Fused heterocyclic compound and use thereof

Abstract

The present application relates to the field of medical chemistry, and relates to a fused heterocyclic compound, a stereoisomer or pharmaceutically acceptable salt thereof, and a use thereof, wherein the fused heterocyclic compound has a structure as shown in formula (I). Specifically, the present application further relates to a preparation method for the compound or a stereoisomer or pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising same, and a use thereof in the treatment of a disease.

Description

Fused heterocyclic compounds and uses thereof

[0001] Reference to Related Applications

[0002] This application claims priority to and the benefit of Chinese Patent Application No. 202410889367.7, filed July 3, 2024, Chinese Patent Application No. 202411295575.0, filed September 14, 2024, Chinese Patent Application No. 202510663274.7, filed May 21, 2025, and Chinese Patent Application No. 202510848690.4, filed June 23, 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 fused heterocyclic compounds, methods of making the same, pharmaceutical compositions containing the same, and uses thereof in the treatment of diseases. BACKGROUND

[0004] Interleukin-1 Receptor-associated Kinase 4 (IRAK4) belongs to the IRAK kinase family (including IRAK1, IRAK2, IRAK3 and IRAK4), which is a serine / threonine protein kinase. Studies have shown that IRAK4 is a key node for transducing Interleukin-1 receptor (IL-1R) and Toll like receptors (TLRs) signals. Therefore, IRAK-4 plays an important role in immune signaling and is expected to become a therapeutic target for autoimmune diseases, inflammatory diseases and other diseases.

[0005] DETAILED DESCRIPTION

[0006] The present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0007] wherein,

[0008] is selected from

[0009] -L A is selected from -LNK A1 -Cy A1 -LNK A2 -Cy A2-LNK A3 -Cy A3 -LNK A4 -;

[0010] -L B - selected from -LNK B1 -Cy B1 -LNK B2 -Cy B2 -LNK B3 -Cy B3 -LNK B4 -;

[0011] -L C - selected from -LNK C1 -Cy C1 -LNK C2 -Cy C2 -LNK C3 -Cy C3 -LNK C4 -;

[0012] -L D - selected from -LNK D1 -Cy D1 -LNK D2 -Cy D2 -LNK D3 -Cy D3 -LNK D4 -;

[0013] X 1 selected from N or CH;

[0014] Ring A is selected from 5-10 membered cycloalkenyl, 5-10 membered heterocycloalkenyl, or 5-10 membered heteroaryl;

[0015] Ring B is selected from phenyl;

[0016] X 2 selected from CH2or C(O);

[0017] each R A , R B , R C , or R D is independently selected from deuterium, oxo, 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 halodicarbon 1-6 Alkylamino;

[0018] p1, p2, p3, or p4 are each independently selected from 0, 1, 2, or 3;

[0019] LNK A1 LNK B1 LNK C1 or LNK D1 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. 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;

[0020] LNK A2 LNK B2 LNK C2 or LNK D2 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. LNK2 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;

[0021] LNK A3 LNK B3 LNK C3 or LNK D3 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. 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;

[0022] LNK A4 or LNK B4 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. LNK4 The following groups are substituted: C 1-6 Alkylene, C2-6 imidene group, C 2-6 Ethyne group, C 1-6 Heteroalkylene, C 1-6 Heteroeneyl, or C 2-6 Hetero-ynyl group;

[0023] LNK C4 or LNK D4 Each is independently selected from one or more R options. LNK4 The following groups are substituted: C 2-6 alkyne or C 2-6 Hetero-ynyl group;

[0024] Each R LNK1 R LNK2 R LNK3 、or R LNK4 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, and 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 halodicarbon 1-6 Alkylamino;

[0025] Cy A1 Cy B1 Cy C1 、or Cy D1 Each is independently selected from a single key, or arbitrarily selected by one or more R keys. Cy1 The following groups are substituted: 3-12 membered cycloalkyl, 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkyl, or 4-12 membered heterocycloalkenyl;

[0026] Cy A2 Cy B2 Cy C2 、or Cy D2 Each is independently selected from a single key, or arbitrarily selected by one or more R keys. Cy2 The following groups are substituted: 3-12 membered cycloalkyl, 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkyl, or 4-12 membered heterocycloalkenyl;

[0027] Cy A3 Cy B3 Cy C3 、or Cy D3 Each is independently selected from a single key, or arbitrarily selected by one or more R keys. Cy3The following groups are substituted: 3-12 membered cycloalkyl, 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkyl, or 4-12 membered heterocycloalkenyl;

[0028] Each R Cy1 R Cy2 、or R Cy3 Each is independently selected from deuterium, oxo, 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 halodicarbon 1-6 Alkylamino;

[0029] Each R 1 Each is independently selected from deuterium, halogens, -OH, -SH, -NH2, -CN, -NO2, and 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;

[0030] -L- is selected from -O-, -S-, -NR L1 -、C 1-6 Alkylene, deuterated C 1-6 Alkylene, Halogenated C 1-6 Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -、-NR L1 C(O)-、-NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-, or optionally by one or more R L2 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;

[0031] R L1 Each is independently selected from H, deuterium, and C.1-6 alkyl, deuterated C 1-6 alkyl, or halogenated C 1-6 alkyl;

[0032] each R L2 is each independently selected from deuterium, oxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6alkylamino, 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] each R 2 is each independently selected from deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 6alkylamino, 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;

[0034] 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 optionally substituted with one or more R E substituted with one or more R

[0035] each R E is each independently selected from deuterium, oxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6alkylamino, 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;

[0036] m is selected from 0, 1, or 2;

[0037] n is selected from 0, 1, 2 or 3;

[0038] provided that when M is selected from then -L- is not selected from -C(O)NH-;

[0039] said R A , R B , R C , R D , R LNK1 , R LNK2 , R LNK3 , R LNK4 , R Cy1 , R Cy2 , R Cy3 , R 1 , R L1 , R L2 , R 2 , or R E are optionally substituted with one or more substituents.

[0040] The present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0041] wherein,

[0042] is selected from

[0043] -L A - is selected from -LNK A1 -Cy A1 -LNK A2 -Cy A2 -LNK A3 -Cy A3 -LNK A4 -;

[0044] -L B - is selected from -LNK B1 -Cy B1 -LNK B2 -Cy B2 -LNK B3 -Cy B3 -LNK B4 -;

[0045] -L C - is selected from -LNK C1 -Cy C1 -LNK C2 -Cy C2 -LNK C3 -Cy C3 -LNK C4 -;

[0046] -L D -Selected from-LNK D1 -Cy D1 -LNK D2 -Cy D2 -LNK D3 -Cy D3 -LNK D4 -;

[0047] X 1 Selected from N or CH;

[0048] Cycle A is selected from 5-10 membered cycloalkenyl, 5-10 membered heterocycloalkenyl, or 5-10 membered heteroaryl;

[0049] Ring B is selected from phenyl;

[0050] X 2 Selected from CH2 or C(O);

[0051] Each R A R B R C 、or R D Each is independently selected from deuterium, oxo, 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 halodicarbon 1-6 Alkylamino;

[0052] p1, p2, p3, or p4 are each independently selected from 0, 1, 2, or 3;

[0053] LNK A1 LNK B1 LNK C1 or LNK D1 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. 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;

[0054] LNK A2 LNKB2 , LNK C2 , or LNK D2 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 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;

[0055] LNK A3 , LNK B3 , LNK C3 , or LNK D3 each independently 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;

[0056] LNK A4 or LNK B4 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK4 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;

[0057] LNK C4 or LNK D4 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK4 C 2-6 alkynylene, or C 2-6 heteroalkynylene;

[0058] each R LNK1 , R LNK2 , R LNK3 , or R LNK4 is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6alkylamino, 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;

[0059] Cy A1 , Cy B1 , Cy C1 , or Cy D1 each independently is selected from a single bond, or is optionally substituted with one or more R Cy1 3-12 membered cycloalkyl, 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkyl, or 4-12 membered heterocycloalkenyl;

[0060] Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently is selected from a single bond, or is optionally substituted with one or more R Cy2 3-12 membered cycloalkyl, 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkyl, or 4-12 membered heterocycloalkenyl;

[0061] Cy A3 , Cy B3 , Cy C3 , or Cy D3 each independently is selected from a single bond, or is optionally substituted with one or more R Cy3 3-12 membered cycloalkyl, 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkyl, or 4-12 membered heterocycloalkenyl;

[0062] each R Cy1 , R Cy2 , or R Cy3 each independently is selected from deuterium, oxo, 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;

[0063] each R 1each independently selected from deuterium, oxo, 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 1-6 alkylamino, or halo-di-C 1-6 alkylamino;

[0064] -L- is selected from -O-, -S-, -NR L1 -, C 1-6 alkylene, deuterated C 1-6 alkylene, halo-C 1-6 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -, -NR L1 S(O)2-, or optionally substituted with one or more R L2 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0065] R L1 each independently selected from H, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, or halo-C 1-6 alkyl;

[0066] each R L2 each independently selected from deuterium, oxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 1-6 alkylamino, or halo-di-C 1-6 alkylamino;

[0067] each R 2each independently selected from deuterium, oxo, 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 1-6 alkylamino, or halo-di-C 1-6 alkylamino;

[0068] 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, optionally substituted with one or more R E substituents;

[0069] each R E each independently selected from deuterium, oxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 1-6 alkylamino, or halo-di-C 1-6 alkylamino;

[0070] m is selected from 0, 1, or 2;

[0071] n is selected from 0, 1, 2 or 3;

[0072] provided that when M is selected from -L- is not selected from -C(O)NH-;

[0073] said R A , R B , R C , R D , R LNK1 , R LNK2 , R LNK3 , R LNK4 , R Cy1 , R Cy2 , R 1 , R L1 , R L2 , R 2 , or R E are optionally substituted with one or more substituents.

[0074] In some embodiments, the R A , R B , R C , R D , R LNK1 , R LNK2 , R LNK3 , R LNK4 , R Cy1 , R Cy2 , R Cy3 , R 1 , R L1 , R L2 , R 2 , or R E is optionally substituted with one or more substituents selected from deuterium, 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 heteroaryl C 1-12 alkylene, 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, C 1-12 acyl, C 1-12 acyloxy, carbamate group, C 1-12 amide group, urea group, epoxy group, C 2-12 amide group, urea group, epoxy group, Cester groups, oxo, and thioxo, optionally substituted with one or more substituents selected from a deuterium atom, oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkylamino, halogenated 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 1-12 alkyl)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl C 1-12 alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryl C 1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered aryl C 1-12 alkylene, or 6-10 membered aryloxy.

[0075] In some embodiments, the R A , R B , R C , R D , R LNK1 , R LNK2 , R LNK3 , R LNK4 , R Cy1 , R Cy2 , R Cy3 , R 1 , R L1 , R L2 , R 2 , or RE optionally substituted with one or more substituents selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1- 3alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, or halogenated C 1-3 alkoxy.

[0076] In some embodiments, selected from

[0077] In some embodiments, selected from

[0078] In some embodiments, selected from

[0079] In some embodiments, selected from

[0080] In some embodiments, ring A is selected from 5-8 membered cycloalkenyl, 5-8 membered heterocycloalkenyl, or 5-8 membered heteroaryl.

[0081] In some embodiments, ring A is selected from 5-7 membered cycloalkenyl, 5-8 membered heterocycloalkenyl, or 5-6 membered heteroaryl.

[0082] In some embodiments, ring A is selected from cyclopentenyl, cyclohexenyl, cycloheptenyl, spirooctenyl, dihydrofuranyl, dihydrothienyl, dihydropyrrolyl, dihydrooxazolyl, dihydrothiazolyl, dihydrooxazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydroazepinyl, tetrahydroazepinyl, azaspirooctenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepinyl, azaspiro[3.4]oct-6-enyl, or pyrrolyl.

[0083] In some embodiments, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepinyl, azaspiro[3.4]oct-6-enyl, or pyrrolyl.

[0084] In some embodiments, selected from

[0085] In some embodiments, L A ​​is connected to ring A by a covalent bond.

[0086] In some embodiments, L A is connected to ring B by a covalent bond.

[0087] In some embodiments, is selected from

[0088] In some embodiments, is selected from

[0089] In some embodiments, X 1 is selected from CH.

[0090] In some embodiments, X 1 is selected from N.

[0091] In some embodiments, is selected from

[0092] In some embodiments, L B is connected to the phenyl ring by a covalent bond.

[0093] In some embodiments, is selected from

[0094] In some embodiments, is selected from

[0095] In some embodiments, L C is connected to the phenyl ring by a covalent bond.

[0096] In some embodiments, is selected from

[0097] In some embodiments, X 2 is selected from CH2.

[0098] In some embodiments, X 2 is selected from C(O).

[0099] In some embodiments, is selected from

[0100] In some embodiments, L D is connected to the phenyl ring by a covalent bond.

[0101] In some embodiments, Selected from

[0102] In some implementation schemes, Selected from In some implementation schemes, Selected from

[0103] In some implementation schemes, R A The substitution sites are located on ring A and / or ring B.

[0104] In some implementation schemes, R A The substitution site is on ring A.

[0105] In some implementation schemes, R A The substitution site is on ring B.

[0106] In some implementation schemes, R B R C 、or R D The substitution sites are on the benzene ring.

[0107] In some implementations, each R A R B R C 、or R D Independently selected from deuterium, oxo, 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.

[0108] In some implementations, each R A R B R C 、or R D Independently selected from deuterium, oxo, 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 diC1-3 alkylamino.

[0109] In some embodiments, each R A , R B , R C , or R D is independently selected from deuterium, oxo, -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.

[0110] In some embodiments, each R A , R B , R C , or R D is independently selected from deuterium, -F, -Cl, or methyl.

[0111] In some embodiments, each of p1, p2, p3, or p4 is independently selected from 0, 1, or 2.

[0112] In some embodiments, each of p1, p2, p3, or p4 is independently selected from 0 or 1.

[0113] In some embodiments, is selected from

[0114] In some embodiments, is selected from

[0115] In some embodiments, is selected from

[0116] In some embodiments, is selected from

[0117] In some embodiments, is selected from

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

[0119] In some implementation schemes, LNK A1 LNK B1 LNK C1 or LNK D1 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. 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 2-6 Heteroeneyl, or C 2-6 Hetero-ynyl group.

[0120] In some implementation schemes, LNK A1 LNK B1 LNK C1 or LNK D1 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. LNK1 The 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.

[0121] In some implementation schemes, LNK A1 LNK B1 LNK C1 or LNK D1 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. LNK1 The following groups are substituted: C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 1-4 Heteroalkylene, C 2-4 Heteroeneyl, or C 2-4 Hetero-ynyl group.

[0122] In some implementation schemes, LNK A1 LNK B1 LNK C1 or LNK D1 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. LNK1 The following groups are substituted: C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C1-3 Heteroalkylene, C 2-3 Heteroeneyl, or C 2-3 Hetero-ynyl group.

[0123] In some implementation schemes, LNK A1 LNK B1 LNK C1 or LNK D1 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. 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-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, -C H2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH= CH-, -CH=CHCH2NH-, -OCH2C≡C-, -C≡CCH2O-, -NHCH2C≡C-, -C≡CCH2NH-, -N(CH3)-, or -N(CH2CH3)-.

[0124] In some implementation schemes, LNK A1 LNK B1 LNK C1 or LNK D1 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. 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-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -N HCH2CH2-, -CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2C≡C-, -C≡CCH2O-, -NHCH2C≡C-, or -C≡CCH2NH-. In some implementations, LNK A1LNK B1 LNK C1 LNK D1 each independently is selected from -N(CH3)- or -N(CH2CH3)-. LNK1 each independently is selected from -N(CH3)- or -N(CH2CH3)-.

[0125] In some embodiments, LNK A1 LNK B1 LNK C1 LNK D1 each independently is selected from a single bond, -O-, or is optionally substituted with one or more R LNK1 each independently is selected from -CH2-, -CH2CH2-, -OCH2-, or -CH2O-.

[0126] In some embodiments, LNK A2 LNK B2 LNK C2 LNK D2 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 each independently is selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 heteroalkylene, C 2-6 heteroalkenylene, or C 2-6 heteroalkynylene.

[0127] In some embodiments, LNK A2 LNK B2 LNK C2 LNK D2 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 each independently is selected from 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.

[0128] In some embodiments, LNK A2 LNK B2 LNK C2 LNK D2 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 each independently is selected from C 1-4alkylene, C 2-4 alkenylene, C 2-4 alkynylene, C 1-4 heteroalkylene, C 2-4 heteroalkenylene, or C 2-4 heteroalkynylene.

[0129] In some embodiments, LNK A2 , LNK B2 , LNK C2 , or LNK D2 is each independently selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 alkylene, 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.

[0130] In some embodiments, LNK A2 , LNK B2 , LNK C2 , or LNK D2 is each independently selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 -CH2-, -CH2CH2-, -CH=CH-, -CH2CH=CH-, -CH=CHCH2-, -CºC-, -CH2CºC-, -CºCCH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, -CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2CºC-, -CºCCH2O-, -NHCH2CºC-, -CºCCH2NH-, -N(CH3)-, or -N(CH2CH3)-.

[0131] In some embodiments, LNK A2 , LNK B2 , LNK C2 , or LNK D2 is each independently selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2-CH2-, -CH2CH2-, -CH=CH-, -CH2CH=CH-, -CH=CHCH2-, -CºC-, -CH2CºC-, -CºCCH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, -CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2CºC-, -CºCCH2O-, -NHCH2CºC-, or -CºCCH2NH-. In some embodiments, LNK A2 , LNK B2 , LNK C2 , or LNK D2 each is independently selected from -CH2-, -CH2CH2-, -OCH2-, or -CH2O-. LNK2 each is independently selected from -N(CH3)- or -N(CH2CH3)-.

[0132] In some embodiments, LNK A2 , LNK B2 , LNK C2 , or LNK D2 each is independently selected from a single bond, -O-, -NH-, or is optionally substituted with one or more R LNK2 each is independently selected from -CH2-, -CH2CH2-, -OCH2-, or -CH2O-.

[0133] In some embodiments, LNK A2 , LNK B2 , LNK C2 , or LNK D2 each is independently selected from a single bond, -O-, or is optionally substituted with one or more R LNK2 each is independently selected from -CH2-, -CH2CH2-, -OCH2-, or -CH2O-. A2 , LNK B2 , LNK C2 , or LNK D2 each is independently selected from -NH-.

[0134] In some embodiments, LNK A3 , LNK B3 , LNK C3 , or LNK D3each independently selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 substituted C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 heteroalkylene, C 2-6 heteroalkenylene, or C 2-6 heteroalkynylene.

[0135] In some embodiments, LNK A3 , LNK B3 , LNK C3 , or LNK D3 each independently selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 substituted 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.

[0136] In some embodiments, LNK A3 , LNK B3 , LNK C3 , or LNK D3 each independently selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 substituted C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, C 1-4 heteroalkylene, C 2-4 heteroalkenylene, or C 2-4 heteroalkynylene.

[0137] In some embodiments, LNK A3 , LNK B3 , LNK C3 , or LNK D3 each independently 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.

[0138] In some embodiments, LNK A3 , LNK B3 , LNK C3 , or LNK D3 is each independently 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-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, -CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2C≡C-, -C≡CCH2O-, -NHCH2C≡C-, or -C≡CCH2NH-.

[0139] In some embodiments, LNK A3 , LNK B3 , LNK C3 , or LNK D3 is each independently 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-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, -CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2C≡C-, -C≡CCH2O-, -NHCH2C≡C-, or -C≡CCH2NH-. In some embodiments, LNK A3 , LNK B3 , LNK C3 , or LNK D3 is each independently selected from optionally substituted with one or more R LNK3The following groups can be substituted: -N(CH3)- or -N(CH2CH3)-.

[0140] In some implementation schemes, LNK A3 LNK B3 LNK C3 or LNK D3 Each is independently selected from a single bond, -O-, or arbitrarily selected by one or more Rs. LNK3 The following groups can be substituted: -CH2-, -CH2CH2-, -OCH2-, or -CH2O-.

[0141] In some implementation schemes, LNK A4 or LNK B4 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. LNK4 The following groups are substituted: C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 1-6 Heteroalkylene, C 2-6 Heteroeneyl, or C 2-6 Hetero-ynyl group.

[0142] In some implementation schemes, LNK A4 or LNK B4 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. LNK4 The 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.

[0143] In some implementation schemes, LNK A4 or LNK B4 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. LNK4 The following groups are substituted: C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 1-4 Heteroalkylene, C 2-4 Heteroeneyl, or C 2-4 Hetero-ynyl group.

