-H) - .

[0549] Step 3:

[0550] Boc-L-pyroglutamic acid methyl ester (50.0 g) was dispersed in 100 mL of anhydrous tetrahydrofuran, and lithium triethylborohydride (1.0 M in tetrahydrofuran, 246.6 mL) was added dropwise at -78 °C under nitrogen protection. The reaction was allowed to react at -78 °C for 2 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (50 mL), extracted with ethyl acetate (200 mL*2) for 2 times, washed with saturated brine (100 mL) for 1 time, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) gave intermediate 1-3 (50.0 g). LC-MS: m / z 228.1 (M-OH) + .

[0551] Step 4:

[0552] To a solution of sodium hydride (9.78 g, 60%) in 200 mL of dry N,N- dimethylformamide, diethyl cyanomethylphosphonate (43.3 g) in 50 mL of N,N- dimethylformamide was added dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 1 h. Intermediate 1-3 (50.0 g) in 50 mL of N,N-dimethylformamide was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (500 mL). The reaction mixture was diluted with 1 L of saturated brine solution. The organic layer was extracted with ethyl acetate (500 mL x 2). The organic layer was washed with saturated brine solution (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5) to give the crude product. The crude product was purified by preparative liquid chromatography (YMC-Cellulose-SC, 30 x 250 mm, 10 pm, mobile phase: A: n-hexane, B: ethanol; gradient: 5% B isocratic, wavelength 210 nm, v = 50 mL / min, rt 10.11 min). The collected fractions were purified by preparative liquid chromatography (YMC*GEL ODS-AQ-HG, 50 x 250 mm, 10 pm, mobile phase: A: pure water, B: acetonitrile; gradient: 10% B - 100% B / 0 - 60 min, wavelength 210 nm, v = 60 mL / min, rt 33 min) to give 7.00 g of intermediate 1-4. LC-MS: m / z 169.1 (M-Boc+H) + .

[0553] Step 5:

[0554] Intermediate 1-4 (7.00 g) was dissolved in 50 mL of dry tetrahydrofuran and 50 mL of dry isopropyl ether under nitrogen atmosphere. Tetraisopropyl titanate (8.16 g) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 5 min. Ethyl magnesium bromide (3.0 M in ethyl ether, 17.4 mL) was added dropwise at -78 °C over 30 min. The reaction mixture was stirred at -78 °C for 30 min. The reaction mixture was allowed to warm to 25 °C and stirred for 1 h. Boron trifluoride etherate (7.74 g) was added dropwise at -20 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction was quenched by the addition of 1 N hydrochloric acid (50 mL). The reaction mixture was extracted with ethyl acetate (50 mL x 1). The aqueous layer was adjusted to pH ~ 9 with saturated sodium carbonate solution. The organic layer was extracted with dichloromethane (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1-10:1) to give intermediate 1-5 (336.0 mg). LC-MS: m / z 299.2 (M+H) + .

[0555] Step 6:

[0556] Intermediate 1-5 (336.0 mg), intermediate 1-2 (804.9 mg) were dissolved in 20 mL acetonitrile, 25 °C for 12 hours, 1 N hydrochloric acid (0.5 mL) was added, 25 °C for 2 hours. Saturated aqueous sodium bicarbonate solution (20 mL) was added, the aqueous phase was extracted with dichloromethane (20 mL*3) for 3 times, dried over anhydrous sodium sulfate, filtered, rotary evaporated, purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to give intermediate 1-6 (468.0 mg). LC-MS: m / z 576.4 (M+H) + .

[0557] Step 7:

[0558] Intermediate 1-6 (468.0 mg), acetic acid (244.1 mg) were dissolved in 20 mL N,N- dimethylformamide, 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.85 g) was added at 0 °C, stirred at 0 °C for 5 minutes, N,N-diisopropyl ethylamine (1.05 g) was added dropwise, stirred at 0 °C for 1 hour, 25 °C for 12 hours, saturated brine (30 mL) was added and washed once, extracted with ethyl acetate (50 mL*2) for 2 times, dried over anhydrous sodium sulfate, filtered, rotary evaporated, purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2-1:1) to give intermediate 1-7 (425.7 mg). LC-MS: m / z 618.4 (M+H) + .

[0559] Step 8:

[0560] Intermediate 1-7 (425.8 mg) was dissolved in 5 mL dichloromethane, trifluoroacetic acid (5 mL) was added at 25 °C, 25 °C for 2 hours. Rotary evaporation gave intermediate 1-8, which was directly used in the next step. LC-MS: m / z 462.4 (M+H) + .

[0561] Step 9:

[0562] Intermediate 1-8 (396.7 mg) was dispersed in 20 mL of N,N-dimethylformamide, 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (394.2 mg) was added at 0 °C, the reaction was stirred at 0 °C for 5 min, N,N-diisopropyl ethylamine (534.6 mg) was added dropwise, the reaction was stirred at 0 °C for 1 h and at 25 °C for 12 h. The N,N-dimethylformamide was evaporated, ethyl acetate (20 mL) was added, washed with saturated brine (20 mL*3) for 3 times, dried over anhydrous sodium sulfate, filtered, evaporated, purified by silica gel column chromatography (dichloromethane:methanol = 200:1-100:1-50:1) to give intermediate 1-9 (180.0 mg). LC-MS: m / z 444.3 (M+H) + .

[0563] Step 10:

[0564] Intermediate 1-9 (180.0 mg), 10% palladium carbon (180.0 mg), di-tert-butyl dicarbonate (265.7 mg) were dispersed in 20 mL of methanol, replaced by hydrogen, the reaction was stirred at 25 °C for 5 h, filtered, evaporated, purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to give intermediate 1-10 (155.0 mg). LC-MS: m / z 410.3 (M+H) + .

[0565] Step 11:

[0566] Intermediate 1-10 (140.0 mg) was dispersed in 8 mL of 1,4-dioxane and 4 mL of water, lithium hydroxide monohydrate (28.0 mg) was added at 0 °C, the reaction was stirred at 25 °C for 2 h, the pH was adjusted to ~3 with acetic acid, purified by preparative liquid chromatography (YMC*GEL ODS-AQ-HG, size 50*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid water, B: acetonitrile; gradient: 5% B-85% B / 0-60 min, wavelength 210 nm, v = 60 mL / min, rt 22 min), the collected fractions were purified again by preparative liquid chromatography (YMC*GEL ODS-AQ-HG, size 50*250 mm, 10 μm, mobile phase: A: pure water, B: acetonitrile; gradient: 5% B-85% B / 0-40 min, wavelength 210 nm, v = 60 mL / min, rt 17 min) to give intermediate 1-11 (108.0 mg). 1H NMR (500 MHz, CDC13) δ 5.76 - 5.63 (m, 1H), 5.14 - 4.97 (m, 1H), 4.57 - 4.27 (m, 2.5H), 3.60 - 2.80 (m, 2.5H), 2.40 - 1.95 (m, 6H), 1.80 - 1.20 (m, 11H), 1.05 - 0.70 (m, 4H). LC-MS: m / z 296.2 (M-Boc+H) + .

[0567] Step 12:

[0568] Compound 5-bromoindole-2-carboxylic acid (18.0 g) was dispersed in 400 mL of toluene, N,N-dimethylformamide di-tert-butyl acetal (30.5 g) was added dropwise under nitrogen protection at 120 °C within 1 hour, and the mixture was reacted at 120 °C for 12 hours. After drying, the product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain intermediate 1-12 (15.5 g). LC-MS: m / z 294.1, 296.1 (M-H) - .

[0569] Step 13:

[0570] Intermediate 1-12 (5.00 g), diethyl phosphite (2.33 g), tris(dibenzylideneacetone)dichloropalladium chloroform adduct (874.7 mg), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (488.9 mg), and triethylamine (1.71 g) were dispersed in 200 mL of toluene, and the mixture was reacted at 90 °C for 12 hours under a carbon monoxide atmosphere. After drying, the product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 4:1) to obtain intermediate 1-13 (4.55 g). LC-MS: m / z 382.1 (M+H) + .

[0571] Step 14:

[0572] Intermediate 1-13 (4.55 g) was dispersed in 20 mL of dichloromethane, and trifluoroacetic acid (20 mL) was added at 25 °C. The mixture was reacted at 25 °C for 2 hours. After drying, the product was washed with methyl tert-butyl ether (10 mL) by slurry, filtered, and the filter cake was washed with methyl tert-butyl ether (10 mL) and dried to obtain intermediate 1-14 (2.83 g). LC-MS: m / z 326.1 (M+H) + .

[0573] Step 15:

[0574] Intermediate 1-14 (2.0 g), pentafluorophenol (1.70 g) were dissolved in 60 mL of dichloromethane, N,N'-dicyclohexylcarbodiimide (1.90 g) was added at 25 °C, and the reaction was performed at 25 °C for 3 h. After drying, purification was performed by column chromatography on silica gel (ethyl acetate: petroleum ether = 1:5-1:2) to obtain intermediate 1-15 (3.0 g). LC-MS: m / z 492.0 (M+H)+.

[0575] Step 16:

[0576] Intermediate 1-15 (2.6 g) was dissolved in 20 mL of dichloromethane, N,O-bis(trimethylsilyl)trifluoroacetamide (5.46 g) was added at 25 °C, and iodotrimethylsilane (2.12 g) was added at 0 °C. The reaction was performed at 25 °C for 12 h. After drying, purification was performed by preparative liquid chromatography (YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: water, B: acetonitrile; gradient: 10%-70% B-60 min, wavelength 254 nm, v = 40 mL / min, rt 25 min) to obtain intermediate 1-16 (1.48 g). LC-MS: m / z 434.0 (M-H) - .

[0577] Step 17:

[0578] Compound 2-chloro-3-bromophenol (9.92 g), triphenylphosphine (13.8 g) were dissolved in 90 mL of anhydrous tetrahydrofuran, and diethyl azodicarboxylate (9.16 g) was added dropwise at 0 °C under nitrogen protection. The reaction was performed at 0 °C for 0.5 h. A solution of (S)-(5-amino-1-hydroxy-5-oxopentan-2-yl)carbamic acid tert-butyl ester (10.0 g) in 10 mL of anhydrous tetrahydrofuran was added dropwise at 25 °C. The reaction was performed at 25 °C for 4 h. After drying, purification was performed by column chromatography on silica gel (ethyl acetate: petroleum ether = 1:1-1:0) to obtain intermediate 1-17 (6.6 g). LC-MS: m / z 321.0 (M-Boc+H) + .

[0579] Step 18:

[0580] Into a reaction flask A, intermediate 1-17 (4.0 g), 4-bromobutyric acid methyl ester (2.58 g) were dispersed in 80 mL of ethylene glycol dimethyl ether, under nitrogen protection, 2.36 g of tris(trimethylsilyl)silane, 1.06 g of Ir[dF(CF3)ppy]2(dtbbpy)PF6, and 3.02 g of sodium carbonate were added at 25 °C. Into another reaction flask B, 254.4 mg of 4,4'-di-tert-butyl-2,2'-bipyridine, 208.2 mg of ethylene glycol dimethyl ether nickel chloride, and 40 mL of ethylene glycol dimethyl ether were mixed for 10 minutes under nitrogen protection. The mixed solution was added into reaction flask A, and reacted under 450 nm blue light at 25 °C for 12 hours under nitrogen protection. After rotary evaporation, column chromatography on silica gel (ethyl acetate: petroleum ether = 1:1-1:0) was performed to obtain intermediate 1-18 (3.60 g), which was directly used in the next reaction. LC-MS: m / z 343.1 (M-Boc+H) + .

