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

Abstract

The present disclosure relates to tropomyosin receptor kinase (TRK) degrading compounds and methods of use. Specifically, the present disclosure relates to divalent compounds (e.g., bifunctional small molecule compounds), compositions comprising one or more divalent compounds, and methods of using the divalent compounds to treat certain diseases in a subject in need thereof. The present disclosure also relates to methods for identifying such divalent compounds.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of February 26, 2021, an application number of 202180031506.7, and an invention title of "Tropomyosin Receptor Kinase (TRK) Degrading Compounds and Methods of Use" (the corresponding PCT application has an application date of February 26, 2021 and an application number of PCT / CN2021 / 078240).

[0002] Cross-reference

[0003] 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 OF THE INVENTION

[0004] The present disclosure relates to bivalent compounds (e.g., bifunctional small molecule compounds), compositions comprising one or more bivalent compounds, and methods of using the bivalent compounds to treat certain diseases in a subject in need thereof. The present disclosure also relates to methods of identifying such bivalent compounds. SUMMARY OF THE INVENTION

[0005] In one aspect, there is provided a compound of formula I:

[0006]

[0007] or a pharmaceutically acceptable salt thereof, wherein

[0008] X 1 and X 2 are independently selected from CH and N;

[0009] X 3 and X 4 are independently selected from C(O) and CR 4 R 5 ;

[0010] R 1 is selected from H, -NR 2 R 3 , halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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;

[0011] R2 , R 3 , R 4 and R 5 are independently selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted 5- to 10-membered heteroaryl group, optionally substituted C 1-6 heteroalkyl, optionally substituted C 1-6 haloalkyl and optionally substituted C 1-6 alkoxy; and

[0012] L is selected from a bond,

[0013] or

[0014] X 3 and X 4 one of which is C(O) and the other is CR 4 R 5 ; and

[0015] L is

[0016] In some embodiments, X 1 and X 2 are each N.

[0017] In some embodiments, X 3 is C(O) and X 4 is CR 4 R 5 . In some embodiments, X 3 is C(O) and X 4 is CR 4 R 5 .

[0018] In some embodiments, X 3 and X 4 are both C(O). In some embodiments, X 3 and X 4 are both CR 4 R 5 .

[0019] In some embodiments, R 1 is -NR 2 R 3 . In some embodiments, R 1 is

[0020] In one aspect, the present disclosure provides a compound of formula Ia:

[0021]

[0022] or a pharmaceutically acceptable salt thereof, wherein

[0023] X 1 and X 2 are independently selected from CH and N;

[0024] X 3 and X 4 are independently selected from C(O), CR 4 R 5 and NR 6 ;

[0025] R 1 is selected from H, -NR 2 R 3 、halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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;

[0026] 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 C 1 -C 6 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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;

[0027] L is selected from a bond, R'-R", R'COR", R'CO 2 R", R'C(O)N(R 7 )R", R'C(S)N(R 7)R”, R’OR”, R’SR”, R’SOR”, R’SO 2 R”, R’SO 2 N(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 C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 aminoalkylene, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0028] wherein L is optionally attached to X 3 or X 4 attached;

[0029] R’ and R” are independently selected from the group consisting of empty, optionally substituted C 1 -C 8 alkylene, optionally substituted C1 -C 8 Heteroalkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkynylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 1 -C 8 Aminoalkylene, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Halogenated alkylene, optionally substituted 3-10 membered carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted C 4 -C 13 Fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C 5 -C 13 Bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spiro carbocyclic group, optionally substituted 5-13 membered spiro heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; and

[0030] R 7 and R 8 are independently selected from hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy-C 1 -C 8 Alkyl, optionally substituted C 1 -C8 Halogenoalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Aminoalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; or

[0031] R’ and R”, R 7 and R 8 , R’ and R 7 , R’ and R 8 , R” and R 7 , R” and R 8 Optionally form a 3- to 20-membered carbocyclic ring or a 3- to 20-membered heterocyclic ring together with the atom to which they are attached;

[0032] In some embodiments, L is selected from

[0033] In some embodiments, X 1 and X 2 are each N.

[0034] In some embodiments, at least one of X 3 and X 4 is NR 6 . In some embodiments, X 3 and X 4 are both NR 6 .

[0035] In some embodiments, either X 3 or X 4 is -N-(2,6-dioxopiperidin-3-yl).

[0036] In some embodiments, R 1 is -NR 2 R 3 . In some embodiments, R 1 is

[0037] In some embodiments, L is attached to X 3 . In some embodiments, L is attached to X 4 .

[0038] In one aspect, the present invention provides a compound of formula II:

[0039]

[0040] or a pharmaceutically acceptable salt thereof, wherein

[0041] X 1 and X 2 are independently selected from CH and N;

[0042] X 3 and X 4 one of which is C(O) and the other is CR 1 R 2 ; and

[0043] L is selected from or

[0044] X 3 and X 4 are each C(O); and

[0045] L is selected from and

[0046] R 1 and R 2 are independently selected from H, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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.

[0047] In some embodiments, X 1 and X 2 are each N.

[0048] In one aspect, the present disclosure provides a compound of Formula III:

[0049]

[0050] or a pharmaceutically acceptable salt thereof, wherein

[0051] X 1 and X 3 are independently selected from CR 1 、CR 1 R 2 、O, N and NR 1 ;

[0052] X 2Selected from N, CO, and CH;

[0053] Y is selected from O, NR 8 and CR 8 R 9 ;

[0054] 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, NO 2 , OR 17 , SR 17 , NR 18 R 19 , COR 17 , CO 2 R 17 , CONR 18 R 19 , SOR 17 , SO 2 R 17 , SO 2 NR 18 R 19 , NR 17 COR 19 , NR 17 C(O)NR 18 R 19 , NR 18 SOR 17 , NR 18 SO 2 R 17 ; optionally substituted C 1-8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C 1-8 alkoxy, optionally substituted C 1-8 alkylamino, optionally substituted C 3-10 carbocyclic group, -O-(optionally substituted C 3-10 carbocyclic group), -NH-(optionally substituted C 3-10 carbocyclic group), optionally substituted 3- to 10-membered heterocyclic group, -O-(optionally substituted 3- to 10-membered heterocyclic group), -NH-(optionally substituted 3- to 10-membered heterocyclic group), optionally substituted C 6-10 aryl, and optionally substituted 5- to 10-membered heteroaryl;

[0055] L is selected from a bond, R'-R", R'COR", R'CO 2 R", R'C(O)N(R 21 )R", R'C(S)N(R 21 )R", R'OR", R'SR", R'SOR", R'SO 2 R", R'SO 2 N(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 C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 aminoalkylene, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0056] wherein L is optionally linked to X 1 or X 3Attachment;

[0057] R’ and R” are independently selected from the group consisting of empty, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 aminoalkylene, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0058] R 1 and R 2 are each independently selected from the group consisting of H, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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;

[0059] R 3Select from key, -OR 14 -、-SR 14 -、-N(R 15 )R 14 -、-COR 14 -、-CO 2 R 14 -、-CON(R 15 )R 14 -、-SOR 14 -、-SO 2 R 14 -、-SO 2 N(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 )SO 2 R 14 -, optionally substituted C 1-8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, 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;

[0060] R 4 , R 5 and R 6 independently selected from hydrogen, halogen, CN, NO 2 , OR 10 , SR 11 NR 12 R 13 , COR 10 , CO 2 R 10 、C(O)NR 12 R 13 、SOR 10 、SO 2 R 10 、SO 2 NR 12 R13 , NR 10 C(O)R 13 , NR 10 C(O)NR 12 R 13 , NR 10 SOR 13 , NR 10 SO 2 R 13 , Optionally substituted C 1-8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C 1-8 alkoxy, optionally substituted C 3-10 carbocyclic group and optionally substituted 3- to 10-membered heterocyclic group;

[0061] R 7 Selected from optionally substituted C 1-8 alkyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0062] 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 carbocyclic group, -O-(optionally substituted C 3-10 carbocyclic group), optionally substituted C 1-8 alkylamino, -NH-(optionally substituted C 3-10 carbocyclic group) and optionally substituted 3- to 10-membered heterocyclic group; or

[0063] R 8 and R 9 together with the atom to which they are attached form an optionally substituted C 3-10 carbocyclic group or an optionally substituted 3- to 10-membered heterocyclic group;

[0064] R 10 , R 11 , R 12 and R 13Independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl; or

[0065] R 12 and R 13 together with the atom to which they are attached form an optionally substituted 3- to 10-membered heterocyclic group;

[0066] R 14 is selected from the empty set, optionally substituted C 1-8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1-8 heteroalkylene, optionally substituted C 1-8 alkoxy, optionally substituted C 3-10 carbocyclic group, -O-(optionally substituted C 3-10 carbocyclic group), optionally substituted C 1-8 alkylamino, -NH-(optionally substituted C 3-10 carbocyclic group), optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0067] R 15 and R 16 are independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C 1-8 alkoxy, optionally substituted C 3-10A carbocyclic group, an optionally substituted 3- to 10-membered heterocyclic group, an optionally substituted C 6-10 aryl, and an optionally substituted 5- to 10-membered heteroaryl; or

[0068] R 14 and R 15 together with the atom to which they are attached optionally form an optionally substituted C 3-10 carbocyclic group or an optionally substituted 3- to 10-membered heterocyclic group;

[0069] R 17 , R 18 and R 19 are independently selected from hydrogen, an optionally substituted C 1-8 alkyl, an optionally substituted C 1 -C 8 heteroalkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 1-8 heteroalkyl, an optionally substituted C 1-8 alkoxy, an optionally substituted C 3-10 carbocyclic group, -O-(optionally substituted C 3-10 carbocyclic group), an optionally substituted 3- to 10-membered heterocyclic group, an optionally substituted C 6-10 aryl, and an optionally substituted 5- to 10-membered heteroaryl; or

[0070] R 18 and R 19 together with the atom to which they are attached form an optionally substituted C 3-10 carbocyclic group or an optionally substituted 3- to 10-membered heterocyclic group; and

[0071] R 21 and R 22 are independently selected from hydrogen, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 heteroalkyl, an optionally substituted C 1 -C 8 alkoxy, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 1 -C 8 alkoxy-C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 haloalkyl, an optionally substituted C1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Aminoalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group; or

[0072] 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 Optionally form a 3- to 20-membered carbocyclic group or a 3- to 20-membered heterocyclic group ring together with the atom to which they are attached.

[0073] In some embodiments, L is selected from

[0074] In some embodiments, R 4 , R 5 and R 6 Are each hydrogen.

[0075] In some embodiments, Y is CR 8 R 9 . In some embodiments, Y is CH 2 .

[0076] In some embodiments, R 7 Is an optionally substituted C 6-10 Aryl group. In some embodiments, R 7 Is

[0077] In some embodiments, Ar is a C 18 R 19 Substituted by NR 6-10 Aryl group. In some embodiments, Ar is

[0078] In some embodiments, R 3 Is an optionally substituted 3- to 10-membered heterocyclic group. In some embodiments, R 3 Is

[0079] In some embodiments, X 1 Is CR 1 , X2 is CH, and X 3 is NR 1 . In some embodiments, X 1 is NR 1 , X 2 is CH, and X 3 is CR 1 . In some embodiments, X 1 is CR 1 , X 2 is N, and X 3 is NR 1 . In some embodiments, X 1 is NR 1 , X 2 is N, and X 3 is CR 1 . In some embodiments, X 1 is NR 1 , X 2 is CH, and X 3 is N. In some embodiments, X 1 is N, X 2 is CH, and X 3 is NR 1 . In some embodiments, X 1 is CR 1 R 2 , X 2 is CO, and X 3 is NR 1 . In some embodiments, X 1 is NR 1 , X 2 is CO, and X 3 is NR 1 . In some embodiments, X 1 is O, X 2 is CO, and X 3 is NR 1 . In some embodiments, X 1 is CR 1 , X 2 is CO, and X 3 is NR 1 . In some embodiments, X 1 is N, X 2 is CO, and X 3 is NR 1 .

[0080] In some embodiments, R 1 is

[0081] In one aspect, the present disclosure provides a compound of Formula IV:

[0082]

[0083] or a pharmaceutically acceptable salt thereof, wherein

[0084] X 1 and X 3 are independently selected from CR 1 、N and NR 1 ;

[0085] X 2 is selected from N and CH;

[0086] Y 1 is selected from N and CR 6 ;

[0087] Y 2 、Y 3 and Y 4 are independently selected from N and C, provided that only one of Y 2 、Y 3 and Y 4 is N;

[0088] Z is selected from nothing, a bond, C(R 5 ) 2 、C(R 5 ) 2 C(R 5 ) 2 、CO、C(R 5 ) 2 CO、CONR 5 、C(R 5 ) 2 O、C(R 5 ) 2 NR 5 and CH 2 NR 5 ;

[0089] Ar 1 and Ar 2 are 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, NO 2 、OR 10 、SR 10 、NR 11 R 12 、COR 10 、CO 2 R 10 、CONR 11 R 12, SOR 10 , SO 2 R 10 , SO 2 NR 11 R 12 , NR 10 COR 12 , NR 10 C(O)NR 11 R 12 , NR 10 SOR 12 , NR 10 SO 2 R 12 , Optionally substituted C 1-8 alkyl, optionally substituted C 1 -C 8 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 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl;

[0090] L is selected from a bond, R'-R", R'COR", R'CO 2 R", R'C(O)N(R 13 )R", R'C(S)N(R 13 )R", R'OR", R'SR", R'SOR", R'SO 2 R", R'SO 2 N(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 C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C8 alkoxy C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 aminoalkylene, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C 5 -C 13 spirocarbocyclic group, optionally substituted 5-13 membered spiroheterocyclic group, optionally substituted 3-10 membered carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0091] wherein L is optionally attached to X 1 or X 3 attached;

[0092] R’ and R” are independently selected from the group consisting of empty, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 aminoalkylene, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkylene, optionally substituted C 1 -C 8Halogenated alkylene group, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C 13 Fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 Bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spiro carbocyclic group, optionally substituted 5- to 13-membered spiro heterocyclic group, optionally substituted aryl group and optionally substituted heteroaryl group;

[0093] R 1 Each occurrence is independently selected from H, halogen, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 heteroalkyl group, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted 5- to 10-membered heteroaryl group, optionally substituted C 1-6 heteroalkyl group, optionally substituted C 1-6 halogenated alkyl group, optionally substituted C 1-6 alkoxy group and optionally substituted 2,6-dioxopiperidin-3-yl;

[0094] R 3 Selected from a bond, -OR 7 -, -SR 7 -, -N(R 8 )R 7 -, -COR 7 -, -CO 2 R 7 -, -CON(R 8 )R 7 -, -SOR 7 -, -SO 2 R 7 -, -SO 2 N(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 )SO 2 R 7 -, optionally substituted C 1-8 alkylene group, optionally substituted C 1 -C 8 heteroalkylene group, optionally substituted C2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkynylene, optionally substituted C 1-8 Heteroalkylene, optionally substituted C 3-10 Carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 6-10 Aryl and optionally substituted 5- to 10-membered heteroaryl;

[0095] R 4 and R 5 are each independently selected from hydrogen, halogen, OH, NH 2 , CN, NO 2 , optionally substituted C 1-4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 1-4 heteroalkyl, optionally substituted C 1-4 haloalkyl, optionally substituted C 3-10 carbocyclic group, -O-(optionally substituted C 3-10 carbocyclic group), -NH-(optionally substituted C 3-10 carbocyclic group) and optionally substituted 3- to 10-membered heterocyclic group;

[0096] R 6 is selected from hydrogen, halogen, CN, NO 2 , optionally substituted C 1-6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3-10 carbocyclic group and optionally substituted 3- to 10-membered heterocyclic group;

[0097] R 7 is selected from empty, optionally substituted C 1-8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1-8 heteroalkylene, optionally substituted C 1-8 alkoxy, optionally substituted C 3-10 carbocyclic group, -O-(optionally substituted C 3-10 carbocyclic group), optionally substituted C 1-8 alkylamino, -NH-(optionally substituted C 3-10carbocyclic group), optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 6-10 aryl, and optionally substituted 5- to 10-membered heteroaryl;

[0098] R 8 and R 9 are independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C 1-8 alkoxy, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 6-10 aryl, and optionally substituted 5- to 10-membered heteroaryl; or

[0099] R 7 and R 8 together with the atoms to which they are attached optionally form an optionally substituted C 3-10 carbocyclic group or an optionally substituted 3- to 10-membered heterocyclic group;

[0100] R 10 、R 11 and R 12 are independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2-8 alkenyl, optionally substituted C 2-8 alkynyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 6-10 aryl, and optionally substituted 5- to 10-membered heteroaryl; or

[0101] R 11 and R 12 together with the atoms to which they are attached form an optionally substituted C 3 -C 10 carbocyclic group or an optionally substituted 3- to 10-membered heterocyclic group;

[0102] R 13 and R 14 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1-C 8 Heteroalkyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy-C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Aminoalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl; or

[0103] 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 atom to which they are attached, optionally form a 3- to 20-membered carbocyclic or 3- to 20-membered heterocyclic ring; and

[0104] n is 0, 1, 2, 3, or 4.

[0105] In some embodiments, L is selected from

[0106] In some embodiments, Y 1 is N, Y 2 is N, Y 3 is C, and Y 4 is C.

[0107] In some embodiments, Ar 1 is aryl optionally substituted with halogen. In some embodiments, Ar 6-10 is 1 is

[0108] In some embodiments, Ar 2 is optionally substituted with NR 11 R12 Substituted C 6-10 aryl. In some embodiments, Ar 2 is

[0109] In some embodiments, R 3 is an optionally substituted 3- to 10-membered heterocyclic group. In some embodiments, R 3 is

[0110] In some embodiments, R 4 is hydrogen.

[0111] In some embodiments, Z is C(R 5 ) 2 . In some embodiments, Z is CH 2 .

[0112] In some embodiments, n is 0.

[0113] In some embodiments, X 1 is CR 1 , X 2 is CH, and X 3 is NR 1 . In some embodiments, X 1 is NR 1 , X 2 is CH, and X 3 is CR 1 . In some embodiments, X 1 is CR 1 , X 2 is N, and X 3 is NR 1 . In some embodiments, X 1 is NR 1 , X 2 is N, and X 3 is CR 1 . In some embodiments, X 1 is NR 1 , X 2 is CH, and X 3 is N. In some embodiments, X 1 is N, X 2 is CH, and X 3 is NR 1 .

[0114] In some embodiments, R 1 is methyl. In some embodiments, R 1 is

[0115] According to one aspect of the present disclosure, the bivalent compounds disclosed herein include a tropomyosin receptor kinase (TRK) ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analogue thereof.

[0116] 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.

[0117] In another embodiment, the TRK ligand is a TRK kinase inhibitor or a part of a TRK kinase inhibitor.

[0118] 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 analogues thereof.

[0119] In another embodiment, the degradation tag binds to an ubiquitin ligase, or the degradation tag is a hydrophobic group or a tag that causes misfolding of the TRK protein.

[0120] In another embodiment, the ubiquitin ligase is an E3 ligase.

[0121] In another embodiment, the E3 ligase is selected from 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.

[0122] In another embodiment, the degrading 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 analogs thereof.

[0123] In another embodiment, the TRK ligand is conjugated to the degrading tag via a linker moiety.

[0124] In another embodiment, the TRK ligand comprises a moiety of Formula 1:

[0125]

[0126] wherein

[0127] X is selected from CR’R”, CO, O, S, SO, SO 2 and NR’, wherein

[0128] R’ and R” are independently selected from hydrogen, halogen, OH, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1-8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 10 carbocyclic, optionally substituted C 3 -C 10 cycloalkoxy and optionally substituted 3-10 membered heterocyclic groups; or

[0129] R’ and R” together with the atoms to which they are attached optionally form an optionally substituted 3-8 membered carbocyclic or heterocyclic ring;

[0130] R is selected from optionally substituted C 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -heteroalkyl, optionally substituted C 3 -C 10 -carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl;

[0131] R 1 、R 2 and R 3 are independently selected from hydrogen, halogen, CN, NO 2 、OR 5 、SR 6 、NR 7 R 8 、COR 5 、CO 2 R 5 、C(O)NR 7 R 8 、SOR 5 、SO 2 R 5 、SO 2 NR 7 R 8 、NR 7 C(O)R 8 、NR 5 C(O)NR 7 R 8 、NR 7 SOR 8 、NR 7 SO 2 R 8 、optionally substituted C 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -heteroalkyl, optionally substituted C 1 -C 8 -alkoxy, optionally substituted C 1 -C 8 -alkoxyC 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -alkylaminoC 1 -C 8 -alkyl, optionally substituted C 3 -C 10 -carbocyclic group, optionally substituted C 3 -C 10 -cycloalkoxy, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C2 -C 8 alkenyl and optionally substituted C 2 -C 8 alkynyl, wherein

[0132] R 5 、R 6 、R 7 and R 8 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C 3 -C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl or optionally substituted heteroaryl, or

[0133] R 7 and R 8 together with the atoms to which they are attached optionally form an optionally substituted 3- to 8-membered heterocyclic group ring;

[0134] R 4 is attached to the linker moiety of the divalent compound and is selected from a bond, -OR 9 -, -SR 9 -, -NR 10 R 11 -, -COR 9 -, -CO 2 R 9 -, -CONR 10 R 11 -, -SOR 9 -, -SO 2 R 9 -, -SO 2 NR 10 R 11 -, -NR 10 COR 11 -, -NR 9 CONR 10 R 11 -、-NR10 SOR 11 -, -NR 10 SO 2 R 11 -, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkylene-O-, optionally substituted C 1 -C 8 alkylene-O-C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8 carbocyclic group-O-, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, aryl and optionally substituted heteroaryl, wherein

[0135] R 9 , R 10 and R 11 are independently selected from the group consisting of empty, bond, hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8Cycloalkyloxy, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkylene-O-, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-, optionally substituted C 1 -C 8 alkylene-O-alkylene, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclylene, optionally substituted C 3 -C 8 carbocyclylene-O-, optionally substituted aryl and optionally substituted heteroaryl, or

[0136] R 10 and R 11 together with the atoms to which they are attached optionally form a 3-8 membered carbocyclic or heterocyclic ring; and

[0137] Ar is selected from aryl and heteroaryl, each of which is optionally substituted by one or more substituents independently selected from hydrogen, halogen, CN, NO 2 、OR 12 、SR 12 、NR 13 R 14 、COR 12 、CO 2 R 12 、CONR 13 R 14 、SOR 12 、SO 2 R 12 、SO 2 NR 13 R 14 、NR 13 COR 14 、NR 15C(O)NR 13 R 14 、NR 13 SOR 14 、NR 13 SO 2 R 14 、 optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0138] R 12 、R 13 、R 14 and R 15 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted C 2 -C8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0139] R 13 and R 14 together with the atoms to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring.