[0144] In some implementation schemes, LNK A4 or LNK B4each independently selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK4 substituted with one or more R 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, C 1-3 heteroalkylene, C 2-3 heteroalkenylene, or C 2-3 heteroalkynylene.

[0145] In some embodiments, LNK A4 or LNK B4 each independently selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK4 -CH2-, -CH2CH2-, -CH=CH-, -CH2CH=CH-, -CH=CHCH2-, -CºC-, -CH2CºC-, -CºCCH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, -CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2CºC-, -CºCCH2O-, -NHCH2CºC-, -CºCCH2NH-, -N(CH3)-, or -N(CH2CH3)-.

[0146] In some embodiments, LNK A4 or LNK B4 each independently selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK4 ​The following groups are substituted: -CH2-, -CH2CH2-, -CH=CH-, -CH2CH=CH-, -CH=CHCH2-, -C≡C-, -CH2C≡C-, -C≡CCH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -N HCH2CH2-, -CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2C≡C-, -C≡CCH2O-, -NHCH2C≡C-, or -C≡CCH2NH-. In some implementations, LNK A4 or LNK B4 Each is independently selected from one or more R options. LNK4 The following groups can be substituted: -N(CH3)- or -N(CH2CH3)-.

[0147] In some implementation schemes, LNK A4 or LNK B4 Each is independently selected from a single bond, -O-, or arbitrarily selected by one or more Rs. LNK4 The following groups can be substituted: -CH2-, -CH2CH2-, -OCH2-, -CH2O-, -C≡C-, or -OCH2C≡C-.

[0148] In some implementation schemes, LNK C4 or LNK D4 Each is independently selected from one or more R options. LNK4 The following groups are substituted: C 2-4 alkyne or C 2-4 Hetero-ynyl group.

[0149] In some implementation schemes, LNK C4 or LNK D4 Each is independently selected from one or more R options. LNK4 The following groups are substituted: C 2-3 Ethyne or C 2-3 Hetero-ynyl group.

[0150] In some implementation schemes, LNK C4 or LNK D4 Each is independently selected from one or more R options. LNK4substituted -CºC-, -CH2CºC-, -CºCCH2-, -OCH2CºC-, -CºCCH2O-, -NHCH2CºC-, or -CºCCH2NH-.

[0151] In some embodiments, LNK C4 or LNK D4 each instance of R LNK4 is independently selected from the group consisting of -CºC- or -OCH2CºC-.

[0152] In some embodiments, each R LNK1 , R LNK2 , R LNK3 , or R LNK4 is independently selected from the group consisting of deuterium, oxo, halogen, -OH, -NH2, -CN, 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.

[0153] In some embodiments, each R LNK1 , R LNK2 , R LNK3 , or R LNK4 is independently selected from the group consisting of deuterium, oxo, halogen, -OH, -NH2, -CN, 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.

[0154] In some embodiments, each R LNK1 , R LNK2 , R LNK3 , or R LNK4each independently selected from deuterium, oxo, -F, -CI, -Br, -OH, -NH2, -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, or di(trifluoromethyl)amino.

[0155] In some embodiments, each R LNK1 , R LNK2 , R LNK3 , or R LNK4 is each independently selected from deuterium, oxo, -F, -CI, or methyl.

[0156] In some embodiments, LNK A1 , LNK B1 , LNK C1 , or LNK D1 is each independently selected from a single bond, -O-, -CH2-, -C(O)-, -CH2CH2-, -CH2C(O)-, -C(O)CH2-, -OCH2-, or -CH2O-.

[0157] In some embodiments, LNK A1 , LNK B1 , LNK C1 , or LNK D1 is each independently selected from a single bond.

[0158] In some embodiments, LNK A2 , LNK B2 , LNK C2 , or LNK D2 is each independently selected from a single bond, -O-, -CH2-, -C(O)-, -CH2CH2-, -CH2C(O)-, -C(O)CH2-, -OCH2-, -CH2O-, or -NH-.

[0159] In some embodiments, LNK A2 , LNK B2 , LNK C2 , or LNK D2 is each independently selected from a single bond, -O-, -CH2-, -C(O)-, -CH2CH2-, -CH2C(O)-, -C(O)CH2-, -OCH2-, or -CH2O-. In some embodiments, LNK A2 , LNK B2 , LNK C2 , or LNK D2each independently selected from -CH2-, -C(O)-, or -NH-.

[0160] In some embodiments, LNK A2 , LNK B2 , LNK C2 , or LNK D2 each independently selected from -CH2-, -C(O)-, or -NH-.

[0161] In some embodiments, LNK A2 , LNK B2 , LNK C2 , or LNK D2 each independently selected from -CH2-. In some embodiments, LNK A2 , LNK B2 , LNK C2 , or LNK D2 each independently selected from -C(O)-. In some embodiments, LNK A2 , LNK B2 , LNK C2 , or LNK D2 each independently selected from -NH-.

[0162] In some embodiments, LNK A3 , LNK B3 , LNK C3 , or LNK D3 each independently selected from a single bond, -O-, -CH2-, -C(O)-, -CH2CH2-, -CH2C(O)-, -C(O)CH2-, -OCH2-, or -CH2O-.

[0163] In some embodiments, LNK A3 , LNK B3 , LNK C3 , or LNK D3 each independently selected from a single bond, -O-, -CH2-, -OCH2-, or -C(O)-.

[0164] In some embodiments, LNK A3 , LNK B3 , LNK C3 , or LNK D3 each independently selected from a single bond, -O-, -CH2-, or -OCH2-. In some embodiments, LNK A3 , LNK B3 , LNK C3 , or LNK D3 each independently selected from -C(O)-.

[0165] In some embodiments, LNK A4 or LNK B4 each independently is selected from a single bond, -O-, -CH2-, -C(O)-, -CH2CH2-, -CH2C(O)-, -C(O)CH2-, -OCH2-, -CH2O-, -CºC-, or -OCH2CºC-.

[0166] In some embodiments, LNK A4 or LNK B4 each independently is selected from a single bond, -CºC-, or -OCH2CºC-.

[0167] In some embodiments, LNK A4 is selected from a single bond.

[0168] In some embodiments, LNK C4 or LNK D4 each independently is selected from -CºC- or -OCH2CH=CH-.

[0169] In some embodiments, the 3-12 membered cycloalkyl group comprises a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered cycloalkyl group.

[0170] In some embodiments, the 4-12 membered cycloalkenyl group comprises a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered cycloalkenyl group.

[0171] In some embodiments, the 4-12 membered heterocycloalkyl group comprises a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocycloalkyl group.

[0172] In some embodiments, the 4-12 membered heterocycloalkenyl group comprises a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocycloalkenyl group.

[0173] In some embodiments, Cy A1 , Cy B1 , Cy C1 , or Cy D1 each independently is selected from a single bond, or is optionally substituted with one or more R Cy1 3-10 membered cycloalkyl, 4-10 membered cycloalkenyl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl.

[0174] In some embodiments, Cy A1 , Cy B1 , Cy C1 , or Cy D1 each independently is selected from a single bond, or is optionally substituted with one or more RCy1 substituted 3-8 membered cycloalkyl, 4-8 membered cycloalkenyl, 4-8 membered heterocycloalkyl, or 4-8 membered heterocycloalkenyl.

[0175] In some embodiments, Cy A1 , Cy B1 , Cy C1 , or Cy D1 are each independently selected from a single bond, or a group optionally substituted with one or more R Cy1 substituted 4-6 membered cycloalkyl, 4-6 membered cycloalkenyl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkenyl.

[0176] In some embodiments, Cy A1 , Cy B1 , Cy C1 , or Cy D1 are each independently selected from a single bond, or a group optionally substituted with one or more R Cy1 substituted cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl.

[0177] In some embodiments, Cy A1 , Cy B1 , Cy C1 , or Cy D1 are each independently selected from a single bond, or a group optionally substituted with one or more R Cy1 substituted:

[0178] In some embodiments, Cy A1 , Cy B1 , Cy C1 , or Cy D1 are each independently selected from a single bond, or a group optionally substituted with one or more R Cy1 substituted:

[0179] In some embodiments, Cy A1 , Cy B1 , Cy C1 , or Cy D1 are each independently selected from a single bond, or a group optionally substituted with one or more R Cy1 substituted: In some embodiments, Cy A1 , Cy B1 , Cy C1 , or Cy D1 are each independently selected from a group optionally substituted with one or more RCy1 substituted with one or more R

[0180] In some embodiments, Cy A2 , Cy B2 , Cy C2 , or Cy D2 is each independently selected from a single bond, or a group that is optionally substituted with one or more R Cy2 substituted with one or more R

[0181] In some embodiments, Cy A2 , Cy B2 , Cy C2 , or Cy D2 is each independently selected from a single bond, or a group that is optionally substituted with one or more R Cy2 substituted with one or more R

[0182] In some embodiments, Cy A2 , Cy B2 , Cy C2 , or Cy D2 is each independently selected from a single bond, or a group that is optionally substituted with one or more R Cy2 substituted with one or more R

[0183] In some embodiments, Cy A2 , Cy B2 , Cy C2 , or Cy D2 is each independently selected from a single bond, or a group that is optionally substituted with one or more R Cy2 substituted with one or more R

[0184] In some embodiments, Cy A2 , Cy B2 , Cy C2 , or Cy D2 is each independently selected from a single bond, or a group that is optionally substituted with one or more R Cy2 substituted with one or more R

[0185] In some embodiments, Cy A2 , Cy B2 , CyC2 , or Cy D2 each independently is selected from a single bond, or the following groups optionally substituted with one or more R Cy2 substituents:

[0186] In some embodiments, Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently is selected from a single bond, or the following groups optionally substituted with one or more R Cy2 substituents: In some embodiments, Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently is selected from the following groups optionally substituted with one or more R Cy2 substituents:

[0187] In some embodiments, Cy A3 , Cy B3 , Cy C3 , or Cy D3 each independently is selected from a single bond, or the following groups optionally substituted with one or more R Cy3 substituents: 3-10 membered cycloalkyl, 4-10 membered cycloalkenyl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl.

[0188] In some embodiments, Cy A3 , Cy B3 , Cy C3 , or Cy D3 each independently is selected from a single bond, or the following groups optionally substituted with one or more R Cy3 substituents: 3-8 membered cycloalkyl, 4-8 membered cycloalkenyl, 4-8 membered heterocycloalkyl, or 4-8 membered heterocycloalkenyl.

[0189] In some embodiments, Cy A3 , Cy B3 , Cy C3 , or Cy D3 each independently is selected from a single bond, or the following groups optionally substituted with one or more R Cy3 substituents: 4-6 membered cycloalkyl, 4-6 membered cycloalkenyl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkenyl.

[0190] In some embodiments, Cy A3 , Cy B3 , CyC3 、or Cy D3 Each is independently selected from a single key, or arbitrarily selected by one or more R keys. Cy3 The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydropyranyl, piperidinyl, piperazineyl, or morpholinyl.

[0191] In some implementations, Cy A3 Cy B3 Cy C3 、or Cy D3 Each is independently selected from a single key, or arbitrarily selected by one or more R keys. Cy3 The following groups are substituted:

[0192] In some implementations, Cy A3 Cy B3 Cy C3 、or Cy D3 Each is independently selected from a single key, or arbitrarily selected by one or more R keys. Cy3 The following groups are substituted:

[0193] In some implementations, Cy A3 Cy B3 Cy C3 、or Cy D3 Each is independently selected from a single key, or arbitrarily selected by one or more R keys. Cy3 The following groups are substituted: In some implementations, Cy A3 Cy B3 Cy C3 、or Cy D3 Each is independently selected from one or more R options. Cy3 The following groups are substituted:

[0194] In some implementations, each R Cy1 R Cy2 、or R Cy3 Each is independently selected from deuterium, oxo, 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 C1-4 alkylamino, or halodialkylamino. 1-4 alkylamino.

[0195] In some embodiments, each R Cy1 , R Cy2 , or R Cy3 is each independently selected from deuterium, oxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, dialkylamino, 1-3 alkylamino, deuteroalkylamino, 1-3 alkyl, halogenalkyl, 1-3 alkyl, halogenalkyl, 1-3 alkoxy, halogenalkoxy, 1-3 alkylamino, or halodialkylamino. 1-3 alkylamino.

[0196] In some embodiments, each R Cy1 , R Cy2 , or R Cy3 is each independently selected from deuterium, oxo, -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.

[0197] In some embodiments, each R Cy1 , R Cy2 , or R Cy3 is each independently selected from deuterium, -F, -Cl, or methyl.

[0198] In some embodiments, Cy A1 , Cy B1 , Cy C1 , or Cy D1 is each independently selected from a single bond, In some embodiments, Cy A1 , Cy B1 , Cy C1 , or Cy D1 is each independently selected from a single bond or

[0199] In some embodiments, Cy A1 , Cy B1 , Cy C1 , or CyD1 each independently selected from a single bond or In some embodiments, Cy A1 , Cy B1 , Cy C1 , or Cy D1 each independently selected from In some embodiments, Cy A1 , Cy B1 , Cy C1 , or Cy D1 each independently selected from

[0200] In some embodiments, Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently selected from a single bond, In some embodiments, Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently selected from a single bond,

[0201] In some embodiments, Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently selected from a single bond or In some embodiments, Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently selected from In some embodiments, Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently selected from

[0202] In some embodiments, Cy A3 , Cy B3 , Cy C3 , or Cy D3 each independently selected from a single bond or

[0203] In some embodiments, -L A is selected from In some embodiments, -L A is selected from

[0204] In some embodiments, -L A - is selected from

[0205] In some embodiments, -L A - is selected from

[0206] In some embodiments, -L A - is selected from In some embodiments, -L A - is selected from In some embodiments, -L A - is selected from

[0207] In some embodiments, -L B - is selected from In some embodiments, -L B - is selected from

[0208] In some embodiments, -L B - is selected from

[0209] In some embodiments, -L B - is selected from

[0210] In some embodiments, -L B - is selected from In some embodiments, -L B - is selected from In some embodiments, -L B - is selected from

[0211] In some embodiments, -L C - is selected from In some embodiments, -L C - is selected from

[0212] In some embodiments, -L C - is selected from

[0213] In some embodiments, -L C - is selected from

[0214] In some embodiments, -L C - is selected from In some embodiments, -L C - is selected from In some embodiments, -L C - is selected from

[0215] In some embodiments, -L D - is selected from In some embodiments, -L D - is selected from

[0216] In some embodiments, -L D - is selected from

[0217] In some embodiments, -L D - is selected from

[0218] In some embodiments, -L D - is selected from In some embodiments, -L D - is selected from In some embodiments, -L D - is selected from

[0219] In some embodiments, -L A -, -L B -, -L C -, or -L D - are each independently selected from

[0220] In some embodiments, -L A -, -L B -, -L C -, or -L D - are each independently selected from In some embodiments, -L A -, -LB -, -L C -, or -L D - are each independently selected from In some embodiments, -L A -, -L B -, -L C -, or -L D - are each independently selected from In some embodiments, is selected from

[0221] In some embodiments, is selected from In some embodiments, is selected from In some embodiments, is selected from

[0222] In some embodiments, is selected from

[0223] In some embodiments, is selected from

[0224] In some embodiments, is selected from In some embodiments, is selected from

[0225] In some embodiments, each R 1 are each independently selected from deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 alkyl, C 1- 4alkoxy, 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 1-4Alkylamino or halogenated diC 1-4 Alkylamino.

[0226] In some implementations, each R 1 Each is independently selected from deuterium, halogens, -OH, -SH, -NH2, -CN, -NO2, and C. 1-3 Alkyl, C 1- 3-alkoxy group, 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.

[0227] In some implementations, each R 1 Each is independently selected from 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.

[0228] In some implementations, each R 1 Each is independently selected from deuterium, -F, -Cl, methyl, methoxy, monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0229] In some implementations, each R 1 Each is independently selected from difluoromethyl groups. In some embodiments, -L- is selected from -O-, -S-, and -NR-. L1 -、C 1-4 Alkylene, deuterated C 1-4 Alkylene, Halogenated C 1-4 Alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -、-NR L1 C(O)-、-NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-, or optionally by one or more R L2 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.

[0230] In some embodiments, -L- is selected from -O-, -S-, -NR L1 -, C 1-3 alkylene, deuterated C 1-3 alkylene, halogenated C 1-3 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -, -NR L1 S(O)2-, or optionally substituted with one or more R L2 substituted with one or more R

[0231] In some embodiments, the 4-12 membered, 4-10 membered, or 4-8 membered heterocyclyl of the present disclosure is selected from 4-12 membered, 4-10 membered, or 4-8 membered heterocycloalkenyl.

[0232] In some embodiments, the 4-12 membered, 4-10 membered, or 4-8 membered heterocyclyl of the present disclosure is selected from 4-12 membered, 4-10 membered, or 4-8 membered heterocycloalkyl.

[0233] In some embodiments, -L- is selected from -O-, -S-, -NR L1 -, C 1-3 alkylene, deuterated C 1-3 alkylene, halogenated C 1-3 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -, -NR L1 S(O)2-, or optionally substituted with one or more R L2 substituted with one or more R cycloheptenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, dihydrofuranyl, dihydropyrrolyl, dihydrooxazolyl, dihydrothiazolyl, dihydropyridinyl, tetrahydropyridinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0234] In some implementations, -L- is selected from -C(O)O-, -OC(O)-, and -C(O)NR. L1 -、-NR L1 C(O)-、-NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -、-NR L1 S(O)2-, or optionally by one or more R L2 The following groups may be substituted: pyrrole, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, or isothiazolyl.

[0235] In some implementation schemes, R L1 Each is independently selected from H, deuterium, and C. 1-4 Alkyl, deuterated C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0236] In some implementation schemes, R L1 Each is independently selected from H, deuterium, and C. 1-3 Alkyl, deuterated C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0237] In some implementation schemes, R L1 Each is independently selected from H, deuterium, or methyl.

[0238] In some implementations, each R L2 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, 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.

[0239] In some implementations, each R L2 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, deuterated C1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylamino, or halo-diC 1-3 alkylamino.

[0240] In some embodiments, each R L2 is each independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -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, or di(trifluoromethyl)amino.

[0241] In some embodiments, each R L2 is each independently selected from deuterium, -F, -Cl, or methyl.

[0242] In some embodiments, -L- is selected from -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -S(O)-, -S(O)2-, -S(O)2NH-, -NHS(O)2-, imidazolyl, 1,2,3-triazolyl, or 1,2,4-triazolyl.

[0243] In some embodiments, -L- is selected from -C(O)NH-, -NHC(O)-, -NHC(O)NH-,

[0244] In some embodiments, -L- is selected from -C(O)NH- or -NHC(O)-.

[0245] In some embodiments, is selected from

[0246] In some embodiments, each R 2 is each independently selected from deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-4 alkyl, C 1- 4alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, diC 1-4 alkyl, haloC 1-4 alkyl, haloC 1-4 alkoxy, haloC 1-4 alkylamino, or halo-diC1-4 alkylamino, diC

[0247] In some embodiments, each R 2 is each independently selected from deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 alkyl, C 1- alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, diC 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylamino, or halo diC 1-3 alkylamino, diC

[0248] In some embodiments, each R 2 is each independently selected from deuterium, -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.

[0249] In some embodiments, each R 2 is each independently selected from deuterium, -F, -Cl, or methyl.

[0250] 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 optionally substituted with one or more R E

[0251] In some embodiments, ring E is selected from 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 4-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl optionally substituted with one or more R E

[0252] In some embodiments, the 4-12 membered, 4-10 membered, or 4-8 membered heterocyclyl is selected from 4-12 membered, 4-10 membered, or 4-8 membered heterocycloalkenyl.

[0253] In some embodiments, the 4-12 membered, 4-10 membered, or 4-8 membered heterocyclyl is selected from 4-12 membered, 4-10 membered, or 4-8 membered heterocycloalkyl.

[0254] 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 optionally substituted with one or more R E ​​substituted with one or more R

[0255] In some embodiments, Ring E is selected from an optionally substituted group consisting of 3-8 membered cycloalkyl or 4-8 membered heterocycloalkyl. E substituted with one or more R

[0256] In some embodiments, Ring E is selected from an optionally substituted group consisting of 3-8 membered cycloalkyl or 4-8 membered heterocycloalkyl. E substituted with one or more R

[0257] In some embodiments, each R E is each independently selected from deuterium, oxo, 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.

[0258] In some embodiments, each R E is each independently selected from deuterium, oxo, 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.