[0581] Step 19:

[0582] Intermediate 1-18 (3.60 g) was dispersed in 10 mL of tetrahydrofuran and 8 mL of water, and 682.1 mg of lithium hydroxide monohydrate in 2 mL of water was added at 0-5 °C. The reaction was stirred at 0-5 °C for 0.5 hours and at 25 °C for 1 hour. Saturated brine (10 mL) was added, and dichloromethane (50 mL*2) was extracted twice. The aqueous phase was adjusted to pH ~ 4.0 with 1M hydrochloric acid, and the aqueous phase was extracted three times with dichloromethane:methanol = 10:1 mixed solvent (50 mL*3). After drying over anhydrous sodium sulfate, filtration and rotary evaporation, intermediate 1-19 (1.87 g) was obtained. 1 H NMR (500 MHz, DMSO-D6) δ 12.05 (s, 1H), 7.29-7.16 (m, 2H), 6.99 (dd, 1H), 6.89 (dd, 1H), 6.79 (d, 1H), 6.72 (s, 1H), 3.92 (d, 2H), 3.76 (td, 1H), 2.70 (dd, 2H), 2.24 (t, 2H), 2.13 (td, 2H), 1.92-1.73 (m, 3H), 1.65-1.59 (m, 1H), 1.38 (s, 9H). LC-MS: m / z 427.1 (M-H) - .

[0583] Step 20:

[0584] Intermediate 1-19 (1.40 g), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1.74 g) were dissolved in 50 mL of N,N-dimethylformamide, 2-(7-azobenzotriazole)-N,N,N',N'- tetramethyluronium hexafluorophosphate (1.86 g) was added at 0 °C, stirred at 0 °C for 5 min, N,N-diisopropylethylamine (1.26 g) was added dropwise, stirred at 0 °C for 1 h, 25 °C for 12 h, washed once with saturated brine (100 mL), extracted with dichloromethane:methanol = 10:1 mixed solvent (50 mL*3) for 3 times, dried over anhydrous sodium sulfate, filtered, rotary evaporated, purified by silica gel column chromatography (dichloromethane:methanol = 200:1-100:1-50:1) to give intermediate 1-20 (2.17 g). LC-MS: m / z 855.3 (M+H) + .

[0585] Step 21:

[0586] Intermediate 1-20 (82.6 mg) was dissolved in 2 mL of dichloromethane, trifluoroacetic acid (2 mL) was added at 25 °C, reacted at 25 °C for 2 h, rotary evaporated to give intermediate 1-21, which was directly used in the next step. LC-MS: m / z 755.2 (M+H) + .

[0587] Step 22:

[0588] Intermediate 1-21 (84.0 mg), intermediate 1-11 (42.0 mg) were dissolved in 2 mL of N,N- dimethylformamide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (55.1 mg) was added at 0 °C, stirred at 0 °C for 5 min, N,N-diisopropylethylamine (74.9 mg) was added dropwise, stirred at 0 °C for 1 h, 25 °C for 12 h, rotary evaporated, purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give intermediate 1-22 (109.0 mg). LC-MS: m / z 1132.8 (M+H) + .

[0589] Step 23:

[0590] Intermediate 1-22 (109.0 mg) was dissolved in 2 mL of dichloromethane, trifluoroacetic acid (2 mL) was added at 25 °C, reacted at 25 °C for 2 h, rotary evaporated to give intermediate 1-23, which was directly used in the next step. LC-MS: m / z 1032.6 (M+H) + .

[0591] Step 24:

[0592] Intermediate 1-23 (110.2 mg), N,N-diisopropylethylamine (74.6 mg) were dissolved in 5 mL of N,N-dimethylformamide, and Intermediate 1-16 (50.3 mg) was added at 0 °C. The reaction was stirred at 25 °C for 12 h. The reaction mixture was purified by liquid chromatography (YMC TA C18, 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia water, B: acetonitrile; gradient: 5%-40% B-60 min, wavelength 254 nm, v = 40 mL / min, rt 34 min) to give the ammonium salt of Compound 1 (78.2 mg). 1 H NMR (500 MHz, DMSO-D6 + D20) δ 8.95 (s, 1H), 8.85-8.82 (m, 1H), 8.39 (d, 1H), 7.98-7.92 (m, 2H), 7.88 (d, 1H), 7.48-7.40 (m, 4H), 7.38-7.34 (m, 2H), 7.20-7.15 (m, 1H), 6.97 (d, 1H), 6.87 (d, 1H), 5.37-5.30 (m, 1H), 4.91-4.85 (m, 1H), 4.72-4.63 (m, 1H), 4.53-4.48 (m, 1H), 4.48-4.38 (m, 2H), 4.37-4.31 (m, 1H), 4.29-4.24 (m, 1H), 4.11-3.95 (m, 2H), 3.94-3.82 (m, 1H), 3.66-3.58 (m, 3H), 2.90-2.74 (m, 2H), 2.70-2.60 (m, 2H), 2.44 (s, 3H), 2.33-2.21 (m, 4H), 2.20-2.08 (m, 4H), 2.06-1.98 (m, 2H), 1.94-1.84 (m, 2H), 1.82-1.64 (m, 5H), 1.58-1.46 (m, 1H), 1.36 (d, 3H), 1.30-1.20 (m, 2H), 1.04-0.88 (m, 13H). LC-HRMS: 642.2386 m / z [(M+2H) / 2] + .

[0593] Example 2

[0594] Step 1:

[0595] Dichlorosulfoxide (1.0 M in dichloromethane, 500.0 mL) was dispersed in 500 mL of acetonitrile and cooled to -40 °C under nitrogen protection. A solution of N-tert-butoxycarbonyl-L-serine benzyl ester (59.0 g) in 250 mL of acetonitrile was added dropwise over 30 min, and the reaction was allowed to proceed at -40 °C for 1.5 h. A solution of pyridine (94.8 g) in 50 mL of acetonitrile was added dropwise, and the reaction was allowed to warm to 25 °C slowly and proceed for 12 h. The reaction was quenched with ice water (500 g), and the product was extracted with ethyl acetate (500 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give intermediate 2-1, which was used directly in the next step.

[0596] Step 2:

[0597] Intermediate 2-1 (68.2 g) and ruthenium chloride trihydrate (1.04 g) were dispersed in 500 mL of acetonitrile and 500 mL of water, and sodium periodate (64.1 g) was added at 0 °C. The reaction was allowed to proceed at 0 °C for 3 h. The product was extracted with ethyl acetate (200 mL*2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5) gave intermediate 2-2 (57.2 g). 1 H NMR (500 MHz, CDCl3) δ 7.42-7.32 (m, 5H), 5.27 (dd, 2H), 4.84-4.80 (m, 1H), 4.77-4.73 (m, 1H), 4.68-4.64 (m, 1H), 1.49 (s, 9H). LC-MS: m / z 356.2 (M-H) - .

[0598] Step 3:

[0599] 1-Amino-N-Boc-[1-(2-hydroxyethyl)]cyclopropane (74.0 g) and ruthenium chloride trihydrate (1.90 g) were dispersed in 700 mL of acetonitrile and 700 mL of water, and sodium periodate (235.9 g) was added in portions at 0 °C. The reaction was allowed to proceed at 25 °C for 12 h. Saturated brine (1 L) was added, and the product was extracted with ethyl acetate (500 mL*3). The combined organic phase was washed with 1 M sodium bisulfite (500 mL), saturated brine (500 mL*2) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give intermediate 2-3 (77.1 g). LC-MS: m / z 214.2 (M-H) - .

[0600] Step 4:

[0601] Intermediate 2-3 (77.1 g), N, O-dimethylhydroxylamine hydrochloride (41.9 g) were dissolved in 600 mL of N, N-dimethylformamide, and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (204.3 g) was added under ice water bath. The mixture was stirred at 0-5 °C for 5 min, and N, N-diisopropylethylamine (138.9 g) was added dropwise. The mixture was stirred at 0-5 °C for 1 h and at 25 °C for 12 h. Saturated brine (2 L) was added, and the mixture was extracted with ethyl acetate (500 mL x 2). The combined organic phase was washed with 1 M citric acid aqueous solution (500 mL), saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 1:2) to give intermediate 2-4 (89.0 g). LC-MS: m / z 259.3 (M+H) + .

[0602] Step 5:

[0603] Intermediate 2-4 (78.0 g) was dissolved in 200 mL of anhydrous tetrahydrofuran, and vinylmagnesium bromide (1.2 L of 1.0 M tetrahydrofuran solution) was added dropwise under nitrogen protection at -15 °C. The mixture was stirred at -5 °C for 12 h. 1 M potassium bisulfate aqueous solution (1500 mL) was added, and the mixture was extracted with ethyl acetate (500 mL x 2). The combined organic phase was washed with saturated brine (150 mL x 5), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 1:4) to give intermediate 2-5 (39.1 g). 1 H NMR (500 MHz, CDC13) δ 1H NMR (500 MHz, CDC13) δ 6.33 (dd, 1H), 6.21 (dd, 1H), 5.85 (dd, 1H), 5.28 (s, 1H), 2.88 (s, 2H), 1.41 (s, 9H), 0.88 (t, 2H), 0.67 (t, 2H). LC-MS: m / z 126.2 (M-Boc+H) + .

[0604] Step 6:

[0605] Intermediate 2-5 (40.0 g), methyl nitroacetate (42.0 g), and sodium methoxide (1.6 mL of 5.4 M methanol solution) were dissolved in 800 mL of methanol, and the mixture was stirred at 25 °C for 12 h under nitrogen protection. Ethyl acetate (500 mL), 1 M potassium bisulfate aqueous solution (5 mL), and saturated brine (500 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (150 mL), and the combined organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and slurried with petroleum ether (100 mL) to give intermediate 2-6 (60.0 g).1 H NMR (500 MHz, CDC13) δ 5.33 - 5.27 (m, 1H), 5.15 (s, 1H), 3.84 (s, 3H), 2.75 - 2.56 (m, 4H), 2.55 - 2.40 (m, 2H), 1.41 (s, 9H), 0.87 (t, 2H), 0.68 (t, 2H). LC-MS: m / z 343.3 (M-H) - .

[0606] Step 7:

[0607] 10% palladium on carbon (60.0 g) was washed with 100 mL of methanol twice, intermediate 2-6 (60.0 g), palladium on carbon (60.0 g), 4A molecular sieves (300.0 g) were dispersed in 500 mL of methanol, hydrogen was replaced, and reacted at 25 °C for 12 hours. 4A molecular sieves (240.0 g) were added, hydrogen was replaced, and reacted at 25 °C for 12 hours. Filtration and rotary evaporation gave intermediate 2-7, which was directly used in the next step. LC-MS: m / z 299.3 (M+H) + .