[0140] In one embodiment, X is selected from CR’R”, O and NR’; wherein

[0141] R’ and R” are independently selected from hydrogen, F, OH, optionally substituted C1-C3 alkyl and optionally substituted C1-C3 alkoxy; or

[0142] R’ and R” together with the atoms to which they are attached optionally form an optionally substituted 3- to 6-membered carbocyclic or heterocyclic ring.

[0143] In another embodiment, X is selected from CH 2 , cyclopropylidene, CHF, CF 2 , O, NH, NCH 3 , NCH 2 CH 3 and N-isopropyl.

[0144] In another embodiment, R is selected from optionally substituted C 3 -C 8 carbocyclic, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl.

[0145] In another embodiment, R is selected from optionally substituted phenyl and optionally substituted heteroaryl.

[0146] In another embodiment, X is CH 2 ; and R is 3,5-difluorophenyl.

[0147] In another embodiment, R 1 , R 2 and R 3 are independently selected from hydrogen, F, Cl and OH.

[0148] In another embodiment, R 4 -Ar is selected from moieties of formulas A1, A2, A3 and A4:

[0149]

[0150] wherein

[0151] * represents the linker moiety attached to the divalent compound; and

[0152] R a Selected from hydrogen, halogen, CN, NO 2 , OR 12 , SR 12 , NR 13 R 14 , COR 12 , CO 2 R 12 , CONR 13 R 14 , SOR 12 , SO 2 R 12 , SO 2 , NR 13 R 14 , NR 15 , COR 14 , NR 15 , C(O)NR 13 R 14 , NR 15 , SOR 14 , NR 15 , SO 2 R 14 , optionally substituted C 1 -C 8 , optionally substituted C 1 -C 8 , optionally substituted C 1 -C 8 , optionally substituted C 1 -C 8 , alkoxy C 1 -C 8 , optionally substituted C 1 -C 8 , alkylamino C 1 -C 8 , optionally substituted C 3 -C 8 , optionally substituted C 3 -C 8 , cycloalkoxy, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted C 2 -C 8 , optionally substituted C 2 -C 8 , optionally substituted aryl and optionally substituted heteroaryl, wherein

[0153] R 12 , R 13 , R 14 and R 15 are independently selected from hydrogen, optionally substituted C 1 -C8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted C 3 -C 8 Cycloalkoxy, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, aryl and optionally substituted heteroaryl, or

[0154] R 13 and R 14 together with the atom to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring.

[0155] In another embodiment, R 4 -Ar is selected from moieties of formulae A1, A3, A3 and A4:

[0156]

[0157] wherein

[0158] * represents the linker moiety attached to the divalent compound; and

[0159] R a is selected from hydrogen, halogen, NR 13 R 14 and NR 13 COR 14 wherein

[0160] R 13 and R 14 are independently selected from hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, phenyl and optionally substituted C 5 -C 6 heteroaryl, or

[0161] R 13 and R 14 together with the atom to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring.

[0162] In another embodiment, R a is selected from H, (tetrahydro-2H-pyran-4-yl)amino and 2-fluoroethylamino.

[0163] In another embodiment, R 4 is selected from optionally substituted

[0164] In another embodiment, the TRK ligand comprises a moiety of Formula 2:

[0165]

[0166] wherein

[0167] X 1 , X 2 , X 3 and X 4 are 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), where

[0168] R’ is selected from hydrogen, halogen, CN, NO 2 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 3 -C 6 carbocyclic group and optionally substituted 3- to 6-membered heterocyclic group;

[0169] X is selected from the group consisting of empty, bond, C(R 2 ) 2 , C(R 2 ) 2 C(R 2 ) 2 , CO, C(R 2 ) 2 CO, CONR 2 , C(R 2 ) 2 O, C(R 2 ) 2 NR 2 and CH 2 NR 2 ;

[0170] R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, OH, NH 2 , CN, NO 2 , optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkylamino, optionally substituted C 1 -C 4 alkoxyalkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 hydroxyalkyl, optionally substituted C 1 -C 4 alkylaminoC 1 -C 4 alkyl, optionally substituted C 3 -C 6 carbocyclic, optionally substituted C 3 -C 6 cycloalkoxy and optionally substituted 3-6 membered heterocyclic group;

[0171] n is from 1 to 4;

[0172] R 3 is directly or through R 4 connected to the linker moiety of the divalent compound;

[0173] R 3 and R 4 are each independently selected from the group consisting of empty, bond, -OR5 -,-SR 5 -,-NR 6 R 7 -,-COR 5 -,-CO 2 R 5 -,-CONR 6 R 7 -,-SOR 5 -,-SO 2 R 5 -,-SO 2 NR 6 R 7 -,-NR 6 COR 7 -,-NR 5 C(O)NR 6 R 7 -,-NR 6 SOR 7 -,-NR 6 SO 2 R 7 -,-optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylene-O-C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclylene, optionally substituted C 3 -C 8 carbocyclylene-O-, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0174] R 5 ,R6 and R 7 are independently selected from the group consisting of void, a bond, hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted heterocarbocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkylene-O-, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-, optionally substituted C 1 -C 8 alkylene-O-alkylene, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 subcarbocyclic group, optionally substituted C 3 -C 8 subcarbocyclic group-O-, optionally substituted 3- to 8-membered carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl, or

[0175] R 6 and R 7 together with the atoms to which they are attached optionally form a 3- to 8-membered carbocyclic or 3- to 8-membered heterocyclic ring; and

[0176] Ar 1 and Ar 2 are independently selected from aryl and heteroaryl, each of which is optionally substituted by one or more substituents independently selected from halogen, CN, NO 2 、OR 10 、SR 10 、NR 11 R12 , COR 10 , CO 2 R 10 , CONR 11 R 12 , SOR 10 , SO 2 R 10 , SO 2 , SONR 11 R 12 , NR 10 , COR 12 , NR 10 , C(O)NR 11 R 12 , NR 10 , SOR 12 , NR 10 , SO 2 R 12 , Optionally substituted C 1 -C 8 , Optionally substituted C 1 -C 8 , Optionally substituted C 1 -C 8 , Alkoxy C 1 -C 8 , Optionally substituted C 1 -C 8 , Optionally substituted C 1 -C 8 , Optionally substituted C 1 -C 8 , Alkylamino C 1 -C 8 , Optionally substituted C 3 -C 7 , Optionally substituted carbocyclic group, optionally substituted 3-7 membered heterocyclic group, optionally substituted C 2 -C 8 , Optionally substituted C 2 -C 8 , Optionally substituted C

[0177] R 10 , R 11 , and R 12 , are each independently selected from the group consisting of nothing, hydrogen, optionally substituted C 1 -C 8 , Optionally substituted C 1 -C 8 , Optionally substituted C 2 -C 8 , Optionally substituted C 2 -C8 Alkynyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3- to 7-membered heterocyclic group, optionally substituted aryl group and optionally substituted heteroaryl group, or

[0178] R 11 and R 12 together with the atoms to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring.

[0179] In one embodiment, X 1 is selected from CR’ and N, where R’ is selected from hydrogen, F, Cl, CH 3 , CF 3 and cyclopropyl.

[0180] In another embodiment, X 2 , X 3 and X 4 are independently selected from C and N.

[0181] In another embodiment, X is selected from a bond, CH 2 , CH 2 CH 2 , CO, CH 2 CO, CONH, CONCH 3 , CH 2 O, CH 2 NH and CH 2 NCH 3 .

[0182] In another embodiment, R 1 and R 2 are independently selected from hydrogen, F, Cl, OH, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkylamino, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 3 -C 6 carbocyclic group, optionally substituted C 3 -C 6 cycloalkoxy and optionally substituted 3- to 6-membered heterocyclic group.

[0183] In another embodiment, X is CH 2 ; and Ar 1is 3-fluorophenyl.

[0184] In another embodiment, R 3 is directly attached to the linker portion of the bivalent compound, and

[0185] R 3 is selected from the group consisting of nothing, a bond, -OR 5 -, -SR 5 -, -NR 6 R 7 -, -COR 5 -, -CO 2 R 5 -, -CONR 6 R 7 -, -SOR 5 -, -SO 2 R 5 -, -SO 2 NR 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 SO 2 R 7 -, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkylene-O-C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted C 2 -C8 Vinylene, optionally substituted C 2 -C 8 Ethynylene, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0186] R 5 、R 6 and R 7 are independently selected from the group consisting of nothing, a bond, hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted heterocarbocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkylene-O-, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-, optionally substituted C 1 -C 8 alkylene-O-alkylene, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8 carbocyclic group-O-, optionally substituted 3- to 8-membered carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, or

[0187] R 6 and R 7 together with the atom to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring.

[0188] In another embodiment, R 3 through R 4a linker moiety attached to a divalent compound, and

[0189] R 3 and R 4 are independently selected from the group consisting of null, a bond, -OR 5 -, -SR 5 -, -NR 6 R 7 -, -COR 5 -, -CO 2 R 5 -, -CONR 6 R 7 -, -SOR 5 -, -SO 2 R 5 -, -SO 2 NR 6 R 7 -, -NR 5 COR 7 -, -NR 5 C(O)NR 6 R 7 -, -NR 5 SOR 7 -, -NR 5 SO 2 R 7 -, optionally substituted C 1 -C 8 -alkylene, optionally substituted C 1 -C 8 -heteroalkylene, optionally substituted C 1 -C 8 -alkylene-O-C 1 -C 8 -alkylene, optionally substituted C 1 -C 8 -haloalkylene, optionally substituted C 1 -C 8 -hydroxyalkylene, optionally substituted C 1 -C 8 -alkylene-N(C 1 -C 8 -alkyl)-C 1 -C 8 -alkylene, optionally substituted C 3 -C 8 -carbocyclic group, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted C 2 -C 8 -alkenylene, optionally substituted C 2 -C 8 -alkynylene, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0190] R 5 , R 6 and R 7 are independently selected from space, a bond, hydrogen, an optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 3 -C 8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 1 -C 8 Alkylene-O-, optionally substituted C 1 -C 8 Alkylene-N(C 1 -C 8 alkyl)-, optionally substituted C 1 -C 8 Alkylene-O-alkylene, optionally substituted C 1 -C 8 Alkylene-N(C 1 -C 8 Alkyl)-C 1 -C 8 Alkylene, optionally substituted C 3 -C 8 Carbocyclylene, optionally substituted C 3 -C 8 carbocyclylene-O-, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0191] 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.

[0192] In another embodiment, Ar 1 Selected from C 6 -C 10 Aryl and C 5 -C 10A heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO 2 , OR 10 , NR 11 R 12 , COR 10 , CO 2 R 10 , CONR 11 R 12 , SOR 10 , SO 2 R 10 , SO 2 , NR 11 R 12 , NR 10 , COR 12 , NR 10 , C(O)NR 11 R 12 , NR 10 , SOR 12 , NR 10 , SO 2 R 12 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkylamino C 1 -C 6 alkyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3-7 membered heterocyclic group, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl and optionally substituted C 4 -C 5 heteroaryl, wherein

[0193] R 10 , R 11 and R 12 are each independently selected, in each occurrence, from the group consisting of empty, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3- to 7-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group, or

[0194] R 11 and R 12 optionally form, together with the atoms to which they are attached, a 3- to 8-membered carbocyclic or heterocyclic ring.

[0195] In another embodiment, Ar 2 is selected from C 6 -C 10 aryl and C 5 -C 10 heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO 2 , OR 13 , NR 14 R 15 , COR 13 , CO 2 R 13 , CONR 14 R 15 , SOR 13 , SO 2 R 13 , SO 2 , NR 14 R 15 , NR 13 , COR 14 , NR 13 , C(O)NR 14 R 15 , NR 13 , SOR 14 , NR 13 , SO 2 R 14 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6Hydroxyalkyl, optionally substituted C 1 -C 6 Alkylamino C 1 -C 6 Alkyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl and optionally substituted C 4 -C 5 Heteroaryl, wherein

[0196] R 13 , R 14 and R 15 is independently selected at each occurrence from void, hydrogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0197] 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.

[0198] In another embodiment, R 3 -Ar 2 A moiety selected from formula B1 and B2:

[0199]

[0200] in

[0201] * indicates a linker moiety attached to a divalent compound;

[0202] 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;

[0203] Each R a is independently selected from hydrogen, halogen, CN, NO 2 , OR 13 , NR 14 R 15 , COR 13 , CO 2 R 13 , CONR 14 R 15 , SOR 13 , SO 2 R 13 , SO 2 , NR 14 R 15 , NR 13 , COR 14 , NR 13 , C(O)NR 14 R 15 , NR 13 , SOR 14 , NR 13 , SO 2 R 14 , optionally substituted C 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -heteroalkyl, optionally substituted C 1 -C 8 -alkoxy, optionally substituted C 1 -C 8 -alkoxyC 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -alkylaminoC 1 -C 8 -alkyl, optionally substituted C 3 -C 8 -carbocyclic group, optionally substituted C 3 -C 8 -cycloalkoxy, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted C 2 -C 8 -alkenyl, optionally substituted C 2 -C 8 -alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0204] R 13 , R 14 and R 15 are each independently selected from hydrogen, optionally substituted C 1 -C 8 -alkyl, optionally substituted C1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0205] R 14 and R 15 together with the atoms to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring;

[0206] m is from 0 to 4; and

[0207] R 3 is as defined in formula 2.

[0208] In another embodiment, R 3 -Ar 2 is selected from moieties of formula B3:

[0209]

[0210] wherein

[0211] * represents the linker moiety attached to the divalent compound;

[0212] Y 1 、Y 2 、Y 3 and Y 4 are independently selected from CR a 、N、O and S, provided that at most 3 of Y 1 、Y 2 、Y 3 and Y 4 are N;

[0213] each R a is independently selected from hydrogen, halogen, CN, NO 2 、OR13 , NR 14 R 15 , COR 13 , CO 2 R 13 , CONR 14 R 15 , SOR 13 , SO 2 R 13 , SO 2 NR 14 R 15 , NR 13 COR 14 , NR 13 C(O)NR 14 R 15 , NR 13 SOR 14 , NR 13 , SO 2 R 14 , Optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0214] R 13 , R 14 and R 15 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted C 3 -C 8 Cycloalkoxy, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0215] R 14 and R 15 together with the atoms to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring;

[0216] m is 0 to 4; and

[0217] R 3 is as defined in Formula 2.

[0218] In another embodiment, X 1 is N; X 2 is N; X 3 is C; X 4 is C; and X is CH 2 .

[0219] In another embodiment, Ar 1 is 3-fluorophenyl.

[0220] In another embodiment, Ar 2 is 2-pyridyl.

[0221] In another embodiment, R 3 is selected from optionally substituted

[0222] In another embodiment, the TRK ligand comprises a moiety of Formula 3:

[0223]

[0224] wherein

[0225] X 1 、X 2 、X 3 and X 4Independently selected from C, CR’, and N (preferably, X 1 and X 4 are independently selected from CR’ and N; X 2 and X 3 are independently selected from C and N), where R’ is selected from hydrogen, halogen, CN, NO 2 and optionally substituted C 1 -C 6 alkyl, C 3 -C 6 carbocyclic group or 3- to 6-membered heterocyclic group;

[0226] X is selected from empty, bond, C(R 2 ) 2 , C(R 2 ) 2 C(R 2 ) 2 , CO, C(R 2 ) 2 CO, NR 2 CO, OC(R 2 ) 2 and NR 2 C(R 2 ) 2 ;

[0227] R 1 and each R 2 are independently selected from hydrogen, halogen, OH, NH 2 , CN, NO 2 , optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkylamino, optionally substituted C 1 -C 4 alkoxyalkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 hydroxyalkyl, optionally substituted C 1 -C 4 alkylaminoC 1 -C 4 alkyl, optionally substituted C 3 -C 6 carbocyclic group, optionally substituted C 3 -C 6 cycloalkoxy and optionally substituted 3- to 6-membered heterocyclic group;

[0228] n is from 1 to 4;

[0229] R 3 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 carbocyclic group, optionally substituted 3- to 6-membered heterocyclic group, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl and optionally substituted C 1 -C 6 alkylamino C 1 -C 6 alkyl;

[0230] R 4 is directly or through R 5 connected to the linker moiety of the divalent compound, wherein

[0231] R 4 and R 5 are independently selected from empty, -OR 6 -, -SR 6 -, -N(R 7 )R 6 -, -COR 6 -, -CO 2 R 6 -, -CON(R 7 )R 6 -, -SOR 6 -, -SO 2 R 6 -, -SO 2 N(R 7 )R 6 -, -NR 8 COR 6 -, -N(R 8 )C(O)N(R 7 )R 6 -, -NR 8 SOR 6 -, -NR 8 SO 2 R 6 -, optionally substituted C 1 -C 8 alkylene, optionally substituted C1 -C 8 alkylene-O-C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 (alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclylene, optionally substituted 3- to 8-membered carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted aryl and optionally substituted heteroaryl;

[0232] R 6 selected from the group consisting of empty, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkylene-O-, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 (alkyl)-, optionally substituted C 1 -C 8 alkylene-O-C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 (alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8 carbocyclic-O-, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0233] R 7 and R 8independently selected from the group consisting of hydrogen, an optionally substituted C 1 -C 8 alkyl group, an optionally substituted C 1 -C 8 heteroalkyl group, an optionally substituted C 2 -C 8 alkenyl group, an optionally substituted C 2 -C 8 alkynyl group, an optionally substituted C 3 -C 8 carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted 3- to 8-membered carbocyclic group, an optionally substituted 3- to 8-membered heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; or

[0234] R 6 and R 7 together with the atom to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring;

[0235] Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO 2 , OR 10 , SR 10 , NR 11 R 12 , COR 10 , CO 2 R 10 , CONR 11 R 12 , SOR 10 , SO 2 R 10 , SO 2 NR 11 R 12 , NR 10 COR 12 , NR 10 C(O)NR 11 R 12 , NR 10 SOR 12 , NR 10 SO 2 R 12 , an optionally substituted C 1 -C 8 alkyl group, an optionally substituted C 1 -C 8 heteroalkyl group, an optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl group, an optionally substituted C 1 -C8 Halogenoalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 3 -C 7 Carbocyclic group, optionally substituted 3-7 membered heterocyclic group, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0236] R 10 、R 11 and R 12 are independently selected from the group consisting of empty, hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3-7 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, or

[0237] R 11 and R 12 together with the atoms to which they are attached optionally form a 3-8 membered carbocyclic or heterocyclic ring.

[0238] In one embodiment, X 1 and X 4 are selected from CR’ and N, and R’ is selected from hydrogen, F, Cl, CH 3 、CF 3 and cyclopropyl.

[0239] In one embodiment, X 1 is N.

[0240] In one embodiment, X 4 is CH.

[0241] In another embodiment, X 2 and X 3 are independently selected from C and N.

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

[0243] In one embodiment, X 3 is C and X 2 is N.

[0244] In another embodiment, X is selected from a bond, CH 2 、CH 2 CH 2 、CO、CH 2 CO、CONH、CONCH 3 、CH 2 O、CH 2 NH and CH 2 NCH 3 .

[0245] In another embodiment, X is CH 2 .

[0246] In another embodiment, R 1 and each R 2 are independently selected from hydrogen, F, Cl, OH, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkylamino, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 3 -C 6 carbocyclic, optionally substituted C 3 -C 6 cycloalkoxy and optionally substituted 3-6 membered heterocyclic group.

[0247] In another embodiment, R 1 and R 2 are hydrogen.

[0248] In another embodiment, R 3 is selected from hydrogen, CH 3 、CH 2 CH 3 、propyl, isopropyl, cyclopropyl, CH 2 F、CHF 2 and CF 3 .

[0249] In another embodiment, R 3 is selected from hydrogen.

[0250] In another embodiment, R 4 is directly attached to the linker portion of the divalent compound, and

[0251] R 4 is selected from nothing, -OR 6 -, -SR 6 -, -N(R 7 )R 6 -, -COR 6 -, -CO 2 R 6 -, -CON(R 7 )R 6 -, -SOR 6 -, -SO 2 R 6 -, -SO 2 N(R 7 )R 6 -, -NR 8 COR 6 -, -N(R 8 )C(O)N(R 7 )R 6 -, -NR 8 SOR 6 -, -NR 8 SO 2 R 6 -, optionally substituted C 1 -C 8 -alkylene, optionally substituted C 1 -C 8 -heteroalkylene, optionally substituted C 1 -C 8 -alkylene-O-C 1 -C 8 -alkylene, optionally substituted C 1 -C 8 -haloalkylene, optionally substituted C 1 -C 8 -hydroxyalkylene, optionally substituted C 1 -C 8 -alkylene-N(C 1 -C 8 -alkyl)-C 1 -C 8 -substituted C 3 -C 8 -carbocyclic group, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted C 2 -C 8Alkenylene, optionally substituted C 2 -C 8 Alkynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0252] R 6 Selected from the group consisting of nothing, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 1 -C 8 Alkylene-O-, optionally substituted C 1 -C 8 Alkylene-N(C 1 -C 8 Alkyl)-, optionally substituted C 1 -C 8 Alkylene-O-C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylene-N(C 1 -C 8 Alkyl)-C 1 -C 8 Alkylene, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted C 3 -C 8 Carbocyclic group-O-, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl;

[0253] R 7 and R 8 Independently selected from the group consisting of nothing, hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted heterocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3- to 8-membered carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl; or

[0254] R 6 and R 7 Together with the atom to which they are attached, optionally form a 3- to 8-membered carbocyclic or heterocyclic ring;

[0255] In another embodiment, R 4 is attached to a linker moiety of a bivalent compound through R 5 , and R 4 and R 5 are independently selected from the group consisting of empty, -OR 6 -, -SR 6 -, -N(R 7 )R 6 -, -COR 6 -, -CO 2 R 6 -, -CON(R 7 )R 6 -, -SOR 6 -, -SO 2 R 6 -, -SO 2 N(R 7 )R 6 -, -NR 8 COR 6 -, -N(R 8 )C(O)N(R 7 )R 6 -, -NR 8 SOR 6 -, -NR 8 SO 2 R 6 -, optionally substituted C 1 -C 8 -alkylene, optionally substituted C 1 -C 8 -heteroalkylene, optionally substituted C 1 -C 8 -alkylene-O-C 1 -C 8 -alkylene, optionally substituted C 1 -C 8 -haloalkylene, optionally substituted C 1 -C 8 -hydroxyalkylene, optionally substituted C 1 -C 8 -alkylene-N(C 1 -C 8 -alkyl)-C 1 -C 8 -alkylene, optionally substituted C 3 -C 8 -carbocyclic group, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted C 2 -C 8 -alkenylene, optionally substituted C 2-C 8 Alkynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0256] R 6 Selected from the group consisting of empty, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 1 -C 8 Alkylene-O-, optionally substituted C 1 -C 8 Alkylene-N(C 1 -C 8 Alkyl)-, optionally substituted C 1 -C 8 Alkylene-O-C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylene-N(C 1 -C 8 Alkyl)-C 1 -C 8 Alkylene, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted C 3 -C 8 Carbocyclic group-O-, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl;

[0257] R 7 and R 8 are independently selected from the group consisting of empty, hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted heterocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3- to 8-membered carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl; or

[0258] R 6 and R 7 together with the atom to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring.