[0259] In some embodiments, each R Eeach independently selected from deuterium, oxo, -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.

[0260] In some embodiments, each R E each independently selected from deuterium, -F, -CI, or methyl.

[0261] In some embodiments, ring E is selected from

[0262] In some embodiments, ring E is selected from

[0263] In some embodiments, ring E is selected from

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

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

[0266] In some embodiments, n is selected from 0 or 1.

[0267] In some embodiments, m and n are both 0.

[0268] In some embodiments, m is 1 and n is 0.

[0269] 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.

[0270] 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.

[0271] In some embodiments, the 3-12 membered of the present disclosure is selected from 3 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered, 11 membered, or 12 membered.

[0272] In some embodiments, the 4-12 membered of the present disclosure is selected from 4 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered, 11 membered, or 12 membered.

[0273] In some embodiments, the C 1-6 is selected from C 1-5 , C1-4 , C 1-3 , or C 1-2 .

[0274] In some embodiments, the C 1-6 alkyl is selected from C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl.

[0275] 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.

[0276] In some embodiments, the C 2-6 alkenylene is selected from C 2-5 alkenylene, C 2-4 alkenylene, or C 2-3 alkenylene.

[0277] In some embodiments, the C 2-6 alkynylene is selected from C 2-5 alkynylene, C 2-4 alkynylene, or C 2-3 alkynylene.

[0278] 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.

[0279] In some embodiments, the C 2-6 heteroalkenylene is selected from C 2-5 heteroalkenylene, C 2-4 heteroalkenylene, or C 2-3 heteroalkenylene.

[0280] In some embodiments, the C 2-6 heteroalkynylene is selected from C 2-5 heteroalkynylene, C 2-4 heteroalkynylene, or C 2-3 heteroalkynylene.

[0281] In some embodiments, the halogen is selected from F, Cl, Br, or I.

[0282] 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.

[0283] 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.

[0284] In some embodiments, the heteroatom in the heterocyclyl, heterocycloalkenyl, or heterocycloalkyl of the present disclosure is selected from N, NH, O, or S. In some embodiments, the heteroatom in the heterocyclyl, heterocycloalkenyl, or heterocycloalkyl of the present disclosure is selected from N, O, or S. In some embodiments, the heteroatom in the heteroaryl of the present disclosure is selected from N, O, S. In some embodiments, the heteroatom in the heteroalkylene of the present disclosure is selected from N, NH, O, S, S(O), or S(O)2. In some embodiments, the heteroatom in the heteroalkenylene of the present disclosure is selected from N, NH, O, S, S(O), or S(O)2. In some embodiments, the heteroatom in the heteroalkynylene of the present disclosure is selected from N, NH, O, S, S(O), or S(O)2.

[0285] In some embodiments, the number of heteroatoms in the heterocyclyl, heterocycloalkenyl, heterocycloalkyl, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroaryl of the present disclosure is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the number of heteroatoms in the heterocyclyl, heterocycloalkenyl, heterocycloalkyl, or heteroaryl of the present disclosure is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the number of heteroatoms in the heterocyclyl, heterocycloalkenyl, heterocycloalkyl, or heteroaryl of the present disclosure is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the number of heteroatoms in the heterocyclyl, heterocycloalkenyl, heterocycloalkyl, or heteroaryl of the present disclosure is selected from 1, 2, 3, or 4. In some embodiments, the number of heteroatoms in the heterocyclyl, heterocycloalkenyl, heterocycloalkyl, or heteroaryl of the present disclosure is selected from 1, 2, or 3.

[0286] In some embodiments, the heterocyclyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl of the present disclosure contains 1 or 2 heteroatoms selected from N, O, or S.

[0287] In some embodiments, the heterocyclyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl of the present disclosure contains 1, 2, or 3 N atoms.

[0288] In some embodiments, the heterocyclyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl of the present disclosure contains 1 O atom.

[0289] In some embodiments, the heterocyclyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl of the present disclosure contains 1 N atom and 1 O atom.

[0290] In some embodiments, the heterocyclyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl of the present disclosure contains 1 N atom and 1 S atom.

[0291] In some embodiments, the heterocyclyl, heterocycloalkyl, or heterocycloalkenyl of the present disclosure comprises a monocyclic, spirocyclic, annulated, or bridged ring. In some embodiments, the heterocyclyl, heterocycloalkyl, or heterocycloalkenyl of the present disclosure comprises a monocyclic or spirocyclic ring. In some embodiments, the heterocyclyl, heterocycloalkyl, or heterocycloalkenyl of the present disclosure comprises a monocyclic or bridged ring.

[0292] The present disclosure relates to a compound of Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), or a pharmaceutically acceptable salt thereof,

[0293] wherein -L A -, X 1 , ring A, ring B, R A , p1, -L B -, R B , p2, -L C -, X 2 , R C , p3, -L D -, R D , p4, R 1 , m, L, R 2 , n, and ring E are as defined in the present disclosure.

[0294] The present disclosure relates to a compound of Formula (II-A), Formula (II-B), Formula (II-C), Formula (II-D), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0295] wherein -L A -, X 1 , ring A, ring B, R A , p1, -L B -, R B , p2, -L C -, X 2 , R C , p3, -L D -, R D , p4, R 1 , and L are as defined in the present disclosure.

[0296] The present disclosure relates to a compound of Formula (I-B-1), Formula (I-C-1), Formula (I-C-2), Formula (I-D-1), Formula (I-D-2), or a pharmaceutically acceptable salt thereof,

[0297] wherein -L B -, R B , p2, -L C -, X 2 , R C , p3, -L D -, R D , p4, R 1 , m, L, R 2 , n, and ring E moiety are as defined in the present disclosure.

[0298] The present disclosure relates to a compound of Formula (II-A-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0299] wherein -L A -, X 1 , ring A, R A , p1, R 1 , and L moiety are as defined in the present disclosure.

[0300] In some embodiments, the present disclosure includes the above-defined variables and embodiments thereof, and any combination thereof.

[0301] The present disclosure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-B-1), Formula (I-C-1), Formula (I-C-2), Formula (I-D-1), or Formula (I-D-2) compounds include stereoisomers thereof.

[0302] The present disclosure also relates to the following compounds, or a pharmaceutically acceptable salt thereof:

[0303] The present disclosure also relates to the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0304] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further includes a pharmaceutically acceptable excipient.

[0305] In some embodiments, a single dose of the pharmaceutical composition of the present disclosure is selected from 0.01-2000 mg, or 0.02-1800 mg.

[0306] In another aspect, the present disclosure relates to a method of treating a disease in a mammal, comprising administering to a mammal (preferably a human) in need of such treatment a therapeutically effective amount of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0307] In another aspect, the present disclosure relates to the use of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a disease.

[0308] In another aspect, the present disclosure relates to the use of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure in treating a disease.

[0309] In another aspect, the present disclosure relates to a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in treating a disease.

[0310] In another aspect, the present disclosure relates to a kit comprising a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, and further comprising instructions for use in treating a disease.

[0311] In some embodiments of the present disclosure, the disease is selected from IRAK4-associated diseases.

[0312] In some embodiments of the present disclosure, the disease (e.g., IRAK4-associated disease) is selected from immune system diseases.

[0313] In some embodiments of the present disclosure, the immune system disease is selected from autoimmune diseases or inflammation.

[0314] In some embodiments of the present disclosure, a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure is used as a monotherapy for treating IRAK4-associated diseases.

[0315] In some embodiments of the present disclosure, a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure is used in combination with other therapeutic agents for treating IRAK4-associated diseases.

[0316] Technical effects

[0317] The compounds of the present disclosure exhibit good intracellular (e.g., THP-1 cell or PBMC cell) IRAK4 protein degradation activity and downstream pathway (e.g., IL-6) inhibition, have good in vitro pharmacokinetic properties (e.g., human and / or mouse liver microsomal stability), and at the same time exhibit good drugability in in vivo pharmacokinetic, bioavailability, and / or pharmacodynamic studies.

[0318] Definitions

[0319] The following terms used in the present disclosure have the following meanings unless otherwise indicated. A particular term should not be construed as undefined or unclear if not specifically defined, 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.

[0320] 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 cannot occur on an aromatic group.

[0321] "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, wherein some non-limiting examples of said "substituents" include deuterium, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl, carboxaldehyde groups, imine groups, 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 groups, amide groups, ureido, epoxy groups, and ester groups, and the like, optionally substituted with one or more groups 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.

[0322] In some embodiments herein, said substituents are selected from deuterium, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl, aldehyde groups, imine groups, 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, and the like, optionally substituted with one or more groups selected from: deuterium, oxo, hydroxy, 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, 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 cycloalkyl C 1-12alkylene, 3-12 membered cycloalkyl, 3-12 membered cycloalkylC 1-12 alkylene, 3-12 membered cycloalkyl, 3-12 membered cycloalkylC 1-12 alkylene, 3-12 membered cycloalkyl, 3-12 membered cycloalkylC 1-12 alkylene, 3-12 membered cycloalkyl, 3-12 membered cycloalkylC 1-12 alkylene, 3-12 membered cycloalkyl, 3-12 membered cycloalkylC

[0323] The term "substitution" or "substituted" means that a specified atom or group of atoms can be replaced with or by a specified other atom or group of atoms. For example, 1 or 2 or 3 -CH2- groups in -CH2CH2CH2- can be replaced with O, S, NH to give -O-CH2-CH2-, -O-CH2-, -CH2-O-CH2-, -CH2-O-, -CH2-CH2-O-, -O-, and the like.

[0324] 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, an ethyl group "optionally" substituted with a halogen means that the ethyl group can be unsubstituted (-CH2CH3), mono-substituted (e.g., -CH2CH2F), poly-substituted (e.g., -CHFCH2F, -CH2CHF2, and the like), or fully substituted (-CF2CF3). One skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is not spatially possible and / or synthetically feasible.

[0325] C m-n , means 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.

[0326] 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.

[0327] 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.

[0328] When one of the variables is selected from a covalent bond, it indicates that the two groups to which it is attached are directly connected, such as L represents a covalent bond in A-L-Z, which indicates that the structure is actually A-Z, such as L1, L2, L3 are selected from a covalent bond in A-L1-L2-L3-Z, which indicates that the structure is actually A-Z.

[0329] When the linking group listed does not indicate its direction of attachment, its direction of attachment is arbitrary, such as in A-L-Z, the linking group L is -M-W-, which indicates that the structure can be either A-M-W-Z or A-W-M-Z.

[0330] When a bond of a substituent crosses over to two atoms on a ring, the substituent can be bonded to any atom on the ring. For example, the structural unit indicates that it can be substituted at any position on the cyclohexyl or cyclohexadiene.

[0331] The term "halo" or "halogen" means fluoro, chloro, bromo, and iodo.

[0332] The term "hydroxy" means an -OH group.

[0333] The term "cyano" means a -CN group.

[0334] The term "mercapto" means an -SH group.

[0335] The term "amino" means an -NH2 group.

[0336] The term "nitro" means an -NO2 group.

[0337] 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 containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or -CH2CH(CH3)-), butylene (-CH2CH2CH2CH2-, -CH2CH(CH3)CH2-, or -CH2CH2CH(CH3)-), and the like.

[0338] The term "alkyl" means a saturated straight or branched chain monovalent hydrocarbon radical of the general formula C n H 2n+1saturated hydrocarbyl group, typically having 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-chained 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).

[0339] 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 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 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 remainder 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.

[0340] 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 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 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 remainder of the molecule. Typically, where more than one heteroatom group is present, the heteroatom groups are not adjacent to one another.

[0341] The term "alkoxy" refers to -O-alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.

[0342] The term "alkylamino" refers to -NH-alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.

[0343] 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.

[0344] 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.

[0345] 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 groups include, but are not limited to, ethenyl, 1- propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0346] 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 groups include, but are not limited to, ethenylene, 1- propenylene, 2-propenylene, 1-butenylene, isobutenylene, 1,3-butadienylene, and the like.

[0347] The term "heteroalkenyl" refers to an alkenyl group in which one or more carbon atoms (and their attached 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, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. For example, the term "C 1-4heteroalkenyl" refers to a heteroalkenyl group containing 1 to 4 carbon atoms and 1-3 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.

[0348] The term "heteroalkenyl" refers to the divalent version of a heteroalkenyl 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(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 heteroalkenyl" refers to a heteroalkenyl group containing 1 to 6 carbon atoms and 1-3 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, -alkenylene-O-, -alkenylene-NH-, -alkenylene-S-, -alkenylene-O-alkylene-, -alkylene-O-alkenylene-, -alkenylene-NH-alkylene-, -alkylene-NH-alkenylene-, -alkenylene-S-alkylene-, -alkylene-S-alkenylene-, -alkenylene-CH=N-, -alkenylene-N=CH-, -alkylene-CH=N-alkenylene-, -alkenylene-CH=N-alkylene-, or -alkylene-NH-alkenylene-O-. In some embodiments, the double bond in the heteroalkenyl group is a carbon-carbon double bond.

[0349] The term "alkynyl" refers to a straight-chain or branched-chain, unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkynyl 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.

[0350] The term "ynynyl" refers to the divalent form of an ynyl group. The ynynyl 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 ynynyl groups include, but are not limited to, ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene, isobutynylene, etc.

[0351] The term "heteroyne" refers to an alkynyl group in which one or more carbon atoms (and their associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. Unless otherwise indicated, the heteroyne group comprises one, two, or three 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 "Hydynyl" refers to a heteroyynyl group containing 2 to 6 carbon atoms and 1 to 3 heteroatom groups. The heteroatom groups can be placed at any position on the heteroyynyl group (e.g., internal or terminal), including positions where the heteroyynyl group is attached to the rest of the molecule. Typically, in the presence of more than one heteroatom group, the heteroatom groups are not adjacent to each other. Exemplary heteroyynyl groups include, but are not limited to, ynyl-O-, ynyl-NH-, ynyl-S-, ynyl-O-alkylene-, alkyl-O-alkylene-, ynyl-NH-alkylene-, alkyl-NH-alkylene-, ynyl-S-alkylene-, or alkyl-S-alkylene-. In some embodiments, the triple bond in the heteroyynyl group is a carbon-carbon triple bond.

[0352] The term "heteroyneyl" refers to the divalent form of a heteroyneyl group. Unless otherwise indicated, the heteroyneyl group comprises one, two, or three 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 "Heteroyynyl" refers to a heteroynyl group containing 2 to 6 carbon atoms and 1 to 3 heteroatomic groups. The heteroatomic groups can be placed at any position on the heteroynyl group (e.g., internal or terminal), including positions where the heteroynyl group is attached to the rest of the molecule. Typically, in the presence of more than one heteroatomic group, the heteroatomic groups are not adjacent to each other. Exemplary heteroynyl groups include, but are not limited to, -ynyl-O-, -ynyl-NH-, -ynyl-S-, -ynyl-O-alkylene-, -alkyl-O-alkylene-, -ynyl-NH-alkylene-, -alkyl-NH-alkylene-, -ynyl-S-alkylene-, or -alkyl-S-alkylene-. In some embodiments, the triple bond in the heteroynyl group is a carbon-carbon triple bond.

[0353] The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated 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 cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

[0354] 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.

[0355] 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). 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.

[0356] 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). Non-limiting examples of heterocycloalkenyl groups include, but are not limited to, dihydrofuranyl, dihydrothienyl, dihydropyrrolyl, dihydrooxazolyl, dihydrothiazolyl, dihydrooxazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydronitrogen heterocycloalkenyl, tetrahydronitrogen heterocycloalkenyl, or azaspirooctenyl, and the like. tetrahydronitrogen heterocycloalkenyl, or azaspirooctenyl, and the like. tetrahydronitrogen heterocycloalkenyl, or azaspirooctenyl, and the like.

[0357] 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. Non-limiting 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, non-limiting examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, non-limiting 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, non-limiting examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl.

[0358] 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.

[0359] 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.

[0360] 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 that are replaced with 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.

[0361] It is to be understood that the definition of the group -L A -, -L B -, -L C -, -L D -, -LNK A1 -, -LNK B1 -, -LNK C1 -, -LNK D1 -, -LNK A2 -, -LNK B2 -, -LNK C2 -, -LNK D2 -, -LNK A3 -, -LNK B3 -, -LNK C3 -, -LNK D3 -, -LNK A4 -, -LNK B4 -, -LNK C4 -, -LNK D4 in the present disclosure is read in the direction from left to right, corresponding to the left-hand group and the right-hand group to which the group is attached in the general formula. For example, when -L A - is -C(O)NH- , the structure is

[0362] It is to be understood that the definition of the group -L- in the present disclosure is read in the direction from left to right, corresponding to the lower-hand group and the upper-hand group to which the group is attached in the general formula. For example, when -L- is -C(O)NH-, the structure is

[0363] 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:

[0364] (i) inhibiting the disease or condition, i.e., arresting its development;

[0365] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0366] 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.

[0367] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the 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 by dosing in conjunction with the patient's own knowledge and practice of the art coupled with the present disclosure.

[0368] The term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0369] 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.

[0370] 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 objective of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.

[0371] 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 applies to the various stages of manufacture of this composition and to the product as it is available for medical use. Suitable excipients are well known to those skilled in the art, e.g., carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0372] The term "single dose" means the content of the active ingredient in the smallest unit of packaging of a pharmaceutical product. For example, if a box of medicine has seven capsules, each capsule is the smallest unit of packaging, and the content of the active ingredient in each capsule is the single dose. The single dose of a pharmaceutical composition of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is 0.01 mg to 2000 mg, meaning that the smallest unit of packaging of the pharmaceutical composition contains 0.01 mg to 2000 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0373] The words "comprise" or "comprising" and variations thereof such as "comprises" or "comprising", when used in relation to a list of items or steps, are to be interpreted as "including but not limited to".

[0374] The compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are encompassed by 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 shift 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, where a proton can migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0375] 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 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, etc. For example, it is understood that compounds of the present disclosure in which one or more hydrogen atoms are replaced by deuterium atoms are within the scope of the present disclosure. The compounds of the present disclosure can exist in zwitterionic form, and all such forms are included within the scope of the present disclosure.

[0376] Certain isotopically-labeled compounds of the present disclosure (for example, those 3 H, and 14 C) 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, and18 F can be used for positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent in a

[0377] In addition, substitution with heavier isotopes such as deuterium (i.e. 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence can be preferred in some circumstances. Deuterium substitution can be in any portion of the molecule that

[0378] The compounds of the present disclosure can be asymmetric, e.g., having one or more stereocenters. Unless otherwise stated, all stereocenters are included, e.g., enantiomers and diastereomers. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active form or as racemates. Optically active forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. All such isomers and mixtures thereof are included within the scope of the present disclosure.

[0379] Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by a wedged and dashed wedge The relative configuration of a stereocenter is indicated by a straight and dashed line The relative configuration of a stereocenter is indicated by a straight and dashed line or a dashed wedge or a wavy line The relative configuration of a stereocenter is indicated by a straight and dashed line

[0380] The compounds of the present disclosure can have one or more atropisomers, which refer to optically active isomers resulting from the restriction of free rotation about a single bond due to steric hindrance. Compounds of the present disclosure containing a chiral axis can be isolated in racemic form. When the energy barrier to free rotation of a single bond of a compound of the present disclosure containing a chiral axis is sufficiently high, its atropisomers can be isolated in optically active form.

[0381] Pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with suitable pharmaceutically acceptable excipients.

[0382] The pharmaceutical compositions of the present disclosure can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing processes, and the like.

[0383] In all of the methods of administration of the compounds of general formula (I) described herein, the dosage administered daily is from 0.001 to 2000 mg / kg body weight, the compounds of the present disclosure can be prepared by a variety of synthetic procedures well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the specific embodiments with other chemical synthetic procedures well known to those skilled in the art, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0384] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. The use of "or" means "and / or" unless context clearly indicates otherwise.

[0385] All patents, patent applications, and other publications identified are expressly incorporated herein by reference for the purpose of describing and disclosing, by indication, the compositions and methodologies described herein, and are made to supplement the disclosure provided herein. Such publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as a limitation on the claims appended hereto. All statements as to the date or representations made by others, in this regard, are based on one of the parties' knowledge at the time of the application, and can not be a consideration of the correct, prior art. Also, there is no admission that any publication is prior art merely by its reference. Any publication can and does include references to scientific and patent literature deemed by the authors to be relevant.

