Tropomyosin receptor kinase (TRK) degrading compounds and methods of use

Abstract

The present disclosure relates to bivalent compounds (e.g., bifunctional small molecule compounds), compositions comprising one or more bivalent compounds, and methods of using bivalent compounds to treat certain diseases in subjects in need thereof. The present disclosure also relates to methods for identifying such bivalent compounds.

Description

[0001] Cross-references

[0002] This application claims the benefit of International Patent Application No. PCT / CN2020 / 076748, filed on February 26, 2020, which is incorporated herein by reference in its entirety. Background Art

[0003] The present disclosure relates to bivalent compounds (e.g., bifunctional small molecule compounds), compositions comprising one or more bivalent compounds, and methods of using bivalent compounds to treat certain diseases in subjects in need thereof. The present disclosure also relates to methods of identifying such bivalent compounds. Summary of the Invention

[0004] In one aspect, provided herein are compounds of Formula I:

[0005]

[0006] or a pharmaceutically acceptable salt thereof, wherein

[0007] X 1 and X 2 are independently selected from CH and N;

[0008] X 3 and X 4 Independently selected from C(O) and CR 4 R 5 ;

[0009] R 1 Selected from H, -NR 2 R 3 , halogen, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 haloalkyl and optionally substituted C 1-6 alkoxy;

[0010] R 2 、R 3 、R 4 and R 5 are independently selected from H, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C1-6 haloalkyl and optionally substituted C 1-6 alkoxy; and

[0011] L is selected from a bond,

[0012] or

[0013] X 3 and X 4 One of them is C(O) and the other is CR 4 R 5 ;and

[0014] L is

[0015] In some embodiments, X 1 and X 2 Each is N.

[0016] In some embodiments, X 3 is C(O) and X 4 CR 4 R 5 In some embodiments, X 3 is C(O) and X 4 CR 4 R 5 .

[0017] In some embodiments, X 3 and X 4 In some embodiments, X 3 and X 4 All CR 4 R 5 .

[0018] In some embodiments, R 1 -NR 2 R 3 In some embodiments, R 1 for

[0019] In one aspect, provided herein are compounds of Formula Ia:

[0020]

[0021] or a pharmaceutically acceptable salt thereof, wherein

[0022] X 1 and X 2 are independently selected from CH and N;

[0023] X3 and X 4 Independently selected from C(O), CR 4 R 5 and NR 6 ;

[0024] R 1 Selected from H, -NR 2 R 3 , halogen, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted aryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 haloalkyl and optionally substituted C 1-6 alkoxy;

[0025] R 2 、R 3 、R 4 、R 5 and R 6 are independently selected from H, halogen, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 Haloalkyl, optionally substituted C 1-6 alkoxy and optionally substituted 2,6-dioxopiperidin-3-yl;

[0026] L is selected from a bond, R'-R", R'COR", R'CO2R", R'C(O)N(R 7 )R”、R'C(S)N(R 7 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 7 )R”、R'N(R 7 )R”、R”N(R 7 )COR”、R'N(R 7 )CON(R 8 )R”、R'N(R 7)C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0027] wherein L is optionally 3 or X 4 Attachment;

[0028] R' and R" are independently selected from null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C4-C8 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0029] R 7 and R 8independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0030] R' and R", R 7 and R 8 , R' and R 7 , R' and R 8 , R” and R 7 , R” and R 8 together with the atoms to which they are attached, optionally form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring;

[0031] In some embodiments, L is selected from

[0032] In some embodiments, X 1 and X 2 Each is N.

[0033] In some embodiments, X 3 and X 4 At least one of them is NR 6 In some embodiments, X 3 and X 4 All are NR 6 .

[0034] In some embodiments, X 3 or X 4 Any one of is -N-(2,6-dioxopiperidin-3-yl).

[0035] In some embodiments, R 1 -NR 2 R 3 In some embodiments, R 1 for

[0036] In some embodiments, L is linked to X 3 In some embodiments, L is linked to X 4 .

[0037] In one aspect, provided herein is a compound of Formula II:

[0038]

[0039] or a pharmaceutically acceptable salt thereof, wherein

[0040] X 1 and X 2 are independently selected from CH and N;

[0041] X 3 and X 4 One of them is C(O) and the other is CR 1 R 2 ;and

[0042] L is selected from or

[0043] X 3 and X 4 each is C(O); and

[0044] L is selected from and

[0045] R 1 and R 2 are independently selected from H, halogen, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 haloalkyl and optionally substituted C 1-6 Alkoxy.

[0046] In some embodiments, X 1 and X 2 Each is N.

[0047] In one aspect, provided herein is a compound of Formula III:

[0048]

[0049] or a pharmaceutically acceptable salt thereof, wherein

[0050] X 1 and X 3 Independently selected from CR 1 , CR 1 R 2 , O, N and NR 1 ;

[0051] X2 selected from N, CO and CH;

[0052] Y is selected from O, NR 8 and CR 8 R 9 ;

[0053] Ar is selected from C 6-10 Aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, CN, NO2, OR 17 SR 17 NR 18 R 19 、COR 17 、CO2R 17 、CONR 18 R 19 、SOR 17 、SO2R 17 、SO2NR 18 R 19 NR 17 COR 19 NR 17 C(O)NR 18 R 19 NR 18 SOR 17 NR 18 SO2R 17 , optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 1-8 Alkylamino, optionally substituted C 3-10 Carbocyclyl, -O-(optionally substituted C 3-10 carbocyclyl), -NH-(optionally substituted C 3-10 carbocyclyl), optionally substituted 3- to 10-membered heterocyclyl, -O-(optionally substituted 3- to 10-membered heterocyclyl), -NH-(optionally substituted 3- to 10-membered heterocyclyl), optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0054] L is selected from a bond, R'-R", R'COR", R'CO2R", R'C(O)N(R 21 )R”、R'C(S)N(R 21 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 21)R”、R'N(R 21 )R”、R”N(R 21 )COR”、R'N(R 21 )CON(R 22 )R”、R'N(R 21 )C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0055] wherein L is optionally 1 or X 3 Attachment;

[0056] R' and R" are independently selected from null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C4-C8 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0057] R 1 and R 2 is independently selected at each occurrence from H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C1-8 Heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 Haloalkyl, optionally substituted C 1-6 alkoxy and optionally substituted 2,6-dioxopiperidin-3-yl;

[0058] R 3 Select from keys, -OR 14 -、-SR 14 -、-N(R 15 )R 14 -、-COR 14 -、-CO2R 14 -、-CON(R 15 )R 14 -、-SOR 14 -、-SO2R 14 -、-SO2N(R 15 )R 14 -、-N(R 16 )COR 14 -、-N(R 16 )CON(R 15 )R 14 -、N(R 16 )SOR 14 -、-N(R 16 )SO2R 14 -, optionally substituted C 1-8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C 1-8 Heteroalkylene, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0059] R 4 、R 5 and R 6 Independently selected from hydrogen, halogen, CN, NO2, OR 10 SR 11 NR 12 R 13 、COR 10 、CO2R 10 、C(O)NR 12 R 13 、SOR 10 、SO2R 10、SO2NR 12 R 13 NR 10 C(O)R 13 NR 10 C(O)NR 12 R 13 NR 10 SOR 13 NR 10 SO2R 13 , optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 carbocyclyl and optionally substituted 3- to 10-membered heterocyclyl;

[0060] R 7 Selected from optionally substituted C 1-8 Alkyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0061] R 8 and R 9 are independently selected from hydrogen, halogen, OH, optionally substituted C 1-8 Alkyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 Carbocyclyl, -O-(optionally substituted C 3-10 carbocyclyl), optionally substituted C 1-8 Alkylamino, -NH-(optionally substituted C 3-10 carbocyclyl) and an optionally substituted 3- to 10-membered heterocyclyl; or

[0062] R 8 and R 9 Together with the atoms to which they are attached, they form an optionally substituted C 3-10 carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl;

[0063] R 10 、R 11 、R 12 and R 13 are independently selected from hydrogen, optionally substituted C 1-8alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl; or

[0064] R 12 and R 13 together with the atoms to which they are attached, form an optionally substituted 3- to 10-membered heterocyclyl;

[0065] R 14 Selected from empty, optionally substituted C 1-8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C 1-8 Heteroalkylene, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 Carbocyclyl, -O-(optionally substituted C 3-10 carbocyclyl), optionally substituted C 1-8 Alkylamino, -NH-(optionally substituted C 3-10 carbocyclyl), optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0066] R 15 and R 16 are independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl; or

[0067] R 14 and R 15 Together with the atoms to which they are attached, they optionally form an optionally substituted C 3-10 carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl;

[0068] R 17 、R 18 and R 19 are independently selected from hydrogen, optionally substituted C1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 Carbocyclyl, -O-(optionally substituted C 3-10 carbocyclyl), optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl; or

[0069] R 18 and R 19 Together with the atoms to which they are attached, they form an optionally substituted C 3-10 carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl; and

[0070] R 21 and R 22 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or

[0071] R' and R", R 21 and R 22 , R' and R 21 , R' and R 22 , R” and R 21 or R" and R 22 Together with the atoms to which they are attached, they optionally form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring.

[0072] In some embodiments, L is selected from

[0073] In some embodiments, R 4 、R 5 and R 6 Each is hydrogen.

[0074] In some embodiments, Y is CR 8 R 9 In some embodiments, Y is CH2.

[0075] In some embodiments, R 7 is an optionally substituted C 6-10 In some embodiments, R 7 yes

[0076] In some embodiments, Ar is replaced by NR 18 R 19 Substituted C 6-10 In some embodiments, Ar is

[0077] In some embodiments, R 3 is an optionally substituted 3- to 10-membered heterocyclyl. 3 yes

[0078] In some embodiments, X 1 It's CR 1 , X 2 is CH, and X 3 It is NR 1 In some embodiments, X 1 It is NR 1 , X 2 is CH, and X 3 It's CR 1 In some embodiments, X 1 It's CR 1 , X 2 is N, and X 3 It is NR 1 In some embodiments, X 1 It is NR 1 , X 2 is N, and X 3 It's CR 1 In some embodiments, X 1 It is NR 1 , X 2 is CH, and X 3 Is N. In some embodiments, X 1 It is N, X 2 is CH, and X 3 It is NR 1 In some embodiments, X 1 It's CR 1 R 2 , X 2 is CO, and X 3 It is NR 1 In some embodiments, X 1 It is NR 1 , X2 is CO, and X 3 It is NR 1 In some embodiments, X 1 It's O, X 2 is CO, and X 3 It is NR 1 In some embodiments, X 1 It's CR 1 , X 2 is CO, and X 3 It is NR 1 In some embodiments, X 1 It is N, X 2 is CO, and X 3 It is NR 1 .

[0079] In some embodiments, R 1 yes

[0080] In one aspect, provided herein is a compound of Formula IV:

[0081]

[0082] or a pharmaceutically acceptable salt thereof, wherein

[0083] X 1 and X 3 Independently selected from CR 1 , N and NR 1 ;

[0084] X 2 selected from N and CH;

[0085] Y 1 Selected from N and CR 6 ;

[0086] Y 2 、Y 3 and Y 4 are independently selected from N and C, provided that Y 2 、Y 3 and Y 4 Only one of them is N;

[0087] Z is selected from space, bond, C(R 5 )2、C(R 5 )2C(R 5 )2、CO、C(R 5 )2CO、CONR 5 、C(R 5 )2O、C(R 5 )2NR 5and CH2NR 5 ;

[0088] Ar 1 and Ar 2 Independently selected from C 6-10 Aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, OR 10 SR 10 NR 11 R 12 、COR 10 、CO2R 10 、CONR 11 R 12 、SOR 10 、SO2R 10 、SO2NR 11 R 12 NR 10 COR 12 NR 10 C(O)NR 11 R 12 NR 10 SOR 12 NR 10 SO2R 12 , optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 1-8 Haloalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0089] L is selected from a bond, R'-R", R'COR", R'CO2R", R'C(O)N(R 13 )R”、R'C(S)N(R 13 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 13 )R”、R'N(R 13 )R”、R”N(R 13 )COR”、R'N(R 13 )CON(R 14 )R”、R'N(R 13)C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0090] wherein L is optionally 1 or X 3 Attachment;

[0091] R' and R" are independently selected from null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C4-C8 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0092] R 1 At each occurrence, is selected from H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 Haloalkyl, optionally substituted C 1-6alkoxy and optionally substituted 2,6-dioxopiperidin-3-yl;

[0093] R 3 Select from keys, -OR 7 -、-SR 7 -、-N(R 8 )R 7 -、-COR 7 -、-CO2R 7 -、-CON(R 8 )R 7 -、-SOR 7 -、-SO2R 7 -、-SO2N(R 8 )R 7 -、-N(R 9 )COR 7 -、-N(R 9 )CON(R 8 )R 7 -、N(R 9 )SOR 7 -、-N(R 9 )SO2R 7 -, optionally substituted C 1-8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C 1-8 Heteroalkylene, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0094] R 4 and R 5 is independently selected at each occurrence from hydrogen, halogen, OH, NH2, CN, NO2, optionally substituted C 1-4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 1-4 Haloalkyl, optionally substituted C 3-10 Carbocyclyl, -O-(optionally substituted C 3-10 carbocyclyl), -NH-(optionally substituted C 3-10 carbocyclyl) and optionally substituted 3- to 10-membered heterocyclyl;

[0095] R 6 Selected from hydrogen, halogen, CN, NO2, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-10 carbocyclyl and optionally substituted 3- to 10-membered heterocyclyl;

[0096] R 7 Selected from empty, optionally substituted C 1-8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C 1-8 Heteroalkylene, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 Carbocyclyl, -O-(optionally substituted C 3-10 carbocyclyl), optionally substituted C 1-8 Alkylamino, -NH-(optionally substituted C 3-10 carbocyclyl), optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0097] R 8 and R 9 are independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl; or

[0098] R 7 and R 8 Together with the atoms to which they are attached, they optionally form an optionally substituted C 3-10 carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl;

[0099] R 10 、R 11 and R 12 are independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl; or

[0100] R 11 and R12 Together with the atoms to which they are attached, they form an optionally substituted C3-C 10 carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl;

[0101] R 13 and R 14 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0102] R' and R", R 13 and R 14 , R' and R 13 , R' and R 14 , R” and R 13 , R” and R 14 together with the atoms to which they are attached, optionally form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring; and

[0103] n is 0, 1, 2, 3 or 4.

[0104] In some embodiments, L is selected from

[0105] In some embodiments, Y 1 It's N, Y 2 It's N, Y 3 is C, and Y 4 It’s C.

[0106] In some embodiments, Ar 1 is C optionally substituted by halogen 6-10 In some embodiments, Ar 1 yes

[0107] In some embodiments, Ar 2 Is optional to be NR 11 R 12 Substituted C 6-10 In some embodiments, Ar 2 yes

[0108] In some embodiments, R3 is an optionally substituted 3- to 10-membered heterocyclyl. 3 yes

[0109] In some embodiments, R 4 It's hydrogen.

[0110] In some embodiments, Z is C(R 5 ) 2. In some embodiments, Z is CH 2 .

[0111] In some embodiments, n is 0.

[0112] In some embodiments, X 1 It's CR 1 , X 2 is CH, and X 3 It is NR 1 In some embodiments, X 1 It is NR 1 , X 2 is CH, and X 3 It's CR 1 In some embodiments, X 1 It's CR 1 , X 2 is N, and X 3 It is NR 1 In some embodiments, X 1 It is NR 1 , X 2 is N, and X 3 It's CR 1 In some embodiments, X 1 It is NR 1 , X 2 is CH, and X 3 Is N. In some embodiments, X 1 It is N, X 2 is CH, and X 3 It is NR 1 .

[0113] In some embodiments, R 1 In some embodiments, R 1 yes

[0114] According to one aspect of the present disclosure, the bivalent compound disclosed herein includes a tropomyosin receptor kinase (TRK) ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof.

[0115] In one embodiment, the TRK ligand is capable of binding to a TRK protein comprising a TRK, a TRK mutant, a TRK deletion, a TRK splice, or a TRK fusion protein.

[0116] In another embodiment, the TRK ligand is a TRK kinase inhibitor or is part of a TRK kinase inhibitor.

[0117] In another embodiment, the TRK ligand is selected from entrectinib (RXDX-101), GNF-8625, larotrectinib (LOXO-101; ARRY-470), altiratinib (DCC2701, DCC-270, DP-5164), sitravatinib (MGCD516), cabozantinib (XL-184, BMS-907351), dovitinib ( (TKI-258, CHIR-258), milciclib (PHA-848125AC), belizatinib (TSR-011), GZ389988, pegcantratinib, AZD7451, TPX-0005, LOXO-195, regorafenib, DS-6051b, F17752, PLX7486, AZD-6918, ASP7962, ONO-4474, PF-06273340, and their analogs.

[0118] In another embodiment, the degradation tag is bound to a ubiquitin ligase, or the degradation tag is a hydrophobic group or a tag that causes misfolding of the TRK protein.

[0119] In another embodiment, the ubiquitin ligase is an E3 ligase.

[0120] In another embodiment, the E3 ligase is selected from the group consisting of cereblon E3 ligase, VHL E3 ligase, IAP ligase, MDM2 ligase, TRIM24 ligase, TRIM21 ligase, KEAP1 ligase, DCAF16 ligase, RNF4 ligase, RNF114 ligase, and AhR ligase.

[0121] In another embodiment, the degradation tag is selected from pomalidomide, thalidomide, lenalidomide, VHL-1, adamantane, 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane, nutlin-3a, RG7112, RG7338, AMG232, AA-115, bestatin, MV-1, LCL161, CPD36, GDC-0152, CRBN-1, CRBN-2, CRBN-3, CRBN-4, CRBN-5, CRBN-6, CRBN-7, CRBN-8, CRBN-9, CRBN-10, CRBN-11 and the like.

[0122] In another embodiment, the TRK ligand is conjugated to the degradation tag via a linker moiety.

[0123] In another embodiment, the TRK ligand comprises a moiety of Formula 1:

[0124]

[0125] in

[0126] X is selected from CR'R", CO, O, S, SO, SO2 and NR', wherein

[0127] R' and R" are independently selected from hydrogen, halogen, OH, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C3-C 10 cycloalkoxy and an optionally substituted 3-10 membered heterocyclyl; or

[0128] R' and R" together with the atoms to which they are attached optionally form an optionally substituted 3-8 membered carbocyclyl or heterocyclyl ring;

[0129] R is selected from the group consisting of optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C3-C 10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0130] R 1 、R 2 and R 3 Independently selected from hydrogen, halogen, CN, NO2, OR 5SR 6 NR 7 R 8 、COR 5 、CO2R 5 、C(O)NR 7 R 8 、SOR 5 、SO2R 5 、SO2NR 7 R 8 NR 7 C(O)R 8 NR 5 C(O)NR 7 R 8 NR 7 SOR 8 NR 7 SO2R 8 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C3-C 10 cycloalkoxy, optionally substituted 3-10 membered heterocyclyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl, wherein

[0131] R 5 、R 6 、R 7 and R 8 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl or optionally substituted heteroaryl, or

[0132] R 7 and R 8 together with the atoms to which they are attached, optionally form an optionally substituted 3-8 membered heterocyclyl ring;

[0133] R 4 A linker moiety attached to a divalent compound and selected from a bond, -OR 9 -、-SR 9 -、-NR 10 R 11 -、-COR 9 -、-CO2R9 -、-CONR 10 R 11 -、-SOR 9 -、-SO2R 9 -、-SO2NR 10 R 11 -、-NR 10 COR 11 -、-NR 9 CONR 10 R 11 -、-NR 10 SOR 11 -、-NR 10 SO2R 11 -, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted C3-C8 carbocyclylene-O-, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, aryl, and optionally substituted heteroaryl, wherein

[0134] R 9 、R 10 and R 11 independently selected from the group consisting of: space, a bond, hydrogen, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 heteroalkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted C1-C8 alkoxyC1-C8 alkyl, an optionally substituted C1-C8 alkylaminoC1-C8 alkyl, an optionally substituted C3-C8 carbocyclyl, an optionally substituted C3-C8 cycloalkyloxy, an optionally substituted 3-8 membered carbocyclyl, an optionally substituted 3-8 membered heterocyclyl, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted C3-C8 carbocyclylene-O-, optionally substituted aryl, and optionally substituted heteroaryl, or

[0135] R 10 and R 11 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or heterocyclyl ring; and

[0136] Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, CN, NO2, OR 12 SR 12 NR 13 R 14 、COR 12 、CO2R 12 、CONR 13 R 14 、SOR 12 、SO2R 12 、SO2NR 13 R 14 NR 13 COR 14 NR 15 C(O)NR 13 R 14 NR 13 SOR 14 NR 13 SO2R 14 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0137] R 12 、R 13 、R 14 and R 15 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0138] R 13 and R 14 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0139] In one embodiment, X is selected from CR'R", O and NR'; wherein

[0140] R' and R" are independently selected from hydrogen, F, OH, optionally substituted C1-C3 alkyl and optionally substituted C1-C3 alkoxy; or

[0141] R' and R" taken together with the atoms to which they are attached optionally form an optionally substituted 3-6 membered carbocyclyl or heterocyclyl ring.