[0259] In another embodiment, R 4 and R 5 are independently selected from the group consisting of empty, optionally substituted

[0260] In another embodiment, R 4 and R 5 are independently selected from the group consisting of empty, optionally substituted

[0261] In another embodiment, -R 4 -R 5 - is selected from the group consisting of empty, optionally substituted

[0262] In another embodiment, -R 4 -R 5 - is optionally substituted

[0263] 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, NO 2 , OR 10 , NR 11 R 12 , COR 10 , CO 2 R 10 , CONR 11 R 12 , SOR 10 , SO 2 R 10 , SO 2 , NR 11 R 12 , NR 10 , COR 12 , NR 10 , C(O)NR 11 R 12 , NR 10 , SOR 12 , NR 10 , SO 2 R 12 , optionally substituted C 1 -C 6 , optionally substituted C 1 -C 6 , optionally substituted C 1 -C 6 , optionally substituted alkoxyalkyl, optionally substituted C 1 -C 6haloalkyl, optionally substituted C 1 -C 6 Hydroxyalkyl, optionally substituted C 1 -C 6 Alkylamino C 1 -C 6 Alkyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl and optionally substituted C 4 -C 5 Heteroaryl, wherein

[0264] R 10 , R 11 and R 12 are independently selected from the group consisting of null, hydrogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0265] 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.

[0266] In another embodiment, Ar is aryl, which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN and NO 2 .

[0267] In another embodiment, Ar is

[0268] In another embodiment, the TRK ligand comprises a moiety of Formula 3A:

[0269]

[0270] in

[0271] X 1 Selected from CR' and N;

[0272] R’ is selected from hydrogen, halogen, CN, NO 2 and optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, C 3 -C 6 carbocyclic group or 3- to 6-membered heterocyclic group;

[0273] X 2 and X 3 are each independently selected from C or N, provided that only one of X 2 and X 3 is N;

[0274] X is selected from a bond, C(R 2 ) 2 , C(R 2 ) 2 C(R 2 ) 2 , CO, C(R 2 ) 2 CO, NR 2 CO, OC(R 2 ) 2 and NR 2 C(R 2 ) 2 ;

[0275] R 1 and each R 2 is independently selected from hydrogen, halogen, OH, NH 2 , CN, NO 2 , optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkylamino, optionally substituted C 1 -C 4 alkoxyalkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 hydroxyalkyl, optionally substituted C 1 -C 4 alkylaminoC 1 -C 4 alkyl, optionally substituted C 3 -C 6 carbocyclic group, optionally substituted C3 -C 6 cycloalkyloxy and optionally substituted 3- to 6-membered heterocyclic group;

[0276] n is from 1 to 4;

[0277] R 3 selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 carbocyclic group, optionally substituted 3- to 6-membered heterocyclic group, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl and optionally substituted C 1 -C 6 alkylamino C 1 -C 6 alkyl;

[0278] R 4 directly or through R 5 connected to the linker moiety of the divalent compound;

[0279] R 4 and R 5 are independently selected from empty, -OR 6 -, -SR 6 -, -N(R 7 )R 6 -, -COR 6 -, -CO 2 R 6 -, -CON(R 7 )R 6 -, -SOR 6 -, -SO 2 R 6 -, -SO 2 N(R 7 )R 6 -, -NR 8 COR 6 -, -N(R 8 )C(O)N(R 7 )R 6 -, -NR 8 SOR 6 -, -NR 8 SO 2 R 6-, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkylene-O-C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted aryl and optionally substituted heteroaryl;

[0280] R 6 selected from the empty, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkylene-O-, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-, optionally substituted C 1 -C 8 alkylene-O-C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8Carbocyclic group -O-, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group;

[0281] R 7 and R 8 are independently selected from the group consisting of nothing, hydrogen, optionally substituted C 1 -C 8 alkyl group, optionally substituted C 1 -C 8 heteroalkyl group, optionally substituted C 2 -C 8 alkenyl group, optionally substituted C 2 -C 8 alkynyl group, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted heterocyclic group, optionally substituted arylalkyl group, optionally substituted heteroarylalkyl group, optionally substituted 3- to 8-membered carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group; or

[0282] R 6 and R 7 together with the atoms to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring;

[0283] Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO 2 、OR 10 、SR 10 、NR 11 R 12 、COR 10 、CO 2 R 10 、CONR 11 R 12 、SOR 10 、SO 2 R 10 、SO 2 NR 11 R 12 、NR 10 COR 12 、NR 10 C(O)NR 11 R 12 、NR 10 SOR 12 、NR 10 SO 2 R 12 、optionally substituted C 1 -C 8 alkyl group, optionally substituted C 1 -C 8Heteroalkyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0284] R 10 , R 11 and R 12 are independently selected from the group consisting of null, hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or

[0285] 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.

[0286] In one embodiment, X 1 and X 3 is selected from CR' and N, and R' is selected from hydrogen, F, Cl, CH 3 CF 3 and cyclopropyl.

[0287] In one embodiment, X 1 It is N.

[0288] In one embodiment, X 1 is CR' and R' is selected from hydrogen, F, Cl, CH 3 CF3 and cyclopropyl.

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

[0290] In one embodiment, X 3 is C and X 2 is N.

[0291] In another embodiment, X is selected from a bond, CH 2 , CH 2 CH 2 , CO, CH 2 CO, CONH, CONCH 3 , CH 2 O, CH 2 NH and CH 2 NCH 3 .

[0292] In another embodiment, X is CH 2 .

[0293] In another embodiment, R 1 and each R 2 is independently selected from hydrogen, F, Cl, OH, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkylamino, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 3 -C 6 carbocyclic, optionally substituted C 3 -C 6 cycloalkoxy and optionally substituted 3-6 membered heterocyclic group.

[0294] In another embodiment, R 1 and R 2 are hydrogen.

[0295] In another embodiment, R 3 is selected from hydrogen, CH 3 , CH 2 CH 3 , propyl, isopropyl, cyclopropyl, CH 2 F, CHF 2 and CF 3。

[0296] In another embodiment, R 3 is selected from hydrogen.

[0297] In another embodiment, R 4 is directly attached to the linker portion of the bivalent compound, and R 4 is selected from nothing, -OR 6 -, -SR 6 -, -N(R 7 )R 6 -, -COR 6 -, -CO 2 R 6 -, -CON(R 7 )R 6 -, -SOR 6 -, -SO 2 R 6 -, -SO 2 N(R 7 )R 6 -, -NR 8 COR 6 -, -N(R 8 )C(O)N(R 7 )R 6 -, -NR 8 SOR 6 -, -NR 8 SO 2 R 6 -, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkylene-O-C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclic, optionally substituted 3-8 membered carbocyclic, optionally substituted 3-8 membered heterocyclic, optionally substituted C 2 -C8 Vinylene, optionally substituted C 2 -C 8 Ethynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0298] R 6 Selected from the group consisting of empty, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 1 -C 8 Alkylene - O -, optionally substituted C 1 -C 8 Alkylene - N(C 1 -C 8 Alkyl)-, optionally substituted C 1 -C 8 Alkylene - O - C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylene - N(C 1 -C 8 Alkyl)-C 1 -C 8 Alkylene, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted C 3 -C 8 Carbocyclic group - O -, optionally substituted 3 - 8 - membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl; and

[0299] R 7 and R 8 Independently selected from the group consisting of empty, hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted heterocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3 - 8 - membered carbocyclic group, optionally substituted 3 - 8 - membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl; or

[0300] R 6 and R 7Optionally form a 3- to 8-membered carbocyclic or heterocyclic ring together with the atoms to which they are attached.

[0301] In another embodiment, R 4 is attached to the linker moiety of the divalent compound through R 5 , and R 4 and R 5 are independently selected from the group consisting of nothing, -OR 6 -, -SR 6 -, -N(R 7 )R 6 -, -COR 6 -, -CO 2 R 6 -, -CON(R 7 )R 6 -, -SOR 6 -, -SO 2 R 6 -, -SO 2 N(R 7 )R 6 -, -NR 8 COR 6 -, -N(R 8 )C(O)N(R 7 )R 6 -, -NR 8 SOR 6 -, -NR 8 SO 2 R 6 -, optionally substituted C 1 -C 8 -alkylene, optionally substituted C 1 -C 8 -heteroalkylene, optionally substituted C 1 -C 8 -alkylene-O-C 1 -C 8 -alkylene, optionally substituted C 1 -C 8 -haloalkylene, optionally substituted C 1 -C 8 -hydroxyalkylene, optionally substituted C 1 -C 8 -alkylene-N(C 1 -C 8 -alkyl)-C 1 -C 8 -alkylene, optionally substituted C 3 -C 8 -carbocyclic, optionally substituted 3- to 8-membered carbocyclic, optionally substituted 3- to 8-membered heterocyclic, optionally substituted C 2 -C8 Vinylene, optionally substituted C 2 -C 8 Ethynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0302] R 6 Selected from the group consisting of empty, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 1 -C 8 Alkylene - O -, optionally substituted C 1 -C 8 Alkylene - N(C 1 -C 8 Alkyl)-, optionally substituted C 1 -C 8 Alkylene - O - C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylene - N(C 1 -C 8 Alkyl)-C 1 -C 8 Alkylene, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted C 3 -C 8 Carbocyclic group - O -, optionally substituted 3 - 8 - membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl;

[0303] R 7 and R 8 Independently selected from the group consisting of empty, hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted heterocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3 - 8 - membered carbocyclic group, optionally substituted 3 - 8 - membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl; or

[0304] R 6 and R 7Optionally form, together with the atoms to which they are attached, a 3- to 8-membered carbocyclic or 3- to 8-membered heterocyclic ring;

[0305] In another embodiment, R 4 and R 5 are independently selected from the group consisting of empty, optionally substituted

[0306] In another embodiment, R 4 and R 5 are independently selected from the group consisting of empty, optionally substituted

[0307] In another embodiment, -R 4 -R 5 - is selected from the group consisting of empty, optionally substituted

[0308] In another embodiment, -R 4 -R 5 - is optionally substituted

[0309] 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, NO 2 , OR 10 , NR 11 R 12 , COR 10 , CO 2 R 10 , CONR 11 R 12 , SOR 10 , SO 2 R 10 , SO 2 , NR 11 R 12 , NR 10 , COR 12 , NR 10 , C(O)NR 11 R 12 , NR 10 , SOR 12 , NR 10 , SO 2 R 12 , optionally substituted C 1 -C 6 , optionally substituted C 1 -C 6 , optionally substituted C 1 -C6 Alkoxyalkyl, optionally substituted C 1 -C 6 Haloalkyl, optionally substituted C 1 -C 6 Hydroxyalkyl, optionally substituted C 1 -C 6 Alkylamino C 1 -C 6 Alkyl, optionally substituted C 3 -C 7 Carbocyclic group, optionally substituted 3- to 7-membered heterocyclic group, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted aryl and optionally substituted C 4 -C 5 Heteroaryl, wherein

[0310] R 10 , R 11 and R 12 are independently selected from the group consisting of empty, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3- to 7-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, or

[0311] R 11 and R 12 together with the atoms to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring.

[0312] In another embodiment, Ar is an aryl optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, and NO 2 .

[0313] In another embodiment, Ar is

[0314] In another embodiment, the TRK ligand comprises a moiety of Formula 12-1 or 12-2:

[0315]

[0316] wherein

[0317] X is selected from CR 5 and N;

[0318] Y is selected from O, S and NR 6 ;

[0319] R 1 、R 3 and R 4 are independently selected from hydrogen, halogen, CN, NO 2 、OR 7 、SR 7 、NR 8 R 9 、COR 7 、CO 2 R 7 、CONR 8 R 9 、SOR 7 、SO 2 R 7 、SO 2 NR 8 R 9 、NR 10 COR 9 、NR 10 C(O)NR 8 R 9 、NR 10 SOR 9 、NR 10 SO 2 R 9 、optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted 3-8 membered carbocyclic group-C 1 -C 8 alkyl, optionally substituted 3-8 membered heterocyclic group-C 1 -C8 alkyl, optionally substituted 3-8 membered carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl-O, and optionally substituted 3-8 membered carbocyclyl-N(C 1 -C 8 alkyl)-, optionally substituted 3-8 membered heterocyclyl-N(C 1 -C 8 alkyl)-, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0320] R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of null, hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 3 -C 8 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-C 1 -C 8 alkyl, optionally substituted 3-8 membered heterocyclyl-C 1 -C 8 alkyl, optionally substituted 3-8 membered carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl-O, optionally substituted 3-8 membered carbocyclyl-N(C 1 -C 8 alkyl)-, and optionally substituted 3-8 membered heterocyclyl-N(C 1 -C 8 alkyl)-, optionally substituted aryl and optionally substituted heteroaryl; or

[0321] R 8 and R 9 together with the atoms to which they are attached, optionally form a 3-8 membered carbocyclyl or heterocyclyl ring;

[0322] R 1 '、R 2 and R 4 'Independently selected from empty, -OR 11-,-SR 11 -,-NR 12 R 11 -,-COR 11 -,-CO 2 R 11 -,-CON(R 12 )R 11 -,-SOR 11 -,-SO 2 R 11 -,-SO 2 N(R 12 )R 11 -,-NR 13 COR 11 -,-NR 13 C(O)N(R 12 )R 11 -,-NR 13 SOR 11 -,-NR 13 SO 2 R 11 -,-Optionally substituted C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 1 -C 8 Alkylene-O-C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Halogenated alkylene, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 1 -C 8 Alkylene-N(C 1 -C 8 Alkyl)-C 1 -C 8 Alkylene, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted 3-8 membered carbocyclic group-C 1 -C 8 Alkylene, optionally substituted 3-8 membered heterocyclic group-C 1 -C 8 Alkylene, optionally substituted 3-8 membered carbocyclic group-O-, optionally substituted 3-8 membered heterocyclic group-O, optionally substituted 3-8 membered carbocyclic group-N(C 1 -C 8 Alkyl)-, and optionally substituted 3-8 membered heterocyclic group-N(C1 -C 8 -alkyl)-, optionally substituted C 2 -C 8 -alkenylene, optionally substituted C 2 -C 8 -alkynylene, optionally substituted aryl and optionally substituted heteroaryl;

[0323] R 11 is selected from the group consisting of empty, optionally substituted C 1 -C 8 -alkylene, optionally substituted C 1 -C 8 -heteroalkylene, optionally substituted C 1 -C 8 -alkylene-O-, optionally substituted C 1 -C 8 -alkylene-N(C 1 -C 8 -alkyl)-, optionally substituted C 1 -C 8 -alkylene-O-alkylene, optionally substituted C 1 -C 8 -alkylene-N(C 1 -C 8 -alkyl)-C 1 -C 8 -alkylene, optionally substituted C 3 -C 8 -carbocyclylene, optionally substituted C 3 -C 8 -carbocyclylene-O-, optionally substituted 3-8 membered carbocyclic ring-C 1 -C 8 -alkylene, optionally substituted 3-8 membered heterocyclic ring-C 1 -C 8 -alkylene, optionally substituted 3-8 membered carbocyclic ring, optionally substituted 3-8 membered heterocyclic ring, optionally substituted aryl and optionally substituted heteroaryl;

[0324] R 12 and R 13 are independently selected from the group consisting of empty, hydrogen, optionally substituted C 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -heteroalkylene, optionally substituted C 2 -C 8 -alkenyl, optionally substituted C 2 -C 8 -alkynyl, optionally substituted C 3 -C 8Carbocyclic group, optionally substituted heterocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclic group-C 1 -C 8 alkyl, optionally substituted 3-8 membered heterocyclic group-C 1 -C 8 alkyl, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; or

[0325] R 11 and R 12 together with the atom to which they are attached optionally form a 3-8 membered carbocyclic or heterocyclic ring;

[0326] R 5 and R 6 each occurrence is independently selected from hydrogen, halogen, CN, NO 2 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8 carbocyclic group and optionally substituted C 3 -C 8 heterocyclic group; and

[0327] n is selected from 0, 1 and 2.

[0328] In another embodiment, X is selected from CH, CF and N.

[0329] In another embodiment, X is CH.

[0330] In another embodiment, X is CF.

[0331] In another embodiment, X is N.

[0332] In another embodiment, Y is selected from O and S.

[0333] In another embodiment, Y is O.

[0334] In another embodiment, Y is S.

[0335] In another embodiment, R 1Selected from optionally substituted acyclic amino groups, optionally substituted cyclic amino groups, optionally substituted phenyl groups, and optionally substituted heteroaryl groups.

[0336] In another embodiment, R 1 is selected from optionally substituted

[0337] In another embodiment, R 1 ' is selected from the empty group, optionally substituted acyclic amino groups, optionally substituted cyclic amino groups, optionally substituted phenyl groups, and optionally substituted heteroaryl groups.

[0338] In another embodiment, R 1 ' is selected from optionally substituted

[0339] In another embodiment, R 2 is selected from the empty group, -O-, -S-, -N(R 12 )-, -C(O)-, -CO 2 -,-CON(R 12 )-,-SO-,-SO 2 -,-SO 2 N(R 12 )-,-N(R 13 )CO-,-N(R 13 )C(O)N(R 12 )-,-N(R 13 )SO-,-N(R 13 )SO 2 - optionally substituted optionally substituted C 3 -C 8 carbocyclic groups and optionally substituted C 3 -C 8 heterocyclic groups, where

[0340] R 12 and R 13 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl groups, optionally substituted C 1 -C 8 heteroalkyl groups, optionally substituted C 2 -C 8 alkenyl groups, optionally substituted C 2 -C 8 alkynyl groups, optionally substituted C 3 -C 8A carbocyclic group, an optionally substituted heterocarbocyclic group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted 3- to 8-membered carbocyclic group, an optionally substituted 3- to 8-membered heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group.

[0341] In another embodiment, R 2 is selected from the group consisting of nothing, -CONH-,

[0342] In another embodiment, R 3 is selected from the group consisting of hydrogen, halogen, CN, NO 2 , OH, NH 2 , -CONH-,

[0343] In another embodiment, R 2 -R 3 is selected from the group consisting of hydrogen, halogen, CN, NO 2 ,

[0344] In another embodiment, R 4 is selected from the group consisting of hydrogen, halogen, CN, NO 2 , an optionally substituted C 1 -C 8 alkyl group, an optionally substituted C 1 -C 8 heteroalkyl group, an optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl group, an optionally substituted C 1 -C 8 haloalkyl group, an optionally substituted C 1 -C 8 hydroxyalkyl group, an optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl group, an optionally substituted C 3 -C 8 carbocyclic group, an optionally substituted 3- to 8-membered carbocyclic group-C 1 -C 8 alkyl group, an optionally substituted 3- to 8-membered heterocyclic group-C 1 -C 8 alkyl group, an optionally substituted 3- to 8-membered carbocyclic group, and an optionally substituted 3- to 8-membered heterocyclic group, an optionally substituted 3- to 8-membered carbocyclic group-C 1 -C 8 alkyl group, and an optionally substituted 3- to 8-membered heterocyclic group-C 1 -C8 alkyl, optionally substituted 3- to 8-membered carbocyclic group -O-, optionally substituted 3- to 8-membered heterocyclic group -O-, optionally substituted 3- to 8-membered carbocyclic group -N(C 1 -C 8 alkyl)-, and optionally substituted 3- to 8-membered heterocyclic group -N(C 1 -C 8 alkyl)-.

[0345] In another embodiment, R 4 is selected from hydrogen, halogen, CN, NO 2 , OCH 3 ,

[0346] In another embodiment, R 4 ’ is selected from empty, -O-, -S-, -N(R 12 ’)-, -C(O)-, -CO 2 -, -CON(R 12 ’)-, -SO-, -SO 2 -, -SO 2 N(R 12 ’)-, -N(R 12 ’)CO-, -N(R 13 ’)C(O)N(R 12 ’)-, -N(R 13 ’)SO-, -N(R 13 ’)SO 2 -, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkylene -O-C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkylene -N(C 1 -C 8 alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted 3- to 8-membered carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted 3- to 8-membered carbocyclic group -C1 -C 8 Alkylene and optionally substituted 3-8 membered heterocyclic group-C 1 -C 8 Alkylene, optionally substituted 3-8 membered carbocyclic group-O-, optionally substituted 3-8 membered heterocyclic group-O-, optionally substituted 3-8 membered carbocyclic group-N(C 1 -C 8 Alkyl)- and optionally substituted 3-8 membered heterocyclic group-N(C 1 -C 8 Alkyl)-, wherein

[0347] R 12 ’ and R 13 ’ are independently selected from hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted heterocarbocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl.