[0386] 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 transformations being effected. In the synthetic schemes and examples that follow, all substituents unless otherwise indicated are as previously defined. Further, the skilled worker will appreciate that the application is not limited to the specific conditions and materials described, but rather the application is more generally applicable as described by the reactions and utility examples. To obtain the compounds of the present disclosure, the synthetic preparation procedures or reaction sequences can need to be modified or selected by one skilled in the art based on the starting materials or reagents available.

[0387] The compounds of formula (I) of the present disclosure, or pharmaceutically acceptable salts thereof, can be prepared by a person skilled in the art of organic synthesis by the following routes, wherein, 1 , ring A, ring B, X 2 , R A , R B , R C , R D , p1, p2, p3, p4, LNK A1 , LNK B1 , LNK C1 , LNK D1 , LNK A2 , LNK B2LNK C2 LNK D2 LNK A3 LNK B3 LNK C3 LNK D3 LNK A4 LNK B4 LNK C4 LNK D4 Cy A1 Cy B1 Cy C1 Cy D1 Cy A2 Cy B2 Cy C2 Cy D2 Cy A3 Cy B3 Cy C3 Cy D3 R 1 -L-, R 2 ring E, m, n are as defined in the disclosure.

[0388] Route One:

[0389] Route Two:

[0390] Route Three:

[0391] Route Four:

[0392] Each product resulting from the reactions in the above routes can be isolated by conventional separation techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Starting materials can be obtained either by synthesis or purchased from commercial suppliers (e.g., but not limited to, Aldrich or Sigma). These starting materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described in the disclosure can be obtained as single isomers or as mixtures of isomers using the synthetic methods described.

[0393] The following abbreviations are used in the disclosure:

[0394] Et represents ethyl; Bn represents benzyl; Ts represents p-toluenesulfonyl; TsCl represents p-toluenesulfonyl chloride; Boc represents tert-butoxycarbonyl; DMF represents N,N-dimethylformamide; DCM represents dichloromethane; TEA represents triethylamine; EA represents ethyl acetate; DMAP represents 4-dimethylaminopyridine; THF represents tetrahydrofuran; MeCN represents acetonitrile; DIPEA represents N,N-diisopropylethylamine; PE represents petroleum ether; HATU represents 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIPEA represents N,N-diisopropylethylamine; DMA represents N,N-dimethylacetamide; NBS represents N-bromosuccinimide.

[0395] The commercially available compounds are used with the supplier's catalog name.

[0396] For the sake of clarity, the present disclosure is further explained with examples, but the examples are not intended to limit the scope of the present disclosure. The present disclosure has been described in detail and specific embodiments thereof have been disclosed with particularity, it will be apparent to those skilled in the art that various changes and modifications of the embodiments described can be made without departing from the spirit and scope of the present disclosure.

[0397] All reagents used in the present disclosure are commercially available and can be used without further purification. Examples

[0398] Example 1

[0399] (1) Preparation method of intermediate A1-1:

[0400] 1H-pyrazole-3-carboxaldehyde (30.00 g) was dispersed in DMF (300 mL), and bromobenzene (56.07 g) and cesium carbonate (127.17 g) were added, and stirred at 20-25°C for 2 hours. After the reaction was completed, the reaction solution was poured into water (1000 mL), extracted with EA (1500 mL*3), the organic phases were combined, concentrated, and the concentrate was separated by column chromatography to obtain intermediate A1-1 (56.70 g).

[0401] MS (ESI) m / z [M+H] + : 187.12

[0402] (2) Preparation method of intermediate A1-2:

[0403] Intermediate A1-1 (56.7 g) was dispersed in DCM (600 mL), cooled to 0-10 °C, bis(2-methoxyethyl)aminosulfur trifluoride (268.95 g) was added, and stirring was resumed at 20-25 °C for 16 h. After the reaction was completed, the reaction was quenched by the addition of methanol (300 mL) at 0-10 °C, and concentrated. The concentrate was separated by column chromatography to give intermediate A1-2 (56.70 g).

[0404] MS (ESI) m / z [M+H] + : 209.10

[0405] (3) Preparation method of intermediate A1-3:

[0406] Intermediate A1-2 (40.40 g) was dispersed in methanol (400 mL), Pd / C (4.04 g, 10%) was added, concentrated hydrochloric acid (45 mL) was added, and hydrogen replacement was performed three times. Stirring was performed at 50 °C for 16 h. After the reaction was completed, the reaction was filtered on filter paper with diatomite, and the filtrate was concentrated to no liquid flow. Intermediate A1-3 (194 mmol) was obtained.

[0407] (4) Preparation method of intermediate A1-4:

[0408] Intermediate A1-3 (194 mmol) was dispersed in concentrated sulfuric acid (200 mL), cooled to 0-10 °C, and potassium nitrate (58.78 g) was added. Stirring was performed for 15 min, and the temperature was increased to 50 °C for stirring for 4 h. After the reaction was completed, the reaction liquid was slowly dropped into ice water (500 mL), extracted with EA (1000 mL*3), the combined organic phases were concentrated, and the concentrate was separated by column chromatography to give intermediate A1-4 (20.75 g).

[0409] MS (ESI) m / z [M-H] + : 162.11

[0410] (5) Preparation method of intermediate A1-5:

[0411] Methyl cis-4-hydroxycyclohexylcarboxylate (30.00 g) was dispersed in DCM (300 mL), cooled to 0-10 °C, TEA (59.70 g), DMAP (4.63 g), and TsCl (54.23 g) were added, and stirring was performed at 20-25 °C for 16 h. After the reaction was completed, the reaction liquid was poured into water (200 mL), and the liquid was separated. The aqueous phase was extracted with DCM (400 mL*2), the combined organic phases were concentrated, and the concentrate was separated by column chromatography to give intermediate A1-5 (47.58 g).

[0412] (6) Preparation method of intermediate A1-6:

[0413] Intermediate A1-5 (39.75 g) was dispersed in DMF (400 mL), potassium carbonate (17.59 g) and intermediate A1-4 (20.75 g) were added, and stirred at 80 °C for 16 h. After the reaction was completed, the reaction solution was poured into water (1000 mL), extracted with DCM (1500 mL*3), the organic phases were combined, concentrated, and the concentrate was separated by column chromatography to obtain intermediate A1-6 (22.46 g).

[0414] (7) Preparation method of intermediate A1-7:

[0415] Intermediate A1-6 (22.46 g) was dispersed in THF (220 mL), cooled to -20 °C, and LiAlH4 (44.44 mL, 2.5 M in THF) was added dropwise, and reacted at -20 °C for 30 min. After the reaction was completed, saturated ammonium chloride solution (25 mL) was added to quench the reaction, water (200 mL) and EA (300 mL*3) were added for extraction, the organic phases were combined, concentrated, and the concentrate was separated by column chromatography to obtain intermediate A1-7 (18.45 g).

[0416] (8) Preparation method of intermediate A:

[0417] Intermediate A1-7 (18.45 g) was dispersed in THF (100 mL) and methanol (100 mL), Pd / C (1.85 g, 10%) was added, replaced with hydrogen gas for 3 times, and stirred at 20-25 °C for 16 h. After the reaction was completed, the filtrate was filtered on filter paper with diatomite, concentrated to no liquid flow, and intermediate A (67 mmol) was obtained.

[0418] MS (ESI) m / z [M+H] + : 246.26

[0419] (9) Preparation method of intermediate B1-1:

[0420] Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (12.87 g) was dispersed in MeCN (150 mL), DIPEA (7.35 mL) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (7.73 g) were added, and stirred at 60 °C for 2 h. After the reaction was completed, water (200 mL) and EA (300 mL*3) were added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to no liquid flow to obtain intermediate B1-1 (57 mmol).

[0421] MS (ESI) m / z [M+H] + : 289.11

[0422] (10) Preparation method of intermediate B:

[0423] Intermediate B1-1 (57 mmol) was dispersed in methanol (150 mL) and water (30 mL), lithium hydroxide monohydrate (4.78 g) was added, and stirring was performed at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated, water (100 mL), DCM (300 mL*3) and ethanol (30 mL) were added to the residue for extraction, the organic phases were combined, and concentrated to no liquid outflow; the residue was dispersed in saturated NaHCO3 solution (100 mL), the water phase was washed with EA (100 mL*3) to remove impurities, 2M hydrochloric acid was used to adjust the pH of the water phase to 3-5, DCM / ethanol (300 mL / 30 mL*3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to no liquid outflow, PE / EA = 30 / 1 (90 mL / 3 mL) was stirred at 50 °C for 30 minutes, slowly reduced to room temperature, suction filtered, and the filter cake was dried to obtain intermediate B (12.83 g)

[0424] MS (ESI) m / z [M+H] + : 261.07

[0425] (11) Preparation method of intermediate C1-1:

[0426] 4-hydroxy piperidine-1-carboxylic acid tert-butyl ester (10.00 g) was dispersed in anhydrous THF (100 mL), cooled to 0-10 °C, NaH (2.38 g, 60%) was added, and stirred for 0.5 hours; 3-bromoprop-1-yne (5.91 g) was added, and stirring was performed at 20-25 °C for 16 hours. After the reaction was completed, water (5 mL) was added to quench the reaction, the reaction solution was diluted with EA (500 mL), the organic phase was washed with saturated brine (100 mL), separated, concentrated, and the concentrate was separated by column chromatography to obtain intermediate C1-1 (10.50 g).

[0427] (12) Preparation method of intermediate C1-2:

[0428] 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.00 g), intermediate C1-1 (1.08 g), dichlorobis(triphenylphosphine)palladium (0.42 g), cuprous iodide (0.11 g), molecular sieves (1.35 g) and cesium carbonate (3.91 g) were dispersed in DMF (10 mL), replaced with nitrogen for 3 times, and stirring was performed at 80 °C for 2 hours. After the reaction was completed, EA (100 mL) and water (20 mL) were added to the reaction solution, EA (100 mL*2) was used for extraction, the organic phases were combined, concentrated, and the concentrate was separated by column chromatography to obtain intermediate C1-2 (0.75 g).

[0429] MS (ESI) m / z [M+H] + : 496.17

[0430] (13) Preparation method of intermediate C:

[0431] Intermediate C1-2 (0.75 g) was dispersed in 1,4-dioxane (5 mL), hydrogen chloride dioxane solution (1 mL, 4 M) was added, and stirred at 20-25 °C for 16 hours. After the reaction was completed, it was concentrated to no liquid effluent to obtain intermediate C (0.62 g).

[0432] MS (ESI) m / z [M+H] + : 396.15

[0433] (14) Preparation method of intermediate D:

[0434] Intermediate B (0.80 g) was dispersed in MeCN (7.5 mL) and DMF (1 mL), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (1.41 g) and 1-methylimidazole (1.11 g) were added, and stirred at 20-25 °C for 0.5 hours. Intermediate A (0.94 g) was added, and stirred at 20-25 °C for 16 hours. After the reaction was completed, the reaction solution was filtered to obtain the filter cake, which was intermediate D (1.2 g).

[0435] MS (ESI) m / z [M+H] + : 488.17

[0436] (15) Preparation method of intermediate E:

[0437] Intermediate D (0.24 g) was dispersed in THF (10 mL), and Dess-Martin oxidant was added, and stirred at 20-25 °C for 1 hour. After the reaction was completed, it was quenched with saturated sodium thiosulfate solution (10 mL), and the reaction solution was washed with saturated sodium bicarbonate solution (2*10 mL), and separated. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to no liquid effluent to obtain intermediate E (0.50 mmol).

[0438] MS (ESI) m / z [M+H] + : 486.15

[0439] (16) Preparation method of compound 1:

[0440] Intermediate C (54 mg) was dispersed in DMF (2 mL) and THF (10 mL), cooled to 0-10 °C, triethylamine (25 mg) was added, and stirred for 0.5 h; glacial acetic acid (23 mg) and intermediate E (0.125 mmol) were added, and stirred at 0-10 °C for 0.5 h; sodium triacetoxyborohydride (53 mg) was added, and stirred at 20-25 °C for 16 h. After the reaction was completed, the reaction was quenched with water (10 mL), extracted with EA (3*20 mL), and the organic phase was evaporated to dryness. The residue was purified by preparative liquid phase to obtain compound 1 (45 mg).

[0441] MS (ESI) m / z [M+H] + : 865.27.

[0442] 1 H NMR (500 MHz, DMSO) δ 11.15 (s, 1H), 9.50 (d, J = 7.9 Hz, 1H), 8.84-8.73 (m, 1H), 8.38 (d, J = 5.5 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 7.97-7.82 (m, 3H), 7.11 (m, 1H), 6.66 (m, 1H), 5.31-5.05 (m, 2H), 4.77 (d, J = 22.4 Hz, 1H), 4.51 (s, 2H), 4.22-4.14 (m, 1H), 3.85-3.79 (m, 2H), 3.76-3.66 (m, 3H), 3.63 (d, J = 11.4 Hz, 1H), 3.60 (s, 1H), 3.45 (d, J = 10.5 Hz, 1H), 2.90 (ddd, J = 17.1, 13.8, 5.4 Hz, 2H), 2.61 (dt, J = 17.1, 3.3 Hz, 1H), 2.55 (d, J = 3.8 Hz, 1H), 2.18 (m, 3H), 2.04 (m, 3H), 1.97-1.84 (m, 5H), 1.80-1.68 (m, 2H), 1.55 (m, 3H), 1.04 (q, J = 10.7 Hz, 2H).

[0443] Example 2

[0444] (1) Preparation method of intermediate C2-1:

[0445] The preparation method of intermediate C1-2 in Reference Example 1 was referred to, 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was replaced by 3-(4-bromo-1- oxoisoindolin-2-yl)piperidine-2,6-dione to obtain intermediate C2-1.

[0446] (2) Preparation method of intermediate C-2:

[0447] The preparation method of compound 1 in Reference Example 1 was referred to, and the intermediate C therein was replaced by intermediate C-2 to give compound 2.

[0448] MS (ESI) m / z [M+H] + : 382.13

[0449] (3) Preparation method of compound 2:

[0450] The preparation method of compound 1 in Reference Example 1 was referred to, and the intermediate C therein was replaced by intermediate C-2 to give compound 2.

[0451] MS (ESI) m / z [M+H] + : 851.59

[0452] 1 H NMR (500 MHz, DMSO) δ 11.02 (s, 1H), 9.51 (d, J = 8.5 Hz, 1H), 8.79 (dd, J = 7.7, 1.8 Hz, 1H), 8.41 (d, J = 5.5 Hz, 1H), 8.26 (d, J = 7.2 Hz, 1H), 7.76 (dd, J = 29.8, 7.2 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.26 - 6.97 (m, 1H), 6.67 (m, 1H), 5.30 - 5.06 (m, 2H), 4.77 (d, J = 27.3 Hz, 1H), 4.54 (d, J = 4.6 Hz, 2H), 4.50 (dd, J = 17.6, 3.6 Hz, 1H), 4.36 (d, J = 17.7 Hz, 1H), 4.24 (m, 1H), 3.98 (s, 1H), 3.85 - 3.80 (m, 2H), 3.74 (m, 1H), 3.64 (m, 1H), 3.60 (s, 1H), 3.45 (m, 1H), 3.39 (m, 1H), 3.12 - 3.05 (m, 1H), 3.03 (m, 1H), 2.92 (m, 1H), 2.65 - 2.57 (m, 1H), 2.54 (s, 1H), 2.44 (qd, J = 13.1, 4.3 Hz, 1H), 2.21 (d, J = 12.1 Hz, 1H), 2.11 - 2.02 (m, 4H), 2.00 - 1.86 (m, 5H), 1.80 (m, 2H), 1.71 (m, 1H), 1.31 - 1.12 (m, 3H).

[0453] Example 3

[0454] (1) Preparation method of intermediate C3-1:

[0455] Reference is made to the preparation method of intermediate C1-2 in Reference Example 1, wherein 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione is replaced by 3-(7-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione to obtain intermediate C3-1.

[0456] (2) Preparation method of intermediate C-3:

[0457] Reference is made to the preparation method of intermediate C in Reference Example 1, wherein intermediate C1-2 is replaced by intermediate C3-1 to obtain intermediate C-3.

[0458] MS (ESI) m / z [M+H]+: 382.14 +

[0459] (3) Preparation method of compound 3:

[0460] Reference is made to the preparation method of compound 1 in Reference Example 1, wherein intermediate C is replaced by intermediate C-3 to obtain compound 3.

[0461] MS (ESI) m / z [M+H]+: 851.56 +

[0462] 1 ​​H NMR (500 MHz, DMSO) δ 11.02 (d, J = 6.7 Hz, 1H), 9.51 (d, J = 8.4 Hz, 1H), 8.79 (dd, J = 7.8, 1.7 Hz, 1H), 8.41 (d, J = 5.3 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 7.63 (d, J = 5.0 Hz, 2H), 7.55 (q, J = 4.0 Hz, 1H), 7.12 (m, 1H), 6.67 (m, 1H), 5.18 (m, 1H), 5.07 - 4.97 (m, 1H), 4.82 - 4.72 (m, 1H), 4.54 (d, J = 8.4 Hz, 2H), 4.45 (dd, J = 17.5, 3.8 Hz, 1H), 4.39 - 4.29 (m, 1H), 4.28 - 4.18 (m, 1H), 4.00 - 3.92 (m, 1H), 3.74 (m, 1H), 3.60 (s, 1H), 3.45 (m, 1H), 3.38 (d, J = 10.4 Hz, 1H), 3.11 (m, 1H), 3.06 - 2.95 (m, 2H), 2.94 - 2.83 (m, 1H), 2.68 - 2.58 (m, 1H), 2.48 - 2.35 (m, 1H), 2.24 (d, J = 12.2 Hz, 1H), 2.17 - 1.64 (m, 14H), 1.29 - 1.12 (m, 3H), 0.84 (m, 1H).

[0463] Example 5

[0464] (1) Preparation method of intermediate C5-1:

[0465] Intermediate C5-1 was prepared according to the method described in Example 1, except that 3-(7,8-dihydro-6H-isoxazolo[5,4-e]isoindol-3-yl)piperidine-2,6-dione hydrochloride (0.23 g) was used instead of 3-(7,8-dihydro-6H-isoxazolo[5,4-e]isoindol-3-yl)piperidine-2,6-dione.

[0466] MS (ESI) m / z [M+H] + : 455.34

[0467] (2) Preparation method of intermediate C-5:

[0468] Intermediate C5-1 (0.75 mmol) was dispersed in 1,4-dioxane (5 mL), hydrogen chloride dioxane solution (1 mL, 4 M) was added, and stirred at 20-25 °C for 16 hours. After the reaction was completed, concentrated to no liquid effluent, and intermediate C-5 (0.75 mmol) was obtained.

[0469] MS (ESI) m / z [M+H] + : 355.29

[0470] (3) Preparation method of compound 5:

[0471] Intermediate C-5 (0.17 mmol) was dispersed in DMF (2 mL) and THF (10 mL), cooled to 0-10 °C, triethylamine (34 mg) was added, and stirred for 0.5 hours; glacial acetic acid (22 mg) and intermediate E (0.09 mmol) were added, and stirred at 0-10 °C for 0.5 hours; sodium triacetoxyborohydride (51 mg) was added, and stirred at 20-25 °C for 16 hours. After the reaction was completed, water (10 mL) was added to quench the reaction, extracted with EA (3*20 mL), and the organic phase was evaporated to dryness. Compound 5 (3 mg) was obtained by preparative liquid chromatography.

[0472] MS (ESI) m / z [M+H] + : 824.46

[0473] 1 H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.50 (d, J = 7.8 Hz, 1H), 8.78 (d, J = 7.5 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.11 (m, 1H), 6.66 (m, 1H), 5.18 (m, 1H), 4.77 (d, J = 22.1 Hz, 1H), 4.60 (dd, J = 11.8, 5.0 Hz, 1H), 4.19 (m, 3H), 4.06 (s, 2H), 3.86 - 3.56 (m, 4H), 3.45 (d, J = 10.5 Hz, 1H), 2.85 (m, 2H), 2.77 (m, 1H), 2.61 (m, 1H), 2.26 - 2.13 (m, 3H), 2.03 (m, 1H), 2.02 - 1.95 (m, 3H), 1.75 (q, J = 10.7 Hz, 2H), 1.54 (m, 4H), 1.32 - 1.20 (m, 5H), 1.06 (q, J = 11.7 Hz, 2H), 0.85 (t, J = 6.9 Hz, 1H).

[0474] Example 6

[0475] (1) Preparation method of intermediate C6-1:

[0476] Reference to the preparation method of intermediate C5-1 in Reference Example 5, replace N-tert-butoxycarbonyl-4-piperidone therein with 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde to obtain intermediate C6-1.