[0142] In another embodiment, X is selected from CH2, cyclopropylene, CHF, CF2, O, NH, NCH3, NCH2CH3 and N-isopropyl.

[0143] In another embodiment, R is selected from optionally substituted C3-C8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0144] In another embodiment, R is selected from optionally substituted phenyl and optionally substituted heteroaryl.

[0145] In another embodiment, X is CH2; and R is 3,5-difluorophenyl.

[0146] In another embodiment, R 1 、R 2 and R 3 are independently selected from hydrogen, F, Cl and OH.

[0147] In another embodiment, R 4 -Ar is selected from the group consisting of moieties of formulae A1, A2, A3 and A4:

[0148]

[0149] in

[0150] * represents a linker moiety attached to a divalent compound; and

[0151] R a Selected from hydrogen, halogen, CN, NO2, OR 12 SR 12 NR 13 R 14 、COR 12 、CO2R 12 、CONR 13 R 14 、SOR 12 、SO2R 12 、SO2NR 13 R 14 NR 15 COR 14 NR 15 C(O)NR 13 R 14 NR15 SOR 14 NR 15 SO2R 14 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0152] R 12 、R 13 、R 14 and R 15 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, aryl and optionally substituted heteroaryl, or

[0153] R 13 and R 14 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0154] In another embodiment, R 4 -Ar is selected from the group consisting of moieties of formulae A1, A3, A3 and A4:

[0155]

[0156] in

[0157] * represents a linker moiety attached to a divalent compound; and

[0158] R a Selected from hydrogen, halogen, NR 13 R 14 and NR 13 COR 14 ,in

[0159] R 13 and R 14independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, phenyl and optionally substituted C5-C6 heteroaryl, or

[0160] R 13 and R 14 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0161] In another embodiment, R a is selected from H, (tetrahydro-2H-pyran-4-yl)amino and 2-fluoroethylamino.

[0162] In another embodiment, R 4 Selected from optionally substituted

[0163] In another embodiment, the TRK ligand comprises a moiety of Formula 2:

[0164]

[0165] in

[0166] X 1 、X 2 、X 3 and X 4 Independently selected from C, CR' and N (preferably, X 1 is selected from CR' and N; and X 2 、X 3 and X 4 are independently selected from C and N), wherein

[0167] R' is selected from hydrogen, halogen, CN, NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C3-C6 carbocyclyl and optionally substituted 3-6 membered heterocyclyl;

[0168] X is selected from the group consisting of space, bond, C(R 2 )2、C(R 2 )2C(R 2 )2、CO、C(R 2 )2CO、CONR 2 、C(R 2 )2O、C(R 2 )2NR 2 and CH2NR2 ;

[0169] R 1 and R 2 is independently selected at each occurrence from hydrogen, halogen, OH, NH2, CN, NO2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 alkoxyalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkylaminoC1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclyl;

[0170] n is 1 to 4;

[0171] R 3 Directly or through R 4 a linker moiety attached to a divalent compound;

[0172] R 3 and R 4 Independently selected from space, bond, -OR 5 -、-SR 5 -、-NR 6 R 7 -、-COR 5 -、-CO2R 5 -、-CONR 6 R 7 -、-SOR 5 -、-SO2R 5 -、-SO2NR 6 R 7 -、-NR 6 COR 7 -、-NR 5 C(O)NR 6 R 7 -、-NR 6 SOR 7 -、-NR 6 SO2R 7-, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted C3-C8 carbocyclylene-O-, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0173] R 5 、R 6 and R 7 independently selected from the group consisting of space, a bond, hydrogen, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 heteroalkyl, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 carbocyclyl, an optionally substituted 3-8 membered heterocyclyl, an optionally substituted heterocarbocyclyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, an optionally substituted C1-C8 alkylene, an optionally substituted C1-C8 heteroalkylene, an optionally substituted C1-C8 alkylene alkyl-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted C3-C8 carbocyclylene-O-, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0174] R 6 and R 7 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring; and

[0175] Ar 1 and Ar 2 independently selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, OR 10 SR 10 NR 11 R 12 、COR 10 、CO2R 10 、CONR 11 R 12 、SOR 10 、SO2R 10 、SO2NR11 R 12 NR 10 COR 12 NR 10 C(O)NR 11 R 12 NR 10 SOR 12 NR 10 SO2R 12 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0176] R 10 、R 11 and R 12 is independently selected at each occurrence from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0177] R 11 and R 12 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0178] In one embodiment, X 1 is selected from CR' and N, wherein R' is selected from hydrogen, F, Cl, CH3, CF3 and cyclopropyl.

[0179] In another embodiment, X 2 、X 3 and X 4 are independently selected from C and N.

[0180] In another embodiment, X is selected from a bond, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH, and CH2NCH3.

[0181] In another embodiment, R 1 and R 2is independently selected at each occurrence from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclyl.

[0182] In another embodiment, X is CH2; and Ar 1 It is 3-fluorophenyl.

[0183] In another embodiment, R 3 A linker moiety directly attached to a divalent compound, and

[0184] R 3 Select from empty, key, -OR 5 -、-SR 5 -、-NR 6 R 7 -、-COR 5 -、-CO2R 5 -、-CONR 6 R 7 -、-SOR 5 -、-SO2R 5 -,-SO2NR 6 R 7 -、-NR 5 COR 7 -、-NR 5 COR 7 -、-NR 5 C(O)NR 6 R 7 -、-NR 5 SOR 7 -、-NR 5 SO2R 7 -, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0185] R 5 、R 6 and R 7independently selected from the group consisting of: null, a bond, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl-O-, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0186] R 6 and R 7 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0187] In another embodiment, R 3 By R 4 a linker moiety attached to a divalent compound, and

[0188] R 3 and R 4 Independently selected from space, bond, -OR 5 -、-SR 5 -、-NR 6 R 7 -、-COR 5 -、-CO2R 5 -、-CONR 6 R 7 -、-SOR 5 -、-SO2R 5 -、-SO2NR 6 R 7 -、-NR 5 COR 7 -、-NR 5 C(O)NR 6 R 7 -、-NR 5 SOR 7 -、-NR 5 SO2R 7-, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0189] R 5 、R 6 and R 7 independently selected from the group consisting of space, a bond, hydrogen, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 heteroalkyl, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 carbocyclyl, an optionally substituted 3-8 membered heterocyclyl, an optionally substituted heterocarbocyclyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, an optionally substituted C1-C8 alkylene, an optionally substituted C1-C8 heteroalkylene, an optionally substituted C1-C8 alkylene alkyl-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted C3-C8 carbocyclylene-O-, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0190] R 6 and R 7 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0191] In another embodiment, Ar 1 Selected from C6-C 10 Aryl and C5-C 10 Heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO2, OR 10 NR 11 R 12 、COR 10 、CO2R 10 、CONR 11 R 12 、SOR 10 、SO2R 10 、SO2NR 11 R12 NR 10 COR 12 NR 10 C(O)NR 11 R 12 NR 10 SOR 12 NR 10 SO2R 12 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl and optionally substituted C4-C5 heteroaryl, wherein

[0192] R 10 、R 11 and R 12 is independently selected at each occurrence from void, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0193] R 11 and R 12 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0194] In another embodiment, Ar 2 Selected from C6-C 10 Aryl and C5-C 10 Heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO2, OR 13 NR 14 R 15 、COR 13 、CO2R 13 、CONR 14 R 15 、SOR 13 、SO2R 13 、SO2NR 14 R 15 NR 13 COR 14 NR 13 C(O)NR 14 R 15 NR13 SOR 14 NR 13 SO2R 14 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl and optionally substituted C4-C5 heteroaryl, wherein

[0195] R 13 、R 14 and R 15 is independently selected at each occurrence from void, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0196] R 14 and R 15 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0197] In another embodiment, R 3 -Ar 2 A moiety selected from formulae B1 and B2:

[0198]

[0199] in

[0200] * indicates a linker moiety attached to a divalent compound;

[0201] Y 1 、Y 2 、Y 3 and Y 4 are independently selected from CH and N, provided that Y 1 、Y 2 、Y 3 and Y 4 At most 3 of them are N;

[0202] Each R a Independently selected from hydrogen, halogen, CN, NO2, OR 13 NR 14 R 15 、COR 13 、CO2R 13 、CONR14 R 15 、SOR 13 、SO2R 13 、SO2NR 14 R 15 NR 13 COR 14 NR 13 C(O)NR 14 R 15 NR 13 SOR 14 NR 13 SO2R 14 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0203] R 13 、R 14 and R 15 is independently selected at each occurrence from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0204] R 14 and R 15 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or heterocyclyl ring;

[0205] m is 0 to 4; and

[0206] R 3 Same as the definition in Equation 2.

[0207] In another embodiment, R 3 -Ar 2 A moiety selected from formula B3:

[0208]

[0209] in

[0210] * indicates a linker moiety attached to a divalent compound;

[0211] Y 1 、Y 2 、Y 3 and Y 4 Independently selected from CR a , N, O and S, provided that Y 1 、Y 2 、Y 3 and Y 4 At most 3 of them are N;

[0212] Each R a Independently selected from hydrogen, halogen, CN, NO2, OR 13 NR 14 R 15 、COR 13 、CO2R 13 、CONR 14 R 15 、SOR 13 、SO2R 13 、SO2NR 14 R 15 NR 13 COR 14 NR 13 C(O)NR 14 R 15 NR 13 SOR 14 NR 13 SO2R 14 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0213] R 13 、R 14 and R 15independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0214] R 14 and R 15 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or heterocyclyl ring;

[0215] m is 0 to 4; and

[0216] R 3 Same as the definition in Equation 2.

[0217] In another embodiment, X 1 It is N; X 2 It is N; X 3 It is C; X 4 is C; and X is CH2.

[0218] In another embodiment, Ar 1 It is 3-fluorophenyl.

[0219] In another embodiment, Ar 2 It is 2-pyridyl.

[0220] In another embodiment, R 3 Selected from optionally substituted

[0221] In another embodiment, the TRK ligand comprises a moiety of Formula 3:

[0222]

[0223] in

[0224] X 1 、X 2 、X 3 and X 4 Independently selected from C, CR' and N (preferably, X 1 and X 4 Independently selected from CR' and N; X 2 and X 3 independently selected from C and N), wherein R' is selected from hydrogen, halogen, CN, NO2 and optionally substituted C1-C6 alkyl, C3-C6 carbocyclyl or 3-6 membered heterocyclyl;

[0225] X is selected from the group consisting of space, bond, C(R 2 )2、C(R 2 )2C(R 2 )2、CO、C(R 2 )2CO、NR 2 CO、OC(R 2 )2 and NR 2 C(R 2 )2;

[0226] R 1 and each R 2 independently selected from hydrogen, halogen, OH, NH2, CN, NO2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 alkoxyalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkylaminoC1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkyloxy and optionally substituted 3-6 membered heterocyclyl;

[0227] n is 1 to 4;

[0228] R 3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, and optionally substituted C1-C6 alkylaminoC1-C6 alkyl;

[0229] R 4 Directly or through R 5 A linker moiety attached to a divalent compound, wherein

[0230] R 4 and R 5 Independently selected from null, -OR 6 -、-SR 6 -、-N(R 7 )R 6 -、-COR 6 -、-CO2R 6 -、-CON(R 7 )R 6 -、-SOR 6 -、-SO2R 6 -、-SO2N(R 7 )R 6 -、-NR 8 COR6 -、-N(R 8 )C(O)N(R 7 )R 6 -、-NR 8 SOR 6 -、-NR 8 SO2R 6 -, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0231] R 6 is selected from the group consisting of null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0232] R 7 and R 8 independently selected from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0233] R 6 and R 7 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or heterocyclyl ring;

[0234] Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, OR 10 SR 10 NR 11 R 12 、COR10 、CO2R 10 、CONR 11 R 12 、SOR 10 、SO2R 10 、SO2NR 11 R 12 NR 10 COR 12 NR 10 C(O)NR 11 R 12 NR 10 SOR 12 NR 10 SO2R 12 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0235] R 10 、R 11 and R 12 is independently selected from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0236] R 11 and R 12 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0237] In one embodiment, X 1 and X 4 is selected from CR' and N, and R' is selected from hydrogen, F, Cl, CH3, CF3 and cyclopropyl.

[0238] In one embodiment, X 1 It's N.

[0239] In one embodiment, X 4 It is CH.

[0240] In another embodiment, X 2 and X 3 are independently selected from C and N.

[0241] In one embodiment, X 2 is C and X 3 It's N.

[0242] In one embodiment, X 3 is C and X 2 It's N.

[0243] In another embodiment, X is selected from a bond, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH, and CH2NCH3.

[0244] In another embodiment, X is CH2.

[0245] In another embodiment, R 1 and each R 2 Independently selected from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkoxy and optionally substituted 3-6 membered heterocyclyl.

[0246] In another embodiment, R 1 and R 2 It's hydrogen.

[0247] In another embodiment, R 3 Selected from hydrogen, CH3, CH2CH3, propyl, isopropyl, cyclopropyl, CH2F, CHF2 and CF3.

[0248] In another embodiment, R 3 Selected from hydrogen.

[0249] In another embodiment, R 4 A linker moiety directly attached to a divalent compound, and

[0250] R 4 Select from empty, -OR 6 -、-SR 6 -、-N(R 7 )R 6 -、-COR 6 -、-CO2R 6 -、-CON(R 7 )R 6 -、-SOR 6 -、-SO2R 6 -、-SO2N(R 7 )R6 -、-NR 8 COR 6 -、-N(R 8 )C(O)N(R 7 )R 6 -、-NR 8 SOR 6 -、-NR 8 SO2R 6 -, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0251] R 6 is selected from the group consisting of null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0252] R 7 and R 8 independently selected from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0253] R 6 and R 7 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or heterocyclyl ring;

[0254] In another embodiment, R 4 By R 5 is connected to a linker portion of a divalent compound, and R 4 and R5 Independently selected from null, -OR 6 -、-SR 6 -、-N(R 7 )R 6 -、-COR 6 -、-CO2R 6 -、-CON(R 7 )R 6 -、-SOR 6 -、-SO2R 6 -、-SO2N(R 7 )R 6 -、-NR 8 COR 6 -、-N(R 8 )C(O)N(R 7 )R 6 -、-NR 8 SOR 6 -、-NR 8 SO2R 6 -, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0255] R 6 is selected from the group consisting of null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0256] R 7 and R 8independently selected from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0257] R 6 and R 7 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0258] In another embodiment, R 4 and R 5 Independently selected from empty, optionally substituted

[0259] In another embodiment, R 4 and R 5 Independently selected from empty, optionally substituted

[0260] In another embodiment, -R 4 -R 5 -Selected from empty, optionally substituted

[0261] In another embodiment, -R 4 -R 5 - is optionally substituted

[0262] In another embodiment, Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO2, OR 10 NR 11 R 12 、COR 10 、CO2R 10 、CONR 11 R 12 、SOR 10 、SO2R 10 、SO2NR 11 R 12 NR 10 COR 12 NR 10 C(O)NR 11 R 12 NR 10 SOR12 NR 10 SO2R 12 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl and optionally substituted C4-C5 heteroaryl, wherein

[0263] R 10 、R 11 and R 12 is independently selected from void, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0264] R 11 and R 12 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0265] In another embodiment, Ar is aryl, optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, and NO2.

[0266] In another embodiment, Ar is

[0267] In another embodiment, the TRK ligand comprises a moiety of Formula 3A:

[0268]

[0269] in

[0270] X 1 Selected from CR' and N;

[0271] R' is selected from hydrogen, halogen, CN, NO2, and optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, C3-C6 carbocyclyl, or 3-6 membered heterocyclyl;

[0272] X 2 and X 3 Selected from C or N, provided that X 2 and X 3 Only one of them is N;

[0273] X is selected from the group consisting of space, bond, C(R2 )2、C(R 2 )2C(R 2 )2、CO、C(R 2 )2CO、NR 2 CO、OC(R 2 )2 and NR 2 C(R 2 )2;

[0274] R 1 and each R 2 independently selected from hydrogen, halogen, OH, NH2, CN, NO2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 alkoxyalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkylaminoC1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkyloxy and optionally substituted 3-6 membered heterocyclyl;

[0275] n is 1 to 4;

[0276] R 3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, and optionally substituted C1-C6 alkylaminoC1-C6 alkyl;

[0277] R 4 Directly or through R 5 a linker moiety attached to a divalent compound;

[0278] R 4 and R 5 Independently selected from null, -OR 6 -、-SR 6 -、-N(R 7 )R 6 -、-COR 6 -、-CO2R 6 -、-CON(R 7 )R 6 -、-SOR 6 -、-SO2R 6 -、-SO2N(R 7 )R 6 -、-NR 8 COR 6 -、-N(R 8)C(O)N(R 7 )R 6 -、-NR 8 SOR 6 -、-NR 8 SO2R 6 -, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0279] R 6 is selected from the group consisting of null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0280] R 7 and R 8 independently selected from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0281] R 6 and R 7 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or heterocyclyl ring;

[0282] Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, OR 10 SR 10 NR 11 R 12 、COR 10 、CO2R10 、CONR 11 R 12 、SOR 10 、SO2R 10 、SO2NR 11 R 12 NR 10 COR 12 NR 10 C(O)NR 11 R 12 NR 10 SOR 12 NR 10 SO2R 12 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0283] R 10 、R 11 and R 12 is independently selected from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0284] R 11 and R 12 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0285] In one embodiment, X 1 and X 3 is selected from CR' and N, and R' is selected from hydrogen, F, Cl, CH3, CF3 and cyclopropyl.

[0286] In one embodiment, X 1 It's N.

[0287] In one embodiment, X 1 is CR' and R' is selected from hydrogen, F, Cl, CH3, CF3 and cyclopropyl.

[0288] In one embodiment, X 2 is C and X 3 It's N.

[0289] In one embodiment, X 3 is C and X 2 It's N.

[0290] In another embodiment, X is selected from a bond, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH, and CH2NCH3.

[0291] In another embodiment, X is CH2.

[0292] In another embodiment, R 1 and each R 2 Independently selected from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkoxy and optionally substituted 3-6 membered heterocyclyl.

[0293] In another embodiment, R 1 and R 2 It's hydrogen.

[0294] In another embodiment, R 3 Selected from hydrogen, CH3, CH2CH3, propyl, isopropyl, cyclopropyl, CH2F, CHF2 and CF3.

[0295] In another embodiment, R 3 Selected from hydrogen.

[0296] In another embodiment, R 4 The linker portion is directly connected to the divalent compound, and R 4 Select from empty, -OR 6 -、-SR 6 -、-N(R 7 )R 6 -、-COR 6 -、-CO2R 6 -、-CON(R 7 )R 6 -、-SOR 6 -、-SO2R 6 -、-SO2N(R 7 )R 6 -、-NR 8 COR 6 -、-N(R 8 )C(O)N(R 7 )R 6 -、-NR8 SOR 6 -、-NR 8 SO2R 6 -, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0297] R 6 is selected from the group consisting of null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0298] R 7 and R 8 independently selected from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0299] R 6 and R 7 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0300] In another embodiment, R 4 By R 5 is connected to a linker portion of a divalent compound, and R 4 and R 5 Independently selected from null, -OR 6 -、-SR 6 -、-N(R 7 )R 6 -、-COR 6-、-CO2R 6 -、-CON(R 7 )R 6 -、-SOR 6 -、-SO2R 6 -、-SO2N(R 7 )R 6 -、-NR 8 COR 6 -、-N(R 8 )C(O)N(R 7 )R 6 -、-NR 8 SOR 6 -、-NR 8 SO2R 6 -, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0301] R 6 is selected from the group consisting of null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0302] R 7 and R 8 independently selected from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0303] R 6 and R 7together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring;

[0304] In another embodiment, R 4 and R 5 Independently selected from empty, optionally substituted

[0305] In another embodiment, R 4 and R 5 Independently selected from empty, optionally substituted

[0306] In another embodiment, -R 4 -R 5 -Selected from empty, optionally substituted

[0307] In another embodiment, -R 4 -R 5 - is optionally substituted

[0308] In another embodiment, Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO2, OR 10 NR 11 R 12 、COR 10 、CO2R 10 、CONR 11 R 12 、SOR 10 、SO2R 10 、SO2NR 11 R 12 NR 10 COR 12 NR 10 C(O)NR 11 R 12 NR 10 SOR 12 NR 10 SO2R 12, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl and optionally substituted C4-C5 heteroaryl, wherein

[0309] R 10 、R 11 and R 12 is independently selected from void, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0310] R 11 and R 12 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0311] In another embodiment, Ar is aryl, optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, and NO2.