[0348] In another embodiment, R 4 ’ is selected from empty, -O-, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 1 -C 8 Alkylene-O-C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylene-N(C 1 -C 8 Alkyl)-C 1 -C 8 Alkylene, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted 3-8 membered carbocyclic group-C 1 -C 8 Alkylene, and optionally substituted 3-8 membered heterocyclic group-C 1 -C 8Alkylene, optionally substituted 3-8-membered carbocyclic group -O-, optionally substituted 3-8-membered heterocyclic group -O-, optionally substituted 3-8-membered carbocyclic group -N(C 1 -C 8 -alkyl)- and optionally substituted 3-8-membered heterocyclic group -N(C 1 -C 8 -alkyl)-.

[0349] In another embodiment, R 4 ' is selected from the group consisting of empty, -O-,

[0350] In another embodiment, the TRK ligand comprises a moiety of Formula 13:

[0351]

[0352] wherein

[0353] X is selected from CR 9 and N;

[0354] R 9 is selected from hydrogen, halogen, CN, NO 2 , optionally substituted C 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -heteroalkyl, optionally substituted C 1 -C 8 -alkoxy, optionally substituted C 1 -C 8 -alkylamino, optionally substituted C 3 -C 8 -carbocyclic group, optionally substituted C 3 -C 8 -carbocyclic group and optionally substituted C 3 -C 8 -heterocyclic group;

[0355] Y is selected from the group consisting of empty, -O-, -N(optionally substituted C 1 -C 8 -alkyl)- and optionally substituted C 1 -C 8 -alkylene;

[0356] R 1 and R 2 are independently selected from hydrogen, halogen, CN, NO 2 , OH, NH 2 , optionally substituted C 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -heteroalkyl, optionally substituted C1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkylamino, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted C 3 -C 8 The carbocyclic group and the optionally substituted C 3 -C 8 Heterocyclic group;

[0357] R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, halogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted C 3 -C 8 The carbocyclic group and the optionally substituted C 3 -C 8 heterocyclic group; or

[0358] 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;

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

[0360] n is selected from 0, 1, 2, 3 and 4;

[0361] R 7 and R 8 Independently selected from null, -OR 10 -、-SR 10 -、-NR 11 R 10 -、-COR 10 -、-CO 2 R 10 -、-CONR 11 R 10 -、-SOR 10 -、-SO 2 R 10 -、-SO 2 NR 11 R 10 -、-NR 12 COR10 -,-NR 12 C(O)NR 11 R 10 -,-NR 12 SOR 10 -,-NR 12 SO 2 R 10 -,optionally substituted C 1 -C 8 alkylene,optionally substituted C 1 -C 8 heteroalkylene,optionally substituted C 1 -C 8 alkylene-O-C 1 -C 8 alkylene,optionally substituted C 1 -C 8 haloalkylene,optionally substituted C 1 -C 8 hydroxyalkylene,optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-C 1 -C 8 alkylene,optionally substituted C 3 -C 8 carbocyclic group,optionally substituted 3-8 membered carbocyclic group,optionally substituted 3-8 membered heterocyclic group,optionally substituted 3-8 membered carbocyclic group-C 1 -C 8 alkylene,optionally substituted 3-8 membered heterocyclic group-C 1 -C 8 alkylene,optionally substituted 3-8 membered carbocyclic group-O-,optionally substituted 3-8 membered heterocyclic group-O,optionally substituted 3-8 membered carbocyclic group-N(C 1 -C 8 alkyl)-,optionally substituted 3-8 membered heterocyclic group-N(C 1 -C 8 alkyl)-,optionally substituted C 2 -C 8 alkenylene,and optionally substituted C 4 -C 13 fused carbocyclic group,optionally substituted 5-13 membered fused heterocyclic group,optionally substituted C 5 -C 13 bridged carbocyclic group,optionally substituted 5-13 membered bridged heterocyclic group,optionally substituted C 5 -C 13 spirocarbocyclic group,optionally substituted 5-13 membered spiroheterocyclic group,optionally substituted C 2 -C 8Alkynylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0362] R 10 Selected from the group consisting of nothing, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkylene - O -, optionally substituted C 1 -C 8 alkylene - N(C 1 -C 8 alkyl)-, optionally substituted C 1 -C 8 alkylene - O - alkylene, optionally substituted C 1 -C 8 alkylene - N(C 1 -C 8 alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclylene, optionally substituted C 3 -C 8 carbocyclylene - O -, optionally substituted 3 - 8 - membered carbocyclic - C 1 -C 8 alkylene, optionally substituted 3 - 8 - membered heterocyclic - C 1 -C 8 alkylene, optionally substituted 3 - 8 - membered carbocyclic, optionally substituted 3 - 8 - membered heterocyclic, optionally substituted C 4 -C 13 fused carbocyclic, optionally substituted 5 - 13 - membered fused heterocyclic, optionally substituted C 5 -C 13 bridged carbocyclic, optionally substituted 5 - 13 - membered bridged heterocyclic, optionally substituted C 5 -C 13 spirocarbocyclic, optionally substituted 5 - 13 - membered spiroheterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;

[0363] R 11 and R 12 are independently selected from the group consisting of nothing, hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8Carbocyclic group, optionally substituted heterocarbocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3- to 8-membered carbocyclic group-C 1 -C 8 alkyl, optionally substituted 3- to 8-membered heterocyclic group-C 1 -C 8 alkyl, optionally substituted C 3 -C 8 carbocyclic group-O-, optionally substituted 3- to 8-membered carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; or

[0364] R 10 and R 11 together with the atom to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring; and

[0365] Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO 2 、OR 14 、SR 14 、NR 15 R 16 、COR 14 、CO 2 R 14 、CONR 15 R 16 、SOR 14 、SO 2 R 14 、SO 2 NR 15 R 16 、NR 14 COR 16 、NR 14 C(O)NR 15 R 16 、NR 14 SOR 16 、NR 14 SO 2 R 16 、optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C8 Heteroalkyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0366] R 14 , R 15 and R 16 are independently selected from the group consisting of null, hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; or

[0367] 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.

[0368] In another embodiment, the TRK ligand comprises a moiety of Formula 13-1:

[0369]

[0370] in

[0371] X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R7 , R 8 , Ar, m, and n are defined in Formula 13.

[0372] In another embodiment, the TRK ligand comprises a moiety of Formula 13-2:

[0373]

[0374] wherein

[0375] 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.

[0376] In another embodiment, X is selected from CH, CF, and N.

[0377] In another embodiment, X is N.

[0378] In another embodiment, Y is selected from -O-, -CH 2 -, and -NH-.

[0379] In another embodiment, Y is -O-.

[0380] In another embodiment, R 1 is selected from hydrogen and NH 2 .

[0381] In another embodiment, R 1 is NH 2 .

[0382] In another embodiment, R 2 is selected from hydrogen, halogen, CN, NO 2 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 carbocyclic group, and optionally substituted C 1 -C 8 alkoxy.

[0383] In another embodiment, R 2 is selected from H, F, Cl, Br, OCH 3 , OCF 3 , and OCHF 2 .

[0384] In another embodiment, R 2 is OCH 3 .

[0385] In another embodiment, R 3 , R 4 , R 5 and R 6 are independently selected from H, F, CH 3 , cyclopropyl, and cyclobutyl.

[0386] In another embodiment, R 3 and R 4 ; and / or R 5 and R 6 optionally form, together with the atoms to which they are attached, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0387] In another embodiment, R 3 , R 4 , R 5 and R 6 are H.

[0388] In another embodiment, R 7 is selected from the empty group, an optionally substituted 3- to 8-membered carbocyclic group, an optionally substituted 3- to 8-membered heterocyclic group, an optionally substituted C 4 -C 13 fused carbocyclic group, an optionally substituted 5- to 13-membered fused heterocyclic group, an optionally substituted C 5 -C 13 bridged carbocyclic group, an optionally substituted 5- to 13-membered bridged heterocyclic group, an optionally substituted C 5 -C 13 spirocarbocyclic group, an optionally substituted 5- to 13-membered spiroheterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group.

[0389] In another embodiment, R 7 is selected from the empty group,

[0390] In another embodiment, R 8 is selected from the empty group, -C(O)-, -C(O)-NH-, an optionally substituted 3- to 8-membered carbocyclic group, an optionally substituted 3- to 8-membered heterocyclic group, an optionally substituted C 4 -C 13 fused carbocyclic group, an optionally substituted 5- to 13-membered fused heterocyclic group, an optionally substituted C 5 -C 13 bridged carbocyclic group, an optionally substituted 5- to 13-membered bridged heterocyclic group, an optionally substituted C 5 -C 13Spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group.

[0391] In another embodiment, R 8 is selected from the group consisting of void, -C(O)-, -C(O)-NH-,

[0392] In another embodiment, R 7 -R 8 is selected from the group consisting of void,

[0393] In another embodiment, Ar is selected from an optionally substituted phenyl group and an optionally substituted pyridyl group.

[0394] In another embodiment, Ar is selected from

[0395] In another embodiment, the TRK ligand is derived from any one of the following:

[0396]

[0397] 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.

[0398] In another embodiment, the TRK ligand is selected from:

[0399]

[0400] In some embodiments, the degradation tag is a moiety selected from Formulas 5A, 5B, 5C, and 5D:

[0401]

[0402] wherein

[0403] V, W, and X are independently selected from CR 2 and N;

[0404] Y is selected from CO, CR 3 R 4 and N=N;

[0405] Z is selected from void, CO, CR 5 R 6 NR 5 O, an optionally substituted C 1 -C10 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 1 -C 10 Alkenylene, optionally substituted C 1 -C 10 Alkynylene, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C 13 Fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 Bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; preferably, Z is selected from the group consisting of empty, CH 2 , CH═CH, C≡C, NH, O, optionally substituted 3- to 7-membered carbocyclic group and optionally substituted 3- to 7-membered heterocyclic group;

[0406] R 1 is selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered carbocyclic group and optionally substituted 3- to 6-membered heterocyclic group;

[0407] R 2 is selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkylamino, optionally substituted 3- to 6-membered carbocyclic group and optionally substituted 3- to 6-membered heterocyclic group;

[0408] R 3 and R 4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered carbocyclic group and optionally substituted 3- to 6-membered heterocyclic group; or R 3 and R 4form a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group together with the atoms to which they are attached; and

[0409] R 5 and R 6 are independently selected from the group consisting of empty, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered carbocyclic group and optionally substituted 3- to 6-membered heterocyclic group; or R 5 and R 6 form a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group together with the atoms to which they are attached.

[0410] In some embodiments, the degradation tag is a moiety selected from Formulas 5E, 5F, 5G, 5H, 5I, 5J, 5K, 5L, 5M, 5N, 5O, 5P, and 5Q:

[0411]

[0412]

[0413] wherein

[0414] U, V, W, X, and X' are independently selected from CR 2 and N;

[0415] Y is selected from CR 3 R 4 , NR 3 and O; preferably, Y is selected from CH 2 , NH, NCH 3 and O;

[0416] Y', Y", and Y"' are independently selected from CR 3 R 4 ;

[0417] Z is selected from the group consisting of empty, CO, CR 5 R 6 , NR 5 , O, optionally substituted C 1 -C 10 alkylene, optionally substituted C 1 -C 10 heteroalkylene, optionally substituted C 1 -C 10 alkenylene, optionally substituted C 1 -C 10 alkynylene, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C13 Fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 Bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group; preferably, Z is selected from the group consisting of empty, CH 2 , CH═CH, C≡C, NH, O, optionally substituted 3- to 7-membered carbocyclic group, and optionally substituted 3- to 7-membered heterocyclic group;

[0418] R 1 independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl group, optionally substituted C 1 -C 6 heteroalkyl group, optionally substituted 3- to 6-membered carbocyclic group, and optionally substituted 3- to 6-membered heterocyclic group;

[0419] R 2 is selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl group, optionally substituted C 1 -C 6 heteroalkyl group, optionally substituted C 1 -C 6 alkoxy group, optionally substituted C 1 -C 6 alkylamino group, optionally substituted 3- to 6-membered carbocyclic group, and optionally substituted 3- to 6-membered heterocyclic group;

[0420] R 3 and R 4 independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl group, optionally substituted C 1 -C 6 heteroalkyl group, optionally substituted 3- to 6-membered carbocyclic group, and optionally substituted 3- to 6-membered heterocyclic group, or

[0421] R 3 and R 4 optionally form, together with the atom to which they are attached, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group; and

[0422] R 5 and R 6 independently selected from the group consisting of empty, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 6 alkyl group, optionally substituted C1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered carbocyclic group, and optionally substituted 3- to 6-membered heterocyclic group; or R 5 and R 6 together with the atom to which they are attached form a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group.

[0423] In one embodiment, the degradation tag is a moiety of Formula 6A:

[0424]

[0425] wherein

[0426] R 1 and R 2 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 aminoalkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3- to 7-membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 2 -C 8 alkynyl; and

[0427] R 3 is hydrogen, optionally substituted C(O)C 1 -C 8 alkyl, optionally substituted C(O)C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C(O)C 1 -C 8 haloalkyl, optionally substituted C(O)C 1 -C 8Hydroxyalkyl, optionally substituted C(O)C 1 -C 8 Aminoalkyl, optionally substituted C(O)C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C(O)C 3 -C 7 Carbocyclic group, optionally substituted C(O)(3-7 membered heterocyclic group), optionally substituted C(O)C 2 -C 8 Alkenyl, optionally substituted C(O)C 2 -C 8 Alkynyl, optionally substituted C(O)OC 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C(O)OC 1 -C 8 Halogenated alkyl, optionally substituted C(O)OC 1 -C 8 Hydroxyalkyl, optionally substituted C(O)OC 1 -C 8 Aminoalkyl, optionally substituted C(O)OC 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C(O)OC 3 -C 7 Carbocyclic group, optionally substituted C(O)O(3-7 membered heterocyclic group), optionally substituted C(O)OC 2 -C 8 Alkenyl, optionally substituted C(O)OC 2 -C 8 Alkynyl, optionally substituted C(O)NC 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C(O)NC 1 -C 8 Halogenated alkyl, optionally substituted C(O)NC 1 -C 8 Hydroxyalkyl, optionally substituted C(O)NC 1 -C 8 Aminoalkyl, optionally substituted C(O)NC 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C(O)NC 3 -C7 Carbocyclic group, optionally substituted C(O)N(3-7-membered heterocyclic group), optionally substituted C(O)NC 2 -C 8 Alkenyl, optionally substituted C(O)NC 2 -C 8 Alkynyl, optionally substituted P(O)(OH) 2 、optionally substituted P(O)(OC 1 -C 8 alkyl) 2 and optionally substituted P(O)(OC 1 -C 8 aryl) 2 。

[0428] In one embodiment, the degradation tag is a moiety selected from Formulas 6B, 6C, 6D, 6E, and 6F:

[0429]

[0430]

[0431] wherein

[0432] R 1 and R 2 are independently selected from hydrogen, halogen, OH, NH 2 , CN, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 aminoalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3-7-membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl and optionally substituted C 2 -C 8 alkynyl; (preferably, R 1Selected from isopropyl or tert-butyl; and R 2 is selected from hydrogen or methyl);

[0433] R 3 is hydrogen, optionally substituted C(O)C 1 -C 8 alkyl, optionally substituted C(O)C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C(O)C 1 -C 8 haloalkyl, optionally substituted C(O)C 1 -C 8 hydroxyalkyl, optionally substituted C(O)C 1 -C 8 aminoalkyl, optionally substituted C(O)C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C(O)C 3 -C 7 carbocyclic group, optionally substituted C(O)(3-7 membered heterocyclic group), optionally substituted C(O)C 2 -C 8 alkenyl, optionally substituted C(O)C 2 -C 8 alkynyl, optionally substituted C(O)OC 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C(O)OC 1 -C 8 haloalkyl, optionally substituted C(O)OC 1 -C 8 hydroxyalkyl, optionally substituted C(O)OC 1 -C 8 aminoalkyl, optionally substituted C(O)OC 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C(O)OC 3 -C 7 carbocyclic group, optionally substituted C(O)O(3-7 membered heterocyclic group), optionally substituted C(O)OC 2 -C 8 alkenyl, optionally substituted C(O)OC 2 -C 8 alkynyl, optionally substituted C(O)NC 1 -C8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C(O)NC 1 -C 8 Halogenoalkyl, optionally substituted C(O)NC 1 -C 8 Hydroxyalkyl, optionally substituted C(O)NC 1 -C 8 Aminoalkyl, optionally substituted C(O)NC 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C(O)NC 3 -C 7 Carbocyclic group, optionally substituted C(O)N(3-7 membered heterocyclic group), optionally substituted C(O)NC 2 -C 8 Alkenyl, optionally substituted C(O)NC 2 -C 8 Alkynyl, optionally substituted P(O)(OH) 2 、Optionally substituted P(O)(OC 1 -C 8 Alkyl) 2 And optionally substituted P(O)(OC 1 -C 8 Aryl) 2 ; And

[0434] R 4 And R 5 Are independently selected from hydrogen, COR 6 、CO 2 R 6 、CONR 6 R 7 、SOR 6 、SO 2 R 6 、SO 2 NR 6 R 7 、Optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8alkyl, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted aryl group and optionally substituted heteroaryl group, wherein

[0435] R 6 and R 7 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted aryl group and optionally substituted heteroaryl group, or

[0436] R 4 and R 5 ; or R 6 and R 7 together with the atoms to which they are attached form a 3-8 membered carbocyclic or heterocyclic ring;

[0437] Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO 2 、OR 8 、NR 8 R 9 、COR 8 、CO 2 R 8 、CONR 8 R 9 、SOR 8 、SO 2 R 8 、SO 2 NR 8 R 9 、NR 10 COR 8 、NR 10 C(O)NR 8 R 9 、NR 10 SOR 8 、NR 10 SO 2 R 8 、optionally substituted C 1-C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkylamino C 1 -C 6 alkyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3-7 membered heterocyclic group, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl and optionally substituted C 4 -C 5 heteroaryl, wherein

[0438] R 8 、R 9 and R 10 are independently selected from the empty, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3-7 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, or

[0439] R 8 and R 9 together with the atoms to which they are attached optionally form a 3-8 membered carbocyclic or heterocyclic ring.

[0440] In another embodiment, the degradation tag is part of Formula 7A:

[0441]

[0442] wherein

[0443] V, W, X and Z are independently selected from CR 4 and N.

[0444] R1 , R 2 , R 3 and R 4 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3- to 7-membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl and optionally substituted C 2 -C 8 alkynyl.

[0445] In another embodiment, the degradation tag is part of Formula 7B:

[0446]

[0447] wherein

[0448] R 1 , R 2 and R 3 are independently selected from hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3- to 7-membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl and optionally substituted C 2 -C 8 alkynyl;

[0449] R 4 and R5 independently selected from hydrogen, COR 6 , CO 2 R 6 , CONR 6 R 7 , SOR 6 , SO 2 R 6 , SO 2 , SONR 6 R 7 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted aryl-C 1 -C 8 alkyl, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0450] R 6 and R 7 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, or

[0451] R 6 and R 7 together with the atom to which they are attached form a 3-8 membered carbocyclic or heterocyclic ring.

[0452] In another embodiment, the degradation tag is derived from any one of the following:

[0453]

[0454] In another embodiment, the degron is derived from any one 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.

[0455] In another embodiment, the degron is selected from:

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463] In another embodiment, the degradation tag is selected from: 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, 8HN, 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, 8IO, 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.

[0464] In some embodiments, the linker moiety has Formula 9:

[0465]

[0466] Wherein

[0467] A, W and B are independently selected at each occurrence from a null or a divalent moiety selected from R'-R", R'COR", R'CO 2 R”、R'C(O)N(R 1 )R”、R'C(S)N(R 1 )R", R'OR", R'SR", R'SOR", R'SO 2 R”、R’SO 2 N(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 C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C 5 -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

[0468] R' and R" are independently selected from empty, optionally substituted (C 1 -C 8 Alkylene)-R r (Preferably, CH 2 -R r ), optionally substituted R r -(C 1 -C 8(alkylene), optionally substituted C 1 -C 8 (alkylene)-R r -(C 1 -C 8 (alkyl), or a moiety selected from the group consisting of: optionally substituted C 1 -C 8 (alkyl), optionally substituted C 1 -C 8 (heteroalkyl), optionally substituted C 2 -C 8 (alkenyl), optionally substituted C 2 -C 8 (alkynyl), optionally substituted C 1 -C 8 (hydroxyalkyl), optionally substituted C 1 -C 8 (alkoxyC 1 -C 8 (alkyl), optionally substituted C 1 -C 8 (alkylaminoC 1 -C 8 (alkyl), optionally substituted C 1 -C 8 (haloalkyl), optionally substituted C 1 -C 8 (alkylene), optionally substituted C 1 -C 8 (heteroalkylene), optionally substituted C 2 -C 8 (alkenylene), optionally substituted C 2 -C 8 (alkynylene), optionally substituted C 1 -C 8 (hydroxyalkylene), optionally substituted C 1 -C 8 (alkoxyC 1 -C 8 (alkylene), optionally substituted C 1 -C 8 (alkylaminoC 1 -C 8 (alkylene), optionally substituted C 1 -C 8 (haloalkylene), optionally substituted 3-10 membered carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted C 4 -C 13 (fused carbocyclic group), optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C 5 -C 13 (bridged carbocyclic group), optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C 5-C 13 Spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group;

[0469] R r Selected from optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C 13 Fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 Bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group;

[0470] R 1 and R 2 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl group, optionally substituted C 1 -C 8 heteroalkyl group, optionally substituted C 2 -C 8 alkenyl group, optionally substituted C 2 -C 8 alkynyl group, optionally substituted C 1 -C 8 alkoxyalkyl group, optionally substituted C 1 -C 8 haloalkyl group, optionally substituted C 1 -C 8 hydroxyalkyl group, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl group, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group;

[0471] R’ and R”, R 1 and R 2 、R’ and R 1 、R’ and R 2 、R” and R 1 or R” and R 2 optionally form, together with the atom to which they are attached, a 3- to 20-membered carbocyclic group or 3- to 20-membered heterocyclic group ring; and

[0472] m is from 0 to 15.