[0477] MS (ESI) m / z [M+H] + : 469.36

[0478] (2) Preparation method of intermediate C-6:

[0479] Reference to the preparation method of intermediate C-5 in Reference Example 5, replace intermediate C5-1 therein with intermediate C6-1 to obtain intermediate C-6.

[0480] MS (ESI) m / z [M+H] + : 369.31

[0481] (3) Preparation method of compound 6:

[0482] Reference to the preparation method of compound 5 in Reference Example 5, replace intermediate C-5 therein with intermediate C-6 to obtain compound 6 (3 mg).

[0483] MS (ESI) m / z [1 / 2M+H] + : 419.97

[0484] 1H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.50 (d, J = 7.9 Hz, 1H), 8.78 (dd, J = 7.7, 1.8 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.11 (m, 1H), 6.66 (m, 1H), 5.18 (m, 1H), 4.77 (dd, J = 21.6, 2.2 Hz, 1H), 4.60 (dd, J = 11.8, 5.0 Hz, 1H), 4.08 (m, 5H), 3.81 (m, 2H), 3.76 - 3.61 (m, 1H), 3.60 (s, 1H), 3.45 (d, 1H), 2.94 (d, J = 11.6 Hz, 2H), 2.77 (ddd, J = 17.2, 12.0, 5.3 Hz, 1H), 2.65 - 2.58 (m, 3H), 2.54 (s, 1H), 2.26 (d, J = 6.9 Hz, 2H), 2.21 (dq, J = 8.2, 4.3 Hz, 1H), 2.09 - 1.87 (m, 8H), 1.82 - 1.70 (m, 4H), 1.32 - 1.13 (m, 3H), 1.07 (q, J = 10.7 Hz, 2H).

[0485] Example 7

[0486] (1) Preparation method of intermediate C7-1:

[0487] Intermediate C7-1 was prepared according to the following method: 3-(7,8,9,10-tetrahydro-6H-isoxazolo[5',4':3,4]benzo[l,2-d]azepin-3-yl)piperidine-2,6-dione hydrochloride (100 mg) was dispersed in THF (5 mL), triethylamine (40 mg) was added, and stirring was performed at 20-25 °C for 20 min; then glacial acetic acid (48 mg) and l-tert-butoxycarbonylpiperidine-4-carbaldehyde (71 mg) were added, and stirring was continued at 20-25 °C for 20 min; finally, sodium triacetoxyborohydride (140 mg) was added, and reaction was performed at 20-25 °C for 2 h. After the reaction was completed, water (20 mL) and ethyl acetate (60 mL) were added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to no liquid flow, to obtain intermediate C7-1 (0.30 mmol).

[0488] MS (ESI) m / z [M+H] + : 497.33

[0489] (2) Preparation method of intermediate C-7:

[0490] Dissolve intermediate C7-1 (0.30 mmol) in ethyl acetate (3 mL), add ethyl acetate hydrogen chloride solution (3 mL, 4 M), continue stirring the reaction at 20-25 °C for 2 hours. After the reaction is completed, concentrate to no liquid effluent under reduced pressure to obtain intermediate C-7 (0.30 mmol).

[0491] MS (ESI) m / z [M+H] + : 397.32

[0492] (3) Preparation method of compound 7:

[0493] Reference the preparation method of compound 5 in Example 5, replace intermediate C-5 therein with intermediate C-7 to obtain compound 7 (30 mg).

[0494] MS (ESI) m / z [M+H] + : 866.46

[0495] 1 H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.51 (d, J = 7.3 Hz, 1H), 8.83-8.68 (m, 1H), 8.33 (m, 2H), 7.53 (d, J = 7.9 Hz, 1H), 7.26-6.97 (m, 2H), 6.63 (m, 1H), 5.17 (m, 1H), 4.77 (m, 1H), 4.55 (m, 1H), 4.16 (m, 1H), 3.89-3.39 (m, 4H), 3.07 (m, 5H), 2.80 (m, 3H), 2.68-2.55 (m, 5H), 2.18 (m, 1H), 2.12 (m, 2H), 1.91 (s, 10H), 1.80-1.65 (m, 4H), 1.54 (m, 2H), 1.08 (m, 4H).

[0496] Example 8

[0497] (1) Preparation method of intermediate C8-1:

[0498] Reference the preparation method of intermediate C7-1 in Example 7, replace 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde therein with N-tert-butoxycarbonyl-4-piperidone to obtain intermediate C8-1.

[0499] MS (ESI) m / z [M+H] + : 483.36

[0500] (2) Preparation method of intermediate C-8:

[0501] Reference is made to the preparation procedure of intermediate C-7 in Reference Example 7, by replacing intermediate C7-1 with intermediate C8-1 to give intermediate C-8.

[0502] MS (ESI) m / z [M+H] + : 383.27

[0503] (3) Preparation method of compound 8:

[0504] Reference is made to the preparation procedure of compound 7 in Reference Example 7, by replacing intermediate C-7 with intermediate C-8 to give compound 8 (28 mg).

[0505] MS (ESI) m / z [M+H] + : 852.48

[0506] 1 H NMR (500 MHz, DMSO) d 11.07 (s, 1H), 9.49 (d, J = 5.3 Hz, 1H), 8.77 (d, J = 6.1 Hz, 1H), 8.46 - 8.16 (m, 2H), 7.52 (d, J = 7.1 Hz, 1H), 7.27 - 6.95 (m, 2H), 6.65 (m, 1H), 5.17 (m, 1H), 4.76 (d, J = 20.7 Hz, 1H), 4.53 (d, J = 6.9 Hz, 1H), 4.15 (m, 1H), 3.80 (m, 1H), 3.69 - 3.55 (m, 1H), 3.44 (m, 1H), 3.06 (m, 2H), 2.86 (m, 1H), 2.66 (m, 3H), 2.19 (s, 1H), 2.12 - 1.78 (m, 16H), 1.77 - 1.66 (m, 2H), 1.62 (m, 2H), 1.49 (m, 4H), 1.23 (s, 2H), 1.10 - 0.91 (m, 2H).

[0507] Example 9

[0508] (1) Preparation method of intermediate C9-1:

[0509] Reference is made to the preparation procedure of intermediate C1-2 in Reference Example 1, by replacing 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione with 3-(7-bromobenzo[d]isoxazol-3-yl)piperidine-2,6-dione to give intermediate C9-1.

[0510] MS (ESI) m / z [M-100+H] + : 368.39

[0511] (2) Preparation method of intermediate C-9:

[0512] Reference to the preparation method of intermediate C in Reference Example 1, replace intermediate C1-2 with intermediate C9-1 to obtain intermediate C-9.

[0513] MS (ESI) m / z [M+H] + : 368.25

[0514] (3) Preparation method of compound 9:

[0515] Reference to the preparation method of compound 1 in Reference Example 1, replace intermediate C with intermediate C-9 to obtain compound 9 (5 mg).

[0516] MS (ESI) m / z [M+H] + : 837.36

[0517] Example 10

[0518] (1) Preparation method of intermediate C10-1:

[0519] Disperse 3-(6,7,8,9-tetrahydroisoxazolo[4,5-h]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride (100 mg) in THF (5 mL), add triethylamine (31 mg), stir at 20-25 °C for 20 minutes; then add glacial acetic acid (19 mg) and 1-tert-butoxycarbonylpiperidine-4-carbaldehyde (100 mg) and continue to stir at 20-25 °C for 20 minutes; finally add sodium triacetoxyborohydride (197 mg) and react at 20-25 °C for 2 hours. Add water (20 mL) and ethyl acetate (60 mL) to extract, separate the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate to no liquid flow to obtain intermediate C10-1 (0.31 mmol).

[0520] MS (ESI) m / z [M+H] + : 483.31

[0521] (2) Preparation method of intermediate C-10:

[0522] Dissolve intermediate C10-1 (0.31 mmol) in ethyl acetate (3 mL), add ethyl acetate hydrogen chloride solution (3 mL, 4M), and continue to stir at 20-25 °C for 2 hours. After the reaction is completed, concentrate to no liquid flow under reduced pressure to obtain intermediate C-10 (0.31 mmol).

[0523] MS (ESI) m / z [M+H] + : 383.27

[0524] (3) Preparation method of compound 10:

[0525] Reference is made to the preparation method of compound 5 in Reference Example 5, by replacing the intermediate C-5 therein with intermediate C-10 to obtain compound 10 (42 mg).

[0526] MS (ESI) m / z [M+H] + : 852.39

[0527] 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 9.49 (d, J = 7.8 Hz, 1H), 8.77 (d, J = 7.6 Hz, 1H), 8.37 (d, J = 6.0 Hz, 1H), 8.25 (d, J = 6.9 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.24 - 6.97 (m, 2H), 6.65 (m, 1H), 5.17 (m, 1H), 4.77 (m, 1H), 4.55 (dd, J = 11.7, 5.0 Hz, 1H), 4.16 (m, 1H), 3.88 - 3.56 (m, 7H), 2.95 (t, J = 5.8 Hz, 2H), 2.90 - 2.57 (m, 7H), 2.40 (d, J = 7.0 Hz, 2H), 2.25 - 1.98 (m, 7H), 1.79 - 1.58 (m, 6H), 1.25 (d, J = 8.4 Hz, 2H), 1.22 - 0.96 (m, 4H), 0.89 - 0.82 (m, 1H).

[0528] Example 11

[0529] (1) Preparation method of intermediate C11-1:

[0530] Reference is made to the preparation method of intermediate C10-1 in Reference Example 10, by replacing the 3-(6,7,8,9-tetrahydroisoxazolo[4,5-h]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride salt therein with 3-(6,7,8,9-tetrahydroisoxazolo[5,4-f]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride salt to obtain intermediate C11-1.

[0531] MS (ESI) m / z [M+H] + : 483.27.

[0532] (2) Preparation method of intermediate C-11:

[0533] Reference is made to the preparation method of intermediate C-10 in Reference Example 10, by replacing the intermediate C10-1 therein with intermediate C11-1 to obtain intermediate C-11.

[0534] (3) Preparation method of compound 11:

[0535] The preparation method of compound 10 in Reference Example 10 was referenced, the intermediate C-10 therein was replaced by intermediate C-11 to obtain compound 11 (73 mg).

[0536] MS (ESI) m / z [M+H] + : 852.40.

[0537] Example 12

[0538] (1) Preparation method of intermediate C12-1:

[0539] The preparation method of intermediate C1-2 in Reference Example 1 was referenced, the 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione therein was replaced by ethyl 2-(6-bromobenzo[D]isoxazol-3-yl)acetate to prepare intermediate C12-1.

[0540] MS (ESI) m / z [M+H] + : 443.19

[0541] (2) Preparation method of intermediate C12-2:

[0542] Intermediate C12-1 (1.00 g) was dispersed in THF (10 mL), cooled to -10 °C, acrylamide (128 mg) and potassium tert-butoxide (380 mg) were added, and stirred under nitrogen protection for 4 hours. After the reaction was completed, the reaction liquid was poured into water (10 mL), washed with aqueous ammonium chloride solution, extracted with ethyl acetate (3*20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate C12-2.

[0543] MS (ESI) m / z [M+H] + : 468.23

[0544] (3) Preparation method of intermediate C-12:

[0545] The preparation method of intermediate C-12 was referenced to the preparation method of C-9 in Example 9, intermediate C9-1 therein was replaced by intermediate C12-2 to prepare intermediate C-12.

[0546] MS (ESI) m / z [M+H] + : 368.22

[0547] (3) Preparation method of compound 12:

[0548] Reference is made to the preparation method of compound 9 in Reference Example 9, wherein the intermediate C-9 is replaced by intermediate C-12 to give compound 12 (18 mg).

[0549] MS (ESI) m / z [M+H] + : 837.36

[0550] Example 13

[0551] (1) Preparation method of intermediate F1-1:

[0552] Reference is made to the preparation method of compound 1 in Reference Example 1, wherein the intermediate C is replaced by methyl 4-piperidinecarboxylate to give intermediate F1-1.

[0553] MS (ESI) m / z [M+H] + : 613.32

[0554] (2) Preparation method of intermediate F1-2:

[0555] Reference is made to the preparation method of intermediate B in Reference Example 1, wherein the intermediate B1-1 is replaced by intermediate F1-1 to give intermediate F1-2.

[0556] (3) Preparation method of compound 13:

[0557] Intermediate F1-2 (0.25 g) was dispersed in DMF (1 mL), HATU (0.32 g) and DIPEA (0.27 g) were added, and then 3-(6,7,8,9-tetrahydroisoxazolo[4,5-h]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride (0.12 g) was added. The mixture was stirred at 20-25 °C for 3 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, and ethyl acetate (30 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid chromatography to give compound 13 (42 mg).

[0558] MS (ESI) m / z [M+H] + : 866.40

[0559] 1H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.50 (d, J = 7.5 Hz, 1H), 8.77 (d, J = 7.8 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 7.65 (m, 1H), 7.25 - 6.96 (m, 2H), 6.65 (m, 1H), 5.18 (m, 1H), 5.04 - 4.73 (m, 3H), 4.63 - 4.55 (m, 1H), 4.17 (m, 1H), 3.91 - 3.38 (m, 7H), 3.02 (t, J = 6.2 Hz, 1H), 2.88 - 2.61 (m, 5H), 2.24 - 1.84 (m, 12H), 1.81 - 1.57 (m, 7H), 1.03 (d, J = 12.4 Hz, 2H).

[0560] Example 14

[0561] (1) Preparation method of intermediate G1-1:

[0562] Intermediate E (500 mg) was dispersed in THF (3 mL) and n-butanol (3 mL), 2-methyl-2-butene (561 mg) was added, and a solution of sodium dihydrogen phosphate (359 mg) and sodium hypochlorite (271 mg) in water (1 mL) was added dropwise, and stirred at 20-25 °C for 1 hour. After the reaction was completed, the reaction was quenched with sodium sulfite and concentrated to no liquid flow to obtain intermediate G1-1 (1.53 mmol).

[0563] MS (ESI) m / z [M+H] + : 502.22

[0564] (2) Preparation method of intermediate G1-2:

[0565] Intermediate G1-1 (0.52 mmol) was dispersed in DMF (5 mL), HATU (228 mg), DIPEA (259 mg) and methyl 4-piperidinecarboxylate (72 mg) were added, and stirred at 20-25 °C for 3 hours. After the reaction was completed, water (20 mL) and dichloromethane (10 mL) were added to the reaction solution, and the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate G1-2 (300 mg).

[0566] MS (ESI) m / z [M+H] + : 627.34

[0567] (3) Preparation method of intermediate G1-3:

[0568] Intermediate G1-2 (250 mg) was dispersed in methanol (5 mL) and water (1 mL), lithium hydroxide (50 mg) was added, and stirring was performed at 20-25 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain intermediate G1-3 (0.40 mmol).

[0569] MS (ESI) m / z [M+H] + : 613.25

[0570] (4) Preparation method of compound 14:

[0571] Intermediate G1-3 (0.16 mmol) was dispersed in DMA (5 mL), HATU (76 mg), DIPEA (82 mg), and 3-(6,7,8,9-tetrahydroisoxazolo[4,5-h]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride (52 mg) were added, and stirring was performed at 20-25 °C for 3 hours. After the reaction was completed, water (20 mL) and dichloromethane (10 mL) were added and extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid chromatography to obtain compound 14 (14 mg).

[0572] MS (ESI) m / z [M+H] + : 880.36

[0573] 1 H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.50 (d, J = 8.2 Hz, 1H), 8.78 (dd, J = 7.7, 1.8 Hz, 1H), 8.40 (d, J = 6.1 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 7.66 (m, 1H), 7.26 - 6.98 (m, 2H), 6.66 (m, 1H), 5.33 - 4.98 (m, 2H), 4.87 (m, 1H), 4.81 - 4.72 (m, 1H), 4.64 - 4.55 (m, 1H), 4.42 (m, 1H), 4.25 (m, 1H), 4.05 (m, 1H), 3.93 - 3.70 (m, 4H), 3.66 - 3.42 (m, 2H), 3.22 - 2.86 (m, 4H), 2.83 - 2.58 (m, 4H), 2.25 - 2.15 (m, 1H), 2.12 - 1.67 (m, 11H), 1.58 (m, 3H), 1.39 (m, 1H).

[0574] Example 15

[0575] (1) Preparation method of intermediate H1-1:

[0576] Intermediate G1-1 (0.52 mmol) was dispersed in DMF (5 mL), HATU (225 mg) and DIPEA (258 mg) were added, and 4-hydroxymethylpiperidine (58 mg) was added. The mixture was stirred at 20-25 °C for 3 hours. After the reaction was completed, water (20 mL) and dichloromethane (10 mL) were added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain intermediate H1-1 (300 mg).

[0577] MS (ESI) m / z [M+H] + : 599.28

[0578] (2) Preparation method of intermediate H1-2:

[0579] The preparation method of intermediate E in Reference Example 1 was used, and intermediate D therein was replaced by intermediate H1-1 to prepare intermediate H1-2.

[0580] MS (ESI) m / z [M+H] + : 597.27

[0581] (3) Preparation method of compound 15:

[0582] The preparation method of compound 11 in Reference Example 11 was used, and intermediate E therein was replaced by intermediate H1-2, and intermediate C-11 was replaced by 3-(6,7,8,9-tetrahydroisoxazolo[4,5-h]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride to prepare compound 15 (45 mg).

[0583] MS (ESI) m / z [M+H] + : 866.68.

[0584] Example 16

[0585] The preparation method of compound 14 in Reference Example 14 was used, and 3-(6,7,8,9-tetrahydroisoxazolo[4,5-h]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride therein was replaced by 3-(7,8-dihydro-6H-isoxazolo[5,4-e]isoindol-3-yl)piperidine-2,6-dione hydrochloride to prepare compound 16.

[0586] MS (ESI) m / z [M+H] + : 866.33

[0587] 1H NMR (500 MHz, DMSO) δ 11.12 (s, 1H), 9.51 (d, J = 8.1 Hz, 1H), 8.77 (dd, J = 7.8, 3.2 Hz, 1H), 8.41 (d, J = 6.0 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 7.83 (m, 1H), 7.39 (m, 1H), 7.11 (m, 1H), 6.65 (m, 1H), 5.34 - 5.03 (m, 3H), 4.91 (s, 1H), 4.84 - 4.73 (m, 2H), 4.64 (ddd, J = 12.1, 5.0, 2.1 Hz, 1H), 4.48 (m, 1H), 4.33 - 4.21 (m, 1H), 4.09 (m, 1H), 3.85 - 3.72 (m, 2H), 3.66 - 3.42 (m, 2H), 3.16 (m, 1H), 3.01 - 2.84 (m, 1H), 2.79 (m, 2H), 2.72 - 2.52 (m, 3H), 2.29 - 2.17 (m, 1H), 2.13 - 1.80 (m, 10H), 1.59 (m, 3H), 1.40 (m, 1H).

[0588] Example 17

[0589] Following the procedure for the preparation of compound 15 in Reference Example 15, replacing the intermediate 3-(6,7,8,9-tetrahydroisoxazolo[4,5- ]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride with 3-(7,8-dihydro-6H- isoxazolo[5,4-e]isoindol-3-yl)piperidine-2,6-dione hydrochloride, compound 17 was prepared.

[0590] MS (ESI) m / z [M+H] + : 852.51

[0591] 1H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.50 (d, J = 8.2 Hz, 1H), 8.78 (dd, J = 7.8, 2.0 Hz, 1H), 8.40 (d, J = 6.3 Hz, 1H), 8.26 (d, J = 6.9 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.11 (m, 1H), 6.65 (m, 1H), 5.18 (m, 1H), 4.83 - 4.71 (m, 1H), 4.60 (dd, J = 11.8, 5.0 Hz, 1H), 4.42 (m, 1H), 4.30 - 3.72 (m, 8H), 3.67 - 3.45 (m, 2H), 3.07 (m, 1H), 2.76 (m, 2H), 2.69 - 2.58 (m, 3H), 2.21 (m, 1H), 2.11 - 1.72 (m, 13H), 1.58 (m, 2H), 1.04 (m, 2H).

[0592] Example 18

[0593] (1) Preparation method of intermediate C13-1:

[0594] Into a reaction flask were added 4-hydroxy-coumarin (52 g), methanol (300 mL), hydroxylamine hydrochloride (52.5 g) and sodium ethoxide (61.9 g) successively, heated to 80 °C for reaction for 16 hours. After the reaction solution was cooled, hydrochloric acid was used to adjust the pH to 5-6, concentrated under reduced pressure, 2 L of water was added, the pH was continuously adjusted to 2-3 under ice bath condition, stirred for 30 minutes, filtered, the filter cake was collected and dried to obtain intermediate C13-1 (42 g).