[0608] Step 8:

[0609] Intermediate 2-7 (52.0 g), N,N-diisopropyl ethylamine (48.8 g) were dispersed in 700 mL of dichloromethane, benzyl chloroformate (35.4 g) was added at 0 °C, and reacted at 25 °C for 3 hours. 1M potassium hydrogen sulfate (100 mL), saturated brine (100 mL) were washed successively, dried over anhydrous sodium sulfate, filtered, rotary evaporated, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10-1:5), then by SFC (YMC-Cellulose-SC, size 30*250mm, 10μm, mobile phase: A: CO2, B: methanol, gradient: 10% B isocratic, wavelength 210 nm, v = 60 mL / min, rt 6 min) to give intermediate 2-8 (24.3 g). LC-MS: m / z 333.3 (M-Boc+H) + .

[0610] Step 9:

[0611] Intermediate 2-8 (24.0 g) was dispersed in 50 mL of ethyl acetate, 250 mL of 4N hydrogen chloride ethyl acetate solution was added at 25 °C, and the reaction was carried out at 25 °C for 5 hours. Water (100 mL) was added, and the mixture was separated. The organic phase was washed with water twice (100 mL), and the combined aqueous phase was adjusted to pH about 9-10 with saturated sodium bicarbonate and extracted with dichloromethane (50 mL*4). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 2-9 (18.4 g). 1H NMR (500 MHz, CDCl3) δ 7.47-7.27 (m, 5H), 5.29-5.00 (m, 2H), 4.47-4.24 (m, 2H), 3.75 (s, 1.1H), 3.59 (s, 1.9H), 2.34-2.24 (m, 1H), 2.13-1.91 (m, 2H), 1.88-1.52 (m, 5H), 0.78-0.30 (m, 4H). LC-MS: m / z 333.3 (M+H) + .

[0612] Step 10:

[0613] Intermediate 2-9 (17.4 g), intermediate 2-2 (37.4 g), and potassium carbonate (14.5 g) were dispersed in 200 mL of dichloromethane, and the reaction was carried out at 25 °C for 12 hours. After concentration, 200 mL of acetonitrile and 100 mL of 1N hydrochloric acid were added, and the reaction was carried out at 25 °C for 1 hour. Dichloromethane (500 mL) and water (500 mL) were added, and the mixture was separated. The aqueous phase was adjusted to pH about 9-10 with saturated sodium bicarbonate, and extracted with dichloromethane (200 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel column chromatography (dichloromethane:methanol = 1:0-200:1-20:1) gave intermediate 2-10 (25.9 g). LC-MS: m / z 610.4 (M+H) + .

[0614] Step 11:

[0615] Intermediate 2-10 (7.50 g) and 10% palladium-carbon (1.50 g) were dispersed in 150 mL of methanol, and the reaction was carried out under hydrogen replacement at 25 °C for 2 hours. After filtration, intermediate 2-11 was obtained and directly used in the next step. LC-MS: m / z 386.3 (M+H) + .

[0616] Step 12:

[0617] Intermediate 2-11 (4.74 g), 1-hydroxy-7-azobenzotriazole (2.51 g) was dispersed in 150 mL of N,N-dimethylformamide, 2-(7-azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (7.01 g), N,N-diisopropyl ethylamine (4.76 g) was added at 0 °C, and the mixture was stirred at 25 °C for 12 h. Ethyl acetate (100 mL) and saturated brine (500 mL) were added, and the mixture was partitioned. The aqueous phase was extracted with ethyl acetate (100 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 1:5-1:2-2:1) to give intermediate 2-12 (2.30 g). LC-MS: m / z 368.3 (M+H) + .

[0618] Step 13:

[0619] Intermediate 2-12 (500.0 mg) and potassium carbonate (1.13 g) were dispersed in 10 mL of DMF, and iodomethane (1.16 g) was added at 25 °C. The mixture was stirred at 25 °C for 12 h. Ethyl acetate (50 mL) and saturated brine (50 mL) were added, and the mixture was partitioned. The organic phase was washed with saturated brine (50 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 1:5-1:3) to give intermediate 2-13 (320.5 mg). LC-MS: m / z 382.3 (M+H) + .

[0620] Step 14:

[0621] Intermediate 2-13 (320.5 mg) was dispersed in 20 mL of 1,4-dioxane and 8 mL of water, and a solution of lithium hydroxide monohydrate (70.5 mg) in 2 mL of water was added at 0 °C. The mixture was stirred at 0 °C for 2 h. The pH was adjusted to 3-4 with 1N hydrochloric acid, and the mixture was purified by preparative liquid chromatography (YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: water, B: acetonitrile; gradient: 5%-65% B 0-30 min, wavelength 210 nm, v = 40 mL / min, rt 11.9 min) to give intermediate 2-14 (234.0 mg). 1H NMR (500 MHz, CD3OD) δ 4.86 - 4.80 (m, 1H), 4.42 - 4.26 (m, 2H), 2.98 - 2.89 (m, 1H), 2.76 - 2.65 (m, 1H), 2.49 (s, 3H), 2.41 (s, 1H), 2.24 - 2.14 (m, 1H), 2.06 - 2.06 (m, 2H), 1.66 - 1.56 (m, 1H), 1.35 (s, 1.4H), 1.30 (s, 7.6H), 1.12 - 0.54 (m, 5H). LC-MS: m / z 368.3 (M+H) + .

[0622] Step 15:

[0623] Intermediate 1-21 was obtained by dispersing intermediate 1-20 (63.5 mg) in 2 mL of dichloromethane, adding trifluoroacetic acid (2 mL) at 25 °C, and reacting for 2 hours at 25 °C. The solvent was removed by rotary evaporation, and the residue was used directly in the next step. LC-MS: m / z 755.2 (M+H) + .

[0624] Step 16:

[0625] Intermediate 2-15 was obtained by dispersing intermediate 1-21 (64.5 mg) and intermediate 2-14 (30.0 mg) in 2 mL of N,N-dimethylformamide, adding 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (42.3 mg) at 0 °C, stirring for 5 minutes at 0 °C, adding N,N-diisopropylethylamine (57.5 mg) dropwise, stirring for 1 hour at 0 °C, and reacting for 12 hours at 25 °C. The solvent was removed by rotary evaporation, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol = 20:1-10:1) to give intermediate 2-15 (50.0 mg). LC-MS: m / z 1104.7 (M+H) + .

[0626] Step 17:

[0627] Intermediate 2-16 was obtained by dispersing intermediate 2-15 (50.0 mg) in 2 mL of dichloromethane, adding trifluoroacetic acid (2 mL) at 25 °C, and reacting for 2 hours at 25 °C. The solvent was removed by rotary evaporation, and the residue was used directly in the next step. LC-MS: m / z 1004.7 (M+H) + .

[0628] Step 18:

[0629] Intermediate 2-16 (50.6 mg), N,N-diisopropylethylamine (35.1 mg) was dissolved in 5 mL of N,N-dimethylformamide, and intermediate 1-16 (23.6 mg) was added at 0°C, and reacted at 25°C for 12 hours. Liquid phase purification (YMC TA C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia water, B: acetonitrile; gradient: 5%-40% B 0-60 min, wavelength 254 nm, v = 40 mL / min, rt 45 min) gave the ammonium salt of compound 2 (35.6 mg). LC-HRMS: 1255.6 m / z (M+H) + . 1 H-NMR (DMSO-d6+D2O) δ 8.97 (1H, s), 8.86 (1H, s), 8.55 (1H, d, J = 7.0), 8.40 (1H, d, J = 7.5), 7.95 (1H, d, J = 9.0), 7.88 (1H, d, J = 9.0), 7.81 (1H, brs), 7.37-7.47 (6H, m), 7.22 (1H, t, J = 8.0), 7.00 (1H, d, J = 7.5), 6.90 (1H, d, J = 7.5), 5.24 (1H, m), 4.90 (1H, m), 4.52 (1H, d, J = 9.5), 4.43 (2H, m), 4.29 (2H, m), 4.13 (1H, m), 3.97 (2H, m), 3.10 (1H, q, J = 7.5), 2.82 (1H, m), 2.69 (4H, m), 2.46 (3H, s), 2.35 (5H, m), 2.02-2.24 (4H, m), 1.91 (3H, m), 1.78 (3H, m), 1.63 (1H, m), 1.38 (3H, d, J = 7.0), 0.94 (14H, m), 0.65 (1H, brs), 0.53 (1H, brs).

[0630] Example 3

[0631] Step 1:

[0632] Intermediate 2-12 (300.0 mg) and triethylamine (825.0 mg) were dissolved in 15 mL of acetonitrile, and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.89 g) was added at 25°C, and reacted at 80°C for 32 hours. Ethyl acetate (50 mL) was added, and the mixture was separated, and the organic phase was washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography (ethyl acetate: petroleum ether = 1:5-1:2) gave intermediate 3-1 (240.7 mg). LC-MS: m / z 450.3 (M+H) + .

[0633] Step 2:

[0634] Intermediate 3-1 (240.7 mg) was dispersed in 20 mL of 1,4-dioxane and 8 mL of water, and a solution of lithium hydroxide monohydrate (44.9 mg) in 2 mL of water was added at 0 °C. The reaction was stirred at 0 °C for 2 h. The pH was adjusted to 3-4 with 1 N hydrochloric acid, and the solution was purified by preparative liquid chromatography (YMC AQ C18, 30*250 mm, 10 pm, mobile phase: A: water, B: acetonitrile; gradient: 20%-70% B 0-60 min, wavelength 254 nm, v = 25 mL / min, rt 47 min) to give intermediate 3-2 (157.0 mg). 1 H NMR (500 MHz, CD3OD) δ 4.85-4.70 (m, 1H), 4.50-4.27 (m, 2H), 3.71-3.59 (m, 1H), 3.52-3.39 (m, 1H), 3.30-3.17 (m, 1H), 2.78 (t, 1H), 2.70-2.45 (m, 1H), 2.35-2.16 (m, 2H), 2.15-1.99 (m, 1H), 1.82-1.71 (m, 1H), 1.48 (s, 1.5H), 1.45 (s, 7.5H), 1.12-0.48 (m, 5H). LC-MS: m / z 434.2 (M-H) - .

[0635] Step 3:

[0636] Intermediate 1-20 (53.6 mg) was dispersed in 2 mL of dichloromethane, and trifluoroacetic acid (2 mL) was added at 25 °C. The reaction was stirred at 25 °C for 2 h, and the solvent was evaporated to give intermediate 1-21, which was used directly in the next step. LC-MS: m / z 755.2 (M+H) + .

[0637] Step 4:

[0638] Intermediate 1-21 (54.4 mg) and intermediate 3-2 (30.0 mg) were dispersed in 2 mL of N,N-dimethylformamide, and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (35.7 mg) was added at 0 °C. The reaction was stirred at 0 °C for 5 min, and N,N-diisopropylethylamine (48.5 mg) was added dropwise. The reaction was stirred at 0 °C for 1 h and at 25 °C for 12 h. The solvent was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1-10:1) to give intermediate 3-3 (73.4 mg). LC-MS: m / z 1172.8 (M+H) + .