[0473] In one embodiment, the linker moiety has the formula 9A:

[0474]

[0475] wherein

[0476] R 1 、R 2 、R 3 and R 4 are each independently selected, at each occurrence, from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino, and optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclic group, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclic amino, optionally substituted 3-8 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, or

[0477] 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 carbocyclic or 3-20 membered heterocyclic ring;

[0478] A, W and B are each independently selected, at each occurrence, from empty or a divalent moiety selected from R'-R", R'COR", R'CO 2 R", R'C(O)N(R 5 )R", R'C(S)N(R 5 )R", R'OR", R'SR", R'SOR", R'SO 2 R", R'SO 2 N(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 C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5 - 13 - membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5 - 13 - membered bridged heterocyclic group, optionally substituted C 5 -C 13 spirocarbocyclic group, optionally substituted 5 - 13 - membered spiroheterocyclic group, optionally substituted 3 - 10 - membered carbocyclic group, optionally substituted 3 - 10 - membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0479] R’ and R” are independently selected from the empty set, optionally substituted (C 1 -C 8 alkylene)-R r (preferably, CH 2 -R r ), optionally substituted R r -(C 1 -C 8 alkylene), optionally substituted (C 1 -C 8 alkylene)-R r -(C 1 -C 8 alkylene), or selected from moieties comprising: optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Haloalkyl, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkynylene, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Haloalkylene, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C 13 Fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 Bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0480] R r Selected from optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C 13 Fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C5 -C 13 Bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group;

[0481] R 5 and R 6 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl group, optionally substituted C 1 -C 8 heteroalkyl group, optionally substituted C 2 -C 8 alkenyl group, optionally substituted C 2 -C 8 alkynyl group, optionally substituted C 1 -C 8 alkoxyalkyl group, optionally substituted C 1 -C 8 haloalkyl group, optionally substituted C 1 -C 8 hydroxyalkyl group, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl group, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group;

[0482] 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 optionally form, together with the atom to which they are attached, a 3- to 20-membered carbocyclic group or a 3- to 20-membered heterocyclic group ring;

[0483] m is from 0 to 15;

[0484] n is from 0 to 15 each time it appears; and

[0485] o is from 0 to 15.

[0486] In another embodiment, the linker moiety has Formula 9B:

[0487]

[0488] wherein

[0489] R 1 and R2 independently selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, and optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino, C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 8-membered cycloalkoxy group, optionally substituted 3- to 10-membered carbocyclic amino group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl, or

[0490] R 1 and R 2 together with the atom to which they are attached, optionally form a 3- to 20-membered carbocyclic or 3- to 20-membered heterocyclic ring;

[0491] A and B are independently selected from empty or divalent moieties each time they appear, the divalent moieties being selected from R'-R", R'COR", R'CO 2 R", R'C(O)N(R 3 )R", R'C(S)N(R 3 )R", R'OR", R'SR", R'SOR", R'SO 2 R", R'SO 2 N(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 C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C8 Vinylene, optionally substituted C 2 -C 8 Ethynylene, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Halogenoalkylene, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 4 -C 13 Fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 Bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0492] R’ and R” are independently selected from the group consisting of void, optionally substituted (C 1 -C 8 alkylene)-R r (preferably, CH 2 -R r ), optionally substituted R r -(C 1 -C 8 alkylene), optionally substituted (C 1 -C 8 alkylene)-R r -(C 1 -C 8 alkylene), or are selected from moieties comprising: optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino C1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0493] R r selected from optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0494] R 3 and R 4 are independently selected from hydrogen, optionally substituted C 1 -C 8Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxyalkyl, optionally substituted C 1 -C 8 Halogenoalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0495] R’ and R”, R 3 and R 4 , R’ and R 3 , R’ and R 4 , R” and R 3 or R” and R 4 together with the atom to which they are attached optionally form a 3- to 20-membered carbocyclic or 3- to 20-membered heterocyclic ring;

[0496] each m is from 0 to 15; and

[0497] n is from 0 to 15.

[0498] In another embodiment, the linker moiety has formula 9C:

[0499]

[0500] wherein

[0501] X is selected from O, NH and NR 7 ;

[0502] 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 C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted 3-10 membered carbocyclic group, optionally substituted 3-8 membered cycloalkoxy group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0503] A and B are independently selected from empty or divalent moieties selected from R'-R", R'COR", R'CO 2 R", R'C(O)N(R 8 )R", R'C(S)N(R 8 )R", R'OR", R'SR", R'SOR", R'SO 2 R", R'SO 2 N(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 C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkynylene, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Haloalkylene, optionally substituted C 1 -C8 Hydroxyalkylene, optionally substituted C 4 -C 13 Fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 Bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0504] R’ and R” are independently selected from the group consisting of empty, optionally substituted (C 1 -C 8 alkylene)-R r (preferably, CH 2 -R r ), optionally substituted R r -(C 1 -C 8 alkylene), optionally substituted (C 1 -C 8 alkylene)-R r -(C 1 -C 8 alkylene), or a moiety selected from the group consisting of optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenylene, optionally substituted C2 -C 8 Ethynylene, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Haloalkylene, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C 13 Fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 Bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0505] R r Selected from optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C 13 Fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 Bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0506] R 7 、R 8 and R 9 are independently selected from hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxyalkyl, optionally substituted C 1 -C8 Halogenated alkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl;

[0507] 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 optionally form, together with the atoms to which they are attached, a 3- to 20-membered carbocyclic or 3- to 20-membered heterocyclic ring;

[0508] m is 0 to 15 each time it appears;

[0509] n is 0 to 15 each time it appears;

[0510] o is 0 to 15; and

[0511] p is 0 to 15.

[0512] In one embodiment, in Formula 9C, m and n are 0 or 1, and p is 0 to 15;

[0513] In one embodiment, in Formula 9C, X is selected from O and NH;

[0514] 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 C 1 -C 6 alkyl.

[0515] In another embodiment, the linker moiety comprises one or more rings selected from 3- to 13-membered rings, 4- to 13-membered fused rings, 5- to 13-membered bridged rings, and 5- to 13-membered spiro rings.

[0516] In another embodiment, the linker moiety comprises rings selected from Formulas C1, C2, C3, C4, and C5:

[0517]

[0518] wherein

[0519] X' and Y' are independently selected from N and CR b ;

[0520] A 1 , B 1 , C 1 and D 1 is independently selected at each occurrence from void, O, CO, SO, SO 2 NR b and CR b R c ;

[0521] A 2 , B 2 , C 2 and D 2 In each occurrence, independently selected from N and CR b ;

[0522] A 3 , B 3 , C 3 , D 3 and E 3 is independently selected at each occurrence from N, O, S, NR b and CR b ;

[0523] R b and R c is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino, and optionally substituted C 1 -C 8 Alkylamino C 1 -C 8alkyl, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 8-membered cycloalkyloxy group, optionally substituted 3- to 10-membered carbocyclic amino group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group;

[0524] R b and R b or R b and R c together with the atom to which they are attached form a 3- to 8-membered carbocyclic or 3- to 8-membered heterocyclic ring; and

[0525] m 1 、n 1 、o 1 and p 1 are independently selected from 0, 1, 2, 3, 4, and 5.

[0526] In one embodiment, A, B, and W are each independently selected, each time they appear, from the group consisting of nothing, optionally substituted -(CH 2 ) 0-8 -, optionally substituted -(CH 2 ) 0-8 -CO-(CH 2 ) 0-8 -, optionally substituted -(CH 2 ) 0-8 -NH-(CH 2 ) 0-8 -, optionally substituted -(CH 2 ) 0-8 -NH-CO-(CH 2 ) 0-8 -, optionally substituted -(CH 2 ) 0-8 -CO-NH-(CH 2 ) 0-8 -, optionally substituted -(CH 2 ) 0-3 -NH-(CH 2 ) 0-3 -CO-NH-(CH 2 ) 0-8 -, optionally substituted -(CH 2 ) 0-3 -NH-(CH 2 ) 1-3 -NH-CO-(CH 2 ) 0-8 -, optionally substituted -(CH 2 ) 0-8 -CO-NH-(CH 2 ) 1-3 -NH-(CH 2 )0-3 -, optionally substituted -(CH 2 ) 0-8 -R r -(CH 2 ) 0-8 -, optionally substituted -(CH 2 ) 0-3 -(CO)-(CH 2 ) 0-3 -R r -(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-3 -(CO-NH)-(CH 2 ) 0-3 -R r -(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-3 -(NH-CO)-(CH 2 ) 0-3 -R r -(CH 2 ) 0-3 - and optionally substituted -(CH 2 ) 0-3 -(NH)-(CH 2 ) 0-3 -R r -(CH 2 ) 0-3 -.

[0527] In one embodiment, R r has formula C1, C2, C3, C4 or C5.

[0528] In one embodiment, R r is selected from

[0529] In another embodiment, the linker has a length of from 0 to 40 atoms.

[0530] In another embodiment, the linker has a length of from 0 to 20 atoms.

[0531] In another embodiment, the linker has a length of from 0 to 10 atoms.

[0532] In another embodiment, the linker is selected from the group consisting of empty, optionally substituted -(CO)-(CH 2 ) 0-8 -, optionally substituted -(CH 2 ) 0-9-, optionally substituted -(CH 2 ) 1-2 -(CO)-NH-(CH 2 ) 0-9 -, optionally substituted -(CH 2 ) 1-2 -(CO)-NH-(CH 2 ) 1-3 -(OCH 2 CH 2 ) 1-7 -, optionally substituted -(CH 2 ) 0-1 -(CO)-(CH 2 ) 1-3 -(OCH 2 CH 2 ) 1-7 -, optionally substituted -(CO)-(CH 2 ) 0-3 -(alkenylene)-(CH 2 ) 0-3 -, optionally substituted -(CO)-(CH 2 ) 0-3 -(alkynylene)-(CH 2 ) 0-3 -, optionally substituted -(CO)-(CH 2 ) 0-3 -(3- to 8-membered carbocyclic group)-(CH 2 ) 0-3 -, optionally substituted -(CO)-(CH 2 ) 0-3 -(3- to 8-membered heterocyclic group)-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-3 -(alkenylene)-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-3 -(alkynylene)-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-3 -(3- to 8-membered carbocyclic group)-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-3 -(3- to 8-membered heterocyclic group)-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-8 -Rr -(CH 2 ) 0-8 -, optionally substituted -(CH 2 ) 0-8 -R r -(CO)-(CH 2 ) 1-8 -, optionally substituted -(CH 2 ) 0-8 -R r -(CH 2 ) 1-2 -(CO)-NH-(CH 2 ) 2-9 -, optionally substituted -(CH 2 ) 0-8 -R r -(CH 2 ) 1-2 -(CO)-NH-(CH 2 ) 1-3 -(OCH 2 CH 2 ) 1-7 -, optionally substituted -(CH 2 ) 0-8 -R r -(CH 2 ) 0-1 -(CO)-(CH 2 ) 1-3 -(OCH 2 CH 2 ) 1-7 -, optionally substituted -(CH 2 ) 0-8 -R r -(CO)-(CH 2 ) 0-3 -(alkenylene)-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-8 -R r -(CO)-(CH 2 ) 0-3 -(alkynylene)-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-8 -R r -(CO)-(CH 2 ) 0-3 -(3- to 8-membered carbocyclic group)-(CH 2 ) 0-3 -, optionally substituted -(CH 2 )0-8 -R r -(CO)-(CH 2 ) 0-3 -(3- to 8-membered heterocyclic group)-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-8 -R r -(CH 2 ) 0-3 -(alkenylene)-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-8 -R r -(CH 2 ) 0-3 -(alkynylene)-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-8 -R r -(CH 2 ) 0-3 -(3- to 8-membered carbocyclic group)-(CH 2 ) 0-3 - and optionally substituted -(CH 2 ) 0-8 -R r -(CH 2 ) 0-3 -(3- to 8-membered heterocyclic group)-(CH 2 ) 0-3 -.

[0533] In one aspect, provided herein is a bivalent compound comprising a tropomyosin receptor kinase (TRK) ligand conjugated to a degron via a linker, or a pharmaceutically acceptable salt or analogue thereof, wherein the linker and the degron are each independently selected from those disclosed herein, and the TRK ligand is a moiety of Formula 10, which is attached to the linker via R 4 attached to the linker:

[0534]

[0535] wherein

[0536] X 1 、X 2 、X 3 、X 4 and X 5 are each independently selected from C, CR 1 and N;

[0537] X is selected from CR 1 R2 , CO, O, S, SO, SO 2 and NR 1 ;

[0538] R is selected from optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 3 -C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, and Ar 1 ; or

[0539] X-R together represent

[0540] U is selected from empty, bond, C(R 2 ) 2 , C(R 2 ) 2 C(R 2 ) 2 , CO, C(R 2 ) 2 CO, CONR 2 , C(R 2 ) 2 O, C(R 2 ) 2 NR 2 and CH 2 NR 2 ;

[0541] R 1 and R 2 are each independently selected from hydrogen, halogen, CN, NO 2 , OR 6 , SR 6 , NR 7 R 8 , COR 6 , CO 2 R 6 , C(O)NR 7 R 8 , SOR 6 , SO 2 R 6 , SO 2 , NR 7 R 8 , NR 6 C(O)R 8 , NR 6 , C(O)NR 7 R 8 , NR 6 , SOR 8, NR 6 SO 2 R 8 , optionally substituted C 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -heteroalkyl, optionally substituted C 1 -C 8 -alkoxy, optionally substituted C 1 -C 8 -alkoxyC 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -alkylaminoC 1 -C 8 -alkyl, optionally substituted C 3 -C 10 -carbocyclic group, optionally substituted C 3 -C 10 -cycloalkoxy, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 2 -C 8 -alkenyl and optionally substituted C 2 -C 8 -alkynyl; or

[0542] 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- to 8-membered carbocyclic or 3- to 8-membered heterocyclic ring;

[0543] R 6 , R 7 and R 8 each occurrence is independently selected from the group consisting of nil, hydrogen, optionally substituted C 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -heteroalkyl, optionally substituted C 2 -C 8 -alkenyl, optionally substituted C 2 -C 8 -alkynyl, optionally substituted C 3 -C 6 -carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted heterocarbocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0544] R 7 and R8 Optionally form a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group ring together with the atoms to which they are attached;

[0545] n is 0, 1, 2, 3 or 4;

[0546] n' is 0, 1, 2 or 3;

[0547] L is Ar 2 , NR 3 CO or NR 3 COAr 2 ;

[0548] R 3 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 carbocyclic group, optionally substituted 3- to 6-membered heterocyclic group, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl and optionally substituted C 1 -C 6 alkylamino C 1 -C 6 alkyl;

[0549] R 4 is directly or through R 5 connected to the linker moiety of the divalent compound, wherein

[0550] R 4 and R 5 are divalent groups independently selected from the empty group, -O-, -S-, -NR 9 -, -CO-, -CO 2 -, -CONR 9 -, -SO-, -SO 2 R 9 -, -SO 2 NR 9 -, -NR 10 CO-, -NR 10 C(O)NR 9 -, -NR 10 SO-, -NR 10 SO 2 -, optionally substituted C 1 -C8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Halogenoalkylene, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkylene, optionally substituted C 3 -C 8 Carbocyclene, optionally substituted 3- to 8-membered heteroaromatic ring, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkynylene, optionally substituted aryl and optionally substituted heteroaryl;

[0551] R 9 Selected from empty, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 1 -C 8 Alkylene-O-, optionally substituted C 1 -C 8 Alkylene-N(C 1 -C 8 alkyl)-, optionally substituted C 1 -C 8 Alkylene-O-C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylene-N(C 1 -C 8 alkyl)-C 1 -C 8 Alkylene, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted C 3 -C 8 Carbocyclic group-O-, optionally substituted 3- to 8-membered heteroaromatic ring, optionally substituted aryl and optionally substituted heteroaryl;

[0552] R 10 Selected from empty, hydrogen, optionally substituted C1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted heterocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3- to 8-membered carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0553] Ar 1 and Ar 2 are independently selected from aryl and heteroaryl, each of which is optionally substituted by one or more substituents independently selected from halogen, CN, NO 2 、OR 11 、SR 11 、NR 12 R 13 、COR 11 、CO 2 R 11 、CONR 12 R 13 、SOR 11 、SO 2 R 11 、SO 2 NR 12 R 13 、NR 11 COR 13 、NR 11 C(O)NR 12 R 13 、NR 11 SOR 13 、NR 11 SO 2 R 13 、optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0554] R 11 , R 12 and R 13 are independently selected from the group consisting of null, hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or

[0555] 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.

[0556] 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 portion 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 of the following to the connector:

[0557]

[0558] in

[0559] V 1 、V 2 、V 3 and V 4 Each independently selected from CR2 ’ and N;

[0560] W 1 、W 2 and W 3 are each independently selected from CO, O, CR 3 ’R 4 ’ and NR 5 ’, where R 5 ’ is selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3- to 7-membered heterocyclic group, and 2,6-dioxopiperidin-3-yl optionally substituted by R 1 ’, provided that no two adjacent CO groups are present;

[0561] Z is selected from empty, CO, CR 3 ’R 4 ’, NR 3 ’, O, optionally substituted C 1 -C 10 alkylene, optionally substituted C 1 -C 10 heteroalkylene, optionally substituted C 2 -C 10 alkenylene, optionally substituted C 2 -C 10 alkynylene, optionally substituted 3- to 7-membered carbocyclic group, and optionally substituted 3- to 7-membered heterocyclic group;

[0562] R 1 ’ is selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted 3- to 6-membered carbocyclic group, and optionally substituted 3- to 6-membered heterocyclic group;

[0563] R 2 ’ is selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6an alkylamino, an optionally substituted 3- to 6-membered carbocyclic group, and an optionally substituted 3- to 6-membered heterocyclic group; and

[0564] R 3 ’ and R 4 ’ are each independently selected, upon each occurrence, from hydrogen, halogen, cyano, nitro, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered carbocyclic group, and an optionally substituted 3- to 6-membered heterocyclic group; or

[0565] R 3 ’ and R 4 ’ together with the atoms to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring.

[0566] In another aspect, the present disclosure provides a bivalent compound comprising a tropomyosin receptor kinase (TRK) ligand conjugated to a degron via a linker, or a pharmaceutically acceptable salt or analog thereof, wherein the TRK ligand and the degron are each independently selected from those disclosed herein, and the linker is a moiety of Formula 9:

[0567]

[0568] wherein

[0569] A and B are each independently selected, upon each occurrence, from empty or a divalent moiety selected from R'-R", R'COR", R'CO 2 R", R'C(O)N(R 1 ")R", R'C(S)N(R 1 ")R", R'OR", R'SR", R'SOR", R'SO 2 R", R'SO 2 N(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", an optionally substituted C 1 -C 8 alkylene, an optionally substituted C 1 -C 8 heteroalkylene, an optionally substituted C 2 -C 8 alkenylene, an optionally substituted C 2 -C 8 alkynylene, an optionally substituted C1 -C 8 alkoxy C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene;

[0570] Each W is independently selected from the group consisting of empty, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C 5 -C 13 spirocarbocyclic group, optionally substituted 5-13 membered spiroheterocyclic group, optionally substituted 3-10 membered carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0571] R’ and R” are independently selected from the group consisting of empty, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1-C 8 alkoxy C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene;

[0572] R 1 ” and R 2 ” are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl; and

[0573] m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0574] In another aspect, the present disclosure provides a bivalent compound comprising a tropomyosin receptor kinase (TRK) ligand conjugated to a degradation tag via a linker, or a pharmaceutically acceptable salt or analogue thereof, wherein the TRK ligand is a moiety of Formula 10, which is linked to the linker via R 4 :

[0575]

[0576] wherein

[0577] X 1 、X 2 、X 3 、X 4 and X 5 are each independently selected from C, CR 1 and N;

[0578] X is selected from CR 1 R 2 , CO, O, S, SO, SO 2 and NR 1 ;

[0579] R is selected from optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group and Ar 1 ; or

[0580] X-R together represent

[0581] U is selected from empty, bond, C(R 2 ) 2 , C(R 2 ) 2 C(R 2 ) 2 , CO, C(R 2 ) 2 CO, CONR 2 , C(R 2 ) 2 , C(R 2 ) 2 NR 2 and CH 2 NR 2 ;

[0582] R 1 and R 2 are each independently selected from hydrogen, halogen, CN, NO 2 , OR 6 , SR 6 , NR 7 R 8 , COR 6 , CO 2 R 6 , C(O)NR 7 R 8 , SOR 6 , SO 2 R 6 , SO 2 NR 7 R 8 , NR 6 C(O)R 8 , NR 6 , C(O)NR 7 R8 , NR 6 SOR 8 , NR 6 SO 2 R 8 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 10 carbocyclic group, optionally substituted C 3 -C 10 cycloalkoxy, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl and optionally substituted C 2 -C 8 alkynyl; or

[0583] 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- to 8-membered carbocyclic ring or a 3- to 8-membered heterocyclic ring;

[0584] R 6 , R 7 and R 8 each occurrence is independently selected from the empty set, hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 6 carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted heterocarbocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0585] R 7 and R 8 optionally form, together with the atoms to which they are attached, a 3- to 8-membered carbocyclic or 3- to 8-membered heterocyclic ring;

[0586] n is 0, 1, 2, 3 or 4;

[0587] n' is 0, 1, 2 or 3;

[0588] L is Ar 2 , NR 3 CO or NR 3 COAr 2 ;

[0589] R 3 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 carbocyclic, optionally substituted 3- to 6-membered heterocyclic, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl and optionally substituted C 1 -C 6 alkylamino C 1 -C 6 alkyl;

[0590] R 4 is directly or through R 5 connected to the linker moiety of the divalent compound, wherein

[0591] R 4 and R 5 are divalent groups independently selected from empty, -O-, -S-, -NR 9 -, -CO-, -CO 2 -, -CONR 9 -, -SO-, -SO 2 R 9 -, -SO 2 NR 9 -, -NR 10 CO-, -NR 10 C(O)NR 9 -, -NR 10 SO-, -NR 10 SO2 -, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted aryl and optionally substituted heteroaryl;

[0592] R 9 selected from empty, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkylene-O-, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-, optionally substituted C 1 -C 8 alkylene-O-C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylene-N(C 1 -C 8 alkyl)-C 1 -C 8 alkylene, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8 carbocyclic group-O-, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0593] R 10 selected from the group consisting of null, hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted heterocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3- to 8-membered carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl;