[0595] MS (ESI) m / z [M+H] + 177.9

[0596] (2) Preparation method of intermediate C13-2:

[0597] Into a reaction flask were added intermediate C13-1 (42 g), ethanol (300 mL), sulfuric acid (97.3 g) successively, heated to 90 °C for reaction for 2 hours. After the reaction was completed, cooled to room temperature, concentrated under reduced pressure, 1 L of water and 1 L of ethyl acetate were added, saturated sodium bicarbonate solution was used to adjust the pH to about 7, the liquid was separated, the aqueous phase was extracted with ethyl acetate twice, the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain intermediate C13-2 (46 g).

[0598] MS (ESI) m / z [M+H] + 206.13

[0599] Method for preparing intermediate C13-3:

[0600] Intermediate C13-2 (25 g) was dispersed in sulfuric acid (200 mL), and a mixed solution of nitric acid (9.2 g) and sulfuric acid (3 mL) was slowly added under ice bath condition. After the dropwise addition was completed, the reaction was slowly raised to 20-25°C for 1 hour. After the reaction was completed, the reaction solution was slowly poured into 2 L of ice water, and extracted with ethyl acetate (300 mL). The aqueous phase was extracted with ethyl acetate twice, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography gave intermediate C13-3 (23.5 g).

[0601] MS (ESI) m / z [M-H] + : 249.23

[0602] Method for preparing intermediate C13-4:

[0603] Intermediate C13-3 (16.5 g) was dispersed in ethanol (165 mL), and stannous chloride dihydrate (74.4 g) was added. The reaction was carried out at 20-25°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and ethyl acetate (300 mL) and a saturated sodium bicarbonate solution (300 mL) were added. The mixture was stirred, and the phases were separated. The aqueous phase was extracted with ethyl acetate once, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography gave intermediate C13-4 (13.6 g).

[0604] Method for preparing intermediate C13-5:

[0605] Intermediate C13-4 (4.4 g) was dispersed in dichloromethane (44 mL), and NBS (3.91 g) was slowly added under ice bath condition. The reaction was stirred at 20-25°C for 1 hour. After the reaction was completed, water (50 mL) and dichloromethane (50 mL) were added. The phases were separated, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography gave intermediate C13-5 (4.7 g).

[0606] MS (ESI) m / z [M+H] + : 299.13

[0607] Method for preparing intermediate C13-6:

[0608] Intermediate C13-5 (4.0 g) was dispersed in THF (40 mL), and glacial acetic acid (504 mg), 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (2.68 g), and sodium triacetoxyborohydride (5.33 g) were added. The reaction was stirred at 60°C for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL), and extracted with EA (3*50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography gave intermediate C13-6 (4.0 g).

[0609] MS (ESI) m / z [M+H] + : 440.10

[0610] (7) Preparation method of intermediate C13-7:

[0611] Into a reaction flask were added intermediate C13-6 (2.5 g), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (1.30 g), potassium carbonate (2.09 g), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.37 g), 1,4-dioxane (25 mL) and water (5 mL) in sequence, replaced with nitrogen for three times, and reacted at 100°C for 2 hours. After the reaction, water (10 mL) was added, EA (3*50 mL) was used for extraction, the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography was performed to obtain intermediate C13-7 (1.5 g).

[0612] (8) Preparation method of intermediate C13-8:

[0613] Into a reaction flask were added intermediate C13-7 (1.5 g), trifluoroacetic acid (3 mL) and dichloromethane (15 mL) in sequence, and reacted at 20-25°C for 2 hours. After the reaction, concentrated under reduced pressure, and column chromatography was performed to obtain intermediate C13-8 (1.0 g).

[0614] MS (ESI) m / z [M+H] + : 342.15

[0615] (9) Preparation method of intermediate C13-9:

[0616] Intermediate C13-8 (1.0 g) was dispersed in dichloromethane (10 mL), di-tert-butyl dicarbonate (0.96 g) and triethylamine (0.89 g) were added, and stirred at 20-25°C for 1 hour. After the reaction, concentrated under reduced pressure, and column chromatography was performed to obtain intermediate C13-9 (1.1 g).

[0617] (9) Preparation method of intermediate C13-10:

[0618] Into a reaction flask were added intermediate C13-9 (700 mg), acrylamide (101 mg) and anhydrous tetrahydrofuran (5 mL) in sequence, potassium tert-butoxide (180 mg) was slowly added at -20°C, and the temperature was increased to 0°C to react for 1 hour. After the reaction, saturated aqueous ammonium chloride solution (20 mL) was added for quenching, EA (3*50 mL) was used for extraction, the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography was performed to obtain intermediate C13-10 (560 mg).

[0619] (10) Preparation method of intermediate C13-11:

[0620] Reference the preparation method of intermediate C in Example 1, replace intermediate C1-2 with intermediate C13-10 to prepare intermediate C13-11.

[0621] MS (ESI) m / z [M+H] + : 367.26

[0622] (11) Preparation method of compound 18:

[0623] Intermediate C13-11 (40 mg) was dispersed in THF (3 mL), cooled to 0-10 °C, triethylamine (20 mg) was added, and stirred for 0.5 h; glacial acetic acid (15 mg) and intermediate E (0.082 mmol) were added, and stirred at 0-10 °C for 0.5 h; sodium triacetoxyborohydride (52 mg) was added, and stirred at 20-25 °C for 2 h. After the reaction was completed, water (10 mL) was added to quench the reaction, EA (3*20 mL) was added for extraction, the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid chromatography to obtain compound 18 (15 mg).

[0624] MS (ESI) m / z [M+H] + : 836.44

[0625] 1 H NMR (500 MHz, DMSO) δ 11.17 (s, 1H), 9.49 (d, J = 7.8 Hz, 1H), 8.77 (d, J = 7.6 Hz, 1H), 8.37 (d, J = 5.5 Hz, 1H), 8.25 (d, J = 6.9 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.57 (m, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.26 - 6.94 (m, 1H), 6.92 - 6.35 (m, 2H), 5.17 (m, 1H), 4.77 (d, J = 22.1 Hz, 1H), 4.69 (dd, J = 11.7, 5.2 Hz, 1H), 4.27 - 4.10 (m, 3H), 3.89 - 3.45 (m, 5H), 2.82 (m, 3H), 2.64 (m, 1H), 2.45 (m, 1H), 2.23 (m, 1H), 2.04 (m, 5H), 1.85 (m, 2H), 1.71 (m, 2H), 1.47 (m, 4H), 1.35 - 1.14 (m, 4H), 1.00 (q, J = 12.8 Hz, 2H).

[0626] Example 19

[0627] Intermediate F1-2 (223 mg) was dispersed in DMF (3 mL), HATU (212 mg) and DIPEA (193 mg) were added, after stirring for 15 min, 3-(7,8-dihydro-6H-isoxazolo[5,4-e]isoindol-3-yl)piperidine-2,6-dione hydrochloride (115 mg) was added, stirred at room temperature for 2 hours. After the reaction was completed, diluted with water (10 mL), extracted with EA (3*20 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by preparative liquid phase to give compound 19 (35 mg).

[0628] MS (ESI) m / z [M+H] + : 852.45

[0629] Example 20

[0630] (1) Preparation method of intermediate C14-1:

[0631] Reference is made to the preparation method of intermediate C7-1 in Reference Example 7, wherein 3-(7,8,9,10-tetrahydro-6H-isoxazolo[5',4':3,4]benzo[1,2-d]azepin-3-yl)piperidine-2,6-dione hydrochloride in the method is replaced by 3-(6,7,8,9-tetrahydroisoxazolo[5,4-f]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride, and 1-tert-butoxycarbonylpiperidine-4-carbaldehyde in the method is replaced by 1-tert-butoxycarbonyl-4-piperidone, to prepare intermediate C14-1.

[0632] MS (ESI) m / z [M+H] + : 469.24

[0633] (2) Preparation method of intermediate C-14:

[0634] Reference is made to the preparation method of intermediate C-7 in Reference Example 7, wherein intermediate C7-1 in the method is replaced by intermediate C14-1, to prepare intermediate C-14.

[0635] MS (ESI) m / z [M+H] + : 369.19

[0636] (3) Preparation method of compound 20:

[0637] Reference is made to the preparation method of compound 5 in Reference Example 5, wherein intermediate C-5 in the method is replaced by intermediate C-14, to obtain compound 20 (28 mg).

[0638] MS (ESI) m / z [M+H] + : 838.39

[0639] 1 H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 9.50 (d, J = 7.6 Hz, 1H), 8.77 (dd, J = 7.7, 2.4 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.26 - 6.95 (m, 2H), 6.65 (m, 1H), 5.18 (m, 1H), 4.77 (dd, J = 21.1, 2.7 Hz, 1H), 4.55 (dd, J = 11.8, 5.0 Hz, 1H), 4.24 - 4.10 (m, 1H), 3.82 (m, 4H), 3.77 - 3.61 (m, 2H), 3.03 - 2.85 (m, 6H), 2.66 - 2.54 (m, 2H), 2.49 - 2.37 (m, 2H), 2.19 (m, 1H), 2.13 - 1.79 (m, 14H), 1.65 - 1.48 (m, 3H), 1.10 - 0.97 (m, 2H).

[0640] Example 21

[0641] (1) Preparation method of intermediate A2-1:

[0642] Reference is made to the preparation method of intermediate A1-5 in Reference Example 1, except that the cis-4-hydroxycyclohexyl formic acid methyl ester therein is replaced by 1-tert-butoxycarbonyl-4-hydroxypiperidine, to give intermediate A2-1.

[0643] (2) Preparation method of intermediate A2-2:

[0644] Reference is made to the preparation method of intermediate A1-6 in Reference Example 1, except that the intermediate A1-5 therein is replaced by intermediate A2-1, to give intermediate A2-2.

[0645] (3) Preparation method of intermediate A2-3:

[0646] Intermediate A2-2 (0.56 g) was dispersed in 1,4-dioxane (5 mL), and hydrochloric acid dioxane solution (4 M, 2 mL) was added, and stirred at 20-25°C for 16 hours. After the reaction was completed, it was concentrated under reduced pressure to give intermediate A2-3 (1.61 mmol).

[0647] MS (ESI) m / z [M+H] + : 247.12

[0648] (4) Preparation method of intermediate A2-4:

[0649] Intermediate 4-(methoxycarbonyl)cyclohexyl-1-carboxylic acid (0.30 g) was dispersed in DMF (5 mL), HATU (0.77 g) and DIPEA (0.83 g) were added, stirred at 20-25 °C for 30 min, then intermediate A2-3 (1.61 mmol) was added, stirred at 20-25 °C for 16 h. After the reaction was completed, water (30 mL) was added, extracted with ethyl acetate (30 mL), separated, and the organic phase was concentrated under reduced pressure. Column chromatography separation gave intermediate A2-4 (572 mg).

[0650] MS (ESI) m / z [M+H] + : 415.21

[0651] (5) Preparation method of intermediate A2-5:

[0652] Intermediate A2-4 (0.57 g) was dispersed in THF (5 mL), cooled to 0-10 °C, and borane dimethyl sulfide solution (10 M, 0.42 mL) was added dropwise. After the dropwise addition was completed, the temperature was raised to 65 °C and the reaction was carried out for 2 h. The temperature was lowered to 0-10 °C, dilute hydrochloric acid was added dropwise to quench the reaction, and the temperature was raised to 65 °C and the reaction was carried out for 6 h. After the reaction was completed, sodium bicarbonate solution was added to adjust the pH to basic, extracted with ethyl acetate (30 mL), separated, and the organic phase was concentrated under reduced pressure. Column chromatography separation gave intermediate A2-5 (385 mg).

[0653] MS (ESI) m / z [M+H] + : 373.31

[0654] (6) Preparation method of intermediate A-2:

[0655] According to the preparation method of intermediate A in Reference Example 1, intermediate A1-7 therein was replaced with intermediate A2-5 to give intermediate A-2.

[0656] MS (ESI) m / z [M+H] + : 343.22

[0657] (7) Preparation method of intermediate I1-1:

[0658] According to the preparation method of intermediate D in Reference Example 1, intermediate A therein was replaced with intermediate A-2 to give intermediate I1-1.

[0659] MS (ESI) m / z [M+H] + : 585.42

[0660] (8) Preparation method of intermediate I1-2:

[0661] According to the preparation method of intermediate E in Reference Example 1, intermediate D therein was replaced with intermediate I1-1 to give intermediate I1-2.

[0662] MS (ESI) m / z [M+H] + 583.3

[0663] (9) Preparation method of compound 21:

[0664] Intermediate 3-(7,8-dihydro-6H-isoxazolo[5,4-e]isoindol-3-yl)piperidine-2,6-dione hydrochloride (30 mg) was dispersed in DMF (2 mL) and THF (10 mL), cooled to 0-10 °C, triethylamine (19 mg) was added, and stirred for 0.5 h; glacial acetic acid (12 mg) and intermediate II-2 (0.096 mmol) were added, and stirred at 0-10 °C for 0.5 h; sodium triacetoxyborohydride (41 mg) was added, and stirred at 20-25 °C for 1 h. After the reaction was completed, the reaction was quenched with water (10 mL), extracted with EA (3*20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by preparative liquid chromatography (column YMC AQ C18, size 30*250, 10 μm, mobile phase: A: 0.1% formic acid / water, B: acetonitrile; gradient: 10% B-70% B (0-60 min), wavelength 254 nm, v = 30 ml / min), and then separated by preparative liquid chromatography (column Waters CSH C18, size 30*250, 5 μm, mobile phase: A: 0.1% formic acid / water, B: methanol; gradient: 20% B-80% B (0-60 min), wavelength 254 nm, v = 20 ml / min) to give compound 21A (27 mg, retention time 26 min, MS (ESI) m / z [1 / 2M+H]+: 419.91) and compound 21B (2 mg, retention time 27 min, MS (ESI) m / z [1 / 2M+H]+: 419.87).

[0665] Compound 21B: 1H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.50 (d, J = 7.8 Hz, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 8.15 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.25 - 6.38 (m, 3H), 5.17 (m, 1H), 4.77 (m, 1H), 4.60 (dd, J = 12.2, 5.2 Hz, 1H), 4.12 (m, 3H), 2.95 (d, J = 10.8 Hz, 2H), 2.68 (m, 1H), 2.26 (m, 2H), 2.00 (m, 10H), 1.74 (m, 2H), 1.61 - 1.13 (m, 14H), 0.85 (m, 1H).

[0666] Example 22

[0667] (1) Preparation method of intermediate C15-1:

[0668] The preparation method of intermediate E in Reference Example 1 was referred to, intermediate D therein was replaced by tert-butyl trans-(4-hydroxymethyl)cyclohexylcarbamate to give intermediate C15-1.

[0669] (2) Preparation method of intermediate C15-2:

[0670] The preparation method of intermediate C5-1 in Reference Example 5 was referred to, N-tert-butoxycarbonyl-4-piperidone therein was replaced by intermediate C15-1 to give intermediate C15-2.

[0671] MS (ESI) m / z [M+H] + : 483.27

[0672] (3) Preparation method of intermediate C-15:

[0673] The preparation method of intermediate C in Reference Example 1 was referred to, intermediate C1-2 therein was replaced by intermediate C15-2 to give intermediate C-15.

[0674] MS (ESI) m / z [M+H] + : 383.29

[0675] (4) Preparation method of intermediate A3-1:

[0676] The preparation method of intermediate A1-5 in Reference Example 1 was referred to, cis 4-hydroxy-cyclohexylcarboxylic acid methyl ester therein was replaced by 4-hydroxycyclohexanone ethylene acetal to give intermediate A3-1.

[0677] (5) Preparation method of intermediate A3-2:

[0678] The preparation method of intermediate A1-6 in Reference Example 1 was referred to, and the intermediate A1-5 therein was replaced by intermediate A3-1 to obtain intermediate A3-2.

[0679] (6) Preparation method of intermediate A-3:

[0680] The preparation method of intermediate A in Reference Example 1 was referred to, and the intermediate A1-7 therein was replaced by intermediate A3-2 to obtain intermediate A-3.

[0681] (7) Preparation method of intermediate J1-1:

[0682] The preparation method of intermediate D in Reference Example 1 was referred to, and the intermediate A therein was replaced by intermediate A-3 to obtain intermediate J1-1.

[0683] MS (ESI) m / z [M+H] + : 516.25

[0684] (8) Preparation method of intermediate J1-2:

[0685] Intermediate J1-1 (258 mg) was dispersed in formic acid (5 mL) and reacted at 20-25 °C for 1 hour. After the reaction was completed, concentration was performed under reduced pressure to obtain intermediate J1-2 (0.50 mmol).

[0686] MS (ESI) m / z [M+H] + : 472.21

[0687] (9) Preparation method of compound 22:

[0688] Intermediate C-15 (0.42 mmol) was dispersed in DMF (2 mL) and THF (10 mL), cooled to 0-10 °C, and triethylamine (84 mg) was added, and stirred for 0.5 hours; glacial acetic acid (50 mg) and intermediate J1-2 (0.50 mmol) were added, and stirred at 0-10 °C for 0.5 hours; sodium triacetoxyborohydride (179 mg) was added, and stirred at 20-25 °C for 1 hour. After the reaction was completed, water (10 mL) was added to quench the reaction, and EA (3*20 mL) was added for extraction, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid chromatography to obtain compound 22 (9 mg).

[0689] MS (ESI) m / z [1 / 2M+H] + : 419.91.

[0690] 1H NMR (500 MHz, DMSO) δ 11.08 (s, 1H), 9.50 (t, J = 6.8 Hz, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.40 (dd, J = 16.5, 5.5 Hz, 1H), 8.25 (d, J = 7.0 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.26 - 6.38 (m, 3H), 5.18 (m, 1H), 4.77 (m, 1H), 4.60 (dd, J = 11.9, 5.0 Hz, 1H), 4.21 (m, 1H), 4.11 (m, 2H), 3.82 (m, 2H), 2.25 - 1.83 (m, 16H), 1.83 - 1.70 (m, 2H), 1.70 - 1.42 (m, 4H), 1.34 - 0.82 (m, 9H).

[0691] Example 23

[0692] (1) Preparation method of intermediate C16-1:

[0693] Reference the preparation method of compound 13 in Reference Example 13, replace intermediate F1-2 therein with 1-N-Boc-3-azetidinecarboxylic acid to obtain intermediate C16-1.

[0694] (2) Preparation method of intermediate C-16:

[0695] Disperse intermediate C16-1 (1 g) in DCM (10 mL), add trifluoroacetic acid (10 mL), and stir at room temperature for 30 minutes. After the reaction is completed, concentrate under reduced pressure to obtain intermediate C-16 (2.13 mmol).

[0696] MS (ESI) m / z [M+H] + : 369.24

[0697] (3) Preparation method of Example 23:

[0698] Disperse intermediate C-16 (167 mg), intermediate E (200 mg) and potassium acetate (81 mg) in DMF (3 mL) and tetrahydrofuran (6 mL), and stir at room temperature for 0.5 hours. Then add sodium triacetoxyborohydride (175 mg), and stir at room temperature for 1 hour. After the reaction is completed, pour the reaction solution into 100 mL of water, and collect the filter cake by suction filtration. Purify by preparative liquid chromatography to obtain compound 23 (18 mg).

[0699] MS (ESI) m / z [M+H] + : 838.63.

[0700] 1 H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.49 (d, J = 7.2 Hz, 1H), 8.78 (d, J = 8.2 Hz, 1H), 8.38 (m, 1H), 8.25 (d, J = 7.0 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.30 - 6.94 (m, 2H), 6.65 (m, 1H), 5.18 (m, 1H), 4.93 - 4.70 (m, 3H), 4.59 (d, J = 11.8 Hz, 1H), 4.16 (m, 1H), 3.80 (s, 2H), 3.61 (m, 3H), 3.50 (m, 2H), 3.16 (m, 2H), 2.94 (m, 2H), 2.76 (m, 1H), 2.61 (m, 1H), 2.29 - 2.14 (m, 3H), 2.02 (m, 3H), 1.98 (m, 2H), 1.79 - 1.62 (m, 2H), 1.52 - 0.97 (m, 7H).

[0701] Example 24

[0702] Intermediate G1-1 (200 mg) was dispersed in DMA (5 mL), HATU (228 mg), DIPEA (488 mg) and intermediate C-16 (221 mg) were added, stirred at 20-25 °C for 3 hours. The reaction solution was poured into 50 mL of water, suction filtered, the filter cake was collected and purified by preparative liquid phase to obtain compound 24 (96 mg).