[0639] Step 5:

[0640] Intermediate 3-3 (73.4 mg) was dispersed in 2 mL of dichloromethane, trifluoroacetic acid (2 mL) was added at 25 °C, and the reaction was allowed to proceed for 2 h at 25 °C. The solvent was evaporated to give intermediate 3-4, which was used directly in the next step. LC-MS: m / z 537.0 [(M+2H) / 2] + .

[0641] Step 6:

[0642] Intermediate 3-4 (74.3 mg) and N,N-diisopropylethylamine (48.5 mg) were dispersed in 5 mL of N,N-dimethylformamide, and intermediate 1-16 (32.7 mg) was added at 0 °C. The reaction was allowed to proceed for 12 h at 25 °C. The product was purified by preparative liquid chromatography (YMC TAC18, 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia water, B: acetonitrile; gradient: 10%-50% B 0-60 min, wavelength 254 nm, v = 25 mL / min, rt 47 min) to give the ammonium salt of compound 3 (34.7 mg). LC-HRMS: 1323.4 m / z (M+H) + . 1 H-NMR (DMSO-d6+D2O) δ 8.97 (1H, s), 8.86 (1H, s), 8.39 (1H, d, J = 8.0), 8.13 (1H, d, J = 8.0), 7.95 (1H, d, J = 8.5), 7.88 (1H, d, J = 9.0), 7.36-7.45 (6H, m), 7.20 (1H, t, J = 8.0), 7.00 (1H, d, J = 7.5), 6.90 (1H, d, J = 7.5), 5.15 (1H, m), 4.90 (1H, m), 4.52 (1H, d, J = 9.0), 4.28-4.44 (4H, m), 4.11 (1H, m), 4.03 (1H, m), 3.93 (1H, m), 3.75 (1H, m), 3.20 (1H, m), 3.09 (1H, q, J = 8.0), 3.00 (1H, m), 2.67 (3H, m), 2.46 (3H, s), 2.18-2.32 (5H, m), 2.04 (3H, m), 1.91 (2H, m), 1.78 (6H, m), 1.38 (3H, d, J = 7.0), 0.93 (11H, m), 0.75 (1H, m), 0.64 (2H, m).

[0643] Example 4

[0644] Step 1:

[0645] Intermediate 2-12 (100.0 mg) was dispersed in 4 mL of 1,4-dioxane and 1 mL of water, and a solution of lithium hydroxide monohydrate (22.8 mg) in 1 mL of water was added at 0 °C. The reaction was stirred at 0 °C for 2 hours. The pH was adjusted to 3-4 with 1 N hydrochloric acid, and the product was purified by preparative liquid chromatography (YMC TA C18, 30*250 mm, 10 μm, mobile phase: A: water, B: acetonitrile; gradient: 40%-100% B 0-60 min, wavelength 254 nm, v = 40 mL / min, rt 30 min) to give intermediate 4-1 (90.0 mg). LC-MS: m / z 354.3 (M+H) + .

[0646] Step 2:

[0647] Intermediate 1-20 (66.0 mg) was dispersed in 2 mL of dichloromethane, and trifluoroacetic acid (2 mL) was added at 25 °C. The reaction was stirred at 25 °C for 2 hours, and the solvent was evaporated to give intermediate 1-21, which was used directly in the next step. LC-MS: m / z 755.2 (M+H) + .

[0648] Step 3:

[0649] Intermediate 1-21 (67.1 mg) and intermediate 4-1 (30.0 mg) were dispersed in 2 mL of N,N-dimethylformamide, and 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (44.0 mg) was added at 0 °C. The reaction was stirred at 0 °C for 5 minutes, and N,N-diisopropylethylamine (59.9 mg) was added dropwise. The reaction was stirred at 0 °C for 1 hour and at 25 °C for 12 hours. The solvent was evaporated, and the product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1-10:1) to give intermediate 4-2 (74.6 mg). LC-MS: m / z 1090.7 (M+H) + .

[0650] Step 4:

[0651] Intermediate 4-2 (74.6 mg) was dispersed in 2 mL of dichloromethane, and trifluoroacetic acid (2 mL) was added at 25 °C. The reaction was stirred at 25 °C for 2 hours, and the solvent was evaporated to give intermediate 4-3, which was used directly in the next step. LC-MS: m / z 990.6 (M+H) + .

[0652] Step 5:

[0653] Intermediate 4-3 (78.8 mg), N,N-diisopropylethylamine (53.0 mg) was dispersed in 5 mL of N,N-dimethylformamide, and Intermediate 1-16 (35.7 mg) was added at 0 °C. The reaction was carried out at 25 °C for 12 hours. Purification by preparative liquid chromatography (YMC TA C18, 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia water, B: acetonitrile; gradient: 5%-45% B 0-60 min, wavelength 254 nm, v = 30 mL / min, rt 32 min) gave the ammonium salt of compound 4 (41.9 mg). LC-HRMS: 1241.4 m / z (M+H) + .

[0654] Example 5

[0655] Step 1:

[0656] Intermediate 2-12 (120.0 mg), cyclopropylcarboxylic acid (140.6 mg) was dispersed in 2 mL of N,N-dimethylformamide, and 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (745.1 mg) was added at 0 °C. The reaction was stirred at 0 °C for 5 minutes, and N,N-diisopropylethylamine (422.1 mg) was added dropwise. The reaction was carried out at 25 °C for 12 hours. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (ethyl acetate: petroleum ether = 1:2-2:1) gave Intermediate 5-1 (130.0 mg). LC-MS: m / z 436.3 (M+H) + .

[0657] Step 2:

[0658] Intermediate 5-1 (130.0 mg) was dispersed in 10 mL of 1,4-dioxane and 4 mL of water, and a solution of lithium hydroxide monohydrate (25.0 mg) in 1 mL of water was added at 0 °C. The reaction was carried out at 0 °C for 2 hours. The pH was adjusted to 3-4 with 1N hydrochloric acid, and purification by preparative liquid chromatography (YMC AQ, 50*250 mm, 10 μm, mobile phase: A: 0.1% formic acid water, B: acetonitrile; gradient: 20% B-60% B / 0-60 min, wavelength 254 nm, v = 50 mL / min, rt 50 min) was performed. The collected fractions were again purified by preparative liquid chromatography to remove the acid to give Intermediate 5-2 (53.6 mg). LC-MS: m / z 444.2 (M+Na) + .

[0659] Step 3:

[0660] Intermediate 1-20 (55.4 mg) was dissolved in 2 mL of dichloromethane, trifluoroacetic acid (2 mL) was added at 25 °C, and the reaction was stirred at 25 °C for 2 h. The solvent was removed by rotary evaporation to give intermediate 1-21, which was used directly in the next step. LC-MS: m / z 755.2 (M+H) + .

[0661] Step 4:

[0662] Intermediate 1-21 (56.3 mg) and intermediate 5-2 (30.0 mg) were dissolved in 2 mL of N,N-dimethylformamide, 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (36.9 mg) was added at 0 °C, and the reaction was stirred at 0 °C for 5 min. N,N-diisopropylethylamine (50.2 mg) was added dropwise, and the reaction was stirred at 0 °C for 1 h and at 25 °C for 12 h. The solvent was removed by rotary evaporation, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol = 20:1-10:1) to give intermediate 5-3 (74.0 mg). LC-MS: m / z 1158.8 (M+H) + .

[0663] Step 5:

[0664] Intermediate 5-3 (74.0 mg) was dissolved in 2 mL of dichloromethane, trifluoroacetic acid (2 mL) was added at 25 °C, and the reaction was stirred at 25 °C for 2 h. The solvent was removed by rotary evaporation to give intermediate 5-4, which was used directly in the next step. LC-MS: m / z 1058.7 (M+H) + .

[0665] Step 6:

[0666] Intermediate 5-4 (74.9 mg) and N,N-diisopropylethylamine (49.6 mg) were dissolved in 5 mL of N,N-dimethylformamide, and intermediate 1-16 (33.3 mg) was added at 0 °C. The reaction was stirred at 25 °C for 12 h, and the product was purified by preparative liquid chromatography (YMC TAC18, 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia water, B: acetonitrile; gradient: 10%-50% B 0-60 min, wavelength 254 nm, v = 25 mL / min, rt 41 min) to give the ammonium salt of compound 5 (27.0 mg). LC-HRMS: 1309.4 m / z (M+H) + .

[0667] Example 6

[0668] The ammonium salt of compound 6 was prepared according to the procedure of Reference Example 1, replacing (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide in Step 20 of Example 1 with compound 6-1. LC-MS: m / z 1299.5 (M+H) + .

[0669] Example 7

[0670] The ammonium salt of compound 7 was prepared according to the procedure of Reference Example 1, replacing (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide in Step 20 of Example 1 with compound 7-1. LC-MS: m / z 1266.6 (M+H) + .

[0671] Example 8

[0672] The ammonium salt of compound 8 was prepared according to the procedure of Reference Example 1, replacing (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide in Step 20 of Example 1 with compound 8-1. LC-MS: m / z 1282.6 (M+H) + .

[0673] Example 9

[0674] The ammonium salt of compound 9 was prepared according to the procedure of Reference Example 1, replacing (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide in Step 20 of Example 1 with compound 9-1. LC-MS: m / z 1280.6 (M+H) + .

[0675] Example 10

[0676] The ammonium salt of compound 10 was prepared according to the procedure of Reference Example 1, replacing (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide in Step 20 of Example 1 with compound 10-1. LC-MS: m / z 1296.6 (M+H) + .

[0677] Example 11

[0678] The ammonium salt of compound 11 was prepared according to the procedure of Reference Example 1, replacing (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide in Step 20 of Example 1 with compound 11-1. LC-MS: m / z 1269.5 (M+H) + .

[0679] Example 12

[0680] The ammonium salt of compound 12 was prepared according to the procedure of Reference Example 1, replacing (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide in Step 20 of Example 1 with compound 12-1. LC-MS: m / z 1285.4 (M+H) + .

[0681] Example 13

[0682] The ammonium salt of compound 13 was prepared according to the procedure of Reference Example 1, replacing (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide in Step 20 of Example 1 with compound 13-1. LC-MS: m / z 1252.6 (M+H) + .

[0683] Example 14

[0684] The ammonium salt of compound 14 was prepared according to the procedure of Reference Example 1, replacing (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide in Step 20 of Example 1 with compound 14-1. LC-MS: m / z 1268.6 (M+H) + .

[0685] Example 15

[0686] The ammonium salt of compound 15 was prepared according to the procedure of Reference Example 1, replacing (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide in Step 20 of Example 1 with compound 15-1. LC-MS: m / z 1266.6 (M+H) + .

[0687] Example 16

[0688] The ammonium salt of compound 16 was prepared according to the procedure of Reference Example 1, replacing (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide in Step 20 of Example 1 with compound 16-1. LC-MS: m / z 1282.6 (M+H) + .