[0312] In another embodiment, Ar is

[0313] In another embodiment, the TRK ligand comprises a moiety of Formula 12-1 or 12-2:

[0314]

[0315] in

[0316] X is selected from CR 5 and N;

[0317] Y is selected from O, S and NR 6 ;

[0318] R 1 、R 3 and R 4 Independently selected from hydrogen, halogen, CN, NO2, OR 7 SR 7 NR 8 R 9 、COR 7 、CO2R 7 、CONR 8 R 9、SOR 7 、SO2R 7 、SO2NR 8 R 9 NR 10 COR 9 NR 10 C(O)NR 8 R 9 NR 10 SOR 9 NR 10 SO2R 9 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted 3-8 membered carbocyclyl- C1-C8 alkyl, optionally substituted 3-8 membered heterocyclyl-C1-C8 alkyl, optionally substituted 3-8 membered carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl-O, and optionally substituted 3-8 membered carbocyclyl-N(C1-C8 alkyl)-, optionally substituted 3-8 membered heterocyclyl-N(C1-C8 alkyl)-, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0319] R 7 、R 8 、R 9 and R 10 independently selected from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted 3-8 membered carbocyclyl-C1-C8 alkyl, optionally substituted 3-8 membered heterocyclyl-C1-C8 alkyl, optionally substituted 3-8 membered carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl-O, optionally substituted 3-8 membered carbocyclyl-N(C1-C8 alkyl)-, and optionally substituted 3-8 membered heterocyclyl-N(C1-C8 alkyl)-, optionally substituted aryl, and optionally substituted heteroaryl; or

[0320] R 8 and R 9 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or heterocyclyl ring;

[0321] R 1 '、R 2 and R 4 'Independently selected from empty, -OR 11 -、-SR 11 -、-NR 12 R 11 -、-COR 11 -、-CO2R 11 -、-CON(R 12 )R 11 -、-SOR 11 -、-SO2R 11 -、-SO2N(R 12 )R 11 -、-NR 13 COR 11 -、-NR 13 C(O)N(R 12 )R 11 -、-NR 13 SOR 11 -、-NR 13 SO2R 11 -, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted optionally substituted 3-8 membered carbocyclyl-C1-C8 alkylene, optionally substituted 3-8 membered heterocyclyl-C1-C8 alkylene, optionally substituted 3-8 membered carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl-O, optionally substituted 3-8 membered carbocyclyl-N(C1-C8 alkyl)-, and optionally substituted 3-8 membered heterocyclyl-N(C1-C8 alkyl)-, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0322] R 11is selected from the group consisting of null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted C3-C8 carbocyclylene-O-, optionally substituted 3-8 membered carbocyclyl-C1-C8 alkylene, optionally substituted 3-8 membered heterocyclyl-C1-C8 alkylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0323] R 12 and R 13 independently selected from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl-C1-C8 alkyl, optionally substituted 3-8 membered heterocyclyl-C1-C8 alkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0324] R 11 and R 12 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or heterocyclyl ring;

[0325] R 5 and R 6 is independently selected at each occurrence from hydrogen, halogen, CN, NO2, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl, and optionally substituted C3-C8 heterocyclyl; and

[0326] n is selected from 0, 1 and 2.

[0327] In another embodiment, X is selected from the group consisting of CH, CF, and N.

[0328] In another embodiment, X is CH.

[0329] In another embodiment, X is CF.

[0330] In another embodiment, X is N.

[0331] In another embodiment, Y is selected from O and S.

[0332] In another embodiment, Y is O.

[0333] In another embodiment, Y is S.

[0334] In another embodiment, R 1 is selected from the group consisting of an optionally substituted acyclic amino group, an optionally substituted cyclic amino group, an optionally substituted phenyl group, and an optionally substituted heteroaryl group.

[0335] In another embodiment, R 1 Selected from optionally substituted

[0336] In another embodiment, R 1 ' is selected from null, optionally substituted acyclic amino, optionally substituted cyclic amino, optionally substituted phenyl and optionally substituted heteroaryl.

[0337] In another embodiment, R 1 'Selected from optionally substituted

[0338] In another embodiment, R 2 Selected from space, -O-, -S-, -N(R 12 )-、-C(O)-、-CO2-、-CON(R 12 )-、-SO-、-SO2-、-SO2N(R 12 )-、-N(R 13 )CO-、-N(R 13 )C(O)N(R 12 )-、-N(R 13 )SO-、-N(R 13 )SO2-, optionally substituted optionally substituted C3-C8 carbocyclyl and optionally substituted C3-C8 heterocyclyl, wherein

[0339] R 12 and R 13 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0340] In another embodiment, R 2 Select from empty, -CONH-,

[0341] In another embodiment, R 3 Selected from hydrogen, halogen, CN, NO2, OH, NH2, -CONH-,

[0342] In another embodiment, R 2 -R 3 Selected from hydrogen, halogen, CN, NO2,

[0343] In another embodiment, R 4 Selected from hydrogen, halogen, CN, NO2, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 3-8 membered carbocyclyl-C1-C8 alkyl, optionally substituted 3-8 membered heterocyclyl -C1-C8 alkyl, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 3-8 membered heterocyclyl, optionally substituted 3-8 membered carbocyclyl-C1-C8 alkyl, and optionally substituted 3-8 membered heterocyclyl-C1-C8 alkyl, optionally substituted 3-8 membered carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl-O-, optionally substituted 3-8 membered carbocyclyl-N(C1-C8 alkyl)- and optionally substituted 3-8 membered heterocyclyl-N(C1-C8 alkyl)-.

[0344] In another embodiment, R 4 Selected from hydrogen, halogen, CN, NO2, OCH3,

[0345] In another embodiment, R 4 'Selected from empty, -O-, -S-, -N(R 12 ')-、-C(O)-、-CO2-、-CON(R 12 ')-、-SO-、-SO2-、-SO2N(R 12 ')-、-N(R 12 ')CO-、-N(R 13 ')C(O)N(R 12 ')-、-N(R 13 ')SO-、-N(R 13')SO2-, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N (C1-C8 alkyl) -C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-C8 -8-membered carbocyclyl, optionally substituted 3-8-membered heterocyclyl, optionally substituted 3-8-membered carbocyclyl-C1-C8 alkylene and optionally substituted 3-8-membered heterocyclyl-C1-C8 alkylene, optionally substituted 3-8-membered carbocyclyl-O-, optionally substituted 3-8-membered heterocyclyl-O-, optionally substituted 3-8-membered carbocyclyl-N(C1-C8 alkyl)- and optionally substituted 3-8-membered heterocyclyl-N(C1-C8 alkyl)-, wherein

[0346] R 12 ' and R 13 ' is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0347] In another embodiment, R 4 ' is selected from the group consisting of empty, -O-, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted 3-8 membered carbocyclyl-C1-C8 alkylene, and optionally substituted 3-8 membered heterocyclyl-C1-C8 alkylene, optionally substituted 3-8 membered carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl-O-, optionally substituted 3-8 membered carbocyclyl-N(C1-C8 alkyl)-, and optionally substituted 3-8 membered heterocyclyl-N(C1-C8 alkyl)-.

[0348] In another embodiment, R 4 'Select from empty, -O-,

[0349] In another embodiment, the TRK ligand comprises a moiety of Formula 13:

[0350]

[0351] in

[0352] X is selected from CR 9 and N;

[0353] R 9 Selected from hydrogen, halogen, CN, NO2, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl and optionally substituted C3-C8 heterocyclyl;

[0354] Y is selected from the group consisting of null, -O-, -N(optionally substituted C1-C8 alkyl)-, and optionally substituted C1-C8 alkylene;

[0355] R 1 and R 2 independently selected from hydrogen, halogen, CN, NO2, OH, NH2, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl, and optionally substituted C3-C8 heterocyclyl;

[0356] R 3 、R 4 、R 5 and R 6 independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl, and optionally substituted C3-C8 heterocyclyl; or

[0357] R 3 and R 4 ; and / or R 5 and R 6 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or heterocyclyl ring;

[0358] m is selected from 1, 2, 3 and 4;

[0359] n is selected from 0, 1, 2, 3 and 4;

[0360] R 7 and R 8 Independently selected from null, -OR 10 -、-SR 10 -、-NR 11 R 10 -、-COR 10 -、-CO2R 10 -、-CONR 11 R 10 -、-SOR10 -、-SO2R 10 -,-SO2NR 11 R 10 -、-NR 12 COR 10 -、-NR 12 C(O)NR 11 R 10 -、-NR 12 SOR 10 -、-NR 12 SO2R 10 -, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-C8 -8-membered heterocyclyl, optionally substituted 3-8-membered carbocyclyl-C1-C8 alkylene, optionally substituted 3-8-membered heterocyclyl-C1-C8 alkylene, optionally substituted 3-8-membered carbocyclyl-O-, optionally substituted 3-8-membered heterocyclyl-O, optionally substituted 3-8-membered carbocyclyl-N(C1-C8 alkyl)-, optionally substituted 3-8-membered heterocyclyl-N(C1-C8 alkyl)-, optionally substituted C2-C8 alkenylene, and optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted C2-C8 alkynylene, optionally substituted aryl and optionally substituted heteroaryl;

[0361] R 10 selected from the group consisting of null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted C3-C8 carbocyclylene-O-, optionally substituted 3-8 membered carbocyclyl-C1-C8 alkylene, optionally substituted 3-8 membered heterocyclyl-C1-C8 alkylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C4-C 13fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0362] R 11 and R 12 independently selected from the group consisting of: void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl-C1-C8 alkyl, optionally substituted 3-8 membered heterocyclyl-C1-C8 alkyl, optionally substituted C3-C8 carbocyclyl-O-, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or

[0363] R 10 and R 11 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or heterocyclyl ring; and

[0364] Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, OR 14 SR 14 NR 15 R 16 、COR 14 、CO2R 14 、CONR 15 R 16 、SOR 14 、SO2R 14 、SO2NR 15 R 16 NR 14 COR 16 NR 14 C(O)NR 15 R 16 NR 14 SOR 16 NR 14 SO2R 16, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0365] R 14 、R 15 and R 16 is independently selected from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0366] R 15 and R 16 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0367] In another embodiment, the TRK ligand comprises a moiety of formula 13-1:

[0368]

[0369] in

[0370] X, Y, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , Ar, m and n are defined in Formula 13.

[0371] In another embodiment, the TRK ligand comprises a moiety of formula 13-2:

[0372]

[0373] in

[0374] X, Y, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and Ar are defined in Formula 13.

[0375] In another embodiment, X is selected from the group consisting of CH, CF, and N.

[0376] In another embodiment, X is N.

[0377] In another embodiment, Y is selected from -O-, -CH2-, and -NH-.

[0378] In another embodiment, Y is -O-.

[0379] In another embodiment, R 1 Selected from hydrogen and NH2.

[0380] In another embodiment, R 1 It's NH2.

[0381] In another embodiment, R 2 is selected from hydrogen, halogen, CN, NO2, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 carbocyclyl and optionally substituted C1-C8 alkoxy.

[0382] In another embodiment, R 2 Selected from H, F, Cl, Br, OCH3, OCF3 and OCHF2.

[0383] In another embodiment, R 2 It is OCH3.

[0384] In another embodiment, R 3 、R 4 、R 5 and R 6 Independently selected from H, F, CH3, cyclopropyl and cyclobutyl.

[0385] In another embodiment, R 3 and R 4 ; and / or R 5 and R 6 Together with the atoms to which they are attached, they optionally form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0386] In another embodiment, R 3 、R 4 、R 5 and R 6 It’s H.

[0387] In another embodiment, R 7 is selected from the group consisting of: null, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C4-C 13fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

[0388] In another embodiment, R 7 Select from empty,

[0389] In another embodiment, R 8 selected from the group consisting of: null, -C(O)-, -C(O)-NH-, an optionally substituted 3-8 membered carbocyclyl, an optionally substituted 3-8 membered heterocyclyl, an optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

[0390] In another embodiment, R 8 Selected from space, -C(O)-, -C(O)-NH-,

[0391] In another embodiment, R 7 -R 8 Select from empty,

[0392] In another embodiment, Ar is selected from optionally substituted phenyl and optionally substituted pyridinyl.

[0393] In another embodiment, Ar is selected from

[0394] In another embodiment, the TRK ligand is derived from any of the following:

[0395]

[0396] In another embodiment, the TRK ligand is derived from the following TRK kinase inhibitors: DS-6051b, F17752, PLX7486, AZD-6918, ASP7962, VM902A, PF-06273340, and ONO-4474.

[0397] In another embodiment, the TRK ligand is selected from:

[0398]

[0399] In some embodiments, the degradation tag is a moiety selected from Formula 5A, 5B, 5C, and 5D:

[0400]

[0401] in

[0402] V, W and X are independently selected from CR 2 and N;

[0403] Y is selected from CO, CR 3 R 4 and N = N;

[0404] Z is selected from empty, CO, CR 5 R 6 NR 5 , O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C 10 Alkenylene, optionally substituted C1-C 10 Alkyne, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; preferably, Z is selected from void, CH2, CH=CH, C≡C, NH, O, optionally substituted 3-7 membered carbocyclyl and optionally substituted 3-7 membered heterocyclyl;

[0405] R 1 is selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered carbocyclyl and optionally substituted 3-6 membered heterocyclyl;

[0406] R 2 is selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-6 membered carbocyclyl and optionally substituted 3-6 membered heterocyclyl;

[0407] R 3 and R 4R is independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered carbocyclyl and optionally substituted 3-6 membered heterocyclyl; or 3 and R 4 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclyl or a 3-6 membered heterocyclyl; and

[0408] R 5 and R 6 R is independently selected from the group consisting of: null, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered carbocyclyl, and optionally substituted 3-6 membered heterocyclyl; or R 5 and R 6 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclic group or a 3-6 membered heterocyclic group.

[0409] In some embodiments, the degradation tag is a moiety selected from Formula 5E, 5F, 5G, 5H, 5I, 5J, 5K, 5L, 5M, 5N, 5O, 5P, and 5Q:

[0410]

[0411]

[0412] in

[0413] U, V, W, X and X' are independently selected from CR 2 and N;

[0414] Y is selected from CR 3 R 4 NR 3 and O; preferably, Y is selected from CH2, NH, NCH3 and O;

[0415] Y', Y" and Y'" are independently selected from CR 3 R 4 ;

[0416] Z is selected from empty, CO, CR 5 R 6 NR 5 , O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 Heteroalkylene, optionally substituted C1-C 10 Alkenylene, optionally substituted C1-C 10 Alkyne, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C4-C 13fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; preferably, Z is selected from void, CH2, CH=CH, C≡C, NH, O, optionally substituted 3-7 membered carbocyclyl and optionally substituted 3-7 membered heterocyclyl;

[0417] R 1 independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered carbocyclyl and optionally substituted 3-6 membered heterocyclyl;

[0418] R 2 is selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-6 membered carbocyclyl and optionally substituted 3-6 membered heterocyclyl;

[0419] R 3 and R 4 is independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl, or

[0420] R 3 and R 4 together with the atoms to which they are attached, optionally form a 3-6 membered carbocyclyl or a 3-6 membered heterocyclyl; and

[0421] R 5 and R 6 R is independently selected from the group consisting of: null, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered carbocyclyl, and optionally substituted 3-6 membered heterocyclyl; or R 5 and R 6 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclic group or a 3-6 membered heterocyclic group.

[0422] In one embodiment, the degradation tag is a moiety of Formula 6A:

[0423]

[0424] in

[0425] R 1 and R 2independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; and

[0426] R 3 is hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)C3-C7 carbocyclyl, optionally substituted C(O)(3- 7-membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)OC3-C7 carbocyclyl, optionally substituted C(O)O(3-7 membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, any Optionally substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)NC3-C7 carbocyclyl, optionally substituted C(O)N(3-7 membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2 and optionally substituted P(O)(OC1-C8 aryl)2.

[0427] In one embodiment, the degradation tag is a moiety selected from Formula 6B, 6C, 6D, 6E, and 6F:

[0428]

[0429]

[0430] in

[0431] R 1 and R 2 R is independently selected from hydrogen, halogen, OH, NH2, CN, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl; (preferably, R 1 is selected from isopropyl or tert-butyl; and R 2 selected from hydrogen or methyl);

[0432] R 3 is hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)C3-C7 carbocyclyl, optionally substituted C(O)(3- 7-membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)OC3-C7 carbocyclyl, optionally substituted C(O)O(3-7 membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)NC3-C7 carbocyclyl, optionally substituted C(O)N(3-7 membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2, and optionally substituted P(O)(OC1-C8 aryl)2; and

[0433] R 4 and R 5 are independently selected from hydrogen, COR 6 、CO2R 6 、CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0434] R 6 and R 7 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0435] R 4 and R 5 ; or R 6 and R 7 Together with the atoms to which they are attached, they form a 3-8 membered carbocyclyl or heterocyclyl ring;

[0436] Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO2, OR 8 NR 8 R 9 、COR 8 、CO2R 8 、CONR 8 R 9 、SOR 8 、SO2R 8 、SO2NR 8 R 9 NR 10 COR 8 NR 10 C(O)NR 8 R 9 NR 10 SOR 8 NR 10 SO2R8 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl and optionally substituted C4-C5 heteroaryl, wherein

[0437] R 8 、R 9 and R 10 is independently selected from void, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0438] R 8 and R 9 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0439] In another embodiment, the degradation tag is a moiety of Formula 7A:

[0440]

[0441] in

[0442] V, W, X and Z are independently selected from CR 4 and N.

[0443] R 1 、R 2 、R 3 and R 4 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl.

[0444] In another embodiment, the degradation tag is a moiety of Formula 7B:

[0445]

[0446] in

[0447] R 1 、R2 and R 3 independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl;

[0448] R 4 and R 5 are independently selected from hydrogen, COR 6 、CO2R 6 、CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted aryl-C1-C8 alkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0449] R 6 and R 7 is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0450] R 6 and R 7 Together with the atoms to which they are attached they form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0451] In another embodiment, the degradation tag is derived from any of the following:

[0452]

[0453] In another embodiment, the degradation tag is derived from any of the following: thalidomide, pomalidomide, lenalidomide, CRBN-1, CRBN-2, CRBN-3, CRBN-4, CRBN-5, CRBN-6, CRBN-7, CRBN-8, CRBN-9, CRBN-10, and CRBN-11.

[0454] In another embodiment, the degradation tag is selected from the group consisting of:

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462] In another embodiment, the degradation tag is selected from the group consisting of: Formula 8A, 8B, 8C, 8D, 8E, 8F, 8G, 8H, 8I, 8J, 8K, 8L, 8M, 8O, 8P, 8Q, 8R, 8AQ, 8AR, 8AS, 8AT, 8AU, 8AV, 8AW, 8AX, 8AY, 8AZ, 8BA, 8BB, 8BC, 8BD, 8BE, 8BF, 8BG, 8BH, 8BI, 8BJ, 8BK, 8BL, 8BM, Formula 8BN, 8BO, 8BP, 8BQ, 8BR, 8BS, 8CB, 8CC, 8CD, 8CE, 8CF, 8CG, 8CH, 8CI, 8CJ, 8CK, 8CL, 8CM, 8CN, 8CO, 8CP, 8CQ, 8CR, 8CS, 8CT, 8CU, 8CV, 8CW, 8CX, 8CY, 8CZ, 8DA, 8DB, 8DC, 8DD, 8DE, 8DF, 8DG, 8DH, 8DI , 8DJ, 8DK, 8DL, 8DM, 8DN, 8DO, 8DP, 8DQ, 8DR, 8DS, 8DT, 8DU, 8DV, 8DW, 8DX, 8DY, 8DZ, 8EA, 8EB, 8EC, 8ED, 8EE, 8EF, 8EG, 8EH, 8EI, 8EJ , 8EK, 8EL, 8EM, 8EN, 8EO, 8EP, 8EO, 8GU, 8GV, 8GW, 8GX, 8GY, 8GZ, 8HA, 8HB, 8HC, 8HD, 8HE, 8HF, 8HG, 8HH, 8HI, 8HJ, 8HK, 8HL, 8HM, 8H N, 8HO, 8HP, 8HQ, 8HR, 8HS, 8HT, 8HU, 8HV, 8HW, 8HX, 8HY, 8HZ, 8IA, 8IB, 8IC, 8ID, 8IE, 8IF, ​​8IG, 8IH, 8II, 8IJ, 8IK, 8IL, 8IM, 8IN, 8 IO, 8IP, 8IQ, 8IR, 8IS, 8IT, 8IU, 8IV, 8IW, 8IX, 8IY, 8IZ, 8JA, 8JB, 8JC, 8JD, 8JE, 8JF, 8JG, 8JH, 8JI, 8JJ, 8JK, 8JL, 8JM, 8JN, 8JO, 8JP, 8JQ, 8JR, 8JS, 8JT, 8JU, 8JV, 8JW, 8JX, 8JY, 8JZ, 8KA, 8KB, 8KC, 8KD, 8KE, 8KF, 8KG, 8KH, 8KI, 8KJ, 8KK, 8KL, 8KM, 8KN, 8KO and 8KP.