[0594] Ar 1 and Ar 2 are independently selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO 2 、OR 11 、SR 11 、NR 12 R 13 、COR 11 、CO 2 R 11 、CONR 12 R 13 、SOR 11 、SO 2 R 11 、SO 2 NR 12 R 13 、NR 11 COR 13 、NR 11 C(O)NR 12 R 13 、NR 11 SOR 13 、NR 11 SO 2 R 13 、optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0595] R 11 , R 12 and R 13 are independently selected from the group consisting of null, hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0596] 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;

[0597] Wherein the degradation tag is a moiety of formula 11, which is represented by Z or V 1 、V 2 、V 3 、V 4 , W 1 , W 2 and W 3 Connect any of the following to the connector:

[0598]

[0599] in

[0600] V 1 、V 2 、V 3 and V 4 Each independently selected from CR 2 ' and N;

[0601] W1 , W 2 and W 3 are each independently selected from CO, O, CR 3 ’R 4 ’ and NR 5 ’ where R 5 ’ is selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3- to 7-membered heterocyclic group and 2,6-dioxopiperidin-3-yl optionally substituted by R 1 ’, provided that no two adjacent CO groups;

[0602] Z is selected from empty, CO, CR 3 ’R 4 ’, NR 3 ’, O, optionally substituted C 1 -C 10 alkylene, optionally substituted C 1 -C 10 heteroalkylene, optionally substituted C 1 -C 10 alkenylene, optionally substituted C 1 -C 10 alkynylene, optionally substituted 3- to 7-membered carbocyclic group and optionally substituted 3- to 7-membered heterocyclic group;

[0603] R 1 ’ is selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered carbocyclic group and optionally substituted 3- to 6-membered heterocyclic group;

[0604] R 2 ’ is selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkylamino, optionally substituted 3- to 6-membered carbocyclic group and optionally substituted 3- to 6-membered heterocyclic group; and

[0605] R 3’ and R 4 ’ is independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 1 -C 6 -heteroalkyl, optionally substituted 3- to 6-membered carbocyclic group, and optionally substituted 3- to 6-membered heterocyclic group; or

[0606] R 3 ’ and R 4 ’ together with the atom to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring; and

[0607] wherein the linker is a moiety of formula 9:

[0608]

[0609] wherein

[0610] A and B are independently selected from empty or a divalent moiety, the divalent moiety is selected from R'-R", R'COR", R'CO 2 R", R'C(O)N(R 1 ")R", R'C(S)N(R 1 ")R", R'OR", R'SR", R'SOR", R'SO 2 R", R'SO 2 N(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 C 1 -C 8 -alkylene, optionally substituted C 1 -C 8 -heteroalkylene, optionally substituted C 2 -C 8 -alkenylene, optionally substituted C 2 -C 8 -alkynylene, optionally substituted C 1 -C 8 -alkoxy C 1 -C 8 -alkylene, optionally substituted C 1 -C 8 -haloalkylene, optionally substituted C 1 -C 8 -hydroxyalkylene;

[0611] Each W is independently selected from the group consisting of empty, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group;

[0612] R’ and R” are independently selected from the group consisting of empty, optionally substituted C 1 -C 8 alkyl group, optionally substituted C 1 -C 8 heteroalkyl group, optionally substituted C 2 -C 8 alkenyl group, optionally substituted C 2 -C 8 alkynyl group, optionally substituted C 1 -C 8 hydroxyalkyl group, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl group, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl group, optionally substituted C 1 -C 8 haloalkyl group, optionally substituted C 1 -C 8 alkylene group, optionally substituted C 1 -C 8 heteroalkylene group, optionally substituted C 2 -C 8 alkenylene group, optionally substituted C 2 -C 8 alkynylene group, optionally substituted C 1 -C 8 hydroxyalkylene group, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkylene group, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkylene group, optionally substituted C 1 -C 8 haloalkylene;

[0613] R 1 ” and R 2 ” are each independently selected from hydrogen, optionally substituted C 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -heteroalkyl, optionally substituted C 2 -C 8 -alkenyl, optionally substituted C 2 -C 8 -alkynyl, optionally substituted C 1 -C 8 -alkoxyalkyl, optionally substituted C 1 -C 8 -haloalkyl, optionally substituted C 1 -C 8 -hydroxyalkyl, optionally substituted C 1 -C 8 -alkylamino C 1 -C 8 -alkyl, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl; and

[0614] m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0615] In certain embodiments of the divalent compounds disclosed herein, U is selected from a bond, CH 2 , CH 2 CH 2 , CO, CH 2 CO, CONH, CONCH 3 , CH 2 O, CH 2 NH, and CH 2 NCH 3 .

[0616] In certain embodiments of the divalent compounds disclosed herein, R 1 and R 2 are each independently selected from hydrogen, F, Cl, OH, optionally substituted C 1 -C 4 -alkyl, optionally substituted C 1 -C 4 -heteroalkyl, optionally substituted C 1 -C 4 -alkoxy, optionally substituted C 1 -C 4 -alkylamino, optionally substituted C 1 -C 4Halogenated alkyl, optionally substituted C 3 -C 6 carbocyclic group, optionally substituted C 3 -C 6 cycloalkyloxy and optionally substituted 3- to 6-membered heterocyclic group.

[0617] In certain embodiments of the divalent compounds disclosed herein, R 1 and R 2 are each independently selected from hydrogen, F, Cl, CH 3 , CF 3 and cyclopropyl.

[0618] In certain embodiments of the divalent compounds disclosed herein, Ar 1 is selected from optionally substituted C 6 -C 10 aryl and optionally substituted C 5 -C 10 heteroaryl.

[0619] In certain embodiments of the divalent compounds disclosed herein, Ar 1 is selected from 3-fluorophenyl, 3,5-difluorophenyl and 2,5-difluorophenyl.

[0620] In certain embodiments of the divalent compounds disclosed herein, L is Ar 2 and R 4 is connected to the linker portion of the divalent compound through R 5 .

[0621] In certain embodiments of the divalent compounds disclosed herein, L is Ar 2 and R 4 is directly connected to the linker portion of the divalent compound.

[0622] In certain embodiments of the divalent compounds disclosed herein, R 4 is selected from

[0623] In certain embodiments of the divalent compounds disclosed herein, L is Ar 2 , and Ar 2 is selected from optionally substituted C 6 -C 10 aryl and optionally substituted C 5 -C 10 heteroaryl.

[0624] In certain embodiments of the divalent compounds disclosed herein, X-R together represents

[0625] In certain embodiments of the divalent compounds disclosed herein, X 1 is N; X 2 is N; X 3 is N; X 4 is CH; X 5 is C; X-R together represents U is CH 2 ; Ar 1 is 3-fluorophenyl; L is Ar 2 ; and Ar 2 is 2-pyridyl.

[0626] In certain embodiments of the divalent compounds disclosed herein, L is Ar 2 or NR 3 COAr 2 and Ar 2 -R 4 is selected from moieties of Formulas B1, B2, and B3:

[0627]

[0628] wherein

[0629] * represents the linker moiety attached to the divalent compound;

[0630] Y 1 , Y 2 , Y 3 and Y 4 are independently selected from CR a and N, provided that at most 3 of Y 1 , Y 2 , Y 3 and Y 4 are N;

[0631] Each R a is independently selected from hydrogen, halogen, CN, NO 2 , OR 14 , NR 15 R 16 , COR 14 , CO 2 R 14 , CONR 15 R 16 , SOR 14 , SO 2 R 14 , SO 2 , NR 15 R 16 , NR 14 , COR 15 , NR 14 , C(O)NR 15 R16 , NR 14 SOR 15 , NR 14 SO 2 R 15 , optionally substituted C 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -heteroalkyl, optionally substituted C 1 -C 8 -alkoxy C 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -haloalkyl, optionally substituted C 1 -C 8 -hydroxyalkyl, optionally substituted C 1 -C 8 -alkylamino C 1 -C 8 -alkyl, optionally substituted C 3 -C 7 -carbocyclic group, optionally substituted 3-7 membered heterocyclic group, optionally substituted C 2 -C 8 -alkenyl, optionally substituted C 2 -C 8 -alkynyl, optionally substituted aryl and optionally substituted heteroaryl; and

[0632] R 14 , R 15 and R 16 are each independently selected from the group consisting of nothing, hydrogen, optionally substituted C 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -heteroalkyl, optionally substituted C 2 -C 8 -alkenyl, optionally substituted C 2 -C 8 -alkynyl, optionally substituted C 3 -C 6 -carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted heterocarbocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0633] R 15 and R 16 together with the atom to which they are attached optionally form a 3-8 membered carbocyclic or 3-8 membered heterocyclic ring.

[0634] In certain embodiments of the divalent compounds disclosed herein, L is Ar2 or NR 3 COAr 2 and Ar 2 -R 4 selected from the moiety of formula B4:

[0635]

[0636] wherein

[0637] * represents the linker moiety attached to the divalent compound;

[0638] Y 1 ’, Y 2 ’, Y 3 ’ and Y 4 ’ are independently selected from CR a , N, O and S, provided that up to 3 of Y 1 ’, Y 2 ’, Y 3 ’ and Y 4 ’ are N;

[0639] each R a is independently selected from hydrogen, halogen, CN, NO 2 , OR 14 , NR 15 R 16 , COR 14 , CO 2 R 14 , CONR 15 R 16 , SOR 14 , SO 2 R 14 , SO 2 , SO 15 NR 16 , NR 14 , COR 15 , NR 14 , C(O)NR 15 R 16 , NR 14 , SOR 15 , NR 14 , SO 2 R 15 , optionally substituted C 1 -C 8 , optionally substituted C 1 -C 8 , optionally substituted C 1 -C 8 , alkoxy C 1 -C 8 , optionally substituted C 1 -C8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C 3 -C 7 carbocyclic group, optionally substituted 3-7 membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl; and

[0640] R 14 、R 15 and R 16 are each independently selected from the group consisting of nothing, hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 6 carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted heterocyclic carbocyclic group, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0641] R 15 and R 16 together with the atom to which they are attached optionally form a 3-8 membered carbocyclic or 3-8 membered heterocyclic ring.

[0642] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 CO, and R 3 is selected from hydrogen, CH 3 、CH 2 CH 3 、propyl, isopropyl, cyclopropyl, CH 2 F、CHF 2 and CF 3 .

[0643] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 CO and R 4 is directly attached to the linker portion of the divalent compound.

[0644] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 CO and R 4 is attached to the linker portion of the divalent compound through R 5

[0645] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 wherein R 3 is selected from hydrogen, CH 3 CH 2 CH 3 propyl, isopropyl, cyclopropyl, CH 2 F, CHF 2 and CF 3 ; and Ar 2 is selected from optionally substituted C 6 -C 10 aryl and optionally substituted C 5 -C 10 heteroaryl.

[0646] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 and R 4 is directly attached to the linker portion of the divalent compound.

[0647] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 and R 4 is attached to the linker portion of the divalent compound through R 5

[0648] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 and Ar 2 -R 4 is selected from moieties of formulae B1, B2 and B3.

[0649] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 and Ar 2 -R 4 is selected from the moiety of formula B1, wherein Y 1 is CH or N.

[0650] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 and Ar​​2 -R 4 Selected from the moiety of formula B2, wherein Y 1 is CR a and R a is H,

[0651] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 and Ar 2 -R 4 is selected from the moiety of formula B3, wherein Y 2 is CR a and R a is

[0652] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 and X-R is X-Ar 1 .

[0653] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 and X-R is X-Ar 1 , wherein X is CH 2 ; and Ar 1 is selected from 3-fluorophenyl, 3,5-difluorophenyl or 2,5-difluorophenyl.

[0654] In certain embodiments of the divalent compounds disclosed herein, V 1 , V 2 , V 3 and V 4 are each independently CR 2 '.

[0655] In certain embodiments of the divalent compounds disclosed herein, at least one of W 1 , W 2 and W 3 is NR 5 '.

[0656] In certain embodiments of the divalent compounds disclosed herein, at least one of W 1 , W 2 and W 3 is NR 5 ', and only one of R 5 ' is 2,6-dioxopiperidin-3-yl optionally substituted by R 1 '.

[0657] In certain embodiments of the divalent compounds disclosed herein, W 1 is CO.

[0658] In certain embodiments of the divalent compounds disclosed herein, W 2 is CO.

[0659] In certain embodiments of the divalent compounds disclosed herein, W 3 is CO.

[0660] In certain embodiments of the divalent compounds disclosed herein, W 1 and W 3 are both CO.

[0661] In certain embodiments of the divalent compounds disclosed herein, W 2 is CO and W 1 and W 3 are both NR 5 ’, and only one of R 5 ’ is 2,6-dioxopiperidin-3-yl optionally substituted by R 1 ’.

[0662] In certain embodiments of the divalent compounds disclosed herein, W is independently selected from formulae C1, C2, C3, C4 and C5 each time it appears:

[0663]

[0664] wherein

[0665] X’ and Y’ are independently selected from N and CR b ;

[0666] A 1 、B 1 、C 1 and D 1 are independently selected from nothing, O, CO, SO, SO 2 、NR b and CR b R c ;

[0667] A 2 、B 2 、C 2 and D 2 are independently selected from N and CR b ;

[0668] A 3 、B 3 、C 3 、D 3 and E3 independently selected from N, O, S, NR at each occurrence b and CR b ;

[0669] R b and R c independently selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino, and optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclic group, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclic amino, optionally substituted 3-8 membered heterocyclic group, 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 form a 3-8 membered carbocyclic or 3-8 membered heterocyclic ring; and

[0670] m 1 、n 1 、o 1 and p 1 are independently selected from 0, 1, 2, 3, 4 and 5.

[0671] In certain embodiments of the divalent compounds disclosed herein, the linker has a length of 3 to 40 atoms.

[0672] In certain embodiments of the divalent compounds disclosed herein, the linker has a length of 3 to 20 atoms.

[0673] In certain embodiments of the divalent compounds disclosed herein, the linker has a length of 3 to 10 atoms.

[0674] In certain embodiments of the divalent compounds disclosed herein, the linker is selected from optionally substituted -(CO)-(CH 2 ) 0-3 -W-(CH 2 ) 0-3 -、-(CH 2 ) 0-3 -W-(CH 2 ) 0-3 -、optionally substituted -(CO)-(CH 2 ) 0-8 -、optionally substituted -(CH 2 ) 0-9 -、optionally substituted -(CH 2 ) 1-2 -(CO)-NH-(CH 2 ) 2-9 -、optionally substituted -(CH 2 ) 1-2 -(CO)-NH-(CH 2 ) 1-3 -(OCH 2 CH 2 ) 1-7 -、optionally substituted -(CH 2 ) 0-1 -(CO)-(CH 2 ) 1-3 -(OCH 2 CH 2 ) 1-7 -、optionally substituted -(CO)-(CH 2 ) 0-3 -(alkenylene)-(CH 2 ) 0-3 -、optionally substituted -(CO)-(CH 2 ) 0-3 -(alkynylene)-(CH 2 ) 0-3 -、optionally substituted -(CH 2 ) 0-3 -(alkenylene)-(CH 2 ) 0-3 -、optionally substituted (CH 2 ) 0-3 -(alkynylene)-(CH 2 ) 0-3 -、optionally substituted -(CH 2 ) 0-3 -(CO)-(CH 2 )0-3 -W-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-3 -O-(CH 2 ) 0-3 -W-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-3 -NH-(CH 2 ) 0-3 -W-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-3 -O-(CH 2 ) 0-3 -W-(CH 2 ) 0-3 -O-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-3 -NH-(CH 2 ) 0-3 -W-(CH 2 ) 0-3 -NH-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-3 -O-(CH 2 ) 0-3 -W-(CH 2 ) 0-3 -NH-(CH 2 ) 0-3 -; and W is selected from optionally substituted 3- to 10-membered carbocyclic groups, optionally substituted 3- to 10-membered heterocyclic groups, optionally substituted C 4 -C 13 -fused carbocyclic groups, optionally substituted 5- to 13-membered fused heterocyclic groups, optionally substituted C 5 -C 13 -bridged carbocyclic groups, optionally substituted 5- to 13-membered bridged heterocyclic groups, optionally substituted C 5 -C 13 -spirocarbocyclic groups, optionally substituted 5- to 13-membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups.

[0675] In certain embodiments of the divalent compounds disclosed herein, the linker is selected from optionally substituted -(CO)-(CH 2 ) 0-3 -(3- to 8-membered carbocyclic group)-(CH2 ) 0-3 -, optionally substituted -(CO)-(CH 2 ) 0-3 -(3- to 8-membered heterocyclic group)-(CH 2 ) 0-3 -, optionally substituted -(CH 2 ) 0-3 -(3- to 8-membered carbocyclic group)-(CH 2 ) 0-3 - and optionally substituted -(CH 2 ) 0-3 -(3- to 8-membered heterocyclic group)-(CH 2 ) 0-3 -.

[0676] In certain embodiments of the divalent compounds disclosed herein, W is selected from

[0677] In some embodiments, the divalent compounds are selected from CPD-001 to CPD-516 or a pharmaceutically acceptable salt or analogue thereof.

[0678] 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-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-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 their pharmaceutically acceptable salts or analogs.

[0679] 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-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 their pharmaceutically acceptable salts or analogs.

[0680] 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-279, 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, 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-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 their pharmaceutically acceptable salts or analogs.

[0681] In some embodiments, the divalent compound is not any one of CPD-001 to CPD-246.

[0682] In some embodiments, the divalent compound is selected from CPD-247 to CPD-516 or their pharmaceutically acceptable salts or analogs.

[0683] 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-284, TR-285, TR-286, TR-287, TR-288, TR-289, TR-290, TR-292, TR-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-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.

[0684] In some embodiments, the divalent compound includes enantiomers of the compounds described herein. In some embodiments, the divalent compound includes the (S) enantiomer. In some embodiments, the divalent compound includes the (R) enantiomer. Some embodiments include a composition comprising the divalent compound. In some embodiments, the composition comprises or consists of the (S) enantiomer of the compound. In some embodiments, the composition comprises or consists of the (R) enantiomer of the compound. In some embodiments, the composition comprises or consists of a mixture of the (S) enantiomer and the (R) enantiomer. In some embodiments, the composition comprises or consists of a racemic mixture of the (S) enantiomer and the (R) enantiomer. In some embodiments, the composition is a pharmaceutical composition.

[0685] 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).

[0686] 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).

[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)ethoxy)isoindoline-1,3-dione (TR-173).

[0688] 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).

[0689] 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).

[0690] 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);

[0691] 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).

[0692] 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).

[0693] 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).

[0694] 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).

[0695] 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).

[0696] 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).

[0697] In some embodiments, the bivalent compound is 3-[5-[3-[4-[6-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridinyl]piperazin-1-yl]propylamino]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (TR-221).

[0698] In some embodiments, the bivalent 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).

[0699] In some embodiments, the bivalent 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).

[0700] In some embodiments, the bivalent 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).

[0701] In some embodiments, the bivalent 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).

[0702] In some embodiments, the bivalent 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).

[0703] 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).

[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)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-249).

[0705] 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).

[0706] 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).

[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)butyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (TR-259).

[0708] 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).

[0709] In some embodiments, the bivalent 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).

[0710] In some embodiments, the bivalent 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).

[0711] In some embodiments, the bivalent 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).

[0712] In some embodiments, the bivalent 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).

[0713] In some embodiments, the bivalent 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).

[0714] In some embodiments, the bivalent 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).

[0715] 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).

[0716] 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).

[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)methyl)piperidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-279).

[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)piperidin-4-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-280).

[0719] 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).

[0720] 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).

[0721] In some embodiments, the bivalent 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).

[0722] In some embodiments, the bivalent 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).

[0723] In some embodiments, the bivalent 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)morpholino)isoindoline-1,3-dione (TR-286).

[0724] In some embodiments, the bivalent 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).

[0725] In some embodiments, the bivalent 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).

[0726] In some embodiments, the bivalent 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).

[0727] In some embodiments, the bivalent 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).

[0728] In some embodiments, the bivalent 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).

[0729] In some embodiments, the bivalent 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).

[0730] In some embodiments, the bivalent 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).

[0731] In some embodiments, the bivalent 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).

[0732] In some embodiments, the bivalent 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).

[0733] In some embodiments, the bivalent 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).

[0734] In some embodiments, the bivalent 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).

[0735] In some embodiments, the bivalent 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).

[0736] In some embodiments, the bivalent 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).

[0737] In some embodiments, the bivalent 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).

[0738] In some embodiments, the bivalent 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).

[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)but-3-yn-1-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-319).

[0740] 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).

[0741] 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).

[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-5-yl)amino)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-324).

[0743] 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).

[0744] In some embodiments, the bivalent 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).

[0745] In some embodiments, the bivalent 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).

[0746] In some embodiments, the bivalent 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).

[0747] In some embodiments, the bivalent 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).

[0748] In some embodiments, the bivalent 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).

[0749] In some embodiments, the bivalent 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).

[0750] In some embodiments, the bivalent 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).

[0751] In some embodiments, the bivalent 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).

[0752] In some embodiments, the bivalent 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).

[0753] In some embodiments, the bivalent 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).

[0754] In some embodiments, the bivalent 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).

[0755] In some embodiments, the bivalent 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).

[0756] In some embodiments, the bivalent 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)pyridinecarboxamide (CPD-470).

[0757] In some embodiments, the bivalent 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)pyridinecarboxamide (CPD-471).

[0758] In some embodiments, the bivalent 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)pyridinecarboxamide (CPD-472).

[0759] In some embodiments, the bivalent 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)pyridinecarboxamide (CPD-473).

[0760] In some embodiments, the bivalent 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)pyridinecarboxamide (CPD-474).

[0761] In some embodiments, the bivalent 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)pyridinecarboxamide (CPD-475).

[0762] In some embodiments, the bivalent 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-tetraoxapentadecan-15-yl)piperidin-4-yl)amino)pyridinecarboxamide (CPD-476).

[0763] In some embodiments, the bivalent 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).

[0764] In some embodiments, the bivalent 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).

[0765] In some embodiments, the bivalent 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).

[0766] In some embodiments, the bivalent 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).

[0767] In some embodiments, the bivalent 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).