[0689] Example 17

[0690] The ammonium salt of compound 17 was prepared according to the procedure of Reference Example 1, replacing intermediate 1-19 in Step 20 of Example 1 with compound 17-1. LC-MS: m / z 1297.4 (M+H) + . 1H-NMR (DMSO-d6+D2O) δ 8.97 (1H, s), 8.85 (2H, m), 8.39 (1H, d, J = 7.5), 7.95~7.98 (2H, m), 7.38~7.48 (6H, m), 7.21 (1H, m), 6.97 (1H, d, J = 8.5), 6.90 (1H, d, J = 7.0), 5.36 (1H, m), 4.91 (1H, m), 4.69 (1H, t, J = 13.0), 4.41~4.51 (3H, m), 4.36 (1H, t, J = 8.0), 4.28 (1H, s), 3.98~4.06 (3H, m), 2.79~2.91 (2H, m), 2.68 (1H, s), 2.46 (3H, s), 2.27 (4H, m), 2.11~2.20 (4H, m), 1.91~2.05 (6H, m), 1.79 (1H, m), 1.70 (1H, m), 1.53 (2H, m), 1.38 (3H, d, J = 6.5), 0.93 (16H, m).

[0691] Example 18

[0692] The ammonium salt of compound 18 was prepared according to the procedure described in Reference Example 1, replacing intermediate 1-19 in step 20 of Example 1 with compound 18-1. LC-MS: m / z 1309.6 (M+H) + .

[0693] Example 19

[0694] The ammonium salt of compound 19 was prepared according to the procedure described in Reference Example 1, replacing intermediate 1-19 in step 20 of Example 1 with compound 19-1. LC-MS: m / z 1295.5 (M+H) + .

[0695] Example 20

[0696] The ammonium salt of compound 20 was prepared according to the procedure described in Reference Example 1, replacing intermediate 1-19 in step 20 of Example 1 with compound 20-1. LC-MS: m / z 1281.5 (M+H) + . 1H-NMR (DMSO-d6+D2O) δ 8.97 (1H, s), 8.85 (2H, m), 8.39 (1H, d, J = 7.5), 7.99 (1H, d, J = 8.5), 7.95 (1H, dd, J = 1.5, 8.5), 7.82 (1H, d, J = 9.0), 7.38-7.48 (6H, m), 6.99 (2H, m), 6.82 (1H, m), 5.36 (1H, m), 4.91 (1H, m), 4.68 (1H, t, J = 13.0), 4.42-4.51 (3H, m), 4.36 (1H, t, J = 7.5), 4.28 (1H, s), 3.87-4.03 (3H, m), 3.11 (1H, q, J = 7.5), 2.79-2.89 (2H, m), 2.58 (1H, m), 2.46 (3H, s), 2.27 (4H, m), 2.13-2.19 (5H, m), 2.03 (3H, m), 1.70-1.92 (2H, m), 1.53 (6H, m), 1.38 (3H, d, J = 7.5), 0.93 (16H, m).

[0697] Example 21

[0698] The ammonium salt of compound 21 was prepared according to the procedure described in Reference Example 1, replacing intermediate 1-19 in step 20 of Example 1 with compound 21-1. LC-MS: m / z 1301.4 (M+H) + .

[0699] Example 22

[0700] The ammonium salt of compound 22 was prepared according to the procedure described in Reference Example 1, replacing intermediate 1-19 in step 20 of Example 1 with compound 22-1. LC-MS: m / z 1281.6 (M+H) + .

[0701] Example 23

[0702] The ammonium salt of compound 23 was prepared according to the procedure described in Reference Example 1, replacing intermediate 1-19 in step 20 of Example 1 with compound 23-1. LC-MS: m / z 1297.5 (M+H) + .

[0703] Example 24

[0704] The ammonium salt of compound 24 was prepared according to the procedure of Reference Example 1 by replacing intermediate 1-19 and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide in Example 1, step 20 with compound 24-1 and compound 24-2, respectively. LC-MS: m / z 1309.4 (M+H) + .

[0705] Example 25

[0706] Step 1:

[0707] Compound 25-1 (74.0 mg), compound 25-2 (50.0 mg), cesium carbonate (50.5 mg) were dispersed in 2 mL of N,N-dimethylformamide and reacted at 25 °C for 12 hours. Saturated brine (55 mL) was added, and dichloromethane (50 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. Purification by silica gel column chromatography (dichloromethane:methanol = 10:1) gave intermediate 25-3 (38.7 mg). LC-MS: m / z 867.4 (M+H) + .

[0708] Step 2:

[0709] The ammonium salt of compound 25 was prepared according to the procedure of Reference Example 1 by replacing intermediate 1-20 in Example 1, step 21 with compound 25-3. LC-MS: m / z 1295.5 (M+H) + .

[0710] Example 26

[0711] The ammonium salt of compound 26 was prepared according to the procedure of Reference Example 25 by replacing intermediate 25-1 in Example 25, step 1 with compound 26-1. LC-MS: m / z 1275.5 (M+H) + .

[0712] Example 27

[0713] The ammonium salt of compound 27 was prepared according to the procedure of Reference Example 25 by replacing intermediate 25-2 in Example 25, step 1 with compound 27-1. LC-MS: m / z 1309.5 (M+H) + .

[0714] Example 28

[0715] Following the procedure for the preparation of Reference Example 1, intermediate 1-16 in Example 1, Step 24 was replaced with compound 28-1 to afford the ammonium salt of compound 28. LC-MS: m / z 1322.4 (M+H) + .

[0716] Example 29

[0717] Following the procedure for the preparation of Reference Example 1, intermediate 1-20 in Example 1, Step 21 was replaced with compound 29-1 to afford the ammonium salt of compound 29. LC-MS: m / z 1323.5 (M+H) + .

[0718] Example 30

[0719] Following the procedure for the preparation of Reference Example 1, intermediate 1-20 in Example 1, Step 21 was replaced with compound 30-1 to afford the ammonium salt of compound 30. LC-MS: m / z 1307.5 (M+H) + .

[0720] Example 31

[0721] Following the procedure for the preparation of Reference Example 1, intermediate 1-20 in Example 1, Step 21 was replaced with compound 31-1 to afford the ammonium salt of compound 31. LC-MS: m / z 1333.5 (M+H) + .

[0722] Example 32

[0723] Following the procedure for the preparation of Reference Example 1, intermediate 1-19 in Example 1, Step 20 was replaced with compound 20-1 and intermediate 1-11 in Example 1, Step 22 was replaced with compound 2-14 to afford the ammonium salt of compound 32. LC-MS: m / z 1253.5 (M+H) + .

[0724] Example 33

[0725] Step 1:

[0726] Intermediate 2-12 (200.0 mg) and potassium carbonate (902.7 mg) were dispersed in 5 mL of DMF, iodoe thane (1.02 g) was added at 25 °C, and the reaction was carried out at 40 °C for 12 h. 50 mL of ethyl acetate and 50 mL of saturated brine were added, and the mixture was separated. The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5-1:3) gave intermediate 33-1 (136.0 mg).

[0727] LC-MS: m / z 396.3 (M+H) + .

[0728] Step 2:

[0729] Intermediate 33-1 (136.0 mg) was dispersed in 4 mL of 1,4-dioxane and 1 mL of water, and a solution of lithium hydroxide monohydrate (29.0 mg) in 1 mL of water was added at 0 °C. The reaction was carried out at 0 °C for 2 h. The pH was adjusted to 3-4 with 1 N hydrochloric acid, and preparative liquid chromatography (YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: water, B: acetonitrile; gradient: 5%-85% B 0-40 min, wavelength 210 nm, v = 40 mL / min, rt 13 min) was used to give intermediate 33-2 (108.8 mg). 1 H NMR (500 MHz, MeOD) δ 5.09 (d, 1H), 4.64-4.40 (m, 2H), 3.10 (dd, 1H), 3.00-2.86 (m, 3H), 2.61 (s, 1H), 2.47-2.38 (m, 1H), 2.23-1.97 (m, 2H), 1.76 (dd, 1H), 1.52 (s, 1.4H), 1.47 (s, 7.6H), 1.44-0.80 (m, 8H). LC-MS: m / z 382.4 (M+H) + .

[0730] Step 3:

[0731] Referring to the preparation method of Example 1, intermediate 1-19 in Example 1 Step 20 was replaced with compound 20-1, and intermediate 1-11 in Example 1 Step 22 was replaced with compound 33-2 to prepare the ammonium salt of compound 33. LC-MS: m / z 1267.5 (M+H) + . 1H-NMR (DMSO-d6+D2O) δ 8.97 (1H, s), 8.86 (1H, s), 8.48 (1H, br s), 8.39 (1H, d, J = 7.5), 7.95 (1H, d, J = 8.5), 7.81 (2H, m), 7.32-7.46 (6H, m), 7.02 (2H, m), 6.82 (1H, m), 5.19 (1H, br s), 4.91 (1H, m), 4.49 (1H, d, J = 9.0), 4.42 (1H, t, J = 9.0), 4.35 (2H, br s), 4.27 (1H, br s), 4.01 (3H, br s), 3.11 (1H, q, J = 7.0), 2.81-2.91 (4H, m), 2.46 (3H, s), 2.01-2.22 (10H, m), 1.77-1.92 (5H, m), 1.64 (1H, m), 1.51 (1H, m), 1.37 (3H, d, J = 7.0), 1.03 (3H, m), 0.92 (14H, m), 0.71 (2H, br s), 0.60 (1H, br s).

[0732] Example 34

[0733] The ammonium salt of compound 34 was prepared according to the procedure described in Reference Example 1 by replacing intermediate 1-19 in Example 1, step 20 with compound 20-1 and replacing intermediate 1-11 in Example 1, step 22 with compound 3-2. LC-MS: m / z 1321.3 (M+H) + .

[0734] Example 35

[0735] The ammonium salt of compound 35 was prepared according to the procedure described in Reference Example 1 by replacing intermediate 1-20 in Example 1, step 21 with compound 30-1 and replacing intermediate 1-11 in Example 1, step 22 with compound 2-14. LC-MS: m / z 1279.5 (M+H) + .

[0736] Example 36

[0737] The ammonium salt of compound 36 was prepared according to the procedure described in Reference Example 1 by replacing intermediate 1-20 in Example 1, step 21 with compound 30-1 and replacing intermediate 1-11 in Example 1, step 22 with compound 3-2. LC-MS: m / z 1347.8 (M+H) + .

[0738] Example 37

[0739] The ammonium salt of compound 37 was prepared according to the procedure of Reference Example 1, replacing intermediate 1-20 in Example 1, step 21 with compound 30-1, and replacing intermediate 1-11 in Example 1, step 22 with compound 33-2. LC-MS: m / z 1293.7 (M+H) + . 1 H-NMR (DMSO-d6+D2O) δ 8.97 (1H, s), 8.84 (1H, s), 8.53 (1H, d, J = 8.0), 8.07 (1H, s), 7.95 (1H, d, J = 9.0), 7.45 (3H, m), 7.37 (3H, m), 7.21 (1H, t, J = 8.0), 6.99 (1H, d, J = 8.0), 6.93 (1H, d, J = 7.5), 5.43 (1H, s), 5.20 (1H, s), 4.92 (1H, m), 4.44 (1H, t, J = 8.5), 4.30-4.34 (3H, m), 4.04 (3H, s), 3.69 (1H, m), 3.10 (1H, q, J = 7.5), 2.68-2.92 (8H, m), 2.46 (3H, s),, 2.21 (2H, t, J = 7.5), 2.09 (3H, m), 1.76-1.92 (7H, m), 1.63 (1H, m), 1.52 (1H, m), 1.39 (3H, d, J = 7.0), 0.96-1.05 (13H, m), 0.61-0.70 (3H, m).