[0463] In some embodiments, the linker moiety has Formula 9:

[0464]

[0465] in

[0466] A, W and B are independently selected at each occurrence from a null or divalent moiety selected from R'-R", R'COR", R'CO2R", R'C(O)N(R 1 )R”、R'C(S)N(R 1 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 1 )R”、R'N(R 1 )R”、R”N(R 1 )COR”、R'N(R 1 )CON(R 2 )R”、R'N(R 1 )C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0467] R' and R" are independently selected from empty, optionally substituted (C1-C8 alkylene)-R r (Preferably, CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r-(C1-C8 alkyl), or a moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 amino alkyl, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0468] R r is selected from an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 3-10 membered heterocyclyl, an optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0469] R 1 and R 2 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0470] R' and R", R 1 and R 2 , R' and R 1 , R' and R 2 , R” and R1 or R" and R 2 together with the atoms to which they are attached, optionally form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring; and

[0471] m is 0 to 15.

[0472] In one embodiment, the linker moiety has Formula 9A:

[0473]

[0474] in

[0475] R 1 、R 2 、R 3 and R 4 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0476] R 1 and R 2 or R 3 and R 4 together with the atoms to which they are attached, optionally form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring;

[0477] A, W and B are independently selected at each occurrence from a null or divalent moiety selected from R'-R", R'COR", R'CO2R", R'C(O)N(R 5 )R”、R'C(S)N(R 5 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 5 )R”、R'N(R 5 )R”、R'N(R 5 )COR”、R'N(R 5 )CON(R 6 )R”、R'N(R 5)C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0478] R' and R" are independently selected from empty, optionally substituted (C1-C8 alkylene)-R r (Preferably, CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkylene), or a moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0479] R r is selected from an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 3-10 membered heterocyclyl, an optionally substituted C4-C 13fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0480] R 5 and R 6 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0481] R' and R", R 5 and R 6 , R' and R 5 , R' and R 6 , R” and R 5 or R" and R 6 together with the atoms to which they are attached, optionally form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring;

[0482] m is 0 to 15;

[0483] n is 0 to 15 at each occurrence; and

[0484] o is 0 to 15.

[0485] In another embodiment, the linker moiety has Formula 9B:

[0486]

[0487] in

[0488] R 1 and R 2is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, nitro, and optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0489] R 1 and R 2 together with the atoms to which they are attached, optionally form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring;

[0490] A and B are independently selected at each occurrence from a null or divalent moiety selected from R'-R", R'COR", R'CO2R", R'C(O)N(R 3 )R”、R'C(S)N(R 3 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 3 )R”、R'N(R 3 )R”、R'N(R 3 )COR”、R'N(R 3 )CON(R 4 )R”、R'N(R 3 )C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0491] R' and R" are independently selected from empty, optionally substituted (C1-C8 alkylene)-R r (Preferably, CH2-R r ), optionally substituted Rr -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkylene), or a moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0492] R r is selected from an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 3-10 membered heterocyclyl, an optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0493] R 3 and R 4 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0494] R' and R", R 3 and R4 , R' and R 3 , R' and R 4 , R” and R 3 or R" and R 4 together with the atoms to which they are attached, optionally form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring;

[0495] Each m is 0 to 15; and

[0496] n is 0 to 15.

[0497] In another embodiment, the linker moiety has Formula 9C:

[0498]

[0499] in

[0500] X is selected from O, NH and NR 7 ;

[0501] R 1 、R 2 、R 3 、R 4 、R 5 and R 6 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0502] A and B are independently selected from a null or divalent moiety selected from R'-R", R'COR", R'CO2R", R'C(O)N(R 8 )R”、R'C(S)N(R 8 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 8 )R”、R'N(R 8 )R”、R'N(R 8 )COR”、R'N(R 8 )CON(R 9 )R”、R'N(R 8)C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0503] R' and R" are independently selected from empty, optionally substituted (C1-C8 alkylene)-R r (Preferably, CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkylene), or a moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0504] R r is selected from an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 3-10 membered heterocyclyl, an optionally substituted C4-C 13fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0505] R 7 、R 8 and R 9 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0506] R' and R", R 8 and R 9 , R' and R 8 , R' and R 9 , R” and R 8 or R" and R 9 together with the atoms to which they are attached, optionally form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring;

[0507] m ranges from 0 to 15 at each occurrence;

[0508] n ranges from 0 to 15 at each occurrence;

[0509] o is 0 to 15; and

[0510] p is 0 to 15.

[0511] In one embodiment, in Formula 9C, m and n are 0 or 1, and p is 0 to 15;

[0512] In one embodiment, in Formula 9C, X is selected from O and NH;

[0513] In one embodiment, in Formula 9C, R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are independently selected from hydrogen and optionally substituted C1-C6 alkyl.

[0514] In another embodiment, the linker moiety comprises one or more rings selected from a 3- to 13-membered ring, a 4- to 13-membered fused ring, a 5- to 13-membered bridged ring, and a 5- to 13-membered spiro ring.

[0515] In another embodiment, the linker moiety comprises a ring selected from the group consisting of Formula C1, C2, C3, C4, and C5:

[0516]

[0517] in

[0518] X' and Y' are independently selected from N and CR b ;

[0519] A 1 、B 1 、C 1 and D 1 independently at each occurrence selected from air, O, CO, SO, SO2, NR b and CR b R c ;

[0520] A 2 、B 2 、C 2 and D 2 independently selected at each occurrence from N and CR b ;

[0521] A 3 、B 3 、C 3 、D 3 and E 3 independently selected at each occurrence from N, O, S, NR b and CR b ;

[0522] R b and R c is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0523] Rb and R b or R b and R c Together with the atoms to which they are attached, they form a 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring; and

[0524] m 1 、n 1 、o 1 and p 1 Independently selected from 0, 1, 2, 3, 4 and 5.

[0525] In one embodiment, A, B and W are independently selected at each occurrence from empty, optionally substituted -(CH2) 0-8 -, optionally substituted -(CH2) 0-8 -CO-(CH2) 0-8 -, optionally substituted -(CH2) 0-8 -NH-(CH2) 0-8 -, optionally substituted -(CH2) 0-8 -NH-CO-(CH2) 0-8 -, optionally substituted -(CH2) 0-8 -CO-NH-(CH2) 0-8 -, optionally substituted -(CH2) 0-3 -NH-(CH2) 0-3 -CO-NH-(CH2) 0-8 -, optionally substituted -(CH2) 0-3 -NH-(CH2) 1-3 -NH-CO-(CH2) 0-8 -, optionally substituted -(CH2) 0-8 -CO-NH-(CH2) 1-3 -NH-(CH2) 0-3 -, optionally substituted -(CH2) 0-8 -R r -(CH2) 0-8 -, optionally substituted -(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3- and optionally substituted -(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -.

[0526] In one embodiment, R r Has formula C1, C2, C3, C4 or C5.

[0527] In one embodiment, R r Selected from

[0528] In another embodiment, the linker is 0 to 40 atoms in length.

[0529] In another embodiment, the linker is 0 to 20 atoms in length.

[0530] In another embodiment, the linker is 0 to 10 atoms in length.

[0531] In another embodiment, the linker is selected from void, optionally substituted -(CO)-(CH2) 0-8 -, optionally substituted -(CH2) 0-9 -, optionally substituted -(CH2) 1-2 -(CO)-NH-(CH2) 0-9 -, optionally substituted -(CH2) 1-2 -(CO)-NH-(CH2) 1-3 -(OCH2CH2) 1-7 -, optionally substituted -(CH2) 0-1 -(CO)-(CH2) 1-3 -(OCH2CH2) 1-7 -, optionally substituted -(CO)-(CH2) 0-3 -(Alkenylene)-(CH2) 0-3 -, optionally substituted -(CO)-(CH2) 0-3 -(Alkynylidene)-(CH2) 0-3 -, optionally substituted -(CO)-(CH2) 0-3 -(3-8 membered carbocyclyl)-(CH2) 0-3 -, optionally substituted -(CO)-(CH2) 0-3 -(3-8 membered heterocyclyl)-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -(Alkenylene)-(CH2) 0-3 -, optionally substituted -(CH2) 0-3-(Alkynylidene)-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -(3-8 membered carbocyclyl)-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -(3-8 membered heterocyclyl)-(CH2) 0-3 -, optionally substituted -(CH2) 0-8 -R r -(CH2) 0-8 -, optionally substituted -(CH2) 0-8 -R r -(CO)-(CH2) 1-8 -, optionally substituted -(CH2) 0-8 -R r -(CH2) 1-2 -(CO)-NH-(CH2) 2-9 -, optionally substituted -(CH2) 0-8 -R r -(CH2) 1-2 -(CO)-NH-(CH2) 1-3 -(OCH2CH2) 1-7 -, optionally substituted -(CH2) 0-8 -R r -(CH2) 0-1 -(CO)-(CH2) 1-3 -(OCH2CH2) 1-7 -, optionally substituted -(CH2) 0-8 -R r -(CO)-(CH2) 0-3 -(Alkenylene)-(CH2) 0-3 -, optionally substituted -(CH2) 0-8 -R r -(CO)-(CH2) 0-3 -(Alkynylidene)-(CH2) 0-3 -, optionally substituted -(CH2) 0-8 -R r -(CO)-(CH2) 0-3 -(3-8 membered carbocyclyl)-(CH2) 0-3 -, optionally substituted -(CH2) 0-8 -R r -(CO)-(CH2) 0-3 -(3-8 membered heterocyclyl)-(CH2) 0-3 -, optionally substituted -(CH2) 0-8 -R r -(CH2) 0-3-(Alkenylene)-(CH2) 0-3 -, optionally substituted -(CH2) 0-8 -R r -(CH2) 0-3 -(Alkynylidene)-(CH2) 0-3 -, optionally substituted -(CH2) 0-8 -R r -(CH2) 0-3 -(3-8 membered carbocyclyl)-(CH2) 0-3 - and optionally substituted -(CH2) 0-8 -R r -(CH2) 0-3 -(3-8 membered heterocyclyl)-(CH2) 0-3 -.

[0532] In one aspect, provided herein is a bivalent compound comprising a tropomyosin receptor kinase (TRK) ligand conjugated to a degradation tag via a linker, or a pharmaceutically acceptable salt or analog thereof, wherein the linker and the degradation tag are each independently selected from those disclosed herein, and the TRK ligand is a moiety of formula 10, which is conjugated to a degradation tag via R 4 Connect to the connector:

[0533]

[0534] in

[0535] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from C, CR 1 and N;

[0536] X is selected from CR 1 R 2 , CO, O, S, SO, SO2 and NR 1 ;

[0537] R is selected from the group consisting of optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted 3-10 membered heterocyclic group and Ar 1 ;or

[0538] XR Together stands for

[0539] U is selected from space, bond, C(R 2 )2、C(R 2 )2C(R 2 )2、CO、C(R 2)2CO、CONR 2 、C(R 2 )2O、C(R 2 )2NR 2 and CH2NR 2 ;

[0540] R 1 and R 2 is independently selected at each occurrence from hydrogen, halogen, CN, NO2, OR 6 SR 6 NR 7 R 8 、COR 6 、CO2R 6 、C(O)NR 7 R 8 、SOR 6 、SO2R 6 、SO2NR 7 R 8 NR 6 C(O)R 8 NR 6 C(O)NR 7 R 8 NR 6 SOR 8 NR 6 SO2R 8 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C3-C 10 cycloalkoxy, optionally substituted 3-10 membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; or

[0541] R 1 and R 2 、R 1 and another R 1 or R 2 and another R 2 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring;

[0542] R 6 、R 7 and R 8is independently selected at each occurrence from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0543] R 7 and R 8 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring;

[0544] n is 0, 1, 2, 3 or 4;

[0545] n' is 0, 1, 2 or 3;

[0546] L is Ar 2 NR 3 CO or NR 3 COAr 2 ;

[0547] R 3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, and optionally substituted C1-C6 alkylaminoC1-C6 alkyl;

[0548] R 4 Directly or through R 5 A linker moiety attached to a divalent compound, wherein

[0549] R 4 and R 5 is a divalent group independently selected from the group consisting of: -O-, -S-, -NR 9 -、-CO-、-CO2-、-CONR 9 -、-SO-、-SO2R 9 -,-SO2NR 9 -、-NR 10 CO-、-NR 10 C(O)NR 9 -、-NR 10 SO-、-NR 10SO2-, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered heterocyclylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0550] R 9 is selected from the group consisting of null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0551] R 10 is selected from the group consisting of void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0552] Ar 1 and Ar 2 independently selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, OR 11 SR 11 NR 12 R 13 、COR 11 、CO2R 11 、CONR 12 R 13 、SOR 11 、SO2R 11 、SO2NR 12 R 13 NR 11 COR 13 NR 11 C(O)NR 12 R 13 NR11 SOR 13 NR 11 SO2R 13 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0553] R 11 、R 12 and R 13 is independently selected from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or

[0554] R 12 and R 13 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0555] In another aspect, provided herein is a bivalent compound comprising a tropomyosin receptor kinase (TRK) ligand conjugated to a degradation tag via a linker, or a pharmaceutically acceptable salt or analog thereof, wherein the TRK ligand and the linker are each independently selected from those disclosed herein, and the degradation tag is a moiety of formula 11, which is conjugated to a degradation tag via Z or V. 1 、V 2 、V 3 、V 4 、W 1 、W 2 and W 3 Connect any one of the following to the connector:

[0556]

[0557] in

[0558] V 1 、V 2 、V 3 and V 4 Each independently selected from CR 2 'and N;

[0559] W 1 、W 2 and W 3Each independently selected from CO, O, CR 3 'R 4 ' and NR 5 ', where R 5 ' is selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl and R 1 'Optionally substituted 2,6-dioxopiperidin-3-yl, provided that there are no two adjacent CO groups;

[0560] Z is selected from empty, CO, CR 3 'R 4 '、NR 3 ', O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 Heteroalkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 alkynylene, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;

[0561] R 1 ' is selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted 3-6 membered carbocyclyl and optionally substituted 3-6 membered heterocyclyl;

[0562] R 2 ' is selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-6 membered carbocyclyl and optionally substituted 3-6 membered heterocyclyl; and

[0563] R 3 ' and R 4 ' is independently selected at each occurrence from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered carbocyclyl and optionally substituted 3-6 membered heterocyclyl; or

[0564] R 3 ' and R 4 ' together with the atoms to which they are attached optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[0565] In another aspect, provided herein is a bivalent compound comprising a tropomyosin receptor kinase (TRK) ligand conjugated to a degradation tag via a linker, or a pharmaceutically acceptable salt or analog thereof, wherein the TRK ligand and the degradation tag are each independently selected from those disclosed herein, and the linker is a moiety of Formula 9:

[0566]

[0567] in

[0568] A and B are independently selected at each occurrence from a null or divalent moiety selected from R'-R", R'COR", R'CO2R", R'C(O)N(R 1 ”)R”、R'C(S)N(R 1 ")R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 1 ”)R”、R'N(R 1 ”)R”、R”N(R 1 ”)COR”、R”N(R 1 ”)CON(R 2 ”)R”、R'N(R 1 ”)C(S)R”, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene;

[0569] Each W is independently selected from empty, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0570] R′ and R″ are independently selected from the group consisting of: C1-C8 alkyl, C1-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 alkylamino, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylene, C1-C8 heteroalkylene, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 alkylamino, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylene, C1-C8 heteroalkylene, C2-C8 alkenyl, C2-C8 alkynylene, C1-C8 hydroxyalkylene, C1-C8 alkoxyalkylene, C1-C8 alkylamino, C1-C8 alkylene, C1-C8 haloalkylene;

[0571] R 1 ” and R 2 " is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0572] m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0573] In another aspect, provided herein is a bivalent compound comprising a tropomyosin receptor kinase (TRK) ligand conjugated to a degradation tag via a linker, or a pharmaceutically acceptable salt or analog thereof, wherein the TRK ligand is a moiety of formula 10, which is conjugated to a degradation tag via R 4 Connect with connector:

[0574]

[0575] in

[0576] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from C, CR 1 and N;

[0577] X is selected from CR 1 R 2 , CO, O, S, SO, SO2 and NR 1 ;

[0578] R is selected from the group consisting of optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkyl, optionally substituted C3-C 10 Carbocyclic group, optionally substituted 3-10 membered heterocyclic group and Ar 1 ;or

[0579] XR Together stands for

[0580] U is selected from space, bond, C(R 2 )2、C(R 2 )2C(R 2 )2、CO、C(R 2 )2CO、CONR 2 、C(R 2 )2O、C(R 2 )2NR 2 and CH2NR 2 ;

[0581] R 1 and R 2 is independently selected at each occurrence from hydrogen, halogen, CN, NO2, OR 6 SR 6 NR 7 R 8 、COR 6 、CO2R 6 、C(O)NR 7 R 8 、SOR 6 、SO2R 6 、SO2NR 7 R 8 NR 6 C(O)R 8 NR 6 C(O)NR 7 R 8 NR 6 SOR 8 NR 6 SO2R 8 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C3-C 10 cycloalkoxy, optionally substituted 3-10 membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; or

[0582] R 1 and R2 、R 1 and another R 1 or R 2 and another R 2 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring;

[0583] R 6 、R 7 and R 8 is independently selected at each occurrence from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0584] R 7 and R 8 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring;

[0585] n is 0, 1, 2, 3 or 4;

[0586] n' is 0, 1, 2 or 3;

[0587] L is Ar 2 NR 3 CO or NR 3 COAr 2 ;

[0588] R 3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, and optionally substituted C1-C6 alkylaminoC1-C6 alkyl;

[0589] R 4 Directly or through R 5 A linker moiety attached to a divalent compound, wherein

[0590] R 4 and R 5 is a divalent group independently selected from the group consisting of: -O-, -S-, -NR 9 -、-CO-、-CO2-、-CONR 9 -、-SO-、-SO2R 9 -、-SO2NR 9 -、-NR10 CO-、-NR 10 C(O)NR 9 -、-NR 10 SO-、-NR 10 SO2-, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered heterocyclylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0591] R 9 is selected from the group consisting of null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0592] R 10 is selected from the group consisting of void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0593] Ar 1 and Ar 2 independently selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, OR 11 SR 11 NR 12 R 13 、COR 11 、CO2R 11 、CONR 12 R 13 、SOR 11 、SO2R 11 、SO2NR 12 R 13NR 11 COR 13 NR 11 C(O)NR 12 R 13 NR 11 SOR 13 NR 11 SO2R 13 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0594] R 11 、R 12 and R 13 is independently selected from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0595] R 12 and R 13 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring;

[0596] wherein the degradation tag is a moiety of formula 11, which is connected to Z or V 1 、V 2 、V 3 、V 4 、W 1 、W 2 and W 3 Connect any one of the following to the connector:

[0597]

[0598] in

[0599] V 1 、V 2 、V 3 and V 4 Each independently selected from CR 2 'and N;

[0600] W 1 、W 2 and W 3Each independently selected from CO, O, CR 3 'R 4 ' and NR 5 ', where R 5 ' is selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl and R 1 'Optionally substituted 2,6-dioxopiperidin-3-yl, provided that there are no two adjacent CO groups;

[0601] Z is selected from empty, CO, CR 3 'R 4 '、NR 3 ', O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 Heteroalkylene, optionally substituted C1-C 10 Alkenylene, optionally substituted C1-C 10 alkynylene, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;

[0602] R 1 ' is selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered carbocyclyl and optionally substituted 3-6 membered heterocyclyl;

[0603] R 2 ' is selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-6 membered carbocyclyl and optionally substituted 3-6 membered heterocyclyl; and

[0604] R 3 ' and R 4 ' is independently selected at each occurrence from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered carbocyclyl and optionally substituted 3-6 membered heterocyclyl; or

[0605] R 3 ' and R 4 ' taken together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or heterocyclyl ring; and

[0606] The connector is the part of formula 9:

[0607]

[0608] in

[0609] A and B are independently selected at each occurrence from a null or divalent moiety selected from R'-R", R'COR", R'CO2R", R'C(O)N(R 1 ”)R”、R'C(S)N(R 1 ")R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 1 ”)R”、R'N(R 1 ”)R”、R”N(R 1 ”)COR”、R”N(R 1 ”)CON(R 2 ”)R”、R'N(R 1 ”)C(S)R”, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene;

[0610] Each W is independently selected from empty, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0611] R′ and R″ are independently selected from the group consisting of: C1-C8 alkyl, C1-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 alkylamino, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylene, C1-C8 heteroalkylene, C2-C8 alkenylene, C2-C8 alkynylene, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 alkylamino, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylene, C1-C8 heteroalkylene, C2-C8 alkenylene, C2-C8 alkynylene, C1-C8 hydroxyalkylene, C1-C8 alkoxyalkylene, C1-C8 alkylamino, C1-C8 alkylene, C1-C8 haloalkylene;

[0612] R 1 ” and R 2" is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0613] m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0614] In certain embodiments of the divalent compounds disclosed herein, U is selected from a bond, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH, and CH2NCH3.