[0768] In some embodiments, the bivalent 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).

[0769] In some embodiments, the bivalent 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).

[0770] In some embodiments, the bivalent 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).

[0771] In some embodiments, the bivalent 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).

[0772] According to one aspect of the present disclosure, the compositions disclosed herein comprise a bivalent compound or a pharmaceutically acceptable salt or analogue thereof, and a pharmaceutically acceptable carrier or diluent.

[0773] According to one aspect of the present disclosure, a method of treating a tropomyosin receptor kinase (TRK)-mediated disease disclosed herein comprises administering to a subject having a TRK-mediated disease a bivalent compound or a pharmaceutically acceptable salt or analogue thereof.

[0774] In one embodiment, the TRK-mediated disease is caused by TRK expression, mutation, or fusion.

[0775] In one embodiment, a subject having a TRK-mediated disease has elevated TRK function relative to a healthy subject without a TRK-mediated disease.

[0776] In one embodiment, the bivalent compound is selected from CPD-001 to CPD-516 or analogs thereof.

[0777] In one embodiment, the bivalent compound is selected from CPD-247 to CPD-516 or analogs thereof.

[0778] 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 an additional treatment regimen for treating cancer to the subject.

[0779] In one embodiment, the additional treatment regimen is selected from surgery, chemotherapy, radiotherapy, hormone therapy, and immunotherapy.

[0780] 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 carcinoma, mammary analogue secretory carcinoma, acute myeloid leukemia, ductal carcinoma, pulmonary neuroendocrine tumor, pheochromocytoma, and Wilms tumor.

[0781] 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, gastric cancer, lung cancer, liver cancer, uterine cancer, adrenal cancer, biliary tract cancer, bowel 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 carcinoma, 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 mesoblastic nephroma, secretory breast cancer, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system neoplasm, osteosarcoma, synovial sarcoma, liposarcoma, soft tissue alveolar sarcoma, Spitzoid carcinoma, Wilms tumor, lymphoma (e.g., including Hodgkin lymphoma, lymphoplasmacytic 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 disease (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, postherpetic 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, toothache, myofascial pain, perioperative pain, dysmenorrhea, myofascial pain, angina, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain caused by central sensitization, generalized cutaneous pruritus, localized cutaneous pruritus, senile pruritus, pruritus gravidarum, pruritus ani, pruritus vulvae, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, bone metastasis, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic disease, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelinating disease, and myelin formation disorder. In certain embodiments, the disease or condition is a recurrent disease.

[0782] In one embodiment, the TRK-mediated disease is recurrent cancer.

[0783] In one embodiment, the TRK-mediated disease is refractory to one or more prior treatments.

[0784] 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:

[0785] providing a heterobifunctional test compound comprising a TRK ligand conjugated to a degron via a linker;

[0786] contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and TRK;

[0787] determining whether the level of TRK in the cell is reduced; and

[0788] identifying the heterobifunctional test compound as a bivalent compound that mediates TRK degradation or reduction.

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

[0790] In one embodiment, the cancer cell is a TRK-mediated cancer cell.

[0791] In one embodiment, the cell is a neuron.

[0792] Incorporated by reference

[0793] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the 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

[0794] The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of the invention will be better understood from the following detailed description, which illustrates illustrative embodiments of the principles of the invention, and the accompanying drawings, in which:

[0795] Figure 1 Panel A shows immunoblots of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with entrectinib or bivalent compounds CPD-001–CPD-022.

[0796] Figure 1 Panel B shows immunoblots of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with entrectinib or bivalent compounds CPD-023–CPD-044.

[0797] Figure 1 Panel C shows the immunoblot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with entrectinib or the bivalent compound CPD-045–CPD-065.

[0798] Figure 2 Shows the immunoblot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with entrectinib or the bivalent compounds CPD-027, CPD-053, and CPD-060 at different time points.

[0799] Figure 3 Shows the immunoblot of the TPM3-TRKA fusion protein expressed in KM12 cells in subcutaneous xenograft tumors after treatment with a range of doses of CPD-027, CPD-053, and CPD-060.

[0800] Figure 4 Panel A shows a graph of the KM12 cell viability versus the concentration of the bivalent compounds CPD-010, CPD-053, and CPD-057.

[0801] Figure 4 Panel B shows the KM12 and H358 cell viability versus the concentration of the bivalent compound CPD-053.

[0802] Figure 5 Panel A shows the immunoblot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with GNF-8625, LOXO101, or the bivalent compound TR-104–TR-129.

[0803] Figure 5 Panel B shows the immunoblot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-115, TR-116, TR-119, TR-123, TR-124, TR-127, or TR-129.

[0804] Figure 5 Panel C shows the immunoblot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-130, TR-131, TR-132, TR-140, TR-146, TR-150, or TR-168.

[0805] Figure 6 Panel A shows the immunoblot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-171, TR-172, TR-173, or TR-176.

[0806] Figure 6Panel B shows the immunoblot of the TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a range of doses of TR-177, TR-181, TR-182, or GNF-8625.

[0807] Figure 6 Panel C shows the immunoblot of the TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a range of doses of TR-186, TR-188, TR-189, or TR-190.

[0808] Figure 6 Panel D shows the immunoblot of the TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a range of doses of TR-191, TR-194, TR-196, TR198, or GNF-8625.

[0809] Figure 7 Shows the immunoblot of overexpressed TPM3-TRKA, AGBL4-TRKB, and ETV6-TRKC fusion proteins in KM12 cells after treatment with a range of doses of TR-123.

[0810] Figure 8 Panel A shows the immunoblot of the TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a range of doses of compound TR-123 or TR-123-negative (TR-123-neg).

[0811] Figure 8 Panel B shows the immunoblot of wild-type TRKA protein expressed by HEL cells after treatment with a range of doses of compound TR-123 or TR-123-negative.

[0812] Figure 9 Panel A shows the immunoblot of the 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.

[0813] Figure 9 Panel B shows the 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.

[0814] Figure 10 Panel A shows the immunoblot of the TPM3-TRKA fusion protein in subcutaneous KM12 xenograft tumors after treatment with a range of doses of TR-123.

[0815] Figure 10Panel B shows a Western blot of the TPM3-TRKA fusion protein expressed in subcutaneous KM12 xenograft tumors after treatment with TR-171, TR-172, TR-173, TR-177, or TR-181.

[0816] Figure 11 A plot showing the plasma concentration of TR-123 versus time points after dosing is presented.

[0817] Figure 12 Panel A shows a plot of the subcutaneous KM12 xenograft tumor volume versus the number of days after treatment with a range of doses of CPD-060.

[0818] Figure 12 Panel B shows a plot of body weight versus the number of days after treatment with a range of doses of CPD-060.

[0819] Figure 13 Panel A shows a Western blot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-202, TR-203, or TR-204.

[0820] Figure 13 Panel B shows a Western blot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-208, TR-210, TR-211, or TR-214.

[0821] Figure 13 Panel C shows a Western blot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-215, TR216, TR-217, TR218, TR-219, or TR-220.

[0822] Figure 13 Panel D shows a Western blot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-221, TR-222, TR-223, TR-224, TR-225, TR-226, or TR-227.

[0823] Figure 13 Panel E shows a Western blot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-231, TR-232, TR-233, TR-234, or TR-235.

[0824] Figure 14 A graph showing the plasma concentration of TR-198 over time after intravenous injection or oral gavage administration is presented.

[0825] Figure 15 Panel A shows a graph of the subcutaneous KM12 xenograft tumor volume as a function of the number of days after treatment with a range of doses of TR-181 or a single dose of TR-198.

[0826] Figure 15 Panel B shows a graph of the body weight as a function of the number of days after treatment with a range of doses of TR-181 or a single dose of TR-198.

[0827] Figure 16 Panel A shows a graph of the percentage of body weight borne by the injured limb after treatment with a single dose of vehicle (Veh), TR-181, or ibuprofen (Ibu) in rats.

[0828] Figure 16 Panel B shows a graph of the percentage of body weight borne by the injured limb after treatment with a single dose of TR-181 or ibuprofen (Ibu) in guinea pigs.

[0829] Figure 17 Panel A shows a Western blot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-247, TR-248, TR-249, TR-250, TR-251, TR-252, or TR-253.

[0830] Figure 17 Panel B shows a Western blot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-254, TR-255, TR-256, TR-257, TR-258, TR-259, or TR-260.

[0831] Figure 17 Panel C shows a Western blot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-261, TR-262, TR-263, TR-264, TR-265, TR-256, or TR-267.

[0832] Figure 18 Panel A shows a Western blot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-268, TR-269, Tr-270, TR-271, or TR-272.

[0833] Figure 18 Panel B shows a Western blot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-273, TR-274, TR-275, TR-276, or TR-277.

[0834] Figure 18 Panel C shows the immunoblot of the TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a range of doses of TR-279, Tr-280, TR-281, TR-282, or TR-283.

[0835] Figure 19 Panel A shows the immunoblot of the TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a range of doses of TR-284, TR-285, TR-286, TR-287, or TR-288.

[0836] Figure 19 Panel B shows the immunoblot of the TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a range of doses of TR-289, TR-290, TR-291, TR-292, TR-293, or TR-294.

[0837] Figure 19 Panel C shows the immunoblot of the TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a range of doses of TR-295, TR-296, TR-297, TR-298, TR-300, or TR-301.

[0838] Figure 20 Panel A shows the immunoblot of the TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a range of doses of TR-302, TR-303, TR-304, TR-305, TR-306, or TR-307.

[0839] Figure 20 Panel B shows the immunoblot of the TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a range of doses of TR-308, TR-309, TR-310, TR-311, TR-312, or TR-313.

[0840] Figure 20 Panel C shows the immunoblot of the TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a range of doses of TR-314, TR-315, TR-316, TR-317, TR-318, TR-319, or TR-320.

[0841] Figure 21 Panel A shows the immunoblot of the TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a range of doses of TR-321, TR-322, TR-323, TR-324, TR-325, TR-326, or TR-327.

[0842] Figure 21 Panel B shows the immunoblot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-328, TR-329, TR-330, TR-331, TR-332, TR-333, or TR-334.

[0843] Figure 21 Panel C shows the immunoblot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-335, TR-336, TR-337, TR-338, TR-339, or TR-340.

[0844] Figure 22 Shows the immunoblot of the NPM-ALK fusion protein expressed in SU-DHL-1 cells after treatment with a range of doses of entrectinib, CPD-032, CPD-037, or CPD-055.

[0845] Figure 23 Panel A shows a plot of the plasma concentrations of TR-231 and TR-275 over time after administration by intravenous injection or oral gavage.

[0846] Figure 23 Panel B shows the immunoblot of the TPM3-TRKA fusion protein expressed in subcutaneous KM12 xenograft tumors after treatment with TR-231 and TR-275 at different oral doses and different time points.

[0847] Figure 24 Panel A shows the growth curve of KM12 xenograft tumors in mice treated twice daily with vehicle or 40 mg / kg TR-231.

[0848] Figure 24 Panel B shows the growth curve of KM12 xenograft tumors in mice treated twice daily with vehicle or 40 mg / kg TR-275.

[0849] Figure 25A - 25C Shows the immunoblot of the TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a heterobifunctional compound.

[0850] Figure 26 Shows the immunoblot of the wild-type TRKA protein expressed in HEL cells after treatment with a heterobifunctional compound.

[0851] Figure 27A - 27CShows a graph of the viability of KM12 cells 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.

[0852] Figure 28A - 28B Shows an immunoblot of the TPM3-TRKA fusion protein expressed in the cell line after treatment with the heterobifunctional compounds. Detailed implementation

[0853] 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 mainly related to 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 neurotrophin for TRKC (Vaishnavi et al., 2015). Binding of the ligand to the extracellular domain of TRK induces dimerization and activation of the receptor, thereby activating downstream signal transduction pathways such as the 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).

[0854] It is further recognized herein that, like many other oncogenic receptor tyrosine kinases, TRK is aberrantly activated in a variety of human malignancies. Interestingly, the main molecular mechanism for activating TRK in cancer is not point mutation, but in-frame fusion of the NTRK gene (Vaishnavi et al., 2015). Generally, due to chromosomal rearrangement, the 3’ region of the NTRK gene joins the 5’ region of a partner gene. The resulting chimeric protein always retains the kinase domain of the TRK protein, indicating that the catalytic function is crucial for transforming activity. Deletion of the 5’ region encoding the autoinhibitory domain in the NTRK gene renders these fusion kinases constitutively active. Additionally, 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). Thus, genetic events result in 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).

[0855] TRK fusions were first reported in human colon cancer and were then 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 fusions have 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 carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, mammary analogue secretory carcinoma, acute myeloid leukemia, and ductal carcinoma (Amatu et al., 2016; Khotskaya et al., 2017). The frequency of TRK fusions is relatively low. For example, approximately 0.5% to 2.7% of colon cancers are affected by TRK fusions (Creancier et al., 2015; Lee et al., 2015). However, for certain cancer types, such as secretory breast carcinoma, TRK fusions are seen in the vast majority of cases (Tognon et al., 2002).

[0856] TRK mutations and deletions have been observed in other human diseases such as pulmonary neuroendocrine tumors, anhidrotic ectodermal dysplasia, obesity, congenital heart defects, and acute myeloid leukemia (Khotskaya et al., 2017). Additionally, 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).

[0857] The roles of nerve growth factor (NGF) and its main receptor tropomyosin receptor kinase A (TRKA) in central and peripheral pain have long been recognized (Denk et al., 2017). Nociceptive neurons express TRKA and mediate pain sensation by transmitting pain signals to the central nervous system. A variety of NGF-neutralizing antibodies, such as tanezumab, are being clinically evaluated in patients with osteoarthritis, low back pain, cancer pain, neuropathic pain, and other pain conditions (Miller et al., 2017). The efficacy of NGF antibodies in pain relief has been clearly demonstrated clinically. However, the administration of NGF-neutralizing antibodies has been shown to cause rapid progressive joint destruction in some patients, leading to total joint replacement (Schnitzer and Marks, 2015). These adverse events may be related to continuous 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 reactions by modulating 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.

[0858] TRK is 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, gastric cancer, lung cancer, liver cancer, uterine cancer, adrenal cancer, biliary tract cancer, bowel 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 carcinoma, salivary gland carcinoma, papillary thyroid carcinoma, ductal carcinoma, acute myeloid leukemia, large cell neuroendocrine tumor, pulmonary neuroendocrine tumor, sarcoma, pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system neoplasm, osteosarcoma, synovial sarcoma, liposarcoma, soft tissue alveolar sarcoma, Spitzoid carcinoma, Wilms tumor, lymphoma (e.g., including Hodgkin lymphoma, lymphoplasmacytic 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 disease (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, postherpetic 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, toothache, myofascial pain, perioperative pain, dysmenorrhea, myofascial pain, angina, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain caused by central sensitization, generalized cutaneous pruritus, localized cutaneous pruritus, senile pruritus, pruritus gravidarum, pruritus ani, pruritus vulvae, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, bone metastasis, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic disease, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelinating disease, and myelin formation disorder.

[0859] 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), atentinib (DCC2701, DCC-270, DP-5164) (Smith et al., 2015), sitravatinib (MGCD516) (Patwardhan et al., 2016), cabozantinib (XL-184, BMS-907351) (Fuse et al., 2017), dovitinib (TKI-258, CHIR-258) (Chong et al., 2017), masitinib (PHA-848125AC) (Brasca et al., 2009), bexarotene (TSR-011) (Ricciuti et al., 2017), GZ389988 (Bailey et al., 2017a,b), pexidartinib (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 tested in basket trials, recruiting patients based on the detection of TRK fusions rather than histology. Phase 2 results of larotrectinib showed that most patients (75%) responded to treatment and 55% remained progression-free at 1 year (Drilon et al., 2018). Phase 1 results of entrectinib also documented significant and durable responses in patients with TRK fusion tumors (Drilon et al., 2017b). The significant efficacy of TRK inhibitors is independent of tumor type. These substantial results together highlight the role of TRK fusions as the sole oncogenic driver in a subgroup of human malignancies, regardless of tissue origin.

[0860] The non-specific side effects of TRK kinase inhibitors and the development of resistance to them remain challenges in the development of effective therapies. Thus, novel small molecules that target TRK by inhibiting and / or degrading its function would be very useful.

[0861] Without wishing to be bound by any theory, the present disclosure is considered to be at least partially based on the finding that novel heterobivalent small molecules that degrade TRK, TRK fusion proteins, TRK splicing, and / or TRK mutant proteins can be used to treat 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 carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, mammary analogue secretory carcinoma, acute osteoblastic leukemia, ductal carcinoma, pulmonary neuroendocrine tumor, pheochromocytoma, and Wilms tumor (Amatu et al., 2016; Khotskaya et al., 2017).The disclosed novel bifunctional TRK degrader can be used to treat TRK-mediated cancers, inflammatory diseases, acute and chronic pain, itching, 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, bowel 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 carcinoma, 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 mesoblastic nephroma, secretory breast cancer, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system neoplasm, osteosarcoma, synovial sarcoma, liposarcoma, soft tissue alveolar sarcoma, Spitzoid carcinoma, Wilms tumor, lymphoma (e.g., including Hodgkin lymphoma, lymphoplasmacytic 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 disease (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, postherpetic neuralgia 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, toothache, myofascial pain, perioperative pain, dysmenorrhea, myofascial pain, angina, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain caused by central sensitization, generalized pruritus, localized pruritus, senile pruritus, pruritus gravidarum, pruritus ani, pruritus vulvae, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, bone metastasis, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic disease, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelinating disease, and myelin formation disorder.

[0862] Selective degradation of target proteins by small molecules can be achieved by recruiting E3 ubiquitin ligases and mimicking protein misfolding with a hydrophobic tag (Buckley and Crews, 2014). In addition, small molecules have a portion that binds to an E3 ubiquitin ligase and another portion that binds to the protein target of interest (Buckley and Crews, 2014). Induced proximity leads to ubiquitination of the target, followed by its degradation via proteasome-mediated proteolysis. Several types of high-affinity small molecule E3 ligase ligands have been identified or developed. 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); (2) VHL-1, a hydroxyproline-containing ligand that binds to the von Hippel-Lindau protein (VHL or CRL2VHL), another component of a 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, an 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). The 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 a bulky and hydrophobic adamantyl group has been developed to mimic protein misfolding, leading to proteasomal degradation of target proteins (Buckley and Crews, 2014). This method has been applied to the selective degradation of the pseudokinase HER3 (Xie et al., 2014). The inventors have not seen any efforts to apply any of these methods to the degradation of TRK, TRK mutants, TRK deletions, TRK splicing, or TRK fusion proteins.

[0863] 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), atetinib (DCC2701, DCC-270, DP-5164) (Smith et al., 2015), sitravatinib (MGCD516) (Patwardhan et al., 2016), cabozantinib (XL-184, BMS-907351) (Fuse et al., 2017), dovitinib (TKI-258, CHIR-258) (Chong et al., 2017), masitinib (PHA-848125AC) (Brasca et al., 2009), bexarotene (TSR-011) (Ricciuti et al., 2017), GZ389988 (Bailey et al., 2017a,b), perzinfostat (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).

[0864] In the present disclosure, a novel approach is adopted: to develop compounds that directly and selectively modulate not only the kinase activity of TRK but also its protein level. Strategies for inducing protein degradation include recruiting E3 ubiquitin ligases, mimicking protein misfolding with hydrophobic tags, and inhibiting molecular chaperones. Such an approach based on the use of bivalent small-molecule compounds allows for more flexible modulation of protein levels in vitro and in vivo compared to techniques such as gene knockout or short hairpin RNA (shRNA)-mediated knockdown. Different from gene knockout or shRNA knockdown, the small-molecule approach further provides opportunities to study dose and time dependence in disease models by modulating the administration route, concentration, and frequency of the corresponding small molecule.

[0865] Bivalent compound

[0866] For the purposes of the present disclosure, the terms "bifunctional compound", "bifunctional degrader", "bifunctional TRK degrader", "bivalent compound", and "heterobifunctional compound" are used interchangeably.

[0867] In some aspects, the present disclosure provides bivalent compounds comprising a TRK ligand conjugated to a degron, or a pharmaceutically acceptable salt or analogue thereof. The TRK ligand can be conjugated directly or via a linker moiety to the degron. In certain embodiments, the TRK ligand can be conjugated directly to the degron. In certain embodiments, the TRK ligand can be conjugated to the degron via a linker moiety.

[0868] As used herein, the terms "tropomyosin receptor kinase ligand" and "TRK ligand" or "TRK targeting moiety" are construed to include any molecule from small molecules to large proteins that associates or binds with the TRK protein. In certain embodiments, the TRK ligand is capable of binding to a TRK protein comprising TRK, a TRK mutant, a TRK deletion, a TRK splice, or a TRK fusion protein. The 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.

[0869] TRK ligand

[0870] The TRK ligand or targeting moiety can be a TRK kinase inhibitor or part of a TRK kinase inhibitor. In certain embodiments, the TRK kinase inhibitor includes, for example, entrectinib (RXDX-101) (Menichincheri et al., 2016), GNF-8625 (Choi et al., 2015), larotrectinib (LOXO-101; ARRY-470) (Drilon et al., 2018), atetinib (DCC2701, DCC-270, DP-5164) (Smith et al., 2015), sitravatinib (MGCD516) (Patwardhan et al., 2016), cabozantinib (XL-184, BMS-907351) (Fuse et al., 2017), dovitinib (TKI-258, CHIR-258) (Chong et al., 2017), masitinib (PHA-848125AC) (Brasca et al., 2009), bexarotene (TSR-011) (Ricciuti et al., 2017), GZ389988 (Bailey et al., 2017a,b), pexidartinib (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), PF-06273340 (Skerratt et al., 2016), and analogs thereof, which are capable of inhibiting the kinase activity of TRK. As used herein, a "TRK kinase inhibitor" refers to a reagent that inhibits, retards, or otherwise causes inhibition of a physiological, chemical, or enzymatic action or function and results in at least a 5% reduction in binding. An inhibitor can also or alternatively refer to a drug, compound, or reagent that blocks or reduces the expression, transcription, or translation of a gene or protein. An inhibitor can reduce or prevent the function of a protein, for example, by binding or activating / inactivating another protein or receptor.