[0740] Example 38

[0741] The ammonium salt of compound 38 was prepared according to the procedure of Reference Example 1, replacing intermediate 1-20 in Example 1, step 21 with compound 38-1, and replacing intermediate 1-11 in Example 1, step 22 with compound 33-2. LC-MS: m / z 1307.6 (M+H) + .

[0742] Example 39

[0743] The ammonium salt of compound 39 was prepared according to the procedure of Reference Example 1, replacing intermediate 1-20 in Example 1, step 21 with compound 39-1, and replacing intermediate 1-11 in Example 1, step 22 with compound 33-2. LC-MS: m / z 1319.7 (M+H)+.

[0744] Example 40

[0745] Following the procedure for the preparation of Reference Example 1, intermediate 1-20 in Step 21 of Example 1 was replaced with compound 40-1 and intermediate 1-11 in Step 22 of Example 1 was replaced with compound 33-2 to provide the ammonium salt of compound 40. LC-MS: m / z 1305.7 (M+H)+.

[0746] Example 41

[0747] Following the procedure for the preparation of Reference Example 1, intermediate 1-20 in Step 21 of Example 1 was replaced with compound 41-1 and intermediate 1-11 in Step 22 of Example 1 was replaced with compound 33-2 to provide the ammonium salt of compound 41. LC-MS: m / z 1291.7 (M+H)+.

[0748] Example 42

[0749] Following the procedure for the preparation of Reference Example 1, intermediate 1-20 in Step 21 of Example 1 was replaced with compound 42-1 and intermediate 1-11 in Step 22 of Example 1 was replaced with compound 33-2 to provide the ammonium salt of compound 42. LC-MS: m / z 1311.5 (M+H)+.

[0750] Example 43

[0751] Following the procedure for the preparation of Reference Example 1, intermediate 1-20 in Step 21 of Example 1 was replaced with compound 43-1 and intermediate 1-11 in Step 22 of Example 1 was replaced with compound 33-2 to provide the ammonium salt of compound 43. LC-MS: m / z 1291.7 (M+H)+.

[0752] Example 44

[0753] Following the procedure for the preparation of Reference Example 1, intermediate 1-20 in Step 21 of Example 1 was replaced with compound 44-1 and intermediate 1-11 in Step 22 of Example 1 was replaced with compound 33-2 to provide the ammonium salt of compound 44. LC-MS: m / z 1307.6 (M+H)+.

[0754] Example 45

[0755] The ammonium salt of compound 45 was prepared according to the procedures described in Reference Example 1, replacing intermediate 1-20 in Example 1, step 21 with compound 45-1, and replacing intermediate 1-11 in Example 1, step 22 with compound 33-2. LC-MS: m / z 1305.7 (M+H)+.

[0756] Example 46

[0757] The ammonium salt of compound 46 was prepared according to the procedures described in Reference Example 1, replacing intermediate 1-20 in Example 1, step 21 with compound 45-1. LC-MS: m / z 1319.6 (M+H)+.

[0758] Experimental Example 1: SU-DHL-1 cell proliferation inhibition activity determination

[0759] Take the SU-DHL-1 cells in good growth state, collect into centrifuge tubes, adjust the cell density to 5x10 4 6 / mL, inoculate on 96-well plates (100 μL / well), at the same time use nanoliter sample injector for compound addition, use solvent DMSO to prepare compound solution, and dilute with DMSO to make the final concentration of the compound 2000 nM-0.91 nM (3-fold gradient dilution), 2 replicate wells, at the same time set up controls (add the same volume of solvent). After 72 hours of continuous culture in the cell incubator, add detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well), incubate in the cell incubator for 3 hours, then detect the absorbance value at 450 nm by PerkinElmer Envision microplate reader, analyze by four parameters, fit the dose-effect curve, and calculate the IC 50 .

[0760] The experimental results of some of the compounds of the present application are shown in Table 1.

[0761] Table 1 Note: A represents ≤10 nM; B represents >10 nM and ≤50 nM; C represents >50 nM and ≤100 nM.

[0762] It can be seen that the compounds of the examples of the present application can exhibit good antitumor activity.

[0763] Experimental Example 2: In vitro cell STAT3 degradation activity determination

[0764] Take the SU-DHL-1 cells in good growth state, collect into centrifuge tubes, adjust the cell density to 5x10 5Compound solution was prepared with solvent DMSO, diluted with DMSO to make the final concentration of compound 1000 nM-0.061 nM (4-fold gradient dilution), 2 replicates, and controls were set (the same volume of solvent was added). After 24 hours of incubation in the cell incubator, the supernatant was discarded, 4% paraformaldehyde (40 μL / well) was added for incubation at room temperature for 20 min, then ice methanol (40 μL / well) was added for incubation at 4°C for 10 min, and PBST was used for washing. After 1 hour of incubation at room temperature after the addition of 5% BSA blocking buffer (20 μL / well), a mixture of STAT3 antibody and GAPDH antibody (20 μL / well) was added for incubation at 4°C overnight, and PBST was used for washing. A mixture of 800 nm and 680 nm fluorescent antibodies (20 μL / well) was added for incubation at room temperature in the dark for 45 min, and PBST was used for washing. The fluorescence values were detected by Azure Multimode Laser Scanning Instrument, four-parameter analysis was performed, the dose-effect curve was fitted, and the DC 50 .

[0765] The experimental results of some compounds of the present application are shown in Table 2.

[0766] Table 2 Note: A represents ≤10 nM; B represents >10 nM and ≤50 nM.

[0767] It can be seen that the compounds of the embodiments of the present application can have good STAT3 degradation activity.

[0768] Experimental Example 3 In vitro liver microsomal stability test

[0769] The liver microsomal incubation sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), test compound and NADPH+MgCl2solution, and incubated 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 with an internal standard acetonitrile solution for protein precipitation to prepare supernatant, and after dilution, it was used for LC / MS / MS determination.

[0770] The experimental results of some compounds of the present application are shown in Table 3.

[0771] Table 3

[0772] Experimental Example 4 In vivo pharmacokinetics

[0773] ICR mice, body weight 18-22 g, after 3-5 days of adaptation, were randomly divided into groups, 9 mice in each group, and were respectively injected intravenously with a solution of the compound of the example (the solvent was DMSO:PEG400:D5W=2:48:50, v / v) at a dose of 1 mg / kg.

[0774] The time points for blood sampling by intravenous injection were 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 1 h, 2 h, 4 h, 6 h, 8 h, 24 h after administration, and blood was taken from the eye socket to prepare the test plasma sample.

[0775] 30 μL of the test plasma sample was taken, and a methanol solution containing an internal standard was added to precipitate the protein to obtain supernatant, which was diluted and used for LC / MS / MS determination.

[0776] Conclusion: The compound in the example of the application can have good pharmacokinetic properties in mice, such as better plasma drug exposure, longer half-life or higher absolute bioavailability.

[0777] Experimental Example 5 Pharmacodynamics in mice: pharmacodynamic evaluation in a SU-DHL-1 human anaplastic large cell lymphoma NOD-SCID mouse subcutaneous transplanted tumor model

[0778] SPF female NOD-SCID mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) were inoculated subcutaneously with SU-DHL-1 cells in the right axillary fossa at 1×10 7 / each, and were F1 generation. The F1 generation mice tumor tissues were used to pass the block method (F2) and were inoculated in the right axillary fossa of NOD-SCID mice. When the average volume of the tumor reached 100-150 mm 3 , the animals were grouped.

[0779] The grouping day was day 0 (d0), and the intravenous injection was administered once a week from day 0. The tumor volume was measured 2-3 times a week, and the mice were weighed, and the data were recorded; the general performance of the mice was observed and recorded daily. After the end of the experiment, the tumors were stripped and weighed, and photographs were taken.

[0780] The detection indexes and calculation formulas are as follows:

[0781] Tumor volume, TV (mm 3 ) = 1 / 2 × (a × b 2 ); wherein a is the long diameter of the tumor, and b is the short diameter of the tumor.

[0782] Relative tumor volume, RTV = TV t / TV0; wherein TV0 is the tumor volume on day 0, and TV t is the tumor volume at each measurement.

[0783] Tumor volume inhibition rate is TGI(TV)(%), TGI(%) = [1-(T-T0) / (C-C0)]x100%; tumor weight inhibition rate is TGI(TW)(%), TGI(%) = (1-TWt / TWc)x100%, wherein, T: tumor volume mean value of treatment group; T0: tumor volume mean value of treatment group at d0; C: tumor volume mean value of control group; C0: tumor volume mean value of control group at d0; TW t : tumor weight of treatment group; TW c : tumor weight of control group.

[0784] Body weight change rate BWC(%) = (Wt t -Wt0) / Wt0x100%; wherein, Wt0 is the body weight of animal at day 0, Wt t is the body weight of animal at each measurement.

[0785] Conclusion: The compound in the embodiments of the present application can exhibit good efficacy in the above mouse model, for example, higher tumor volume inhibition rate (for example, TGI(TV)(%) of 16 days >70% at a dosage of 4 mg / kg) and / or tumor weight inhibition rate (for example, TGI(TW)(%) of 16 days >70% at a dosage of 4 mg / kg), and lower body weight change rate.