[0615] In certain embodiments of the bivalent compounds disclosed herein, R 1 and R 2 is independently selected at each occurrence from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclyl.

[0616] In certain embodiments of the bivalent compounds disclosed herein, R 1 and R 2 is independently selected at each occurrence from hydrogen, F, Cl, CH3, CF3 and cyclopropyl.

[0617] In certain embodiments of the bivalent compounds disclosed herein, Ar 1 Selected from optionally substituted C6-C 10 Aryl and optionally substituted C5-C 10 Heteroaryl.

[0618] In certain embodiments of the bivalent compounds disclosed herein, Ar 1 Selected from 3-fluorophenyl, 3,5-difluorophenyl and 2,5-difluorophenyl.

[0619] In certain embodiments of the bivalent compounds disclosed herein, L is Ar 2 And R 4 By R 5 A linker moiety attached to a divalent compound.

[0620] In certain embodiments of the bivalent compounds disclosed herein, L is Ar 2 And R 4 A linker moiety that is directly attached to a divalent compound.

[0621] In certain embodiments of the bivalent compounds disclosed herein, R 4 Selected from

[0622] In certain embodiments of the bivalent compounds disclosed herein, L is Ar 2 , and Ar 2 Selected from optionally substituted C6-C 10 Aryl and optionally substituted C5-C 10 Heteroaryl.

[0623] In certain embodiments of the bivalent compounds disclosed herein, XR taken together represent

[0624] In certain embodiments of the bivalent compounds disclosed herein, X 1 It is N; X 2 It is N; X 3 It is N; X 4 is CH; X 5 It is C; XR together represents U is CH2; Ar 1 is 3-fluorophenyl; L is Ar 2 ; and Ar 2 It is 2-pyridyl.

[0625] In certain embodiments of the bivalent compounds disclosed herein, L is Ar 2 or NR 3 COAr 2 And Ar 2 -R 4 A moiety selected from formulae B1, B2 and B3:

[0626]

[0627] in

[0628] * indicates a linker moiety attached to a divalent compound;

[0629] Y 1 、Y 2 、Y 3 and Y 4 Independently selected from CR a and N, conditional on Y 1 、Y 2 、Y 3 and Y4 At most 3 of them are N;

[0630] Each R a Independently selected from hydrogen, halogen, CN, NO2, OR 14 NR 15 R 16 、COR 14 、CO2R 14 、CONR 15 R 16 、SOR 14 、SO2R 14 、SO2NR 15 R 16 NR 14 COR 15 NR 14 C(O)NR 15 R 16 NR 14 SOR 15 NR 14 SO2R 15 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0631] R 14 、R 15 and R 16 is independently selected at each occurrence from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0632] R 15 and R 16 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring.

[0633] In certain embodiments of the bivalent compounds disclosed herein, L is Ar 2 or NR 3 COAr 2 And Ar 2 -R4 A moiety selected from formula B4:

[0634]

[0635] in

[0636] * indicates a linker moiety attached to a divalent compound;

[0637] Y 1 '、Y 2 '、Y 3 ' and Y 4 'Independently selected from CR a , N, O and S, provided that Y 1 '、Y 2 '、Y 3 ' and Y 4 'Up to 3 of them are N;

[0638] Each R a Independently selected from hydrogen, halogen, CN, NO2, OR 14 NR 15 R 16 、COR 14 、CO2R 14 、CONR 15 R 16 、SOR 14 、SO2R 14 、SO2NR 15 R 16 NR 14 COR 15 NR 14 C(O)NR 15 R 16 NR 14 SOR 15 NR 14 SO2R 15 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0639] R 14 、R 15 and R 16is independently selected at each occurrence from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0640] R 15 and R 16 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring.

[0641] In certain embodiments of the bivalent compounds disclosed herein, L is NR 3 CO, and R 3 Selected from hydrogen, CH3, CH2CH3, propyl, isopropyl, cyclopropyl, CH2F, CHF2 and CF3.

[0642] In certain embodiments of the bivalent compounds disclosed herein, L is NR 3 CO and R 4 A linker moiety that is directly attached to a divalent compound.

[0643] In certain embodiments of the bivalent compounds disclosed herein, L is NR 3 CO and R 4 By R 5 A linker moiety attached to a divalent compound.

[0644] In certain embodiments of the bivalent compounds disclosed herein, L is NR 3 COAr 2 , where R 3 is selected from hydrogen, CH3, CH2CH3, propyl, isopropyl, cyclopropyl, CH2F, CHF2 and CF3; and Ar 2 Selected from optionally substituted C6-C 10 Aryl and optionally substituted C5-C 10 Heteroaryl.

[0645] In certain embodiments of the bivalent compounds disclosed herein, L is NR 3 COAr 2 And R 4 A linker moiety that is directly attached to a divalent compound.

[0646] In certain embodiments of the bivalent compounds disclosed herein, L is NR 3 COAr 2 And R 4 By R 5A linker moiety attached to a divalent compound.

[0647] In certain embodiments of the bivalent compounds disclosed herein, L is NR 3 COAr 2 And Ar 2 -R 4 A moiety selected from the group consisting of formulae B1, B2, and B3.

[0648] In certain embodiments of the bivalent compounds disclosed herein, L is NR 3 COAr 2 And Ar 2 -R 4 A moiety selected from formula B1, wherein Y 1 It is CH or N.

[0649] In certain embodiments of the bivalent compounds disclosed herein, L is NR 3 COAr 2 And Ar 2 -R 4 A moiety selected from formula B2, wherein Y 1 It's CR a , and R a It is H.

[0650] In certain embodiments of the bivalent compounds disclosed herein, L is NR 3 COAr 2 And Ar 2 -R 4 A moiety selected from formula B3, wherein Y 2 It's CR a , and R a yes

[0651] In certain embodiments of the bivalent compounds disclosed herein, L is NR 3 COAr 2 And XR is X-Ar 1 .

[0652] In certain embodiments of the bivalent compounds disclosed herein, L is NR 3 COAr 2 And XR is X-Ar 1 , wherein X is CH2; and Ar 1 Selected from 3-fluorophenyl, 3,5-difluorophenyl or 2,5-difluorophenyl.

[0653] In certain embodiments of the bivalent compounds disclosed herein, V 1 、V 2、V 3 and V 4 Each independently CR 2 '.

[0654] In certain embodiments of the bivalent compounds disclosed herein, W 1 、W 2 and W 3 At least one of them is NR 5 '.

[0655] In certain embodiments of the bivalent compounds disclosed herein, W 1 、W 2 and W 3 At least one of them is NR 5 ', and R 5 Only one of them is R 1 'Optionally substituted 2,6-dioxopiperidin-3-yl.

[0656] In certain embodiments of the bivalent compounds disclosed herein, W 1 It's CO.

[0657] In certain embodiments of the bivalent compounds disclosed herein, W 2 It's CO.

[0658] In certain embodiments of the bivalent compounds disclosed herein, W 3 It's CO.

[0659] In certain embodiments of the bivalent compounds disclosed herein, W 1 and W 3 All are CO.

[0660] In certain embodiments of the bivalent compounds disclosed herein, W 2 is CO and W 1 and W 3 All are NR 5 ', and R 5 Only one of them is R 1 'Optionally substituted 2,6-dioxopiperidin-3-yl.

[0661] In certain embodiments of the bivalent compounds disclosed herein, W at each occurrence is independently selected from the group consisting of Formulae C1, C2, C3, C4, and C5:

[0662]

[0663] in

[0664] X' and Y' are independently selected from N and CR b ;

[0665] A 1 、B 1 、C 1 and D 1 independently at each occurrence selected from air, O, CO, SO, SO2, NR b and CR b R c ;

[0666] A 2 、B 2 、C 2 and D 2 independently selected at each occurrence from N and CR b ;

[0667] A 3 、B 3 、C 3 、D 3 and E 3 independently selected at each occurrence from N, O, S, NR b and CR b ;

[0668] R b and R c R is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or R b and R b or R b and R c Together with the atoms to which they are attached, they form a 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring; and

[0669] m 1 、n 1 、o 1 and p 1 Independently selected from 0, 1, 2, 3, 4 and 5.

[0670] In certain embodiments of the bivalent compounds disclosed herein, the linker is 3 to 40 atoms in length.

[0671] In certain embodiments of the bivalent compounds disclosed herein, the linker is 3 to 20 atoms in length.

[0672] In certain embodiments of the bivalent compounds disclosed herein, the linker is 3 to 10 atoms in length.

[0673] In certain embodiments of the bivalent compounds disclosed herein, the linker is selected from optionally substituted -(CO)-(CH2) 0-3 -W-(CH2) 0-3 -、-(CH2) 0-3 -W-(CH2) 0-3 -, optionally substituted -(CO)-(CH2) 0-8 -, optionally substituted -(CH2) 0-9 -, optionally substituted -(CH2) 1-2 -(CO)-NH-(CH2) 2-9 -, optionally substituted -(CH2) 1-2 -(CO)-NH-(CH2) 1-3 -(OCH2CH2) 1-7 -, optionally substituted -(CH2) 0-1 -(CO)-(CH2) 1-3 -(OCH2CH2) 1-7 -, optionally substituted -(CO)-(CH2) 0-3 -(Alkenylene)-(CH2) 0-3 -, optionally substituted -(CO)-(CH2) 0-3 -(Alkynylidene)-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -(Alkenylene)-(CH2) 0-3 -, optionally substituted (CH2) 0-3 -(Alkynylidene)-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -(CO)-(CH2) 0-3 -W-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -O-(CH2) 0-3 -W-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -NH-(CH2) 0-3 -W-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -O-(CH2) 0-3 -W-(CH2) 0-3 -O-(CH2)0-3 -, optionally substituted -(CH2) 0-3 -NH-(CH2) 0-3 -W-(CH2) 0-3 -NH-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -O-(CH2) 0-3 -W-(CH2) 0-3 -NH-(CH2) 0-3 -; and W is selected from an optionally substituted 3-10 membered carbocyclylene, an optionally substituted 3-10 membered heterocyclylene, an optionally substituted C4-C 13 fused carbocyclyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted C5-C 13 bridged carbocyclyl, optionally substituted 5-13 membered heterocyclyl, optionally substituted C5-C 13 spirocarbocyclylene, optionally substituted 5-13 membered spiroheterocyclylene, optionally substituted arylene and optionally substituted heteroarylene.

[0674] In certain embodiments of the bivalent compounds disclosed herein, the linker is selected from optionally substituted -(CO)-(CH2) 0-3 -(3-8 membered carbocyclyl)-(CH2) 0-3 -, optionally substituted -(CO)-(CH2) 0-3 -(3-8 membered heterocyclyl)-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -(3-8 membered carbocyclyl)-(CH2) 0-3 - and optionally substituted -(CH2) 0-3 -(3-8 membered heterocyclyl)-(CH2) 0-3 -.

[0675] In certain embodiments of the bivalent compounds disclosed herein, W is selected

[0676] In some embodiments, the bivalent compound is selected from CPD-001 to CPD-516, or a pharmaceutically acceptable salt or analog thereof.

[0677] In some embodiments, the divalent compound is selected from CPD-009, CPD-010, CPD-013, CPD-014, CPD-015, CPD-021, CPD-022, CPD-023, CPD-024, CPD-025, CPD-026, CPD-027, CPD-028, CPD-029, CPD-030, CPD-031, CPD-032, CPD-033, CPD-044, CPD-047, CPD-049, CPD-050, CPD-051, CPD-052, CPD-053, CPD-054, CPD-055, CPD-056, CPD-057, CPD-059, CPD-060, CPD-062, CPD-064, CPD-065, TR-104, TR-105, TR-106, TR-107, TR-108, TR-109, TR-113, TR-115, TR-116, TR-117, TR-118, TR-119, TR-120, TR-121, TR-122, TR-123, TR-124, TR-125, TR-127, TR-128, TR-129, TR-130, TR-131, TR-132, TR-134, TR-135, TR-137, TR-140, TR-141, TR-142, TR-143, TR-144, TR-145, TR-146, TR-147, TR-149, TR-151, TR-152, TR-153, TR-155, TR-156, TR-157, TR-158, TR-160, TR-161, TR-162, TR-163, TR-164, TR-165, TR-166, TR-167, TR-168, TR-169, TR-171, TR-172, TR-173, TR-176, TR-177, TR-181, TR-182, TR-184, TR-185, TR-186, TR-189, TR-190, TR-191, TR-194, TR-196, TR-198, TR-202, TR-203, TR-204, TR-208, TR-211, TR-216, TR-217, TR-220, TR-221, TR-223, TR-224, TR-225, TR-226, TR-TR-231, TR-232, TR-233, TR-235, TR-241, TR-247, TR-249, TR-250, TR-253, TR-254, TR-255, TR-258, TR-259, TR-260, TR-263, TR-264, TR-265, TR-266, TR-267TR-268, TR-270, TR-275, TR-276, TR-279, TR-280, TR-281, TR-282, TR-284, TR-285, TR-286, TR-287, TR-288, TR-289, TR-290, TR-292, TR-293, TR-2 94. TR-301, TR-302, TR-303, TR-304, TR-305, TR-306, TR-308, TR-309, TR-315, TR-316, TR-317, TR-318, TR-319, TR-320, TR-321, TR-324, TR-325, T R-326, TR-327, TR-331, TR-332, TR-333, TR-335, TR-336, TR-337, TR-338, TR-339, TR-340, TR-341, TR-342, TR-343, TR-344, CPD-470, CPD-471, CPD-472, CPD-473, CPD-474, CPD-475, CPD-476, CPD-478, CPD-480, CPD-481, CPD-482, CPD-483, CPD-484, CPD-499, CPD-500, CPD-501, and pharmaceutically acceptable salts or analogs thereof.

[0678] In some embodiments, the divalent compound is selected from TR-106, TR-108, TR-109, TR-113, TR-115, TR-116, TR-117, TR-119, TR-121, TR-122, TR-123, TR-124, TR-125, TR-127, TR-128, TR-129, TR-130, TR-131, TR-132, TR-135, TR-137, TR-140, TR-141, TR-142, TR-143, TR-144, TR-145, TR-146, TR-149, TR-151, TR-152, TR-155, TR-156, TR-160, TR-161, TR-162, TR-165, TR-166, TR-167, TR-168, TR-169, TR-171, TR-172, TR-173, TR-176, TR-177, TR-181, TR-182, TR-184, TR-185, TR-186, TR-189, TR-190, TR-191, TR-194, TR-196, TR-198, TR-204, TR-208, TR-211, TR-216, TR-217, TR-220, TR-221, TR-224, TR-225, TR-226, TR-TR-231, TR-232, TR-233, TR-241, TR-247, TR-249, TR-250, TR-253, TR-254, TR-255, TR-258, TR-259, TR-260, TR-263, TR-264, TR-265, TR-266, TR-267, TR-270, TR-275, TR-276, TR-279, TR-280, TR-281, TR-282, TR-284, TR-285, TR-286, TR-287, TR-288, TR-289, TR-290, TR-292, TR-293, TR-301, TR-302, TR-304, TR-305, TR-306, TR-308, TR-309, TR-315, TR-316, TR-317, TR-318, TR-319, TR-320, TR-321, TR-324, TR-325, TR-331, TR-332, TR-335, TR-336, TR-337, TR-338, TR-339, TR-340, TR-341, TR-342, TR-343, TR-34, CPD-470, CPD-471, CPD-472, CPD-473, CPD-474, CPD-475, CPD-476, CPD-478, CPD-480CPD-481, CPD-482, CPD-483, CPD-484, CPD-499, CPD-500, CPD-501, and pharmaceutically acceptable salts or analogs thereof.

[0679] In some embodiments, the divalent compound is selected from TR-123, TR-172, TR-173, TR-181, TR-182, TR-184, TR-185, TR-186, TR-191, TR-196, TR-198, TR-204, TR-221, TR-224, TR-225, TR-226, TR-231, TR-233, TR-241, TR-249, TR-254, TR-258, TR-259, TR-260, TR-263, TR-264, TR-265, TR-266, TR-267, TR-270, TR-275, TR-276, TR-27 9. TR-280, TR-281, TR-282, TR-284, TR-285, TR-286, TR-287, TR-288, TR-290, TR-292, TR-293, TR- 301, TR-302, TR-304, TR-306, TR-308, TR-309, TR-315, TR-316, TR-317, TR-318, TR-319, TR-320, T R-321, TR-324, TR-325, TR-331, TR-332, TR-335, TR-336, TR-337, TR-338, TR-339, TR-340, TR-341 , TR-342, TR-343, TR-344, CPD-470, CPD-471, CPD-472, CPD-473, CPD-474, CPD-475, CPD-476, CPD-478, CPD-480, CPD-481, CPD-482, CPD-483, CPD-484, CPD-499, CPD-500, CPD-501, and pharmaceutically acceptable salts or analogs thereof.

[0680] In some embodiments, the bivalent compound is not any of CPD-001 to CPD-246.

[0681] In some embodiments, the bivalent compound is selected from CPD-247 to CPD-516, or a pharmaceutically acceptable salt or analog thereof.

[0682] In some embodiments, the divalent compound is selected from TR-247, TR-249, TR-250, TR-253, TR-254, TR-255, TR-258, TR-259, TR-260, TR-263, TR-264, TR-265, TR-266, TR-267, TR-268, TR-270, TR-275, TR-276, TR-279, TR-280, TR-281, TR-282, TR-283, TR-284, TR-285, TR-286, TR-287, TR-288, TR-289, TR-290, TR-291, TR-292, TR-293, TR-294, TR-295, TR-296, TR-297, TR-298, TR-299, TR-300, TR-301, TR-302, TR-303, TR-304, TR-305, TR-306, TR-307, TR-308, TR-309, TR-310, TR-311, TR-312, TR-313, TR-314, TR-315 -280, TR-281, TR-282, TR-284, TR-285, TR-286, TR-287, TR-288, TR-289, TR-290, TR-292, T R-293, TR-294, TR-301, TR-302, TR-303, TR-304, TR-305, TR-306, TR-308, TR-309, TR-315, TR-316, TR-317, TR-318, TR-319, TR-320, TR-321, TR-324, TR-325, TR-326, TR-327, TR-33 1. TR-332, TR-333, TR-335, TR-336, TR-337, TR-338, TR-339, TR-340, TR-341, TR-342, TR-3 43, TR-344, CPD-470, CPD-471, CPD-472, CPD-473, CPD-474, CPD-475, CPD-476, CPD-478, CPD-480, CPD-481, CPD-482, CPD-483, CPD-484, CPD-499, CPD-500, CPD-501, and pharmaceutically acceptable salts or analogs thereof.

[0683] In some embodiments, the bivalent compound includes an enantiomer of a compound described herein. In some embodiments, the bivalent compound includes an (S) enantiomer. In some embodiments, the bivalent compound includes an (R) enantiomer. Some embodiments include a composition comprising a bivalent compound. In some embodiments, the composition includes or consists of the (S) enantiomer of the compound. In some embodiments, the composition includes or consists of the (R) enantiomer of the compound. In some embodiments, the composition includes or consists of a mixture of the (S) enantiomer and the (R) enantiomer. In some embodiments, the composition includes or consists of a racemic mixture of the (S) enantiomer and the (R) enantiomer. In some embodiments, the composition is a pharmaceutical composition.

[0684] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione (TR-123).

[0685] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)isoindoline-1,3-dione (TR-172).

[0686] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)isoindoline-1,3-dione (TR-173).

[0687] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)isoindoline-1,3-dione (TR-181).

[0688] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)piperidin-1-yl)isoindoline-1,3-dione (TR-182).

[0689] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione (TR-184);

[0690] In some embodiments, the divalent compound is 3-(6-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-185).

[0691] In some embodiments, the divalent compound is 3-(5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-186).

[0692] In some embodiments, the divalent compound is 3-(5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-191).

[0693] In some embodiments, the divalent compound is 3-(6-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-196).

[0694] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione (TR-198).

[0695] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)isoindoline-1,3-dione (TR-204).

[0696] In some embodiments, the divalent compound is 3-[5-[3-[4-[6-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]piperazin-1-yl]propylamino]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (TR-221).

[0697] In some embodiments, the divalent compound is 3-((S)-5-(4-(3-(4-(6-(6-((S)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione (TR-224).

[0698] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)isoindoline-1,3-dione (TR-225).

[0699] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (TR-226).

[0700] In some embodiments, the divalent compound is N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (TR-231).

[0701] In some embodiments, the divalent compound is N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-233).

[0702] In some embodiments, the divalent compound is 3-(4-(4-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)butyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (TR-241).

[0703] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-249).

[0704] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-254).

[0705] In some embodiments, the divalent compound is 3-(4-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (TR-258).