[0871] In certain embodiments, the TRK ligand is derived from a TRK kinase inhibitor and includes:

[0872]

[0873] In certain embodiments, the 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).

[0874] In one aspect, the present disclosure provides a compound of Formula I:

[0875]

[0876] or a pharmaceutically acceptable salt thereof, wherein

[0877] X 1 and X 2 are independently selected from CH and N;

[0878] X 3 and X 4 are independently selected from C(O) and CR 4 R 5 ;

[0879] R 1 is selected from H, -NR 2 R 3 , halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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;

[0880] R 2 、R 3 、R 4 and R 5 are independently selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted 5- to 10-membered heteroaryl group, optionally substituted C 1-6 heteroalkyl, optionally substituted C 1-6 haloalkyl and optionally substituted C 1-6 alkoxy; and

[0881] L is selected from a bond,

[0882] or

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

[0884] L is

[0885] In some embodiments, X 1 and X 2 are each N.

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

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

[0888] In one aspect, the present disclosure provides a compound 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 are independently selected from C(O), CR 4 R 5 and NR 6 ;

[0893] R 1 is selected from H, -NR 2 R 3 、halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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 C 1 -C 6 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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'CO 2 R", R'C(O)N(R 7 )R", R'C(S)N(R 7)R”, R’OR”, R’SR”, R’SOR”, R’SO 2 R”, R’SO 2 N(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 C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 aminoalkylene, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5 - 13 - membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5 - 13 - membered bridged heterocyclic group, optionally substituted C 5 -C 13 spirocarbocyclic group, optionally substituted 5 - 13 - membered spiroheterocyclic group, optionally substituted 3 - 10 - membered carbocyclic group, optionally substituted 3 - 10 - membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

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

[0897] R’ and R” are independently selected from the empty, optionally substituted C 1 -C 8 alkylene, optionally substituted C1 -C 8 Heteroalkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkynylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 1 -C 8 Aminoalkylene, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Halogenoalkylene, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C 13 Fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 Bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; and

[0898] R 7 and R 8 are independently selected from hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy-C 1 -C 8 Alkyl, optionally substituted C 1 -C8 Halogenoalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Aminoalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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 Optionally form a 3- to 20-membered carbocyclic group or a 3- to 20-membered heterocyclic group ring together with the atom to which they are attached;

[0900] In some embodiments, L is selected from

[0901] In some embodiments, X 1 and X 2 are each N.

[0902] In some embodiments, at least one of X 3 and X 4 is NR 6 。In some embodiments, X 3 and X 4 are both NR 6 。

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

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

[0905] In some embodiments, L is attached to X 3 。In some embodiments, L is attached to X 4 。

[0906] In one aspect, the present invention provides 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 which is C(O) and the other is CR 1 R 2 ; and

[0911] L is selected from or

[0912] X 3 and X 4 are each 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 C 1 -C 6 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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 are each N.

[0916] In one aspect, the present invention provides a compound of formula III:

[0917]

[0918] or a pharmaceutically acceptable salt thereof, wherein

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

[0920] X 2Selected 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, NO 2 , OR 17 , SR 17 , NR 18 R 19 , COR 17 , CO 2 R 17 , CONR 18 R 19 , SOR 17 , SO 2 R 17 , SO 2 NR 18 R 19 , NR 17 COR 19 , NR 17 C(O)NR 18 R 19 , NR 18 SOR 17 , NR 18 SO 2 R 17 optionally substituted C 1-8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C 1-8 alkoxy, optionally substituted C 1-8 alkylamino, optionally substituted C 3-10 carbocyclic group, -O-(optionally substituted C 3-10 carbocyclic group), -NH-(optionally substituted C 3-10 carbocyclic group), optionally substituted 3- to 10-membered heterocyclic group, -O-(optionally substituted 3- to 10-membered heterocyclic group), -NH-(optionally substituted 3- to 10-membered heterocyclic group), 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'CO 2 R", R'C(O)N(R 21 )R", R'C(S)N(R 21 )R", R'OR", R'SR", R'SOR", R'SO 2 R", R'SO 2 N(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 C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 aminoalkylene, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted C 5 -C 13 spirocarbocyclic group, optionally substituted 5-13 membered spiroheterocyclic group, optionally substituted 3-10 membered carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

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

[0925] R’ and R” are independently selected from the group consisting of empty, optionally substituted C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 aminoalkylene, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C 13 fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0926] R 1 and R 2 are each independently selected from the group consisting of H, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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 3Select from key, -OR 14 -、-SR 14 -、-N(R 15 )R 14 -、-COR 14 -、-CO 2 R 14 -、-CON(R 15 )R 14 -、-SOR 14 -、-SO 2 R 14 -、-SO 2 N(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 )SO 2 R 14 -, optionally substituted C 1-8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, 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, NO 2 , OR 10 , SR 11 NR 12 R 13 , COR 10 , CO 2 R 10 、C(O)NR 12 R 13 , SOR 10 、SO 2 R 10 、SO 2 NR 12 R13 , NR 10 C(O)R 13 , NR 10 C(O)NR 12 R 13 , NR 10 SOR 13 , NR 10 SO 2 R 13 , optionally substituted C 1-8 -alkyl, optionally substituted C 1 -C 8 -heteroalkyl, optionally substituted C 2 -C 8 -alkenyl, optionally substituted C 2 -C 8 -alkynyl, optionally substituted C 1-8 -heteroalkyl, optionally substituted C 1-8 -alkoxy, optionally substituted C 3-10 -carbocyclic group and optionally substituted 3- to 10-membered heterocyclic group;

[0929] R 7 is selected from optionally substituted C 1-8 -alkyl, optionally substituted C 1-8 -heteroalkyl, optionally substituted C 3-10 -carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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 -carbocyclic group, -O-(optionally substituted C 3-10 -carbocyclic group), optionally substituted C 1-8 -alkylamino, -NH-(optionally substituted C 3-10 -carbocyclic group) and optionally substituted 3- to 10-membered heterocyclic group; or

[0931] R 8 and R 9 together with the atom to which they are attached form an optionally substituted C 3-10 -carbocyclic group or optionally substituted 3- to 10-membered heterocyclic group;

[0932] R 10 , R 11 , R 12 and R 13Independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl; or

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

[0934] R 14 is selected from the empty group, optionally substituted C 1-8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1-8 heteroalkylene, optionally substituted C 1-8 alkoxy, optionally substituted C 3-10 carbocyclic group, -O-(optionally substituted C 3-10 carbocyclic group), optionally substituted C 1-8 alkylamino, -NH-(optionally substituted C 3-10 carbocyclic group), optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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 C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C 1-8 alkoxy, optionally substituted C 3-10A carbocyclic group, an optionally substituted 3- to 10-membered heterocyclic group, an optionally substituted C 6-10 aryl, and an optionally substituted 5- to 10-membered heteroaryl; or

[0936] R 14 and R 15 together with the atom to which they are attached optionally form an optionally substituted C 3-10 carbocyclic group or an optionally substituted 3- to 10-membered heterocyclic group;

[0937] R 17 , R 18 and R 19 are independently selected from hydrogen, an optionally substituted C 1-8 alkyl, an optionally substituted C 1 -C 8 heteroalkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 1-8 heteroalkyl, an optionally substituted C 1-8 alkoxy, an optionally substituted C 3-10 carbocyclic group, -O-(optionally substituted C 3-10 carbocyclic group), an optionally substituted 3- to 10-membered heterocyclic group, an optionally substituted C 6-10 aryl, and an optionally substituted 5- to 10-membered heteroaryl; or

[0938] R 18 and R 19 together with the atom to which they are attached form an optionally substituted C 3-10 carbocyclic group or an optionally substituted 3- to 10-membered heterocyclic group; and

[0939] R 21 and R 22 are independently selected from hydrogen, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 heteroalkyl, an optionally substituted C 1 -C 8 alkoxy, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 1 -C 8 alkoxy-C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 haloalkyl, an optionally substituted C1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Aminoalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group; 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 Optionally form a 3- to 20-membered carbocyclic group or a 3- to 20-membered heterocyclic group ring together with the atom to which they are attached.

[0941] In some embodiments, L is selected from

[0942] In some embodiments, R 4 , R 5 and R 6 are each hydrogen.

[0943] In some embodiments, Y is CR 8 R 9 . In some embodiments, Y is CH 2 .

[0944] In some embodiments, R 7 is optionally substituted C 6-10 aryl. In some embodiments, R 7 is

[0945] In some embodiments, Ar is C 18 substituted by NR 19 R 6-10 aryl. In some embodiments, Ar is

[0946] In some embodiments, R 3 is optionally substituted 3- to 10-membered heterocyclic group. In some embodiments, R 3 is

[0947] In some embodiments, X 1 is CR 1 , X2 is CH, and X 3 is NR 1 . In some embodiments, X 1 is NR 1 , X 2 is CH, and X 3 is CR 1 . In some embodiments, X 1 is CR 1 , X 2 is N, and X 3 is NR 1 . In some embodiments, X 1 is NR 1 , X 2 is N, and X 3 is CR 1 . In some embodiments, X 1 is NR 1 , X 2 is CH, and X 3 is N. In some embodiments, X 1 is N, X 2 is CH, and X 3 is NR 1 . In some embodiments, X 1 is CR 1 R 2 , X 2 is CO, and X 3 is NR 1 . In some embodiments, X 1 is NR 1 , X 2 is CO, and X 3 is NR 1 . In some embodiments, X 1 is O, X 2 is CO, and X 3 is NR 1 . In some embodiments, X 1 is CR 1 , X 2 is CO, and X 3 is NR 1 . In some embodiments, X 1 is N, X 2 is CO, and X 3 is NR 1 .

[0948] In some embodiments, R 1 is

[0949] In one aspect, the present disclosure provides a compound of Formula IV:

[0950]

[0951] or a pharmaceutically acceptable salt thereof, wherein

[0952] X 1 and X 3 are independently selected from CR 1 、N and NR 1 ;

[0953] X 2 is selected from N and CH;

[0954] Y 1 is selected from N and CR 6 ;

[0955] Y 2 、Y 3 and Y 4 are independently selected from N and C, provided that only one of Y 2 、Y 3 and Y 4 is N;

[0956] Z is selected from a bond, a carbon-carbon double bond, C(R 5 ) 2 、C(R 5 ) 2 C(R 5 ) 2 、CO、C(R 5 ) 2 CO、CONR 5 、C(R 5 ) 2 O、C(R 5 ) 2 NR 5 and CH 2 NR 5 ;

[0957] Ar 1 and Ar 2 are 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, NO 2 、OR 10 、SR 10 、NR 11 R 12 、COR 10 、CO 2 R 10 、CONR 11 R 12, SOR 10 , SO 2 R 10 , SO 2 NR 11 R 12 , NR 10 COR 12 , NR 10 C(O)NR 11 R 12 , NR 10 SOR 12 , NR 10 SO 2 R 12 , Optionally substituted C 1-8 alkyl, optionally substituted C 1 -C 8 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 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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'CO 2 R", R'C(O)N(R 13 )R", R'C(S)N(R 13 )R", R'OR", R'SR", R'SOR", R'SO 2 R", R'SO 2 N(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 C 1 -C 8 alkylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 1 -C8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Halogenated alkylene, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 1 -C 8 Aminoalkylene, optionally substituted C 4 -C 13 Fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 Bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spirocarbocyclic group, optionally substituted 5- to 13-membered spiroheterocyclic group, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl;

[0959] Wherein L is optionally attached to X 1 or X 3 attached;

[0960] R’ and R” are independently selected from the empty set, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkynylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 1 -C 8 Aminoalkylene, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkylene, optionally substituted C 1 -C 8Halogenated alkylene group, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 4 -C 13 Fused carbocyclic group, optionally substituted 5- to 13-membered fused heterocyclic group, optionally substituted C 5 -C 13 Bridged carbocyclic group, optionally substituted 5- to 13-membered bridged heterocyclic group, optionally substituted C 5 -C 13 Spiro carbocyclic group, optionally substituted 5- to 13-membered spiro heterocyclic group, optionally substituted aryl group and optionally substituted heteroaryl group;

[0961] R 1 Each occurrence is independently selected from H, halogen, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 heteroalkyl group, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted 5- to 10-membered heteroaryl group, optionally substituted C 1-6 heteroalkyl group, optionally substituted C 1-6 halogenated alkyl group, optionally substituted C 1-6 alkoxy group and optionally substituted 2,6-dioxopiperidin-3-yl;

[0962] R 3 Selected from a bond, -OR 7 -, -SR 7 -, -N(R 8 )R 7 -, -COR 7 -, -CO 2 R 7 -, -CON(R 8 )R 7 -, -SOR 7 -, -SO 2 R 7 -, -SO 2 N(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 )SO 2 R 7 -, optionally substituted C 1-8 alkylene group, optionally substituted C 1 -C 8 heteroalkylene group, optionally substituted C2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkynylene, optionally substituted C 1-8 Heteroalkylene, optionally substituted C 3-10 Carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 6-10 Aryl and optionally substituted 5- to 10-membered heteroaryl;

[0963] R 4 and R 5 Each occurrence independently is selected from hydrogen, halogen, OH, NH 2 , CN, NO 2 , optionally substituted C 1-4 Alkyl, optionally substituted C 1 -C 4 Heteroalkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 1-4 Halogenated alkyl, optionally substituted C 3-10 Carbocyclic group, -O-(optionally substituted C 3-10 carbocyclic group), -NH-(optionally substituted C 3-10 carbocyclic group) and optionally substituted 3- to 10-membered heterocyclic group;

[0964] R 6 is selected from hydrogen, halogen, CN, NO 2 , optionally substituted C 1-6 Alkyl, optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted C 3-10 Carbocyclic group and optionally substituted 3- to 10-membered heterocyclic group;

[0965] R 7 is selected from empty, optionally substituted C 1-8 Alkylene, optionally substituted C 1 -C 8 Heteroalkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkynylene, optionally substituted C 1-8 Heteroalkylene, optionally substituted C 1-8 Alkoxy, optionally substituted C 3-10 Carbocyclic group, -O-(optionally substituted C 3-10 carbocyclic group), optionally substituted C 1-8 Alkylamino, -NH-(optionally substituted C 3-10(carbocyclic group), optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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 C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C 1-8 alkoxy, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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, optionally form an optionally substituted C 3-10 carbocyclic group or an optionally substituted 3- to 10-membered heterocyclic group;

[0968] R 10 , R 11 and R 12 are independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2-8 alkenyl, optionally substituted C 2-8 alkynyl, optionally substituted C 3-10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 6-10 aryl, and optionally substituted 5- to 10-membered heteroaryl; or

[0969] R 11 and R 12 together with the atoms to which they are attached, form an optionally substituted C 3 -C 10 carbocyclic group or an optionally substituted 3- to 10-membered heterocyclic group;

[0970] R 13 and R 14 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1-C 8 Heteroalkyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy-C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Halogenoalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Aminoalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted 3- to 10-membered carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, 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 Optionally form, together with the atom to which they are attached, a 3- to 20-membered carbocyclic or 3- to 20-membered heterocyclic 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 is N, Y 2 is N, Y 3 is C, and Y 4 is C.

[0975] In some embodiments, Ar 1 is aryl optionally substituted with halogen. In some embodiments, Ar 6-10 is 1 is

[0976] In some embodiments, Ar 2 is optionally substituted with NR 11 R12 Substituted C 6-10 aryl. In some embodiments, Ar 2 is

[0977] In some embodiments, R 3 is an optionally substituted 3- to 10-membered heterocyclic group. In some embodiments, R 3 is

[0978] In some embodiments, R 4 is 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 is CR 1 , X 2 is CH, and X 3 is NR 1 . In some embodiments, X 1 is NR 1 , X 2 is CH, and X 3 is CR 1 . In some embodiments, X 1 is CR 1 , X 2 is N, and X 3 is NR 1 . In some embodiments, X 1 is NR 1 , X 2 is N, and X 3 is CR 1 . In some embodiments, X 1 is NR 1 , X 2 is CH, and X 3 is N. In some embodiments, X 1 is N, X 2 is CH, and X 3 is NR 1 .

[0982] In some embodiments, R 1 is methyl. In some embodiments, R 1 is

[0983] In another embodiment, the TRK ligand comprises a moiety of Formula 1;

[0984]

[0985] wherein,

[0986] R 1 、R 2 、R 3 、R 4 、Ar and X are as defined above.

[0987] In another embodiment, the TRK ligand contains a moiety of Formula 1:

[0988]

[0989] where

[0990] X is selected from CR’R”, CO, O, S, SO, 2 and NR’, wherein

[0991] R’ and R” are independently selected from hydrogen, halogen, OH, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1-8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 10 carbocyclic, optionally substituted C 3 -C 10 cycloalkoxy and optionally substituted 3-10 membered heterocyclic group; or

[0992] R’ and R” together with the atom(s) to which they are attached optionally form an optionally substituted 3-8 membered carbocyclic or heterocyclic ring;

[0993] R is selected from optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 3 -C 10carbocyclyl, 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, NO 2 , OR 5 , SR 6 NR 7 R 8 , COR 5 , CO 2 R 5 、C(O)NR 7 R 8 、SOR 5 、SO 2 R 5 、SO 2 NR 7 R 8 NR 7 C(O)R 8 NR 5 C(O)NR 7 R 8 NR 7 SOR 8 NR 7 SO 2 R 8 , optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 3 -C 10 Carbocyclic group, optionally substituted C 3 -C 10 cycloalkoxy, optionally substituted 3-10 membered heterocyclic group, optionally substituted C 2 -C 8 Alkenyl and optionally substituted C 2 -C 8 Alkynyl, where

[0995] R 5 , R 6, R 7 and R 8 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C 3 -C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 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- to 8-membered heterocyclic group ring;

[0997] R 4 is attached to the linker moiety of the divalent compound and is selected from a bond, OR 9 , SR 9 , NR 10 R 11 , COR 9 , CO 2 R 9 , CONR 10 R 11 , SOR 9 , SO 2 R 9 , SO 2 , NR 10 R 11 , NR 10 , COR 11 , NR 9 , CONR 10 R 11 , NR 10 , SOR 11 , NR 10 , SO 2 R 11 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8Heteroalkyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic group, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, aryl and optionally substituted heteroaryl, wherein

[0998] R 9 , R 10 and R 11 are independently selected from space, a bond, hydrogen, an optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Heteroalkyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic group, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 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, NO 2 、OR 12 、SR 12 、NR 13 R 14 、COR 12 、CO 2 R 12 、CONR 13 R 14 、SOR 12 、SO 2 R 12 、SO 2 、NR 13 R 14 、NR 13 COR 14 、NR 15 C(O)NR 13 R 14 、NR 13 SOR 14 、NR 13 、SO 2 R 14 、optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[1001] R 12 、R 13 、R 14 and R 15 are independently selected from hydrogen, optionally substituted C 1-C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C 3 -C 8 carbocyclic group, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[1002] R 13 and R 14 together with the atoms to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocyclic ring.

[1003] In one embodiment,

[1004] X is selected from CR’R”, O and NR’, where

[1005] R’ and R” are independently selected from hydrogen, F, OH, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 heteroalkyl and optionally substituted C 1 -C 3 alkoxy, or

[1006] R’ and R” together with the atoms to which they are attached form an optionally substituted 3- to 6-membered carbocyclic or heterocyclic ring.

[1007] In another embodiment, X is selected from CH 2 , cyclopropylidene, CHF, CF 2 , O, NH, NCH 3 , NCH 2 CH 3 and N-isopropyl.

[1008] In another embodiment, R is selected from optionally substituted C 3 -C8 Carbocyclic group, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group.

[1009] In another embodiment, R is selected from optionally substituted phenyl and optionally substituted heteroaryl.

[1010] In another embodiment, X is CH 2 ; 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 moieties of formulae A1, A2, A3, and A4:

[1013]

[1014] wherein

[1015] * represents the linker moiety attached to the divalent compound; and

[1016] R a is selected from hydrogen, halogen, CN, NO 2 , OR 12 , SR 12 , NR 13 R 14 , COR 12 , CO 2 R 12 , CONR 13 R 14 , SOR 12 , SO 2 R 12 , SO 2 , SO 13 NR 14 , NR 13 , COR 14 , NR 15 , C(O)NR 13 R 14 , NR 13 , SOR 14 , NR 13 , SO 2 R 14 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 3 -C 8 Carbocyclic group, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic group, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroar...

Claims

1. A divalent compound of formula II: or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 are independently selected from CH and N; X 3 and X 4 one of which is C(O) and the other is CR 1 R 2 ; and L is selected from or X 3 and X 4 each is C(O); and L is selected from and R 1 and R 2 is H.

2. The divalent compound according to claim 1, wherein X 1 and X 2 are each N.

3. A divalent compound selected from: 3-(7-((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)-2-oxobenz[d]oxazol-3(2H)-yl)piperidine-2,6-dione (CPD-247); 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)methyl)azetidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (CPD-250); 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 (CPD-258); 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 (CPD-259); 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 (CPD-260); 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)morpholino)isoindoline-1,3-dione (CPD-286); 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 (CPD-287); 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 (CPD-288); 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 (CPD-292); 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 (CPD-293); 2-(2,6-Dioxopiperidin-3-yl)-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)methyl)isoindoline-1,3-dione (CPD-294); 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 (CPD-302); 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 (CPD-308); 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 (CPD-317); 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 (CPD-331); 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)pyridinecarboxamide (CPD-470); 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)pyridinecarboxamide (CPD-471); 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)pyridinecarboxamide (CPD-473); 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)pyridinecarboxamide (CPD-474); 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)pyridinecarboxamide (CPD-475); and 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-tetraoxapentadecan-15-yl)piperidin-4-yl)amino)pyridinecarboxamide (CPD-476); or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the bivalent compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

5. A pharmaceutical composition comprising the bivalent compound according to claim 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

6. Use of the bivalent compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disease mediated by tropomyosin receptor kinase (TRK).

7. Use of the bivalent compound or a pharmaceutically acceptable salt thereof according to claim 3 in the preparation of a medicament for treating a disease mediated by tropomyosin receptor kinase (TRK).

8. Use according to claim 6 or claim 7, wherein the TRK-mediated disease is cancer.

9. Use according to claim 6 or claim 7, wherein the TRK-mediated disease is acute pain or chronic pain.

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