Claims

1. A compound of formula (I’), or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from optionally substituted 3-6 membered cycloalkyl, 4-6 membered cycloalkenyl, or 4-6 membered heterocyclyl; A substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substit Ring B is selected from optionally substituted 4-12 membered heterocyclyl; B substituted 4-12 membered heterocyclyl; Ring C is selected from optionally substituted 4-12 membered heterocyclyl; C substituted 4-12 membered heterocyclyl; Ring D is selected from optionally substituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; D substituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Each R A R B R C 、or R D Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1- 6-alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, Halogenated diC 1-6 Alkylamino, -C(O)C 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl group, -NHC(O)C 1- 6-alkyl, -N(C) 1-6 Alkyl)C(O)C 1-6 Alkyl group, -C(O)NHC 1-6 Alkyl, -C(O)N(C) 1-6 Alkyl)2、-SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C) 1-6 Alkyl)SO2C 1-6 Alkyl group, -SO2NHC 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl group 2, -C(O)-(3-6 membered cycloalkyl group), -C(O)-(3-6 membered cycloalkenyl group) or -C(O)-(4-6 membered heterocyclic group); Q is selected from -0-, -S-, -S(O)-, -S(0)2-, -NR Q -, -C(O)-, or -C(R Q )2-; Each R Q Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; Y 1 selected from OR P1 or N(R P1 )2; Y 2 selected from OR P2 or N(R P2 )2; R P1 R P2 Each is independently selected from H, deuterium, or arbitrarily selected by one or more R. P3 Replacement C 1-6 Alkyl, or optionally with one or more R P4 The following groups may be substituted: 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; or R P1 , R P2 , together with the atom to which they are attached, form a 4-12 membered heterocyclyl optionally substituted with one or more R P5 substituents; Each R P3 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, or optionally influenced by one or more R. P3a The following groups are substituted: C 1-12 Alkoxy, C 1-12 Alkylamino, diC 1-12 Alkylamino, -C(O)C 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl group, -NHC(O)C 1-12 Alkyl, -N(C) 1-6 Alkyl)C(O)C 1-12 Alkyl group, -C(O)NHC 1- 12 Alkyl, -C(O)N(C) 1-12 alkyl)2、-NHC(O)NHC 1-12 Alkyl, -SO2C 1-12 Alkyl, -S(O)C 1-12 Alkyl, -NHSO2C 1-12 Alkyl group, -NHS(O)C 1-12 Alkyl, -N(C) 1-6 Alkyl)SO2C 1-12 Alkyl group, -SO2NHC 1-12 Alkyl group, -S(O)NHC 1-12 Alkyl group, -SO2N(C) 1-12 Alkyl)2, S(O)N(C 1-12 Alkyl)2、-SC(O)C 1-12 Alkyl, -C(O)C 0-6 Alkylene (4-6 membered heterocyclic group), -C(O)OC 0-6 Alkylene (4-6 membered heterocyclic group), -OC(O)C 0-6 Alkylene (4-6 membered heterocyclic group), -OC(O)OC 0-6 Alkylene (4-6 membered heterocyclic group), -SC(O)C 0-6 Alkylene (4-6 membered heterocyclic group), -C(O)C 0-6 Alkylene (3-6 membered cycloalkyl), -C(O)OC 0-6 Alkylene (3-6 membered cycloalkyl), -OC(O)C 0-6 Alkylene (3-6 membered cycloalkyl), -OC(O)OC 0-6 Alkylene (3-6 membered cycloalkyl), -SC(O)C 0-6 Alkylene (3-6 membered cycloalkyl), -C(O)C 0-6 alkylene phenyl, -C(O)OC 0-6 alkylene phenyl, -SC(O)C 0-6 alkylene phenyl, -C(O)OC 0-6 alkylene (5-6 membered heteroaryl), or -SC(O)C 0-6 alkylene (5-6 membered heteroaryl); each R P3a are each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-3 alkoxy, C 1-3 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1- 6alkoxy, halo-C 1-3 alkoxy, C 1-3 alkoxy, halo-C 1-6 alkylamino, or halo-di-C 1-6 alkylamino; Each R P4 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; each R P5 each independently is selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is a substituted or unsubstituted group selected from C P5a alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Each R P5a Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; R 1 selected from H, deuterium, or is optionally substituted C 1a alkyl; and n is 1 or 2. 1-6 alkyl; and n is 1 or 2. Each R 1a Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, -COOH, -C(O)NH2, -SO2NH2, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, Halogenated diC 1- 6-alkylamino, -C(O)C 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl, -N(C) 1-6 Alkyl)C(O)C 1-6 Alkyl group, -C(O)NHC 1-6 Alkyl, -C(O)N(C) 1-6 alkyl)2、-NHC(O)NHC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C) 1-6 Alkyl)SO2C 1-6 Alkyl group, -SO2NHC 1-6 Alkyl, or -SO2N(C 1-6 Alkyl)2; - L- is selected from -LNK 1 - Cy 1 - LNK 2 - Cy 2 - LNK 3 - ; LNK 1 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK1 substituted with one or more R 1-12 alkylene, C 2-12 alkenylene, C 2-12 alkynylene, C 1-12 heteroalkylene, C 1-12 heteroalkenylene, or C 2-12 heteroalkynylene; LNK 2 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK2 The following groups are substituted: C 1-12 Alkylene, C 2-12 imidene group, C 2-12 Ethyne group, C 1-12 Heteroalkylene, C 1-12 Heteroeneyl, or C 2-12 Hetero-ynyl group; LNK 3 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 substituted alkyl, C 1-12 substituted alkenyl, C 2-12 substituted alkynyl, C 2-12 substituted alkenyl, C 1-12 substituted alkynyl, C 1-12 substituted alkenyl, C 2-12 substituted alkynyl, C Each R LNK1 R LNK2 、or R LNK3 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, or optionally influenced by one or more R. LNKa The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-4 Alkylene, 3-12 membered cycloalkenyl C 1-4 Alkylene, 4-12 membered heterocyclic C 1-4 Alkylene, 6-10 aryl C 1-4 alkylene or 5-10 heteroaryl C 1-4 Alkylene; Each R LNKa Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; Cy 1 is selected from a single bond, or a group optionally substituted with one or more R Cy1 substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more Cy 2 is selected from a single bond, or a group optionally substituted with one or more R Cy2 substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more each R Cy1 or R Cy2 each independently is selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1- 6alkylamino, or halogenated di-C 1-6 alkylamino; ULM is selected from - L A - is selected from a single bond, -O-, -S-, -NR A1 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR LA1 -, -NR LA1 C(O)-, -NR LA1 C(O)NR LA1 -, -S(O)-, -S(O)2-, -S(O)2NR LA1 -, -NR LA1 S(O)2-, or optionally substituted with one or more R LA2 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; each R LA1 are each independently selected from H, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, or halogenated C 1-6 alkyl; Each R LA2 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; R 2 is selected from H, deuterium, or is optionally substituted with one or more R 2a substituted C 1-6 alkyl, 3-6 membered cycloalkyl, -3-6 membered cycloalkenyl, or 4-6 membered heterocyclyl; Each R 2a Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; X 1 , X 2 , or X 3 is each independently selected from a single bond, -O-, -S-, -S(O)-, -S(O)2-, -NR XA -, -C(O)-, or -C(R XA )2-; Each R XA Each is independently selected from H, deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6-alkylamino, di-C 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, Halogenated diC 1-6 alkylamino or hydroxy C 1-6 alkyl; Or, two Rs XA Together they form an optional combination of one or more R XA1 The following groups are substituted: 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl; Each R XA1 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; Ring E is selected from 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Each R E Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, or optionally influenced by one or more R. E1 The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; Each R E1 Each is independently selected from deuterium, oxo, thio, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; n is selected from 0, 1, 2, 3, 4, or 5; Ring F is selected from 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-12 membered heteroaryl; each R F are each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, or is a group selected from C F1 substituted alkyl, C 1-6 substituted alkoxy, C 1-6 substituted alkyl, C 1-6 substituted alkyl, C 1-6 substituted alkyl, C each R F1 are each independently selected from deuterium, oxo, thioxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC m is selected from 0, 1, 2, 3, 4, or 5; R A , R B , R C , R D , R Q , R P3 , R 1a , R LNKa , R Cy1 , R Cy2 , R LA1 , R LA2 , R 2a , R XA , R XA1 , R E1 , or R F1 is optionally substituted with one or more substituents.

2. The compound of formula (I') according to claim 1, wherein Ring A is selected from optionally substituted 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl; A substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R Alternatively, ring A can be selected from one or more R's. A The following groups may be substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, or piperazineyl; Alternatively, ring A can be selected from one or more R's. A The following groups are substituted: cyclopropyl or cyclobutyl; or, Ring A is selected from cyclopropyl or cyclobutyl; or, ring B is selected from optionally substituted 4-10 membered heterocyclyl; B substituted 4-10 membered heterocyclyl; or, ring B is selected from optionally substituted 6-9 membered heterocyclyl; B substituted 6-9 membered heterocyclyl; or, ring B is selected from optionally substituted B substituted piperidinyl, piperazinyl, azepanyl, diazepanyl, azocanyl, diazocanyl, azonanyl, or diazonanyl; Alternatively, ring B can be selected from oxidized, -C(O)CH3, methyl, ethyl, or other compounds. substituted with azacyclooctane or diazacyclooctane; or, ring C is selected from optionally substituted 4-10 membered heterocyclyl; C substituted 4-10 membered heterocyclyl; or, ring C is selected from optionally substituted 4-7 membered heterocyclyl; C substituted 4-7 membered heterocyclyl; or, ring C is selected from optionally substituted C substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with or, Ring C is selected from tetrahydropyrrolyl; or a structural unit of formula (II) selected from the group consisting of or a structural unit of formula (II) selected from the group consisting of or a structural unit of formula (II) selected from the group consisting of or a structural unit of formula (II) selected from the group consisting of 3. The compound of formula (I') according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, selected from the group consisting of optionally substituted 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; D substituted 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; or, Ring D is selected from optionally substituted 5-10 membered cycloalkyl, 5-10 membered cycloalkenyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; D substituted 5-10 membered cycloalkyl, 5-10 membered cycloalkenyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Alternatively, ring D is selected from one or more R. D The following groups are substituted: phenyl, naphthyl, benzo5-6 heteroaryl, or 5-6 heteroaryl-5-6 heteroaryl; Alternatively, ring D is selected from one or more R. D The following groups may be substituted: naphthyl, benzopyrroleyl, benzopyrazolyl, benzoimidazolyl, benzofuranyl, benzooxazolyl, benzothiophenyl, benzothiazolyl, benzopyridyl, or benzopyrimidinyl; or, Ring D is selected from optionally substituted D substituted wherein, U is O, S or NH or, Ring D is selected from the group consisting of optionally substituted: D substituted as follows: Alternatively, ring D is selected from wherein, U is O, S or NH; Alternatively, ring D is selected from wherein, is connected to Q.