[0706] In some embodiments, the divalent compound is 3-(5-(4-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)butyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (TR-259).

[0707] In some embodiments, the divalent compound is 3-(5-(4-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)but-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (TR-260).

[0708] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)piperazin-1-yl)benzamide (TR-263).

[0709] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)benzamide (TR-264).

[0710] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzamide (TR-265).

[0711] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)-2-((2-fluoroethyl)amino)benzamide (TR-266).

[0712] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((2-fluoroethyl)amino)benzamide (TR-267).

[0713] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-270).

[0714] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-275).

[0715] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-276).

[0716] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-279).

[0717] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-280).

[0718] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-281).

[0719] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)morpholin-2-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-282).

[0720] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-284).

[0721] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)pyrrolidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-285).

[0722] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(2-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)morpholinyl)isoindoline-1,3-dione (TR-286).

[0723] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(3-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione (TR-287).

[0724] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(3-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)amino)azetidin-1-yl)isoindoline-1,3-dione (TR-288).

[0725] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-6-azaspiro[3.4]octan-2-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-290).

[0726] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(1-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)azetidin-3-yl)isoindoline-1,3-dione (TR-292).

[0727] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(1-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)azetidin-3-yl)isoindoline-1,3-dione (TR-293).

[0728] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-301).

[0729] In some embodiments, the divalent compound is 3-(5-(1-(1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-302).

[0730] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)butyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-304).

[0731] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)but-3-yn-1-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-306).

[0732] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(1-(1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)azetidin-3-yl)isoindoline-1,3-dione (TR-308).

[0733] In some embodiments, the divalent compound is 3-(6-(1-(1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-309).

[0734] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)amino)propyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-315).

[0735] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)propyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-316).

[0736] In some embodiments, the divalent compound is 3-(6-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-317).

[0737] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-318).

[0738] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-319).

[0739] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-320).

[0740] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-321).

[0741] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-324).

[0742] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)amino)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-325).

[0743] In some embodiments, the divalent compound is 3-(5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-331).

[0744] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-332).

[0745] In some embodiments, the divalent compound is 3-(6-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-335).

[0746] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-336).

[0747] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)amino)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-337).

[0748] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-1-yl)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-338).

[0749] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-1-yl)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-339).

[0750] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-340).

[0751] In some embodiments, the divalent compound is (S)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-341).

[0752] In some embodiments, the divalent compound is (R)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-342).

[0753] In some embodiments, the divalent compound is (S)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-343).

[0754] In some embodiments, the divalent compound is (R)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-344).

[0755] In some embodiments, the divalent compound is N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-6-((1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butanoyl)piperidin-4-yl)amino)picolinamide (CPD-470).

[0756] In some embodiments, the divalent compound is N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-6-((1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoyl)piperidin-4-yl)amino)picolinamide (CPD-471).

[0757] In some embodiments, the divalent compound is N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-6-((1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoyl)piperidin-4-yl)amino)picolinamide (CPD-472).

[0758] In some embodiments, the divalent compound is N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-6-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoyl)piperidin-4-yl)amino)picolinamide (CPD-473).

[0759] In some embodiments, the divalent compound is N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-6-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)picolinamide (CPD-474).

[0760] In some embodiments, the divalent compound is N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-6-((1-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)picolinamide (CPD-475).

[0761] In some embodiments, the divalent compound is N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-6-((1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12-tetraoxopentadec-15-yl)piperidin-4-yl)amino)picolinamide (CPD-476).

[0762] In some embodiments, the divalent compound is N-(2-(4-carbamoylpiperidin-1-yl)-4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)methyl)phenyl)-2-morpholinooxazole-4-carboxamide (CPD-478).

[0763] In some embodiments, the divalent compound is N-(2-(4-carbamoylpiperidin-1-yl)-4-((4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)methyl)phenyl)-2-morpholinooxazole-4-carboxamide (CPD-480).

[0764] In some embodiments, the divalent compound is N-(2-(4-carbamoylpiperidin-1-yl)-4-((4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)methyl)phenyl)-2-morpholinooxazole-4-carboxamide (CPD-481).

[0765] In some embodiments, the divalent compound is N-(2-(4-carbamoylpiperidin-1-yl)-4-((4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)methyl)phenyl)-2-morpholinooxazole-4-carboxamide (CPD-482).

[0766] In some embodiments, the divalent compound is N-(2-(4-carbamoylpiperidin-1-yl)-4-((4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)methyl)phenyl)-2-morpholinooxazole-4-carboxamide (CPD-483).

[0767] In some embodiments, the divalent compound is N-(2-(4-carbamoylpiperidin-1-yl)-4-((4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoyl)piperazin-1-yl)methyl)phenyl)-2-morpholinooxazole-4-carboxamide (CPD-484).

[0768] In some embodiments, the divalent compound is 2-(4-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)acetamide (CPD-499).

[0769] In some embodiments, the divalent compound is 2-(4-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide (CPD-500).

[0770] In some embodiments, the divalent compound is 2-(4-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)acetamide (CPD-501).

[0771] According to one aspect of the present disclosure, the composition disclosed herein comprises a bivalent compound or a pharmaceutically acceptable salt or analog thereof, and a pharmaceutically acceptable carrier or diluent.

[0772] According to one aspect of the present disclosure, the methods disclosed herein for treating a tropomyosin receptor kinase (TRK)-mediated disease comprise administering a bivalent compound or a pharmaceutically acceptable salt or analog thereof to a subject suffering from a TRK-mediated disease.

[0773] In one embodiment, the TRK-mediated disease is caused by TRK expression, mutation, or fusion.

[0774] In one embodiment, the subject having the TRK-mediated disease has elevated TRK function relative to a healthy subject without the TRK-mediated disease.

[0775] In one embodiment, the bivalent compound is selected from CPD-001 to CPD-516 or analogs thereof.

[0776] In one embodiment, the divalent compound is selected from CPD-247 to CPD-516 or analogs thereof.

[0777] In one embodiment, the bivalent compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally. In one embodiment, the method further comprises administering to the subject an additional therapeutic regimen for treating the cancer.

[0778] In one embodiment, the additional treatment option is selected from surgery, chemotherapy, radiation therapy, hormone therapy, and immunotherapy.

[0779] In one embodiment, the TRK-mediated disease is selected from non-small cell lung cancer, colorectal cancer, gastric cancer, liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, bladder cancer, endometrial cancer, prostate cancer, low-grade glioma, glioblastoma, Spitzoid carcinoma, soft tissue sarcoma, papillary thyroid cancer, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast cancer, mammary secretory carcinoma, acute myeloid leukemia, ductal carcinoma, pulmonary neuroendocrine tumor, pheochromocytoma and Wilms' tumor.

[0780] In one embodiment, TRK-mediated diseases or conditions include cancer, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, and other diseases, including but not limited to neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, stomach cancer, lung cancer, liver cancer, uterine cancer, adrenal cancer, biliary system cancer, intestinal cancer, colorectal cancer, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, breast cancer, esophageal cancer, bladder cancer, endometrial cancer, brain cancer, low grade glioma, glioblastoma, medulloblastoma, secretory breast cancer, secretory breast cancer, salivary gland cancer, papillary thyroid cancer, ductal carcinoma, adult myeloid leukemia, acute myeloid leukemia, large cell neuroendocrine tumor, pulmonary neuroendocrine tumor, sarcoma, pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenital mesodermal nephroma, secretory breast cancer, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system neoplasms, osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft tissue sarcoma, Spitzoid carcinoma, Wilms' tumor, lymphoma (e.g., including Hodgkin lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt lymphoma, and T-cell anaplastic large cell lymphoma), inflammatory lung disease ( For example, asthma), inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease), inflammatory skin diseases (e.g., atopic dermatitis, eczema, and psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, osteoarthritis pain, chronic low back pain, osteoporosis low back pain, fracture pain, rheumatoid arthritis pain, post-herpetic pain, diabetic neuropathy pain, fibromyalgia, pancreatitis pain, interstitial cystitis pain, endometriosis pain, irritable bowel syndrome pain, migraine, pulpitis pain, interstitial cystitis pain, bladder pain syndrome, central pain syndrome, postoperative pain syndrome, bone and joint pain syndrome, In some embodiments, the disease or condition is a recurrent disease or condition.

[0781] In one embodiment, the TRK-mediated disease is recurrent cancer.

[0782] In one embodiment, the TRK-mediated disease is refractory to one or more prior therapies.

[0783] According to one aspect of the present disclosure, a method for identifying a bivalent compound that mediates TRK degradation or reduction is disclosed. The method comprises:

[0784] providing a heterobifunctional test compound comprising a TRK ligand conjugated to a degradation tag via a linker;

[0785] contacting a heterobifunctional test compound with cells containing a ubiquitin ligase and a TRK;

[0786] determining whether TRK levels are reduced in the cells; and

[0787] Heterobifunctional test compounds are identified as bivalent compounds that mediate degradation or reduction of TRK.

[0788] In one embodiment, the cell is a cancer cell.

[0789] In one embodiment, the cancer cell is a TRK-mediated cancer cell.

[0790] In one embodiment, the cell is a neuron.

[0791] Incorporation by reference

[0792] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0793] The novel features of the present invention are particularly set forth in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by referring to the following detailed description which illustrates illustrative embodiments utilizing the principles of the present invention and the accompanying drawings, in which:

[0794] Figure 1 Center A shows immunoblots of TPM3-TRKA fusion proteins expressed in KM12 cells after treatment with entrectinib or the bivalent compounds CPD-001–CPD-022.

[0795] Figure 1 Middle B shows immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with entrectinib or the bivalent compounds CPD-023–CPD-044.

[0796] Figure 1 Middle C shows immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with entrectinib or the bivalent compounds CPD-045–CPD-065.

[0797] Figure 2 Shown are immunoblots of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with entrectinib or the bivalent compounds CPD-027, CPD-053, and CPD-060 at different time points.

[0798] Figure 3 Shown are immunoblots of TPM3-TRKA fusion protein expressed by KM12 cells in subcutaneous xenograft tumors following treatment with a dose range of CPD-027, CPD-053, and CPD-060.

[0799] Figure 4 Center A shows the relationship between KM12 cell viability and the concentrations of the bivalent compounds CPD-010, CPD-053, and CPD-057.

[0800] Figure 4 Panel B shows the viability of KM12 and H358 cells versus the concentration of the bivalent compound CPD-053.

[0801] Figure 5 Center A shows immunoblots of TPM3-TRKA fusion proteins expressed in KM12 cells after treatment with GNF-8625, LOXO101, or the bivalent compounds TR-104–TR-129.

[0802] Figure 5 Middle B shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of TR-115, TR-116, TR-119, TR-123, TR-124, TR-127, or TR-129.

[0803] Figure 5 Center C shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of TR-130, TR-131, TR-132, TR-140, TR-146, TR-150, or TR-168.

[0804] Figure 6 Center A shows immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-171, TR-172, TR-173, or TR-176.

[0805] Figure 6Middle B shows immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-177, TR-181, TR-182, or GNF-8625.

[0806] Figure 6 Center C shows immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-186, TR-188, TR-189, or TR-190.

[0807] Figure 6 Middle D shows immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-191, TR-194, TR-196, TR198, or GNF-8625.

[0808] Figure 7 Shown are immunoblots of overexpressed TPM3-TRKA, AGBL4-TRKB, and ETV6-TRKC fusion proteins in KM12 cells after treatment with a dose range of TR-123.

[0809] Figure 8 Center A shows immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of compound TR-123 or TR-123-negative (TR-123-negative).

[0810] Figure 8 Panel B shows immunoblot of wild-type TRKA protein expressed in HEL cells after treatment with a dose range of compound TR-123 or TR-123-negative.

[0811] Figure 9 Center A shows immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a single dose of TR-123 or in combination with MG-132, bortezomib, or MLN4924.

[0812] Figure 9 Center B shows immunoblot of wild-type TRKA protein expressed by HEL cells after treatment with a single dose of TR-123 or in combination with MG-132, bortezomib, MLN4924, or pomalidomide.

[0813] Figure 10 Center A shows immunoblotting of TPM3-TRKA fusion protein in subcutaneous KM12 xenograft tumors after treatment with a dose range of TR-123.

[0814] Figure 10Middle B shows immunoblot of TPM3-TRKA fusion protein expressed in subcutaneous KM12 xenograft tumors after treatment with TR-171, TR-172, TR-173, TR-177, or TR-181.

[0815] Figure 11 A graph showing the relationship between the plasma concentration of TR-123 and the time point after administration is shown.

[0816] Figure 12 Middle A shows a graph of subcutaneous KM12 xenograft tumor volume versus days after treatment with a dose range of CPD-060.

[0817] Figure 12 Panel B shows a graph of body weight versus days after treatment with a dose range of CPD-060.

[0818] Figure 13 Center A shows immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-202, TR-203, or TR-204.

[0819] Figure 13 Middle B shows immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-208, TR-210, TR-211, or TR-214.

[0820] Figure 13 Center C shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of TR-215, TR216, TR-217, TR218, TR-219, or TR-220.

[0821] Figure 13 Middle D shows an immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-221, TR-222, TR-223, TR-224, TR-225, TR-226, or TR-227.

[0822] Figure 13 Middle E shows immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-231, TR-232, TR-233, TR-234, or TR-235.

[0823] Figure 14 Shown is a graph showing the plasma concentration of TR-198 over time following administration by intravenous injection or oral gavage.

[0824] Figure 15 Middle A shows a graphic representation of subcutaneous KM12 xenograft tumor volume as a function of days following treatment with a dose range of TR-181 or a single dose of TR-198.

[0825] Figure 15 Panel B shows a graphic representation of body weight changes over days following treatment with a dose range of TR-181 or a single dose of TR-198.

[0826] Figure 16 Panel A shows a graphic representation of the percentage of body weight borne by the injured limb following treatment with a single dose of vehicle (Veh), TR-181, or ibuprofen (Ibu) in rats.

[0827] Figure 16 Panel B shows a graphic representation of the percentage of body weight borne on the injured limb following treatment with a single dose of TR-181 or ibuprofen (Ibu) in guinea pigs.

[0828] Figure 17 Center A shows immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of TR-247, TR-248, TR-249, TR-250, TR-251, TR-252, or TR-253.

[0829] Figure 17 Middle B shows an immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-254, TR-255, TR-256, TR-257, TR-258, TR-259, or TR-260.

[0830] Figure 17 Center C shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of TR-261, TR-262, TR-263, TR-264, TR-265, TR-256, or TR-267.

[0831] Figure 18 Center A shows immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-268, TR-269, TR-270, TR-271, or TR-272.

[0832] Figure 18 Middle B shows immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-273, TR-274, TR-275, TR-276, or TR-277.

[0833] Figure 18 Center C shows immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-279, TR-280, TR-281, TR-282, or TR-283.

[0834] Figure 19 Center A shows immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-284, TR-285, TR-286, TR-287, or TR-288.

[0835] Figure 19 Middle B shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of TR-289, TR-290, TR-291, TR-292, TR-293, or TR-294.

[0836] Figure 19 Center C shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of TR-295, TR-296, TR-297, TR-298, TR-300, or TR-301.

[0837] Figure 20 Center A shows immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of TR-302, TR-303, TR-304, TR-305, TR-306, or TR-307.

[0838] Figure 20 Middle B shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of TR-308, TR-309, TR-310, TR-311, TR-312, or TR-313.

[0839] Figure 20 Center C shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of TR-314, TR-315, TR-316, TR-317, TR-318, TR-319, or TR-320.

[0840] Figure 21 Center A shows immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of TR-321, TR-322, TR-323, TR-324, TR-325, TR-326, or TR-327.

[0841] Figure 21 Middle B shows an immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-328, TR-329, TR-330, TR-331, TR-332, TR-333, or TR-334.

[0842] Figure 21 Middle C shows an immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a dose range of TR-335, TR-336, TR-337, TR-338, TR-339, or TR-340.

[0843] Figure 22 Shown is an immunoblot of NPM-ALK fusion protein expressed in SU-DHL-1 cells following treatment with a dose range of entrectinib, CPD-032, CPD-037, or CPD-055.

[0844] Figure 23 Panel A shows a graphical representation of the plasma concentrations of TR-231 and TR-275 over time following administration by intravenous injection or oral gavage.

[0845] Figure 23 Panel B shows immunoblots of TPM3-TRKA fusion proteins expressed in subcutaneous KM12 xenograft tumors after treatment with TR-231 and TR-275 at different oral doses and time points.

[0846] Figure 24 Panel A shows KM12 xenograft tumor growth curves in mice treated twice daily with vehicle or 40 mg / kg TR-231.

[0847] Figure 24 Panel B shows KM12 xenograft tumor growth curves in mice treated twice daily with vehicle or 40 mg / kg TR-275.

[0848] Figures 25A-25C Shown is an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with heterobifunctional compounds.

[0849] Figure 26 Shown is an immunoblot of wild-type TRKA protein expressed by HEL cells after treatment with heterobifunctional compounds.

[0850] Figures 27A-27CShown is a graph of KM12 cell viability versus the concentration of the heterobifunctional compounds CPD-470, CPD-471, CPD-474, CPD-480, CPD-481, CPD-482, CPD-499, CPD–500, and CPD-501.

[0851] Figures 28A-28B Shown are immunoblots of TPM3-TRKA fusion proteins expressed in cell lines after treatment with heterobifunctional compounds. DETAILED DESCRIPTION

[0852] It is recognized in the present disclosure that the tropomyosin receptor kinase (TRK) receptor family includes three members: TRKA, TRKB and TRKC, which are encoded by the NTRK1, NTRK2 and NTRK3 genes, respectively. TRK is a receptor tyrosine kinase that is primarily associated with the development and function of neuronal tissue. The main ligands of TRK include nerve growth factor (NGF) for TRKA, brain-derived growth factor (BDGF) for TRKB and neurotrophins for TRKC (Vaishnavi et al., 2015). Binding of ligands to the extracellular domain of TRK induces dimerization and activation of the receptor, thereby activating downstream signal transduction pathways such as PI3K / AKT, RAF / MEK / ERK and PLCγ pathways. These pathways have well-defined roles in supporting cell proliferation, survival and promoting tumorigenesis (Hanahan and Weinberg, 2011).

[0853] It is further recognized herein that, like many other oncogenic receptor tyrosine kinases, TRK is abnormally activated in a variety of human malignancies. Interestingly, the main molecular mechanism of TRK activation in cancer is not point mutation, but in-frame fusion of the NTRK gene (Vaishnavi et al., 2015). Typically, due to chromosomal rearrangements, the 3' region of the NTRK gene is joined to the 5' region of the partner gene. The resulting chimeric protein always retains the kinase domain of the TRK protein, indicating that catalytic function is essential for transforming activity. The deletion of the 5' region encoding the autoinhibitory domain in the NTRK gene makes these fusion kinases constitutively active. In addition, the expression of the chimeric protein is driven by the promoter of the fusion partner, which often leads to overexpression. The most common TRK fusions include LMNA-TRKA, TPM3-TRKA, and ETV6-TRKC (Amatu et al., 2016). Therefore, genetic events lead to overexpression and constitutive activity of TRK fusion kinases. These fusions are oncogenic, as shown by their ability to transform mouse embryonic fibroblasts and normal epithelium (Russell et al., 2000; Vaishnavi et al., 2015).

[0854] TRK fusion was first reported in human colon cancer, where it was named oncD (Martin-Zanca et al., 1986). Recent advances in high-throughput RNA sequencing have greatly improved the efficiency of identifying chromosomal rearrangement events in patient samples. As a result, TRK fusion has been found in a wide variety of human malignancies, including but not limited to non-small cell lung cancer, colorectal cancer, gastric cancer, low-grade glioma, glioblastoma, spitzoid carcinoma, soft tissue sarcoma, papillary thyroid cancer, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesodermal nephroma, secretory breast cancer, mammary secretory carcinoma, acute myeloid leukemia and ductal carcinoma (Amatu et al., 2016; Khotskaya et al., 2017). The frequency of TRK fusion is relatively low. For example, approximately 0.5% to 2.7% of colon cancers are affected by TRK fusion (Creancier et al., 2015; Lee et al., 2015). However, for certain cancer types, such as secretory breast cancer, TRK fusions are found in the vast majority of cases (Tognon et al., 2002).

[0855] TRK mutations and deletions have been observed in other human diseases such as pulmonary neuroendocrine tumors, anhidrosis, obesity, congenital heart defects, and acute myeloid leukemia (Khotskaya et al., 2017). In addition, TRK amplification has been associated with several human diseases such as liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, bladder cancer, endometrial cancer, pheochromocytoma, Wilms' tumor, and prostate cancer (Khotskaya et al., 2017).