[0703] MS (ESI) m / z [M+H] + : 852.63.

[0704] 1H NMR (500 MHz, DMSO) δ 11.09 (sp, 1 H), 9.50 (d, J = 7.9 Hz, 1 H), 8.78 (d, J = 7.8 Hz, 1 H), 8.39 (m, 1 H), 8.26 (d, J = 7.0 Hz, 1 H), 7.67 (m, 1 H), 7.27 - 6.94 (m, 2 H), 6.66 (m, 1 H), 5.28 - 5.07 (m, 1 H), 4.59 (m, 2 H), 4.51 - 4.17 (m, 4 H), 4.12 - 3.92 (m, 3 H), 3.91 - 3.78 (m, 3 H), 3.77 - 3.40 (m, 4 H), 2.98 (m, 2 H), 2.84 - 2.72 (m, 1 H), 2.66 - 2.57 (m, 1 H), 2.54 (m, 1 H), 2.34 (t, J = 12.1 Hz, 1 H), 2.20 (m, 1 H), 2.10 - 1.90 (m, 4 H), 1.82 (m, 4 H), 1.59 - 1.44 (m, 2 H).

[0705] Example 25

[0706] (1) Preparation method of intermediate C17-1:

[0707] Reference the preparation method of compound 13 in Reference Example 13, replace intermediate F1-2 therein with 1-N-Boc-3-azetidinecarboxylic acid, and replace 3-(6,7,8,9-tetrahydroisoxazolo[4,5- h]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride with 3-(6,7,8,9-tetrahydroisoxazolo[5,4- f]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride to obtain intermediate C17-1.

[0708] (2) Preparation method of intermediate C-17:

[0709] Intermediate C17-1 (1 g) was dispersed in DCM (15 mL), and trifluoroacetic acid (15 mL) was added, and stirred at room temperature for 30 minutes. After the reaction was completed, intermediate C-17 (2.13 mmol) was obtained by concentration under reduced pressure.

[0710] MS (ESI) m / z [M+H] + : 369.29

[0711] (3) Preparation method of Example 25:

[0712] Intermediate C-17 (167 mg), intermediate E (200 mg) and potassium acetate (81 mg) were dispersed in DMF (3 mL) and tetrahydrofuran (6 mL), after stirring at room temperature for 0.5 hours, sodium triacetoxyborohydride (175 mg) was added, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into 100 mL of water, and the filter cake was collected by suction filtration, and purified by preparative liquid chromatography to obtain compound 25 (57 mg).

[0713] MS (ESI) m / z [M+H] + : 838.64.

[0714] 1 H NMR (500 MHz, DMSO) δ 11.08 (s, 1H), 9.49 (d, J = 7.6 Hz, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.45 - 8.33 (m, 1H), 8.25 (d, J = 7.0 Hz, 1H), 7.65 (m, 1H), 7.28 - 6.96 (m, 2H), 6.66 (m, 1H), 5.17 (m, 1H), 4.84 - 4.62 (m, 3H), 4.57 (dd, J = 12.0, 5.0 Hz, 1H), 4.20 (m, 1H), 3.87 - 3.71 (m, 3H), 3.71 - 3.54 (m, 4H), 3.54 - 3.43 (m, 3H), 3.18 - 2.94 (m, 4H), 2.83 - 2.71 (m, 1H), 2.61 (m, 1H), 2.38 - 2.14 (m, 3H), 2.07 (m, 2H), 2.06 - 1.93 (m, 4H), 1.81 (m, 2H), 1.55 (s, 1H), 1.28 (m, 1H), 1.06 (m, 1H).

[0715] Example 26

[0716] (1) Preparation method of intermediate C18-1:

[0717] Reference the preparation method of intermediate C10-1 in Reference Example 10, replace 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde with tert-butyl 3-formylazetidine-1-carboxylate to obtain intermediate C18-1.

[0718] MS (ESI) m / z [M+H] + : 455.43

[0719] (2) Preparation method of intermediate C-18:

[0720] Reference the preparation method of intermediate C-16 in Reference Example 23, replace intermediate C16-1 with intermediate C18-1 to obtain intermediate C-18.

[0721] (3) Preparation method of compound 26:

[0722] Intermediate G1-1 (200 mg) was dispersed in DMA (5 mL), HATU (228 mg), DIPEA (488 mg) and C-18 (212 mg) were added, stirred at 20-25 °C for 3 hours. The reaction solution was poured into 50 mL of water, suction filtration, the filter cake was collected and purified by preparative liquid phase to give compound 26 (102 mg)

[0723] MS (ESI) m / z [M+H] + : 838.64.

[0724] 1 H NMR (500 MHz, DMSO) δ 11.11 (s, 1H), 9.50 (d, J = 8.1 Hz, 1H), 8.78 (dd, J = 7.7, 1.6 Hz, 1H), 8.40 (d, J = 6.0 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.11 (m, 1H), 6.66 (m, 1H), 5.18 (m, 1H), 4.77 (m, 1H), 4.63 (dd, J = 12.2, 5.0 Hz, 2H), 4.43 - 4.35 (m, 1H), 4.31 - 4.21 (m, 1H), 4.10 - 4.00 (m, 2H), 3.81 (m, 2H), 3.75 (m, 2H), 3.71 - 3.64 (m, 4H), 3.60 (m, 2H), 3.45 (d, J = 10.0 Hz, 2H), 2.79 (ddd, J = 17.4, 12.2, 5.4 Hz, 1H), 2.62 (dt, J = 17.3, 4.1 Hz, 1H), 2.54 (mp, 1H), 2.31 (t, J = 12.2 Hz, 1H), 2.20 (dq, J = 13.6, 4.8 Hz, 1H), 2.12 - 1.92 (m, 4H), 1.89 - 1.73 (m, 4H), 1.54 (m, 2H), 1.23 (m, 1H).

[0725] Example 27

[0726] Intermediate G1-1 (200 mg) was dispersed in DMA (5 mL), HATU (228 mg), DIPEA (488 mg) and intermediate C-17 (221 mg) were added, stirred at 20-25 °C for 3 hours. The reaction solution was poured into 50 mL of water, suction filtration, the filter cake was collected and purified by preparative liquid phase to give compound 27 (85 mg)

[0727] MS (ESI) m / z [M+H] + : 852.68.

[0728] 1 H NMR (500 MHz, DMSO) δ 11.08 (s, 1H), 9.50 (d, J = 7.8 Hz, 1H), 8.78 (dd, J = 7.7, 1.4 Hz, 1H), 8.39 (m, 1H), 8.26 (d, J = 7.0 Hz, 1H), 7.67 (m, 1H), 7.31 - 6.95 (m, 2H), 6.66 (m, 1H), 5.18 (m, 1H), 4.93 - 4.66 (m, 3H), 4.58 (dd, J = 12.1, 5.0 Hz, 1H), 4.37 (m, 2H), 4.24 (m, 1H), 4.12 - 4.04 (m, 1H), 4.03 - 3.57 (m, 8H), 3.11 - 2.96 (m, 2H), 2.77 (tq, J = 10.4, 5.2 Hz, 1H), 2.61 (m, 1H), 2.33 (q, J = 12.4 Hz, 1H), 2.24 - 2.14 (m, 1H), 2.11 - 2.00 (m, 4H), 1.80 (q, J = 11.8 Hz, 4H), 1.52 (m, 2H), 1.23 (s, 1H).

[0729] Example 28

[0730] (1) Preparation method of intermediate C19-1:

[0731] The preparation method of intermediate C10-1 in Reference Example 10 was referred to, 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde was replaced by tert-butyl 3-formylazetidine-1-carboxylate, and 3-(6,7,8,9-tetrahydroisoxazolo[4,5-h]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride was replaced by 3-(6,7,8,9-tetrahydroisoxazolo[5,4-f]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride to obtain intermediate C19-1.

[0732] (2) Preparation method of intermediate C-19:

[0733] The preparation method of intermediate C-16 in Reference Example 23 was referred to, intermediate C16-1 was replaced by intermediate C19-1 to obtain intermediate C-19.

[0734] (3) Preparation method of compound 28:

[0735] Intermediate G1-1 (200 mg) was dispersed in DMA (5 mL), HATU (228 mg), DIPEA (488 mg) and intermediate C-19 (187 mg) were added, stirred at 20-25 °C for 3 hours. The reaction was poured into 50 mL water, suction filtered, the filter cake was collected and purified by preparative liquid chromatography to give compound 28 (68 mg).

[0736] MS (ESI) m / z [M+H]+: 755.54. + : 838.64.

[0737] 1 H NMR (500 MHz, CDC13) δ 9.60 (s, 1H), 8.42 (m, 2H), 8.34 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.77 (m, 1H), 6.12 (d, J = 7.8 Hz, 1H), 5.44 (s, 1H), 4.81 (s, 1H), 4.39 - 4.25 (m, 2H), 4.13 (m, 2H), 3.94 (m, 3H), 3.85 - 3.69 (m, 3H), 3.62 - 3.43 (m, 2H), 2.98 (m, 2H), 2.86 (ddq, J = 17.3, 12.6, 6.4 Hz, 4H), 2.75 (m, 1H), 2.66 - 2.53 (m, 1H), 2.43 (mp, 1H), 2.17 (m, 6H), 2.00 (m, 1H), 1.91 (m, 2H), 1.85 - 1.67 (m, 4H), 1.31 - 1.21 (m, 1H).

[0738] Example 29

[0739] Intermediate E (150 mg), 3-(6,7,8,9-tetrahydroisoxazolo[4,5-h]isoquinolin-3-yl)piperidine- 2,6-dione hydrochloride (99 mg) and potassium acetate (61 mg) were dispersed in DMF (3 mL) and tetrahydrofuran (6 mL), stirred at 20-25 °C for 0.5 hours, sodium triacetoxyborohydride (131 mg) was added, stirred at room temperature for 1 hour. The reaction was poured into 100 mL water, suction filtered, the filter cake was collected and purified by preparative liquid chromatography to give compound 29 (25 mg).

[0740] MS (ESI) m / z [M+H]+: 755.54.

[0741] 1H NMR (500 MHz, DMSO) δ 11.94 (s, 1H), 11.08 (s, 1H), 9.50 (d, J = 7.6 Hz, 1H), 8.78 (d, J = 7.8 Hz, 1H), 8.40 (d, J = 5.8 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.27 - 6.97 (m, 2H), 6.66 (m, 1H), 5.18 (m, 1H), 4.77 (d, J = 20.8 Hz, 1H), 4.56 (dd, J = 11.9, 5.0 Hz, 1H), 4.21 (m, 1H), 3.81 - 3.41 (m, 5H), 2.97 (t, J = 5.9 Hz, 2H), 2.75 (m, 3H), 2.61 (m, 1H), 2.42 (d, J = 7.1 Hz, 2H), 2.20 (m, 1H), 2.06 (m, 3H), 1.96 (m, 3H), 1.80 (m, 3H), 1.23 (s, 1H), 1.12 (m, 2H).

[0742] Example 30

[0743] Example 30

[0744] MS (ESI) m / z [M+H] + : 755.55.

[0745] 1H NMR (500 MHz, DMSO) δ 11.08 (s, 1H), 9.50 (d, J = 7.8 Hz, 1H), 8.78 (dd, J = 7.7, 1.6 Hz, 1H), 8.40 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 8.01 - 7.43 (m, 2H), 7.25 - 7.07 (m, 2H), 6.66 (m, 1H), 5.18 (m, 1H), 4.77 (dd, J = 21.5, 2.7 Hz, 1H), 4.56 (dd, J = 11.8, 5.0 Hz, 1H), 4.27 - 4.15 (m, 1H), 3.86 - 3.57 (m, 6H), 3.45 (d, J = 10.2 Hz, 1H), 3.00 (t, J = 6.1 Hz, 2H), 2.77 (h, J = 5.6 Hz, 3H), 2.61 (dt, J = 17.3, 4.3 Hz, 1H), 2.37 (d, J = 7.2 Hz, 2H), 2.19 (dq, J = 13.6, 4.9 Hz, 1H), 2.12 - 1.98 (m, 3H), 1.79 (m, 3H), 1.35 - 0.82 (m, 4H).

[0746] Example 31

[0747] Intermediate E (50 mg) was added, and stirring was continued at 20-25 °C for 1 hour. Finally, sodium triacetoxyborohydride (42 mg) was added, and the reaction was allowed to proceed at 20-25 °C for 2 hours. After the reaction was completed, water (20 mL) and ethyl acetate (60 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative liquid chromatography gave compound 31 (19 mg).

[0748] MS (ESI) m / z [M+H] + : 741.57.

[0749] 1H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.51 (d, J = 7.6 Hz, 1H), 8.78 (dd, J = 7.9, 1.9 Hz, 1H), 8.41 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.12 (td, J = 53.9, 4.8 Hz, 1H), 6.66 (dd, J = 206.8, 7.8 Hz, 1H), 5.18 (d, J = 107.3 Hz, 1H), 4.77 (m, 1H), 4.60 (dd, J = 11.9, 5.0 Hz, 1H), 4.28 - 4.18 (m, 1H), 4.15 (s, 2H), 4.04 (s, 2H), 3.78 (m, 2H), 3.68 - 3.43 (m, 2H), 2.77 (ddd, J = 17.2, 12.0, 5.4 Hz, 1H), 2.69 - 2.56 (m, 3H), 2.21 (dp, J = 9.2, 5.0 Hz, 1H), 2.01 - 1.88 (m, 4H), 1.87 - 1.74 (m, 2H), 1.66 (m, 1H), 1.35 - 1.07 (m, 5H).

[0750] Example 32

[0751] Intermediate G1-1 (200 mg) was dispersed in DMA (5 mL), HATU (228 mg), DIPEA (488 mg) and 3-(6,7,8,9-tetrahydroisoxazolo[4,5-h]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride (128 mg) were added, stirred at 20-25 °C for 3 hours. The reaction solution was poured into 50 mL of water, suction filtered, the filter cake was collected and purified by preparative liquid phase to give compound 32 (129 mg).

[0752] MS (ESI) m / z [M+H] + : 769.55.

[0753] 1H NMR (500 MHz, DMSO) δ 8.77 (d, J = 7.8 Hz, 1H), 8.41 (d, J = 6.3 Hz, 1H), 8.27 (d, J = 6.6 Hz, 1H), 7.67 (m, 1H), 7.28 - 6.98 (m, 2H), 6.68 (m, 1H), 6.10 (m, 2H), 5.07 (d, J = 15.2 Hz, 1H), 4.88 (s, 1H), 4.78 (m, 1H), 4.63 (dt, J = 11.8, 5.7 Hz, 1H), 4.29 (m, 1H), 3.90 (t, J = 5.8 Hz, 1H), 3.83 (dd, J = 10.2, 5.9 Hz, 2H), 3.77 - 3.39 (m, 3H), 3.09 - 2.76 (m, 4H), 2.68 - 2.58 (m, 1H), 2.26 - 2.15 (m, 1H), 2.14 - 1.80 (m, 9H), 1.70 - 1.55 (m, 2H), 1.23 (s, 1H).

[0754] Example 33

[0755] Intermediate G1-1 (200 mg) was dispersed in DMA (5 mL), HATU (228 mg), DIPEA (488 mg) and 3-(6,7,8,9-tetrahydroisoxazolo[5,4-f]isoquinolin-3-yl)piperidine-2,6-dione hydrochloride (128 mg) were added, stirred at 20-25 °C for 3 hours. The reaction solution was poured into 50 mL of water, suction filtered, the filter cake was collected and purified by preparative liquid phase to give compound 33 (108 mg).

[0756] MS (ESI) m / z [M+H] + : 769.55.

[0757] 1 H NMR (500 MHz, CDCl3) δ 9.61 (s, 1H), 8.50 - 8.39 (m, 2H), 8.36 - 8.20 (m, 2H), 7.59 - 7.41 (m, 1H), 7.18 - 6.63 (m, 2H), 6.32 - 6.08 (m, 1H), 5.46 (s, 1H), 4.92 - 4.79 (m, 2H), 4.32 (m, 1H), 4.22 - 4.10 (m, 1H), 4.02 - 3.45 (m, 7H), 3.20 (m, 1H), 3.12 (m, 1H), 3.00 (m, 1H), 2.86 (mp, 1H), 2.81 - 2.56 (m, 3H), 2.46 (dq, J = 12.2, 5.6 Hz, 1H), 2.28 (m, 3H), 2.09 (m, 4H), 1.91 (m, 2H).

[0758] Example 34

[0759] Intermediate G1-1 (50 mg) was dispersed in DMF (5 mL), HATU (42 mg) and DIPEA (22 mg) were added, stirred at 20-25 °C for 30 min, 3-(7,8-dihydro-6H-isoxazolo[5,4- e]isoindol-3-yl)piperidine-2,6-dione hydrochloride (26 mg) was added, stirred at 20-25 °C for 3 h. After the reaction was completed, water (20 mL) and ethyl acetate (60 mL) were added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and compound 34 (46 mg) was obtained by preparative liquid phase purification.

[0760] MS (ESI) m / z [M+H] + : 755.48.

[0761] 1 H NMR (500 MHz, DMSO) d 11.11 (s, 1H), 9.52 (d, J = 7.1 Hz, 1H), 8.78 (dd, J = 7.8, 2.0 Hz, 1H), 8.43 (dd, J = 5.7, 4.0 Hz, 1H), 8.27 (dd, J = 6.9, 2.0 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.40 (dd, J = 14.9, 8.2 Hz, 1H), 7.13 (m, 1H), 6.66 (m, 1H), 5.31 - 5.04 (m, 3H), 4.64 (ddd, J = 12.0, 5.0, 1.9 Hz, 1H), 3.64 - 3.40 (m, 2H), 3.14 - 2.88 (m, 1H), 2.84 - 2.53 (m, 4H), 2.27 - 2.18 (m, 1H), 2.14 - 1.93 (m, 7H), 1.71 - 1.58 (m, 2H), 1.33 - 1.12 (m, 5H), 0.85 (m, 1H).

[0762] Experimental Example 1 HTRF method for detecting the degradation ability of IRAK4 protein

[0763] The IRAK4 protein degradation activity of the compound was determined by a homogeneous time-resolved fluorescence (HTRF) assay. The experiment was completed using a Cisbio kit (63ADK108PEH). In the HTRF assay, a europium (Eu) conjugated anti-total-IRAK4 antibody (Eu-IRAK4 antibody, HTRF donor) and a d2 conjugated anti-total-IRAK4 antibody (d2-IRAK4 antibody, HTRF acceptor) can form a complex with the Total-IRAK4 protein, which produces a HTRF signal under excitation light. The degradation of intracellular Total-IRAK4 protein by the test compound will cause the HTRF signal to decrease. By the degree of signal decrease, the strength of the compound and the degradation IRAK4 activity can be determined. THP-1 cells were collected, the supernatant was discarded, and 1% FBS in phenol red-free RPMI1640 medium was added to resuspend the cells, which were then uniformly blown and formed a single cell suspension. The cells were diluted and inoculated in a 384-well plate, 12 μL per well. The test compound was added to the culture medium and placed in an incubator for further culture for 24 h, then 4 μL of supplemented lysis buffer (4X) was added to each well, the cells were shaken and mixed, and the cells were lysed at room temperature for 30 min. 4 μL of premixed antibody solution was added to each well, and incubated at room temperature overnight. The HTRF signal was determined by reading the excitation at 340 nm and the emission fluorescence at 620 nm and 665 nm on a plate reader.

[0764] The HTRF ratio (Ratio, R) signal was calculated by the following formula: R = F 665 / F 620 *10 4 ;

[0765] wherein F 665 is the fluorescence intensity of the sample at 665 nm after background subtraction; F 620 is the fluorescence intensity of the sample at 620 nm after background subtraction.

[0766] Four-parameter analysis was performed within the GraphPad Prism software, the dose-effect curve was fitted, and the DC 50 value and Dmax were calculated.

[0767] Some of the experimental results are shown in Table 1.

[0768] Table 1

[0769] Experimental Example 2 In vitro liver microsomal stability assay

[0770] Preparation of incubation samples: Mix PBS buffer (PH 7.4), liver microsomes solution (0.5 mg / mL), test compound (1 μM final concentration) and NADPH + Incubate MgCl2solution at 37°C and 300 rpm.