4. The compound of formula (I') according to any one of claims 1 to 3, wherein R P1 , R P2 each independently is selected from H, deuterium, C P3 1-6 alkyl, or is a group optionally substituted with one or more R 1-4 each independently is selected from H, deuterium, C P4 1-6 alkyl, or is a group optionally substituted with one or more R P1 , R P2 and the atom to which they are attached to form a 4-10 membered heterocyclyl group optionally substituted with one or more R P5 each independently is selected from H, deuterium, C 1-6 alkyl, or is a group optionally substituted with one or more R or R P1 , R P2 are each independently selected from H, deuterium, C P3 1-6 alkyl, or is a group optionally substituted with one or more R 1-4 1-6 alkyl, or is a group optionally substituted with one or more R P4 1-6 alkyl, or is a group optionally substituted with one or more R P1 1-6 alkyl, or is a group optionally substituted with one or more R P2 1-6 alkyl, or is a group optionally substituted with one or more R P5 1-6 alkyl, or is a group optionally substituted with one or more R or R P1 , R P2 each independently is selected from H, deuterium, or is a group optionally substituted with one or more R P3 methyl, ethyl, n-propyl or i-propyl, or is a group optionally substituted with one or more R P4 phenyl or naphthyl; or R P1 , R P2 together with the atom to which they are attached form a group optionally substituted with one or more R P5 methyl, ethyl, n-propyl or i-propyl, or is a group optionally substituted with one or more R or R P1 or R P2 are each independently selected from H, deuterium, methyl, ethyl, or R P1 or R P2 with the atom to which they are attached, form or a structural unit of formula (II) selected from the group consisting of 5. The compound of formula (I) according to any one of claims 1 to 4, wherein, ###00002### (I) or a pharmaceutically acceptable salt thereof. R 1 selected from H, deuterium, or is optionally substituted C 1a alkyl; and n is 1 or 2. 1-4 alkyl; and n is 1 or 2. or R is selected from H, deuterium, or is optionally substituted C 1 alkyl; R is selected from H, deuterium, or is optionally substituted C 1a alkyl; R is selected from H, deuterium, or is optionally substituted C 1-3 alkyl; R is selected from H, deuterium, or is optionally substituted C or R is selected from H, deuterium, or is optionally substituted with one or more R 1 substituted with one or more R 1a substituted with one or more R Or, R 1 Selected from H, deuterium, or arbitrarily selected by one or more R 1a Substituted ethyl groups; or R 1 selected from 6. The compound of formula (I') according to any one of claims 1 to 5, wherein LNK 1 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK1 The following groups are substituted: C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 1-6 Heteroalkylene, C 1-6 Heteroeneyl, or C 2-6 Hetero-ynyl group; Or, LNK 1 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK1 The following groups are substituted: C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 2-3 Heteroeneyl, or C 2-3 Hetero-ynyl group; or LNK 1 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK1 -CH2-, -CH2CH2-, -CH=CH-, -CH2CH=CH-, -CH=CHCH2-, -C≡C-, -CH2C≡C-, -C≡CCH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -CH2OCH2CH2-, -CH2CH2OCH2-, -OCH2CH2CH2-, -CH2CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, -CH2CH2NH-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, -NHCH2CH2CH2-, -CH2CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2CH≡CH-, -CH≡CHCH2O-, -NHCH2CH≡CH-, or -CH≡CHCH2NH-; or LNK 1 is selected from a single bond, -O-, or is optionally substituted with one or more R LNK1 substituted with one or more R or LNK 1 selected from a single bond, -CH2O-, -C(O)O-, -CH2NHCH2CH2-, -C(O)NHCH2C(O)-, or LNK 2 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 substituted with one or more R 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 heteroalkylene, C 1-8 heteroalkenylene, or C 2-8 heteroalkynylene; or LNK 2 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 substituted with one or more R 3-5 alkylene, C 3-5 alkenylene, C 3-5 alkynylene, C 2-5 heteroalkylene, C 2-5 heteroalkenylene, or C 2-5 heteroalkynylene; or LNK 2 is selected from a single bond, -0-, -S-, -NH-, or is optionally substituted with one or more R LNK2 -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH=CH-, -CH=CHCH2-, -CH2CH=CHCH2-, -CH2CH2CH=CH-, -CH=CHCH2CH2-, -CH2C≡C-, -C≡CCH2-, -CH2C≡CCH2-, -CH2CH2C≡C-, -C≡CCH2CH2-, -CH2CH2CH2C≡C-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -CH2OCH2CH2-, -CH2CH2OCH2-, -OCH2CH2CH2-, -CH2CH2CH2O-, -CH2CH2CH2CH2O-, -CH2NHCH2-, -NHCH2CH2-, -CH2CH2NH-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, -NHCH2CH2CH2-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2CH≡CH-, -CH≡CHCH2O-, -NHCH2CH≡CH-, or -CH≡CHCH2NH-; or LNK 2 is selected from a single bond, -O-, or is optionally substituted with one or more R LNK2 substituted -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CºC-, or -CH2CH2CH2O-; or LNK 2 is selected from a single bond, -0-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CºC-, or -CH2CH2CH2O-; Or, LNK 3 Selected from single bonds, -O-, -S-, -NH-, or optionally by one or more R LNK3 The following groups are substituted: C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 1-6 Heteroalkylene, C 1-6 Heteroeneyl, or C 2-6 Hetero-ynyl group; or LNK 3 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 substituted C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, C 1-3 heteroalkylene, C 2-3 heteroalkenylene, or C 2-3 heteroalkynylene; or LNK 3 is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 -CH2-, -CH2CH2-, -CH=CH-, -CH2CH=CH-, -CH=CHCH2-, -C≡C-, -CH2C≡C-, -C≡CCH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -CH2OCH2CH2-, -CH2CH2OCH2-, -OCH2CH2CH2-, -CH2CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, -CH2CH2NH-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, -NHCH2CH2CH2-, -CH2CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2CH≡CH-, -CH≡CHCH2O-, -NHCH2CH≡CH-, or -CH≡CHCH2NH-; or LNK 3 is selected from a single bond, -O-, or is optionally substituted with one or more R LNK3 substituted -CH2-, -CH2CH2-, -CºC-, -CH2CºC-, or -CH2O-; or LNK 3 is selected from a single bond, -0-, -CH2-, -CH2CH2-, -CºC-, -CH2CºC-, or -CH2O-; or -L- is selected from f is 1, 2 or 3; or -L- is selected from wherein each R Cy1 each is independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-6 alkyl, or haloC 1-6 alkyl, k1 is 0, 1, 2, or 3, f is 1, 2, or 3, g is 1, 2, 3, 4, 5, or 6, and h is 0 or 1.

7. The compound of Formula (I') according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein, Cy 1 is selected from a single bond, or a group optionally substituted with one or more R Cy1 substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more Or, Cy 1 Selected from a single key, or optionally by one or more R keys Cy1 The following groups are substituted: 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 4-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; Or, Cy 1 Selected from a single key, or optionally by one or more R keys Cy1 The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, azacyclobutyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; Or, Cy 1 Selected from a single key, or optionally by one or more R keys Cy1 The following groups are substituted: piperidinyl or phenyl; or Cy is selected from a single bond, 1 selected from a single bond, Or, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups may be substituted: 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; Or, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups are substituted: 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 4-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; or, Cy is selected from the group consisting of a single bond, or optionally substituted: cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; 2 or, Cy is selected from the group consisting of a single bond, or optionally substituted: cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; Cy2 or, Cy is selected from the group consisting of a single bond, or optionally substituted: cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperid Or, Cy 2 Selected from a single key, or optionally by one or more R keys Cy2 The following groups are substituted: piperidinyl or phenyl; or Cy is selected from the group consisting of a single bond, 2 is selected from the group consisting of a single bond, 8. The compound of formula (I') according to any one of claims 1 to 7, wherein - L A - is selected from a single bond, -O-, -S-, -NR A1 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR LA1 -, -NR LA1 C(O)-, -NR LA1 C(O)-, -NR LA1 -, -S(O)-, -S(O)2-, -S(O)2NR LA1 -, -NR LA1 S(O)2-, or is optionally substituted with one or more R LA2 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Or, -L A - Selected from single bond, -O-, -S-, -NR A1 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR LA1 -、-NR LA1 C(O)-、-NR LA1 C(O)NR LA1 -, -S(O)-, -S(O)2-, -S(O)2NR LA1 -、-NR LA1 S(O)2-, or optionally by one or more R LA2 The following groups are substituted: 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 4-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; Or, -L A - Selected from single bond, -O-, -S-, -NR A1 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR LA1 -、-NR LA1 C(O)-、-NR LA1 C(O)NR LA1 -, -S(O)-, -S(O)2-, -S(O)2NR LA1 -、-NR LA1 S(O)2-, or optionally by one or more R LA2 The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, azircyclobutyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazine, morpholinyl, dihydrofuranyl, dihydropyrrolyl, dihydrooxazolyl, dihydrothiazolyl, dihydropyridinyl, tetrahydropyridinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazine, or pyridazine; or, -L A - is selected from a single bond, -C(O)O-, -OC(O)-, -C(O)NR LA1 -, -NR LA1 C(O)-, -S(O)2NR LA1 -, -NR LA1 S(O)2-, or a group selected from pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, or isothiazolyl optionally substituted with one or more R LA2 groups; or, -L A - is selected from a single bond, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH-, -NHS(O)2-, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, or isothiazolyl; or, -L A - is selected from a single bond, -C(O)NH-, 9. The compound of Formula (I') according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein, X 1 , X 2 , or X 3 is each independently selected from a single bond, -O-, -NR XA -, -C(O)-, or -C(R XA )2-; or X 1 , X 2 , or X 3 are each independently selected from -C(O)- or -C(R XA )2-; or X 1 , X 2 , or X 3 are each independently selected from -C(O)-, -CH2-, -C(CH3)2-, or X 1 or X 2 is selected from -C(O)-; or X is -CH2-, 3 selected from -CH2-, 10. The compound of Formula (I') according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein, Ring E is selected from 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; or, Ring E is selected from 5-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 4-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or, Ring E is selected from phenyl or 5-6 membered heteroaryl; or, Ring E is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; or, Ring E is selected from phenyl; or a structural unit selected from the group consisting of or a structural unit of formula (II) selected from the group consisting of R E selected from ethynyl, 11. The compound of Formula (I') according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein, Ring F is selected from 9-12 membered heterocyclyl, 6-10 membered aryl, or 9-12 membered heteroaryl; or, Ring F is selected from benzo 5-6 membered heterocycloalkenyl, naphthyl, or benzo 5-6 membered heteroaryl; or, Ring F is selected from dihydrobenzimidazolyl, dihydroindolyl, dihydroisoindolyl, naphthyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, benzopyridinyl, or benzopyrimidinyl; Alternatively, ring F is selected from Alternatively, ring F is selected from wherein With is connected to Q. Alternatively, ring F is selected from wherein With is connected to Q. Alternatively, formula (B) is selected from 12. The compound of Formula (I') according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, selected from a compound of Formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, ring A, R B , R C , ring D, Q, Y 1 , Y 2 , R 1 , -L- and ULM are as described in any one of claims 1-11; Z is selected from NH or CH2; b1or b2are each independently selected from 0, 1, 2, or 3, and b1+b2≤ 3; c1is selected from 0, 1, 2, or 3; p is selected from 0, 1, 2, 3, or 4; q is selected from 0, 1, or 2; or it is selected from a compound of Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Rings A, R B R C Rings D, Q, R P1 R P2 R 1 -L- and ULM are as defined in the present disclosure; Z is selected from NH or CH2; b1or b2are each independently selected from 0, 1, 2, or 3, and b1+b2≤ 3; c1is selected from 0, 1, 2, or 3; p is selected from 0, 1, 2, 3, or 4; q is selected from 0, 1, or 2; or it is selected from the group consisting of a compound of Formula (II-1), Formula (II-1'), Formula (II-2), Formula (II-2'), Formula (III-1), Formula (III-1'), Formula (III-2), Formula (III-2'), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, R B , R C , p, q, ring D, Q, R P1 , R P2 , Y 1 , Y 2 , R 1 , -L- and ULM are as described in any one of claims 1 to 11.

13. A compound of Formula (I') according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, selected from the following compounds or a pharmaceutically acceptable salt thereof: or it is selected from the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

14. A pharmaceutical composition comprising a compound of Formula (I’) or a pharmaceutically acceptable salt thereof as described in any one of claims 1-13; optionally, further comprising a pharmaceutically acceptable excipient.

15. A compound of Formula (I’) or a pharmaceutically acceptable salt thereof as described in any one of claims 1-13 or a pharmaceutical composition of claim 14 for use in the treatment of a STAT3 related disease.

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