[0856] The role of nerve growth factor (NGF) and its main receptor tropomyosin receptor kinase A (TRKA) in central and peripheral pain has long been recognized (Denk et al., 2017). Nociceptive neurons express TRKA and mediate pain sensation by transmitting pain signals to the central nervous system. Various NGF neutralizing antibodies, such as tanezumab, are being clinically evaluated in patients with osteoarthritis, low back pain, cancer pain, neuropathic pain and other painful conditions (Miller et al., 2017). The efficacy of NGF antibodies in relieving pain has been clearly demonstrated clinically. However, the administration of NGF neutralizing antibodies has been shown to lead to rapidly progressive joint destruction in some patients, leading to total joint replacement (Schnitzer and Marks, 2015). These adverse events may be related to continued exposure to NGF antibodies. Targeting TRK represents another promising therapeutic strategy for blocking the NGF / TRK signaling pathway for pain management. However, currently available pan-TRK kinase inhibitors may induce significant on-target adverse effects by regulating TRK family members in the central nervous system. Peripherally restricted TRK bifunctional degraders are expected to selectively block the NGF / TRK pathway in peripheral nerves while sparing these targets in the central nervous system.

[0857] TRKs are associated with the following diseases: cancer, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases and other diseases, including but not limited to neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, stomach cancer, lung cancer, liver cancer, uterine cancer, adrenal cancer, biliary system cancer, intestinal cancer, colorectal cancer, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, breast cancer, esophageal cancer, bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secretory breast cancer, salivary gland cancer, papillary thyroid cancer, ductal carcinoma, acute myeloid leukemia, large cell neuroendocrine tumors, lung cancer. Neuroendocrine tumors, sarcomas, pheochromocytomas, fibrosarcomas, congenital fibrosarcomas, congenital mesodermal nephroma, secretory breast cancer, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system neoplasms, osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft tissue sarcoma, Spitzoid carcinoma, Wilms' tumor, lymphomas (e.g., including Hodgkin lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt lymphoma, and T-cell anaplastic large cell lymphoma), inflammatory lung diseases (e.g., asthma), inflammatory bowel diseases (e.g., (e.g., ulcerative colitis, Crohn's disease), inflammatory skin diseases (e.g., atopic dermatitis, eczema, and psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, osteoarthritis pain, chronic low back pain, osteoporosis low back pain, fracture pain, rheumatoid arthritis pain, post-herpetic pain, diabetic neuropathy pain, fibromyalgia, pancreatitis pain, interstitial cystitis pain, endometriosis pain, irritable bowel syndrome pain, migraine headaches, pulpitis pain, interstitial cystitis pain, bladder pain syndrome, central pain syndrome, postoperative pain syndrome, bone and joint pain, recurrent Pain associated with sexual exertion, dental pain, myofascial pain, perioperative pain, dysmenorrhea, myofascial pain, angina pectoris, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain due to central sensitization, generalized pruritus, localized pruritus, senile pruritus, pruritus of pregnancy, pruritus anus, pruritus vulvae, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic bone diseases, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelinating diseases, and myelinating disorders.

[0858] TRK kinase inhibitors are currently in clinical or preclinical development, including but not limited to entrectinib (RXDX-101) (Menichincheri et al., 2016), GNF-8625 (Choi et al., 2015), larotrectinib (LOXO-101; ARRY-470) (Drilon et al., 2018), atertinib (DCC2701, DCC-270, DP-5164) (Smith et al., 2015), and entrectinib (RXDX-101) (Menichincheri et al., 2016). ), cetirizine (MGCD516) (Patwardhan et al., 2016), cabozantinib (XL-184, BMS-907351) (Fuse et al., 2017), dovitinib (TKI-258, CHIR-258) (Chong et al., 2017), imipenem (PHA-848125AC) (Brasca et al., 2009), bezatinib (TSR-011) (Ricciuti et al., 201 7), GZ389988 (Bailey et al., 2017a,b), pegrettinib (Cranston et al., 2017), AZD7451 (Tatematsu et al., 2014), TPX-0005 (Cui et al., 2016), LOXO-195 (Blake et al., 2016), regorafenib (Subbiah et al., 2017), DS-6051b (Fujiwara et al., 2018), F17752 (Amatu et al., 2016), PLX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a,b), VM902A (Bailey et al., 2017a,b), ONO-4474 (Bailey et al., 2017a,b), and PF-06273340 (Skerratt et al., 2016). The most advanced are entrectinib and larotrectinib (Khotskaya et al., 2017). These drugs are being tested in basket trials, which recruit patients based on the detection of TRK fusions rather than histology. Phase 2 results of larotrectinib showed that the majority of patients (75%) responded to treatment, with 55% remaining progression-free at 1 year (Drilon et al., 2018). Phase 1 results of entrectinib also documented significant and durable responses in patients with tumors harboring TRK fusions (Drilon et al., 2017b). The remarkable efficacy of TRK inhibitors was independent of tumor type. Together, these substantive results underscore the role of TRK fusions as unique oncogenic drivers in a subset of human malignancies, regardless of tissue origin.

[0859] The nonspecific side effects of TRK kinase inhibitors and the development of resistance to them remain challenges in developing effective treatments. Therefore, novel small molecules targeting TRK function through inhibition and / or degradation would be very useful.

[0860] Without wishing to be bound by any theory, the present disclosure is believed to be based, at least in part, on the discovery that novel heterobivalent small molecules that degrade TRK, TRK fusion proteins, TRK splicing and / or TRK mutant proteins are useful for treating TRK-mediated diseases, particularly non-small cell lung cancer, colorectal cancer, gastric cancer, liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, bladder cancer, endometrial cancer, prostate cancer, low-grade glioma, glioblastoma, spitzoid carcinoma, soft tissue sarcoma, papillary thyroid cancer, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast cancer, mammary secretory carcinoma, acute osteoid leukemia, ductal carcinoma, neuroendocrine tumor of the lung, pheochromocytoma, and Wilms' tumor (Amatu et al., 2016; Khotskaya et al., 2017).The disclosed novel bifunctional TRK degraders can be used to treat TRK-mediated cancers, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases and other diseases, including but not limited to neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric cancer, lung cancer, liver cancer, uterine cancer, adrenal cancer, biliary system cancer, intestinal cancer, colorectal cancer, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, breast cancer, esophageal cancer, bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secretory breast cancer, secretory breast cancer, salivary gland cancer, papillary thyroid cancer, ductal carcinoma, adult myeloid leukemia , acute myeloid leukemia, large cell neuroendocrine tumor, pulmonary neuroendocrine tumor, sarcoma, pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenital mesodermal nephroma, secretory breast cancer, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system neoplasms, osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft tissue sarcoma, Spitzoid carcinoma, Wilms' tumor, lymphoma (including, for example, Hodgkin lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt lymphoma, and T-cell anaplastic large cell lymphoma), inflammatory lung disease (e.g., asthma), inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease), inflammatory skin diseases (e.g., atopic dermatitis, eczema, and psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, osteoarthritis pain, chronic low back pain, osteoporosis low back pain, fracture pain, rheumatoid arthritis pain, post-herpetic pain, diabetic neuropathy pain, fibromyalgia, pancreatitis pain, interstitial cystitis pain, endometriosis pain, irritable bowel syndrome pain, migraine, pulpitis pain, interstitial cystitis pain, bladder pain syndrome, central pain syndrome, postoperative pain syndrome, bone and Joint pain, repetitive motion pain, dental pain, myofascial pain, perioperative pain, dysmenorrhea, myofascial pain, angina pectoris, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain due to central sensitization, generalized pruritus, localized pruritus, senile pruritus, pruritus of pregnancy, pruritus anus, pruritus vulvae, metastatic bone disease, therapy-induced bone loss, osteoporosis, rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic bone diseases, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelinating diseases, and myelinating disorders.

[0861] Small molecule-induced selective degradation of target proteins can be achieved by recruiting E3 ubiquitin ligases and mimicking protein misfolding with hydrophobic tags (Buckley and Crews, 2014). Furthermore, small molecules possess a moiety that binds to the E3 ubiquitin ligase and another moiety that binds to the protein target of interest (Buckley and Crews, 2014). Induced proximity leads to ubiquitination of the target, followed by its proteolytic degradation via proteasome-mediated proteolysis. Several types of high-affinity small molecule E3 ligase ligands have been identified or are in development. They include (1) immunomodulatory drugs (IMiDs), such as thalidomide and pomalidomide, which bind to cereblon (CRBN or CRL4CRBN), a component of the cullin-RING ubiquitin ligase (CRL) complex (Bondeson et al., 2015; Chamberlain et al., 2014; Fischer et al., 2014; Ito et al., 2010; Winter et al., 2015); and (2) VHL-1, a hydroxyproline-containing ligand that binds to the van Hippel-Lindau protein (VHL or CRL2VHL). Hippel-Lindau protein is a component of another CRL complex (Bondeson et al., 2015; Buckley et al., 2012a; Buckley et al., 2012b; Galdeano et al., 2014; Zengerle et al., 2015); (3) compound 7, which selectively binds to KEAP1, a component of the CRL3 complex (Davies et al., 2016); (4) AMG232, which selectively binds to MDM2, a heterodimeric RING E3 ligase (Sun et al., 2014); and (5) LCL161, which selectively binds to IAP, a homodimeric RING E3 ligase (Ohoka et al., 2017; Okuhira et al., 2011; Shibata et al., 2017). E3 ligase recruitment bifunctional degrader technology has been applied to the degradation of a variety of protein targets (Bondeson et al., 2015; Buckley et al., 2015; Lai et al., 2016; Lu et al., 2015; Winter et al., 2015; Zengerle et al., 2015). In addition, a hydrophobic tagging method using bulky and hydrophobic adamantyl groups has been developed to mimic protein misfolding, leading to proteasomal degradation of target proteins (Buckley and Crews, 2014). This method has been applied to selectively degrade the pseudokinase HER3 (Xie et al., 2014). The present inventors are not aware of any efforts to apply any of these methods to the degradation of TRK, TRK mutants, TRK deletions, TRK splicing, or TRK fusion proteins.

[0862] Currently available small molecules targeting TRK focus on inhibiting the kinase activity of TRK. Many selective small molecule TRK kinase inhibitors have been reported, such as entrectinib (RXDX-101) (Menichincheri et al., 2016), GNF-8625 (Choi et al., 2015), larotrectinib (LOXO-101; ARRY-470) (Drilon et al., 2018), atentinib (DCC2701, DCC-270, DP-5164) (Smith et al., 2015), cetrimoxetine (DCC-2701, DCC-270, DP-5164) (Smith et al., 2015), and selenitinib (DCC-2701, DCC-270, DP-5164) (Smith et al., 2015). Azatinib (MGCD516) (Patwardhan et al., 2016), cabozantinib (XL-184, BMS-907351) (Fuse et al., 2017), dovitinib (TKI-258, CHIR-258) (Chong et al., 2017), imipenem (PHA-848125AC) (Brasca et al., 2009), bezatinib (TSR-011) (Ricciuti et al., 2017), GZ389988 (Bailey et al., 2017a,b), pegrettinib (Cranston et al., 2017), AZD7451 (Tatematsu et al., 2014), TPX-0005 (Cui et al., 2016), LOXO-195 (Blake et al., 2016), regorafenib (Subbiah et al., 2017), DS-6051b (Fujiwara et al., 2018), F 17752 (Amatu et al., 2016), PLX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a,b), VM902A (Bailey et al., 2017a,b), ONO-4474 (Bailey et al., 2017a,b), and PF-06273340 (Skerratt et al., 2016).

[0863] In the present disclosure, a novel approach is adopted: developing compounds that not only directly and selectively regulate the kinase activity of TRK, but also directly and selectively regulate its protein level. Strategies for inducing protein degradation include recruiting E3 ubiquitin ligases, simulating protein misfolding with hydrophobic tags, and inhibiting molecular chaperones. Compared with technologies such as gene knockout or short hairpin RNA-mediated (shRNA) knockdown, such methods based on the use of bivalent small molecule compounds allow for more flexible regulation of protein levels in vitro and in vivo. Unlike gene knockout or shRNA knockdown, small molecule methods further provide the opportunity to study dose and time dependence in disease models by regulating the route of administration, concentration, and frequency of administration of the corresponding small molecules.

[0864] Divalent compounds

[0865] For purposes of this disclosure, the terms "bifunctional compound," "bifunctional degrader," "bifunctional TRK degrader," "bivalent compound," and "heterobifunctional compound" are used interchangeably.

[0866] In some aspects, the present disclosure provides a bivalent compound comprising a TRK ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof. The TRK ligand can be conjugated to the degradation tag directly or through a linker portion. In certain embodiments, the TRK ligand can be conjugated directly to the degradation tag. In certain embodiments, the TRK ligand can be conjugated to the degradation tag via a linker portion.

[0867] As used herein, the terms "tropomyosin receptor kinase ligand" and "TRK ligand" or "TRK targeting moiety" are to be construed to include any molecule, from small molecules to large proteins, that associates with or binds to a TRK protein. In certain embodiments, a TRK ligand is capable of binding to a TRK protein comprising a TRK, a TRK mutant, a TRK deletion, a TRK splice, or a TRK fusion protein. A TRK ligand can be, for example, but not limited to, a small molecule compound (i.e., a molecule having a molecular weight of less than about 1.5 kilodaltons (kDa)), a peptide or polypeptide, a nucleic acid or oligonucleotide, a carbohydrate (such as an oligosaccharide), or an antibody or fragment thereof.

[0868] TRK ligands

[0869] A TRK ligand or targeting moiety can be a TRK kinase inhibitor or a portion of a TRK kinase inhibitor. In certain embodiments, TRK kinase inhibitors include (e.g., entrectinib (RXDX-101) (Menichincheri et al., 2016), GNF-8625 (Choi et al., 2015), larotrectinib (LOXO-101; ARRY-470) (Drilon et al., 2018), atentinib (DCC2701, DCC-270, DP-5164) (Smith et al., 2015), cetirizine (MGCD5 16)(Patwardhan et al., 2016), cabozantinib (XL-184, BMS-907351) (Fuse et al., 2017), dovitinib (TKI-258, CHIR-258) (Chong et al., 2017), imipenem (PHA-848125AC) (Brasca et al., 2009), bezatinib (TSR-011) (Ricciuti et al., 2017), GZ389988 (Baile y et al., 2017a,b), pegrettinib (Cranston et al., 2017), AZD7451 (Tatematsu et al., 2014), TPX-0005 (Cui et al., 2016), LOXO-195 (Blake et al., 2016), regorafenib (Subbiah et al., 2017), DS-6051b (Fujiwara et al., 2018), F17752 (Amatu et al., 2016), P One or more of LX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a, b), VM902A (Bailey et al., 2017a, b), ONO-4474 (Bailey et al., 2017a, b), PF-06273340 (Skerratt et al., 2016), and their analogs) that are capable of inhibiting the kinase activity of TRK. As used herein, a "TRK" kinase inhibitor" refers to an agent that inhibits, delays, or otherwise causes an inhibition of a physiological, chemical, or enzymatic action or function, and results in a reduction of at least 5% in binding. An inhibitor may also or alternatively refer to a drug, compound, or agent that prevents or reduces the expression, transcription, or translation of a gene or protein. An inhibitor may reduce or prevent the function of a protein, for example, by binding to or activating / inactivating another protein or receptor.

[0870] In certain embodiments, the TRK ligand is derived from a TRK kinase inhibitor, including:

[0871]

[0872] In certain embodiments, TRK ligands include, but are not limited to, DS-6051b (Fujiwara et al., 2018), F17752 (Amatu et al., 2016), PLX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a,b), VM902A (Bailey et al., 2017a,b), PF-06273340 (Skerratt et al., 2016), and ONO-4474 (Bailey et al., 2017a,b). In certain embodiments, the TRK ligand is derived from any one or more of DS-6051b (Fujiwara et al., 2018), F17752 (Amatu et al., 2016), PLX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a,b), VM902A (Bailey et al., 2017a,b), PF-06273340 (Skerratt et al., 2016), and ONO-4474 (Bailey et al., 2017a,b).

[0873] In one aspect, provided herein are compounds of Formula I:

[0874]

[0875] or a pharmaceutically acceptable salt thereof, wherein

[0876] X 1 and X 2 are independently selected from CH and N;

[0877] X 3 and X 4 Independently selected from C(O) and CR 4 R 5 ;

[0878] R 1 Selected from H, -NR 2 R 3 , halogen, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 haloalkyl and optionally substituted C 1-6 alkoxy;

[0879] R 2 、R3 、R 4 and R 5 are independently selected from H, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 haloalkyl and optionally substituted C 1-6 alkoxy; and

[0880] L is selected from a bond,

[0881]

[0882] or

[0883] X 3 and X 4 One of them is C(O) and the other is CR 4 R 5 ;and

[0884] L is

[0885] In some embodiments, X 1 and X 2 Each is N.

[0886] In some embodiments, X 3 is C(O) and X 4 CR 4 R 5 In some embodiments, X 3 is C(O) and X 4 CR 4 R 5 In some embodiments, X 3 and X 4 In some embodiments, X 3 and X 4 All CR 4 R 5 .

[0887] In some embodiments, R 1 -NR 2 R 3 In some embodiments, R 1 yes

[0888] In one aspect, provided herein are compounds of Formula Ia:

[0889]

[0890] or a pharmaceutically acceptable salt thereof, wherein

[0891] X 1 and X 2 are independently selected from CH and N;

[0892] X 3 and X 4 Independently selected from C(O), CR 4 R 5 and NR 6 ;

[0893] R 1 Selected from H, -NR 2 R 3 , halogen, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted aryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 haloalkyl and optionally substituted C 1-6 alkoxy;

[0894] R 2 、R 3 、R 4 、R 5 and R 6 are independently selected from H, halogen, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 Haloalkyl, optionally substituted C 1-6 alkoxy and optionally substituted 2,6-dioxopiperidin-3-yl;

[0895] L is selected from a bond, R'-R", R'COR", R'CO2R", R'C(O)N(R 7 )R”、R'C(S)N(R 7 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 7 )R”、R'N(R 7 )R”、R”N(R 7)COR”、R'N(R 7 )CON(R 8 )R”、R'N(R 7 )C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0896] wherein L is optionally 3 or X 4 Attachment;

[0897] R' and R" are independently selected from null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C4-C8 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0898] R 7 and R 8independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0899] R' and R", R 7 and R 8 , R' and R 7 , R' and R 8 , R” and R 7 , R” and R 8 together with the atoms to which they are attached, optionally form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring;

[0900] In some embodiments, L is selected from

[0901] In some embodiments, X 1 and X 2 Each is N.

[0902] In some embodiments, X 3 and X 4 At least one of them is NR 6 In some embodiments, X 3 and X 4 All are NR 6 .

[0903] In some embodiments, X 3 or X 4 Any one of is -N-(2,6-dioxopiperidin-3-yl).

[0904] In some embodiments, R 1 -NR 2 R 3 In some embodiments, R 1 yes

[0905] In some embodiments, L is linked to X 3 In some embodiments, L is linked to X 4 .

[0906] In one aspect, provided herein is a compound of Formula II:

[0907]

[0908] or a pharmaceutically acceptable salt thereof, wherein

[0909] X 1 and X 2 are independently selected from CH and N;

[0910] X 3 and X 4 One of them is C(O) and the other is CR 1 R 2 ;and

[0911] L is selected from or

[0912] X 3 and X 4 each is C(O); and

[0913] L is selected from and

[0914] R 1 and R 2 are independently selected from H, halogen, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 haloalkyl and optionally substituted C 1-6 Alkoxy.

[0915] In some embodiments, X 1 and X 2 Each is N.