[0771] Sample the reaction solution at 15 and 60 minutes. The 0 hour sample is a mix of PBS buffer (PH 7.4), liver microsomes solution (0.5 mg / mL) and test compound. Sample is added to acetonitrile solution containing internal standard, prepared supernatant by protein precipitation, diluted and used for LC-MS / MS determination.

[0772] The results of the test are shown in Table 2.

[0773] Table 2

[0774] Example 3 IRAK4 degradation activity in PBMC cells in vitro

[0775] Take PBMC cells, collect into centrifuge tubes, adjust cell density to 1.2*10 7 6 in culture medium (1% FBS + phenol red-free 1640 medium), inoculate in 384-well plates (12 μL / well), use nanoliter sample injector to add compound, use solvent DMSO to prepare compound solution, dilute with DMSO to make the final concentration of compound 500 nM-0.12 nM (4-fold gradient dilution), 2 replicate wells, set up controls (add the same volume of solvent) at the same time. Continue to culture in the cell incubator for 24 hours, then use IRAK4 detection kit (manufacturer: Revvity), read values on Envision 2014 Multilable Reader, calculate DC 50 .

[0776] The results of the test are shown in Table 3.

[0777] Table 3

[0778] Example 4 IL-6 detection in PBMC cells in vitro

[0779] Take PBMC cells, collect into centrifuge tubes, adjust cell density to 2*10 6The cells were seeded in 96-well plates (100 μL / well) at a density of 5 x 104cells / mL, and the compounds were added using a nanoliter dispenser. The compound solutions were prepared in DMSO, and the dilution was performed in DMSO to give a final concentration of 2500 nM to 0.15 nM (4-fold dilution) of the compounds. Two replicates were used, and controls were set up by adding the same volume of solvent. After 24 hours of incubation in the cell incubator, the LPS was diluted in assay medium, and 50 μL was added to each well to give a final concentration of 100 ng / mL. The same volume of assay medium was added to the control wells. The cells were incubated for another 24 hours in the cell incubator. The 96-well plates to be harvested were removed and centrifuged at 2000 rpm for 10 minutes. The supernatant was collected. The IL-6 detection kit (manufacturer: R&D) was used, and the absorbance was measured at 450 / 570 nm using a PerkinElmer Envision plate reader. A four-parameter analysis was performed to fit the dose-response curve, and the EC50values were calculated. 50 .

[0780] The results are shown in Table 4.

[0781] Table 4

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein, selected from the group consisting of - L A - selected from -LNK A1 - Cy A1 - LNK A2 - Cy A2 - LNK A3 - Cy A3 - LNK A4 - ; - L B - selected from -LNK B1 - Cy B1 - LNK B2 - Cy B2 - LNK B3 - Cy B3 - LNK B4 - ; - L C - selected from -LNK C1 - Cy C1 - LNK C2 - Cy C2 - LNK C3 - Cy C3 - LNK C4 - ; - L D - selected from -LNK D1 - Cy D1 - LNK D2 - Cy D2 - LNK D3 - Cy D3 - LNK D4 - ; X 1 is selected from N or CH; Ring A is selected from 5-10 membered cycloalkenyl, 5-10 membered heterocycloalkenyl, or 5-10 membered heteroaryl; Ring B is selected from phenyl; X 2 is selected from CH2or C(O); each R A , R B , R C , or R D is each independently selected from deuterium, oxo, 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 1-6 alkylamino, or halo-di-C 1-6 alkylamino; p1, p2, p3, or p4 are each independently selected from 0, 1, 2, or 3; LNK A1 , LNK B1 , LNK C1 , or LNK D1 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK1 substituents; 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; LNK A2 , LNK B2 , LNK C2 , or LNK D2 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 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; LNK A3 , LNK B3 , LNK C3 , or LNK D3 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 substituents; 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; LNK A4 or LNK B4 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. LNK4 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; LNK C4 or LNK D4 each independently is selected from the group consisting of optionally substituted C LNK4 substituted with one or more R 2-6 alkynylene or C 2-6 heteroalkynylene; Each R LNK1 R LNK2 R LNK3 、or R LNK4 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, and 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 halodicarbon 1-6 Alkylamino; Cy A1 , Cy B1 , Cy C1 , or Cy D1 each independently is selected from a single bond, or a group that is optionally substituted with one or more R Cy1 3-12 membered cycloalkyl, 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkyl, or 4-12 membered heterocycloalkenyl; Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently is selected from a single bond, or a group that is optionally substituted with one or more R Cy2 3-12 membered cycloalkyl, 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkyl, or 4-12 membered heterocycloalkenyl; Cy A3 , Cy B3 , Cy C3 , or Cy D3 each independently is selected from a single bond, or is optionally substituted with one or more R Cy3 3- to 12-membered cycloalkyl, 4- to 12-membered cycloalkenyl, 4- to 12-membered heterocycloalkyl, or 4- to 12-membered heterocycloalkenyl; each R Cy1 , R Cy2 , or R Cy3 is each independently selected from deuterium, oxo, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 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 di-C 1-6 alkylamino; each R is independently selected from deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1 each R is independently selected from 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, or halogenated di-C 1-6 alkylamino; - L- is selected from -0-, -S-, -NR L1 - C(O)-, -NR 1-6 alkylene, deuterated C 1-6 alkylene, halogenated C 1-6 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -, -NR L1 S(O)2-, or optionally substituted by one or more R L2 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; R L1 each independently selected from H, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, or halogenated C 1-6 alkyl; Each R L2 Each is independently selected from deuterium, oxo, 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 2 Each is independently selected from deuterium, halogens, -OH, -SH, -NH2, -CN, -NO2, and 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 optionally substituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 4-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; E substituted 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, 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; m is selected from 0, 1, or 2; n is selected from 0, 1, 2, or 3; provided that when M is selected from when -L- is not selected from -C(O)NH-; R A , R B , R C , R D , R LNK1 , R LNK2 , R LNK3 , R LNK4 , R Cy1 , R Cy2 , R Cy3 , R 1 , R L1 , R L2 , R 2 , or R E is optionally substituted with one or more substituents.

2. The compound of Formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from 5-8 membered cycloalkenyl, 5-8 membered heterocycloalkenyl, or 5-8 membered heteroaryl; or, Ring A is selected from 5-7 membered cycloalkenyl, 5-8 membered heterocycloalkenyl, or 5-6 membered heteroaryl; Alternatively, ring A is selected from cyclopentenyl, cyclohexenyl, cycloheptenyl, spiroctenyl, dihydrofuranyl, dihydrothiophenyl, dihydropyrroleyl, dihydrooxazolyl, dihydrothiazolyl, dihydrooxazinyl, dihydropyridyl, tetrahydropyridyl, and dihydroazapyridine. Base, tetrahydroazepine azaspiro[3.4]oct-6-enyl, or pyrrolyl; Alternatively, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrazinyl azaspiro[3.4]oct-6-enyl, or pyrrolyl; or selected from the group consisting of or 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 or selected from the group consisting of or selected from the group consisting of or selected from the group consisting of or selected from the group consisting of or selected from the group consisting of 4. The compound of Formula (I) according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein, Each R LNK1 R LNK2 R LNK3 、or R LNK4 Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -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 or halogenated diC 1-4 Alkylamino; or each R LNK1 , R LNK2 , R LNK3 , or R LNK4 is each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, 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; Or, each R LNK1 R LNK2 R LNK3 、or R LNK4 Each is independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, 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 each R LNK1 , R LNK2 , R LNK3 , or R LNK4 is each independently selected from deuterium, oxo, -F, -Cl, or methyl.

5. The compound of Formula (I) according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein, LNK A1 , LNK B1 , LNK C1 , or LNK D1 each independently 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; or LNK A1 , LNK B1 , LNK C1 , or LNK D1 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK1 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 A1 LNK B1 LNK C1 or LNK D1 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. LNK1 The following groups are substituted: -N(CH3)-, -N(CH2CH3)-, -CH2-, -CH2CH2-, -CH=CH-, -CH2CH=CH-, -CH=CHCH2-, -C≡C-, -CH2C≡C-, -C≡CCH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -NHCH2-, -CH2NH-, -CH 2NHCH2-, -NHCH2CH2-, -CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH -, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2C≡C-, -C≡CCH2O-, -NHCH2C≡C-, or -C≡CCH2NH-; or LNK A1 , LNK B1 , LNK C1 , or LNK D1 each independently is selected from a single bond, -O-, or is optionally substituted with one or more R LNK1 -CH2-, -CH2CH2-, -OCH2-, or -CH2O-; or LNK A2 , LNK B2 , LNK C2 , or LNK D2 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 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; or LNK A2 , LNK B2 , LNK C2 , or LNK D2 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK2 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 A2 , LNK B2 , LNK C2 , or LNK D2 each independently is selected from a single bond, -0-, -S-, -NH-, or is optionally substituted with one or more R LNK2 -N(CH3)-, -N(CH2CH3)-, -CH2-, -CH2CH2-, -CH=CH-, -CH2CH=CH-, -CH=CHCH2-, -C≡C-, -CH2C≡C-, -C≡CCH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, -CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2C≡C-, -C≡CCH2O-, -NHCH2C≡C-, or -C≡CCH2NH-; or LNK A2 , LNK B2 , LNK C2 , or LNK D2 each independently is selected from a single bond, -O-, -NH-, or is optionally substituted with one or more R LNK2 -CH2-, -CH2CH2-, -OCH2-, or -CH2O-; or LNK A3 , LNK B3 , LNK C3 , or LNK D3 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 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; or LNK A3 , LNK B3 , LNK C3 , or LNK D3 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK3 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 A3 , LNK B3 , LNK C3 , or LNK D3 each independently is selected from a single bond, -0-, -S-, -NH-, or is optionally substituted with one or more R LNK3 substituents; -N(CH3)-, -N(CH2CH3)-, -CH2-, -CH2CH2-, -CH=CH-, -CH2CH=CH-, -CH=CHCH2-, -C≡C-, -CH2C≡C-, -C≡CCH2-, -OCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2O-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH2CH2-, -CH2CH2NH-, -OCH=CH-, -CH=CHO-, -OCH2CH=CH-, -CH=CHCH2O-, -NHCH=CH-, -CH=CHNH-, -NHCH2CH=CH-, -CH=CHCH2NH-, -OCH2C≡C-, -C≡CCH2O-, -NHCH2C≡C-, or -C≡CCH2NH-; or LNK A3 , LNK B3 , LNK C3 , or LNK D3 each independently is selected from a single bond, -O-, or is optionally substituted with one or more R LNK3 -CH2-, -CH2CH2-, -OCH2-, or -CH2O-; Or, LNK A4 or LNK B4 Each is independently selected from a single bond, -O-, -S-, -NH-, or optionally by one or more R- bonds. LNK4 The 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; or LNK A4 or LNK B4 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK4 substituted alkylene, C 1-3 substituted alkenylene, C 2-3 substituted alkynylene, C 2-3 substituted alkynylene, C 1-3 substituted heteroalkylene, C 2-3 substituted heteroalkenylene, or C 2-3 substituted heteroalkynylene; or LNK A4 or LNK B4 each independently is selected from a single bond, -O-, -S-, -NH-, or is optionally substituted with one or more R LNK4 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 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 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 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 sub or LNK A4 or LNK B4 each independently is selected from a single bond, -0-, or is optionally substituted with one or more R LNK4 substituted -CH2-, -CH2CH2-, -OCH2-, -CH2O-, -CºC-, or -OCH2CºC-; or LNK C4 or LNK D4 each independently is selected from the group consisting of optionally substituted C LNK4 substituted with one or more R 2-4 alkynylene or C 2- 4heteroalkynylene; or LNK C4 or LNK D4 each independently is selected from the group consisting of optionally substituted C LNK4 substituted with one or more R 2-3 alkynylene or C 2- 3 heteroalkynylene; Or, LNK C4 or LNK D4 Each is independently selected from one or more R options. LNK4 The following groups are substituted: -C≡C-, -CH2C≡C-, -C≡CCH2-, -OCH2C≡C-, -C≡CCH2O-, -NHCH2C≡C-, or -C≡CCH2NH-; or LNK C4 or LNK D4 each independently is selected from the group consisting of -CºC- or -OCH2CºC- optionally substituted with one or more R LNK4 substituted with one or more R 6. The compound of Formula (I) according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein, Each R Cy1 R Cy2 、or R Cy3 Each is independently selected from deuterium, oxo, 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 each R Cy1 , R Cy2 , or R Cy3 is each independently selected from deuterium, oxo, 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; Or, each R Cy1 R Cy2 、or R Cy3 Each is independently selected from deuterium, oxo, -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; or each R Cy1 , R Cy2 , or R Cy3 is each independently selected from deuterium, -F, -Cl, or methyl.

7. The compound of Formula (I) according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein, Cy A1 , Cy B1 , Cy C1 , or Cy D1 each independently is selected from a single bond, or a group that is optionally substituted with one or more R Cy1 3-10 membered cycloalkyl, 4-10 membered cycloalkenyl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; or Cy A1 , Cy B1 , Cy C1 , or Cy D1 each independently is selected from a single bond, or is optionally substituted with one or more R Cy1 3-8 membered cycloalkyl, 4-8 membered cycloalkenyl, 4-8 membered heterocycloalkyl, or 4-8 membered heterocycloalkenyl; or Cy A1 , Cy B1 , Cy C1 , or Cy D1 each independently is selected from a single bond, or a group that is optionally substituted with one or more R Cy1 4-6 membered cycloalkyl, 4-6 membered cycloalkenyl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkenyl; or Cy A1 , Cy B1 , Cy C1 , or Cy D1 each independently is selected from a single bond, or a group optionally substituted with one or more R Cy1 substituents: cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl; or Cy A1 , Cy B1 , Cy C1 , or Cy D1 each independently is selected from a single bond, or a group optionally substituted with one or more R Cy1 substituents: or Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently is selected from a single bond, or is optionally substituted with one or more R Cy2 3-10 membered cycloalkyl, 4-10 membered cycloalkenyl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; or Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently is selected from a single bond, or a group that is optionally substituted with one or more R Cy2 3-8 membered cycloalkyl, 4-8 membered cycloalkenyl, 4-8 membered heterocycloalkyl, or 4-8 membered heterocycloalkenyl; or Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently is selected from a single bond, or is optionally substituted with one or more R Cy2 4-6 membered cycloalkyl, 4-6 membered cycloalkenyl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkenyl; or Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently is selected from a single bond, or a group optionally substituted with one or more R Cy2 substituents; cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl; or Cy A2 , Cy B2 , Cy C2 , or Cy D2 each independently is selected from a single bond, or a group optionally substituted with one or more R Cy2 substituents: or Cy A3 , Cy B3 , Cy C3 , or Cy D3 each independently is selected from a single bond, or a group that is optionally substituted with one or more R Cy3 3-10 membered cycloalkyl, 4-10 membered cycloalkenyl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkenyl; or Cy A3 , Cy B3 , Cy C3 , or Cy D3 each independently is selected from a single bond, or is optionally substituted with one or more R Cy3 3-8 membered cycloalkyl, 4-8 membered cycloalkenyl, 4-8 membered heterocycloalkyl, or 4-8 membered heterocycloalkenyl; or Cy A3 , Cy B3 , Cy C3 , or Cy D3 each independently is selected from a single bond, or a group that is optionally substituted with one or more R Cy3 4-6 membered cycloalkyl, 4-6 membered cycloalkenyl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkenyl; or Cy A3 , Cy B3 , Cy C3 , or Cy D3 each independently is selected from a single bond, or a group optionally substituted with one or more R Cy3 substituents: cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl; or Cy A3 , Cy B3 , Cy C3 , or Cy D3 each independently is selected from a single bond, or a group optionally substituted with one or more R Cy3 substituents:

8. The compound of Formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein, Each R 1 Each is independently selected from deuterium, halogens, -OH, -SH, -NH2, -CN, -NO2, 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 or halogenated diC 1-4 Alkylamino; or each R is independently selected from deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1 each R is independently selected from deuterium, 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; Or, each R 1 Each is independently selected from 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; or each R is independently selected from the group consisting of deuterium, -F, -Cl, methyl, methoxy, monofluoromethyl, difluoromethyl, or trifluoromethyl. 1 each R is independently selected from the group consisting of deuterium, -F, -Cl, methyl, methoxy, monofluoromethyl, difluoromethyl, or trifluoromethyl.

9. The compound of Formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein, - L- is selected from -0-, -S-, -NR L1 - C 1-4 alkylene, deuterated C 1-4 alkylene, halogenated C 1-4 alkylene, -C(O)-, -C(0)0-, -OC(O)-, -C(0)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)NR L1 -, -S(O)-, -S(0)2-, -S(0)2NR L1 -, -NR L1 S(O)2-, or optionally substituted with one or more R L2 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; or -L- is selected from -O-, -S-, -NR L1 -, C 1-3 alkylene, deuterated C 1-3 alkylene, halogenated C 1-3 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -, -NR L1 S(O)2-, or optionally substituted with one or more R L2 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 4-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or, -L- is selected from -O-, -S-, -NR L1 -, C 1-3 alkylene, deuterated C 1-3 alkylene, halogenated C 1-3 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -, -NR L1 S(O)2-, or optionally substituted with one or more R L2 substituted with one or more R cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, dihydrofuranyl, dihydropyrrolyl, dihydrooxazolyl, dihydrothiazolyl, dihydropyridinyl, tetrahydropyridinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; or -L- is selected from -C(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O)2-, -S(O)2NR L1 -, -NR L1 S(O)2-, or optionally substituted by one or more R L2 pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, or isothiazolyl; or, -L- is selected from -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -S(O)-, -S(O)2-, -S(O)2NH-, -NHS(O)2-, imidazolyl, 1,2,3-triazolyl, or 1,2,4-triazolyl; Alternatively, -L- can be selected from -C(O)NH-, -NHC(O)-, -NHC(O)NH-, 10. The compound of Formula (I) according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein, Each R 2 Each is independently selected from deuterium, halogens, -OH, -SH, -NH2, -CN, -NO2, 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 or halogenated diC 1-4 Alkylamino; or each R is independently selected from deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 2 each R is independently selected from deuterium, halogen, -OH, -SH, -NH2, -CN, -NO2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl, C 1-3 alkyl, C Or, each R 2 Each is independently selected from 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; or each R is independently selected from the group consisting of deuterium, -F, -Cl, or methyl. 2 each R is independently selected from the group consisting of deuterium, -F, -Cl, or methyl.

11. The compound of Formula (I) according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein, Ring E is selected from optionally substituted 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; E substituted 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Alternatively, ring E can be selected from one or more R. E The following groups are substituted: 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 4-8 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; or, ring E is selected from optionally substituted 3-8 membered cycloalkyl or 4-8 membered heterocycloalkyl; E 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 or, ring E is selected from optionally substituted cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, azabicyclo[2.2.1]heptanyl, or oxazabicyclo[2.2.1]heptanyl; E or, ring E is selected from optionally substituted cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, azabicyclo[2.2.1]heptanyl, or oxazabicyclo[2.2.1]heptanyl; or, ring E is selected from optionally substituted 2-oxa-5-azabicyclo[2.2.1]heptyl; E substituted 2-oxa-5-azabicyclo[2.2.1]heptyl; Alternatively, ring E is selected from 12. The compound of formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of formula (I-A), formula (I-B), formula (I-C), formula (I-D), or a pharmaceutically acceptable salt thereof, wherein, - L A -, X 1 , ring A, ring B, R A , p1, -L B -, R B , p2, -L C -, X 2 , R C , p3, -L D -, R D , p4, R 1 , m, L, R 2 , n and ring E moiety are as described in any one of claims 1-11; or it is selected from a compound of formula (I-B-1), formula (I-C-1), formula (I-C-2), formula (I-D-1), formula (I-D-2), or a pharmaceutically acceptable salt thereof, wherein -L B - and R B , p2, -L C - and X 2 , R C , p3, -L D - and R D , p4, R 1 , m, L, R 2 , n and the ring E moiety are as described in any one of claims 1 to 11 ; or it is selected from a compound of Formula (II-A), Formula (II-B), Formula (II-C), Formula (II-D), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -L A -, X 1 , ring A, ring B, R A , p1, -L B -, R B , p2, -L C -, X 2 , R C , p3, -L D -, R D , p4, R 1 and L moieties are as described in any one of claims 1 to 11; or it is selected from a compound of Formula (II-A-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -L A - and X 1 , ring A, R A , p1, R 1 and L are as described in any one of claims 1 to 11.

13. The compound of formula (I) according to any one of claims 1 to 12, 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) according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof; optionally, further comprising a pharmaceutically acceptable excipient.

15. Use of a compound of Formula (I) according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament for the treatment of a disease.

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