[0916] In one aspect, provided herein is a compound of Formula III:

[0917]

[0918] or a pharmaceutically acceptable salt thereof, wherein

[0919] X 1 and X 3 Independently selected from CR 1 , CR 1 R 2 , O, N and NR 1 ;

[0920] X 2 selected from N, CO and CH;

[0921] Y is selected from O, NR 8 and CR 8 R 9 ;

[0922] Ar is selected from C 6-10 Aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, CN, NO2, OR 17 SR 17 NR 18 R 19 、COR 17 、CO2R 17 、CONR 18 R 19 、SOR 17 、SO2R 17 、SO2NR 18 R 19 NR 17 COR 19 NR 17 C(O)NR 18 R 19 NR 18 SOR 17 NR 18 SO2R 17 , optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 1-8 Alkylamino, optionally substituted C 3-10 Carbocyclyl, -O-(optionally substituted C 3-10 carbocyclyl), -NH-(optionally substituted C 3-10 carbocyclyl), optionally substituted 3- to 10-membered heterocyclyl, -O-(optionally substituted 3- to 10-membered heterocyclyl), -NH-(optionally substituted 3- to 10-membered heterocyclyl), optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0923] L is selected from a bond, R'-R", R'COR", R'CO2R", R'C(O)N(R 21 )R”、R'C(S)N(R 21 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 21 )R”、R'N(R 21)R”、R”N(R 21 )COR”、R'N(R 21 )CON(R 22 )R”、R'N(R 21 )C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0924] wherein L is optionally 1 or X 3 Attachment;

[0925] R' and R" are independently selected from null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C4-C8 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0926] R 1 and R 2 is independently selected at each occurrence from H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 Haloalkyl, optionally substituted C 1-6 alkoxy and optionally substituted 2,6-dioxopiperidin-3-yl;

[0927] R 3 Select from keys, -OR 14 -、-SR 14 -、-N(R 15 )R 14 -、-COR 14 -、-CO2R 14 -、-CON(R 15 )R 14 -、-SOR 14 -、-SO2R 14 -、-SO2N(R 15 )R 14 -、-N(R 16 )COR 14 -、-N(R 16 )CON(R 15 )R 14 -、N(R 16 )SOR 14 -、-N(R 16 )SO2R 14 -, optionally substituted C 1-8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C 1-8 Heteroalkylene, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0928] R 4 、R 5 and R 6 Independently selected from hydrogen, halogen, CN, NO2, OR 10 SR 11 NR 12 R 13 、COR 10 、CO2R 10 、C(O)NR 12 R 13 、SOR 10 、SO2R 10 、SO2NR 12 R13 NR 10 C(O)R 13 NR 10 C(O)NR 12 R 13 NR 10 SOR 13 NR 10 SO2R 13 , optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 carbocyclyl and optionally substituted 3- to 10-membered heterocyclyl;

[0929] R 7 Selected from optionally substituted C 1-8 Alkyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0930] R 8 and R 9 are independently selected from hydrogen, halogen, OH, optionally substituted C 1-8 Alkyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 Carbocyclyl, -O-(optionally substituted C 3-10 carbocyclyl), optionally substituted C 1-8 Alkylamino, -NH-(optionally substituted C 3-10 carbocyclyl) and an optionally substituted 3- to 10-membered heterocyclyl; or

[0931] R 8 and R 9 Together with the atoms to which they are attached, they form an optionally substituted C 3-10 carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl;

[0932] R 10 、R 11 、R 12 and R 13 are independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1-8Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl; or

[0933] R 12 and R 13 together with the atoms to which they are attached, form an optionally substituted 3- to 10-membered heterocyclyl;

[0934] R 14 Selected from empty, optionally substituted C 1-8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C 1-8 Heteroalkylene, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 Carbocyclyl, -O-(optionally substituted C 3-10 carbocyclyl), optionally substituted C 1-8 Alkylamino, -NH-(optionally substituted C 3-10 carbocyclyl), optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0935] R 15 and R 16 are independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl; or

[0936] R 14 and R 15 Together with the atoms to which they are attached, they optionally form an optionally substituted C 3-10 carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl;

[0937] R 17 、R 18 and R 19 are independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-8 Heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 Carbocyclyl, -O-(optionally substituted C 3-10 carbocyclyl), optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl; or

[0938] R 18 and R 19 Together with the atoms to which they are attached, they form an optionally substituted C 3-10 carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl; and

[0939] R 21 and R 22 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or

[0940] R' and R", R 21 and R 22 , R' and R 21 , R' and R 22 , R” and R 21 or R" and R 22 Together with the atoms to which they are attached, they optionally form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring.

[0941] In some embodiments, L is selected from

[0942] In some embodiments, R 4 、R 5 and R 6 Each is hydrogen.

[0943] In some embodiments, Y is CR 8 R 9 In some embodiments, Y is CH2.

[0944] In some embodiments, R 7 is an optionally substituted C 6-10In some embodiments, R 7 yes

[0945] In some embodiments, Ar is replaced by NR 18 R 19 Substituted C 6-10 In some embodiments, Ar is

[0946] In some embodiments, R 3 is an optionally substituted 3- to 10-membered heterocyclyl. 3 yes

[0947] In some embodiments, X 1 It's CR 1 , X 2 is CH, and X 3 It is NR 1 In some embodiments, X 1 It is NR 1 , X 2 is CH, and X 3 It's CR 1 In some embodiments, X 1 It's CR 1 , X 2 is N, and X 3 It is NR 1 In some embodiments, X 1 It is NR 1 , X 2 is N, and X 3 It's CR 1 In some embodiments, X 1 It is NR 1 , X 2 is CH, and X 3 Is N. In some embodiments, X 1 It is N, X 2 is CH, and X 3 It is NR 1 In some embodiments, X 1 It's CR 1 R 2 , X 2 is CO, and X 3 It is NR 1 In some embodiments, X 1 It is NR 1 , X 2 is CO, and X 3 It is NR 1In some embodiments, X 1 It's O, X 2 is CO, and X 3 It is NR 1 In some embodiments, X 1 It's CR 1 , X 2 is CO, and X 3 It is NR 1 In some embodiments, X 1 It is N, X 2 is CO, and X 3 It is NR 1 .

[0948] In some embodiments, R 1 yes

[0949] In one aspect, provided herein is a compound of Formula IV:

[0950]

[0951] or a pharmaceutically acceptable salt thereof, wherein

[0952] X 1 and X 3 Independently selected from CR 1 , N and NR 1 ;

[0953] X 2 selected from N and CH;

[0954] Y 1 Selected from N and CR 6 ;

[0955] Y 2 、Y 3 and Y 4 are independently selected from N and C, provided that Y 2 、Y 3 and Y 4 Only one of them is N;

[0956] Z is selected from space, bond, C(R 5 )2、C(R 5 )2C(R 5 )2、CO、C(R 5 )2CO、CONR 5 、C(R 5 )2O、C(R 5 )2NR 5 and CH2NR 5 ;

[0957] Ar1 and Ar 2 Independently selected from C 6-10 Aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, OR 10 SR 10 NR 11 R 12 、COR 10 、CO2R 10 、CONR 11 R 12 、SOR 10 、SO2R 10 、SO2NR 11 R 12 NR 10 COR 12 NR 10 C(O)NR 11 R 12 NR 10 SOR 12 NR 10 SO2R 12 , optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 1-8 Haloalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0958] L is selected from a bond, R'-R", R'COR", R'CO2R", R'C(O)N(R 13 )R”、R'C(S)N(R 13 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 13 )R”、R'N(R 13 )R”、R”N(R 13 )COR”、R'N(R 13 )CON(R 14 )R”、R'N(R 13)C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C4-C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0959] wherein L is optionally 1 or X 3 Attachment;

[0960] R' and R" are independently selected from null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C4-C8 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C5-C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C5-C 13 spirocarbocyclyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0961] R 1 At each occurrence, is selected from H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 Haloalkyl, optionally substituted C 1-6alkoxy and optionally substituted 2,6-dioxopiperidin-3-yl;

[0962] R 3 Select from keys, -OR 7 -、-SR 7 -、-N(R 8 )R 7 -、-COR 7 -、-CO2R 7 -、-CON(R 8 )R 7 -、-SOR 7 -、-SO2R 7 -、-SO2N(R 8 )R 7 -、-N(R 9 )COR 7 -、-N(R 9 )CON(R 8 )R 7 -、N(R 9 )SOR 7 -、-N(R 9 )SO2R 7 -, optionally substituted C 1-8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C 1-8 Heteroalkylene, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0963] R 4 and R 5 is independently selected at each occurrence from hydrogen, halogen, OH, NH2, CN, NO2, optionally substituted C 1-4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 1-4 Haloalkyl, optionally substituted C 3-10 Carbocyclyl, -O-(optionally substituted C 3-10 carbocyclyl), -NH-(optionally substituted C 3-10 carbocyclyl) and optionally substituted 3- to 10-membered heterocyclyl;

[0964] R 6 Selected from hydrogen, halogen, CN, NO2, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-10 carbocyclyl and optionally substituted 3- to 10-membered heterocyclyl;

[0965] R 7 Selected from empty, optionally substituted C 1-8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C 1-8 Heteroalkylene, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 Carbocyclyl, -O-(optionally substituted C 3-10 carbocyclyl), optionally substituted C 1-8 Alkylamino, -NH-(optionally substituted C 3-10 carbocyclyl), optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0966] R 8 and R 9 are independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl; or

[0967] R 7 and R 8 Together with the atoms to which they are attached, they optionally form an optionally substituted C 3-10 carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl;

[0968] R 10 、R 11 and R 12 are independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl; or

[0969] R 11 and R12 Together with the atoms to which they are attached, they form an optionally substituted C3-C 10 carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl;

[0970] R 13 and R 14 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0971] R' and R", R 13 and R 14 , R' and R 13 , R' and R 14 , R” and R 13 , R” and R 14 together with the atoms to which they are attached, optionally form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring; and

[0972] n is 0, 1, 2, 3 or 4.

[0973] In some embodiments, L is selected from

[0974] In some embodiments, Y 1 It's N, Y 2 It's N, Y 3 is C, and Y 4 It’s C.

[0975] In some embodiments, Ar 1 is C optionally substituted by halogen 6-10 In some embodiments, Ar 1 yes

[0976] In some embodiments, Ar 2 Is optional to be NR 11 R 12 Substituted C 6-10 In some embodiments, Ar 2 yes

[0977] In some embodiments, R3 is an optionally substituted 3- to 10-membered heterocyclyl. 3 yes

[0978] In some embodiments, R 4 It's hydrogen.

[0979] In some embodiments, Z is C(R 5 ) 2. In some embodiments, Z is CH 2 .

[0980] In some embodiments, n is 0.

[0981] In some embodiments, X 1 It's CR 1 , X 2 is CH, and X 3 It is NR 1 In some embodiments, X 1 It is NR 1 , X 2 is CH, and X 3 It's CR 1 In some embodiments, X 1 It's CR 1 , X 2 is N, and X 3 It is NR 1 In some embodiments, X 1 It is NR 1 , X 2 is N, and X 3 It's CR 1 In some embodiments, X 1 It is NR 1 , X 2 is CH, and X 3 Is N. In some embodiments, X 1 It is N, X 2 is CH, and X 3 It is NR 1 .

[0982] In some embodiments, R 1 In some embodiments, R 1 yes

[0983] In another embodiment, the TRK ligand comprises a moiety of Formula 1;

[0984]

[0985] in,

[0986] R 1 、R 2 、R 3 、R 4 , Ar and X are as defined above.

[0987] In another embodiment, the TRK ligand comprises a moiety of Formula 1:

[0988]

[0989] in

[0990] X is selected from CR'R", CO, O, S, SO, SO2 and NR', wherein

[0991] R' and R" are independently selected from hydrogen, halogen, OH, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C3-C 10 cycloalkoxy and an optionally substituted 3-10 membered heterocyclyl; or

[0992] R' and R" together with the atoms to which they are attached optionally form an optionally substituted 3-8 membered carbocyclyl or heterocyclyl ring;

[0993] R is selected from the group consisting of optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C3-C 10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0994] R 1 、R 2 and R 3 Independently selected from hydrogen, halogen, CN, NO2, OR 5 SR 6 NR 7 R 8 、COR 5 、CO2R 5 、C(O)NR 7 R 8 、SOR 5 、SO2R 5 、SO2NR 7 R 8 NR 7 C(O)R 8 NR 5 C(O)NR 7 R8 NR 7 SOR 8 NR 7 SO2R 8 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C3-C 10 cycloalkoxy, optionally substituted 3-10 membered heterocyclyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl, wherein

[0995] R 5 、R 6 、R 7 and R 8 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl or optionally substituted heteroaryl, or

[0996] R 7 and R 8 together with the atoms to which they are attached, optionally form an optionally substituted 3-8 membered heterocyclyl ring;

[0997] R 4 A linker moiety attached to a divalent compound and selected from a bond, an OR 9 SR 9 NR 10 R 11 、COR 9 、CO2R 9 、CONR 10 R 11 、SOR 9 、SO2R 9 、SO2NR 10 R 11 NR 10 COR 11 NR 9 CONR 10 R 11 NR 10 SOR 11 NR 10 SO2R 11, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, aryl and optionally substituted heteroaryl, wherein

[0998] R 9 、R 10 and R 11 is independently selected from the group consisting of: space, a bond, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0999] R 10 and R 11 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or heterocyclyl ring; and

[1000] Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, CN, NO2, OR 12 SR 12 NR 13 R 14 、COR 12 、CO2R 12 、CONR 13 R 14 、SOR 12 、SO2R 12 、SO2NR 13 R 14 NR 13 COR 14 NR 15 C(O)NR 13 R 14 NR 13 SOR 14 NR 13 SO2R 14, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[1001] R 12 、R 13 、R 14 and R 15 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[1002] R 13 and R 14 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[1003] In one embodiment,

[1004] X is selected from CR'R", O and NR', wherein

[1005] R' and R" are independently selected from hydrogen, F, OH, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl and optionally substituted C1-C3 alkoxy, or

[1006] R' and R" together with the atoms to which they are attached form an optionally substituted 3-6 membered carbocyclyl or heterocyclyl ring.

[1007] In another embodiment, X is selected from CH2, cyclopropylene, CHF, CF2, O, NH, NCH3, NCH2CH3 and N-isopropyl.

[1008] In another embodiment, R is selected from optionally substituted C3-C8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[1009] In another embodiment, R is selected from optionally substituted phenyl and optionally substituted heteroaryl.

[1010] In another embodiment, X is CH2; and R is 3,5-difluorophenyl.

[1011] In another embodiment, R 1 、R 2 and R 3 are independently selected from hydrogen, F, Cl and OH.

[1012] In another embodiment, R 4 -Ar is selected from the group consisting of moieties of formulae A1, A2, A3 and A4:

[1013]

[1014] in

[1015] * represents a linker moiety attached to a divalent compound; and

[1016] R a Selected from hydrogen, halogen, CN, NO2, OR 12 SR 12 NR 13 R 14 、COR 12 、CO2R 12 、CONR 13 R 14 、SOR 12 、SO2R 12 、SO2NR 13 R 14 NR 13 COR 14 NR 15 C(O)NR 13 R 14 NR 13 SOR 14 NR 13 SO2R 14 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[1017] R 12 、R 13 、R 14 and R 15independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, aryl and optionally substituted heteroaryl, or

[1018] R 13 and R 14 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[1019] In another embodiment, R 4 -Ar is selected from the group consisting of moieties of formulae A1, A3, A3 and A4:

[1020]

[1021] in

[1022] * represents a linker moiety attached to a divalent compound; and

[1023] R a Selected from hydrogen, halogen, NR 13 R 14 and NR 13 COR 14 ,in

[1024] R 13 and R 14 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, phenyl and optionally substituted C5-C6 heteroaryl, or

[1025] R 13 and R 14 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[1026] In another embodiment, R a is selected from H, (tetrahydro-2H-pyran-4-yl)amino and 2-fluoroethyl)amino.

[1027] In another embodiment, R4 Selected from

[1028] In another embodiment, the TRK ligand comprises a moiety of Formula 2;

[1029]

[1030] in,

[1031] R 1 、R 2 、R 3 、R 4 、Ar 1 、Ar 2 ,X,X 1 、X 2 、X 3 、X 4 and n are as defined above.

[1032] In another embodiment, the TRK ligand comprises a moiety of Formula 2:

[1033]

[1034] in

[1035] X 1 、X 2 、X 3 and X 4 Independently selected from C, CR' and N (preferably, X 1 Selected from CR' and N, X 2 、X 3 and X 4 are independently selected from C and N), wherein

[1036] R' is selected from hydrogen, halogen, CN, NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 carbocyclyl and optionally substituted 3-6 membered heterocyclyl;

[1037] X is selected from the group consisting of space, bond, C(R 2 )2、C(R 2 )2C(R 2 )2、CO、C(R 2 )2CO、CONR 2 、C(R 2 )2O、C(R 2 )2NR 2 and CH2NR 2 ;

[1038] R 1 and R 2is independently selected at each occurrence from hydrogen, halogen, OH, NH2, CN, NO2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 alkoxyalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkylaminoC1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclyl;

[1039] n is 1 to 4;

[1040] R 3 Directly or through R 4 a linker moiety attached to a divalent compound;

[1041] R 3 and R 4 Independently selected from null, bond, OR 5 SR 5 NR 6 R 7 、COR 5 、CO2R 5 、CONR 6 R 7 、SOR 5 、SO2R 5 、SO2NR 6 R 7 NR 6 COR 7 NR 5 C(O)NR 6 R 7 NR 6 SOR 7 NR 6 SO2R 7 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[1042] R 5 、R 6 and R 7is independently selected from space, a bond, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[1043] R 6 and R 7 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring; and

[1044] Ar 1 and Ar 2 independently selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, OR 10 SR 10 NR 11 R 12 、COR 10 、CO2R 10 、CONR 11 R 12 、SOR 10 、SO2R 10 、SO2NR 11 R 12 NR 10 COR 12 NR 10 C(O)NR 11 R 12 NR 10 SOR 12 NR 10 SO2R 12 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[1045] R 10 、R 11 and R 12is independently selected at each occurrence from void, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[1046] R 11 and R 12 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[1047] In one embodiment, X 1 is selected from CR' and N, wherein R' is selected from hydrogen, F, Cl, CH3, CF3 and cyclopropyl.

[1048] In another embodiment, X 2 、X 3 and X 4 are independently selected from C and N.

[1049] In another embodiment, X is selected from a bond, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH, and CH2NCH3.

[1050] In another embodiment, R 1 and R 2 is independently selected at each occurrence from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclyl.

[1051] In another embodiment, X is CH2; and Ar 1 It is 3-fluorophenyl.

[1052] In another embodiment, R 3 The linker portion is directly connected to the divalent compound, and R 3 Select from empty, key, -OR 5 -、-SR 5 -、-NR 6 R 7 -、-COR 5 -、-CO2R 5 -、-CONR 6 R 7 -、-SOR 5 -、-SO2R 5 -, -SO2NR6 R 7 -、-NR 5 COR 7 -、-NR 5 C(O)NR 6 R 7 -、-NR 5 SOR 7 -、-NR 5 SO2R 7 -, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[1053] R 5 、R 6 and R 7 is independently selected from space, a bond, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[1054] R 6 and R 7 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[1055] In another embodiment, R 3 By R 4 is connected to a linker portion of a divalent compound, and R 3 and R 4 Independently selected from space, bond, -OR 5 -、-SR 5 -、-NR 6 R 7 -、-COR 5 -、-CO2R 5 -、-CONR 6 R 7 -、-SOR 5 -、-SO2R 5 -、-SO2NR 6 R 7 -、-NR 5COR 7 -、-NR 5 C(O)NR 6 R 7 -、-NR 5 SOR 7 -、-NR 5 SO2R 7 -, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[1056] R 5 、R 6 and R 7 is independently selected from space, a bond, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[1057] R 6 and R 7 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[1058] In another embodiment, Ar 1 Selected from C6-C 10 Aryl and C5-C 10 Heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO2, OR 10 NR 11 R 12 、COR 10 、CO2R 10 、CONR 11 R 12 、SOR 10 、SO2R 10 、SO2NR 11 R 12 NR 10 COR 12 NR 10 C(O)NR 11 R 12NR 10 SOR 12 NR 10 SO2R 12 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl and optionally substituted C4-C5 heteroaryl, wherein

[1059] R 10 、R 11 and R 12 is independently selected at each occurrence from void, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[1060] R 11 and R 12 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[1061] In another embodiment, Ar 2 Selected from C6-C 10 Aryl and C5-C 10 Heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO2, OR 13 NR 14 R 15 、COR 13 、CO2R 13 、CONR 14 R 15 、SOR 13 、SO2R 13 、SO2NR 14 R 15 NR 13 COR 14 NR 13 C(O)NR 14 R 15 NR 13 SOR 14 NR 13 SO2R 14, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl and optionally substituted C4-C5 heteroaryl, wherein

[1062] R 13 、R 14 and R 15 is independently selected at each occurrence from void, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[1063] R 14 and R 15 Together with the atoms to which they are attached, they optionally form a 3-8 membered carbocyclyl or heterocyclyl ring.

[1064] In another embodiment, R 3 -Ar 2 A moiety selected from formulae B1 and B2:

[1065]

[1066] in

[1067] * indicates a linker moiety attached to a divalent compound;

[1068] Y 1 、Y 2 、Y 3 and Y 4 are independently selected from CH and N, provided that Y 1 、Y 2 、Y 3 and Y 4 At most 3 of them are N;

[1069] Each R a Independently selected from hydrogen, halogen, CN, NO2, OR 13 NR 14 R 15 、COR 13 、CO2R 13 、CONR 14 R 15 、SOR 13 、SO2R 13、SO2NR 14 R 15 NR 13 COR 14 NR 13 C(O)NR 14 R 15 NR 13 SOR 14 NR 13 SO2R 14 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[1070] R 13 、R 14 and R 15 is independently selected at each occurrence from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally subs...

Claims

1. A divalent compound selected from: N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((2-fluoroethyl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)morpholin-2-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)pyrrolidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-6-azaspiro[3.4]octan-2-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)amino)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-1-yl)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-1-yl)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; (S)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; and (R)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; or a pharmaceutically acceptable salt thereof.

2. A divalent compound selected from: (S)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; and (R)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide; or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising the divalent compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. 4 . A pharmaceutical composition comprising the divalent compound according to claim 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

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