Tropomyosin receptor kinase (TRK) degrading compounds and methods of using the same

Abstract

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

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of International Patent Application No. PCT / CN2020 / 076748, filed on February 26, 2020, which is hereby incorporated by reference in its entirety into this specification.

Background Art

[0002] The present disclosure relates to a divalent compound (e.g., a bifunctional small - molecule compound), a composition comprising one or more of such divalent compounds, and methods of using the divalent compounds for treating some diseases of a subject in need of treatment. The present disclosure also relates to methods for identifying such divalent compounds.

Summary of the Invention

[0003] In one aspect herein, a compound of formula I:

[0004]

Chemical Formula

[0005]

Chemical formula

[0006]

Chemical formula

[0007]

[0008] In some embodiments, X 1 and X 2 are each N.

[0008] In some embodiments, X 3 is C(O) and X 4 is CR 4 5 In some embodiments, X 3 is C(O) and X 4 is CR 4R 5 is.

[0009] 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 is.

[0010] In some embodiments, R 1 is -NR 2 R 3 is. In some embodiments, R 1 is

[0011]

Chemical formula

[0012] In one aspect of the present specification, formula Ia:

[0013]

Chemical formula

[0014] In some embodiments, L is

[0015] [Chemical formula] selected from.

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

[0017] 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 6is.

[0018] In some embodiments, X 3 or X 4 is -N-(2,6-dioxopiperidin-3-yl).

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

[0020]

Chemical formula

[0021] In some embodiments, L is connected to X 3 In some embodiments, L is connected to X 4 is connected to.

[0022] In one aspect herein, Formula II:

[0023]

Chemical formula

[0024]

Chemical formula

[0025]

Chem.

[0026] In some embodiments, X 1 and X 2 are each N.

[0027] In one aspect herein, Formula III:

[0028]

Chem.

[0029] In some embodiments, L is

[0030]

Chemical Structure

[0031] In some embodiments, R 4 , R 5 , and R 6 are each hydrogen.

[0032] In some embodiments, Y is CR 8 R 9 is. In some embodiments, Y is CH2.

[0033] In some embodiments, R7 is optionally substituted C 6-10 aryl. In some embodiments, R 7 is

[0034] [Chemical formula] as shown.

[0035] In some embodiments, Ar is NR 18 R 19 substituted C 6-10 aryl. In some embodiments, Ar is

[0036] [Chemical formula] as shown.

[0037] In some embodiments, R 3 is an optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, R 3 is

[0038] [Chemical formula] as shown.

[0039] In some embodiments, X 1 is CR 1 and X 2 is CH, and X 3 is NR 1 In some embodiments, X 1 is NR 1 and X 2 is CH, and X 3 is CR 1 In some embodiments, X 1 is CR 1 and X 2 is N, and X 3 is NR 1 In some embodiments, X 1 is NR 1and X 2 is N, and X 3 is CR 1 is. In some embodiments, X 1 is NR 1 and X 2 is CH, and X 3 is N. In some embodiments, X 1 is N, and X 2 is CH, and X 3 is NR 1 is. In some embodiments, X 1 is CR 1 R 2 and X 2 is CO, and X 3 is NR 1 is. In some embodiments, X 1 is NR 1 and X 2 is CO, and X 3 is NR 1 is. In some embodiments, X 1 is O, and X 2 is CO, and X 3 is NR 1 is. In some embodiments, X 1 is CR 1 and X 2 is CO, and X 3 is NR 1 is. In some embodiments, X 1 is N, and X 2 is CO, and X 3 is NR 1 is.

[0040] In some embodiments, R 1 is

[0041]

Chemical formula

[0042] In one aspect of the present specification, Formula IV:

[0043]

Chemical formula

[0044] In some embodiments, L is

[0045]

Chemical Structure

[0046] In some embodiments, Y 1 is N, Y 2 is N, Y 3 is C, Y 4 is C.

[0047] In some embodiments, Ar 1 is C optionally substituted by halogen 6-10It is aryl. In some embodiments, Ar 1 is

[0048]

Chem.

[0049] In some embodiments, Ar 2 is NR 11 R 12 optionally substituted C 6-10 aryl. In some embodiments, Ar 2 is

[0050]

Chem.

[0051] In some embodiments, R 3 is an optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, R 3 is

[0052]

Chem.

[0053] In some embodiments, R 4 is hydrogen.

[0054] In some embodiments, Z is C(R 5 )2. In some embodiments, Z is CH2.

[0055] In some embodiments, n is 0.

[0056] In some embodiments, X 1 is CR 1 , X 2 is CH, X 3 is NR 1 . In some embodiments, X1 is NR 1 and X 2 is CH and X 3 is CR 1 is. In some embodiments, X 1 is CR 1 and X 2 is N and X 3 is NR 1 is. In some embodiments, X 1 is NR 1 and X 2 is N and X 3 is CR 1 is. In some embodiments, X 1 is NR 1 and X 2 is CH and X 3 is N. In some embodiments, X 1 is N and X 2 is CH and X 3 is NR 1 is.

[0057] In some embodiments, R 1 is methyl. In some embodiments, R 1 is

[0058]

Chemical formula

[0059] According to one aspect of the present disclosure, the divalent compounds disclosed herein, or pharmaceutically acceptable salts or analogs thereof, comprise tropomyosin receptor kinase (TRK) ligands conjugated to degradation tags.

[0060] In one embodiment, the TRK ligand is capable of binding to a TRK protein comprising a TRK, a TRK mutation, a TRK deletion, a TRK splicing, or a TRK fusion protein.

[0061] In another embodiment, the TRK ligand is a TRK kinase inhibitor or a part thereof.

[0062] 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), citralbatinib (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 analogs thereof.

[0063] In another embodiment, the degradation tag is a hydrophobic group or tag that binds to a ubiquitin ligase or causes misfolding of the TRK protein.

[0064] In another embodiment, the ubiquitin ligase is an E3 ligase.

[0065] In another embodiment, the E3 ligase is selected from the group consisting of cereblon E3 ligase, VHL E3 ligase, IAP ligase, MDM2 ligase, TRIM24 ligase, TRIM21 ligase, KEAP ligase, DCAF16 ligase, RNF4 ligase, RNF114 ligase, and AhR ligase.

[0066] In another embodiment, the degron 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.

[0067] In another embodiment, the TRK ligand is conjugated to the degron via a linker moiety.

[0068] In another embodiment, the TRK ligand has the formula 1:

[0069]

Chemical formula

[0070] In one embodiment, X is selected from CR’R”, O, and NR, where R’ and R” are independently selected from hydrogen, F, OH, optionally substituted C1-C3 alkyl, and optionally substituted C1-C3 alkoxy, or R’ and R” together with the atom to which they are attached, optionally form an optionally substituted 3- to 8-membered carbocyclic or heterocyclic ring.

[0071] In another embodiment, X is selected from CH2, cyclopropylene, CHF, CF2, O, NH, NCH3, NCH2CH3, and N-isopropyl.

[0072] In another embodiment, R is selected from optionally substituted C3-C8 carbocyclyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0073] In another embodiment, R is selected from optionally substituted phenyl and optionally substituted heteroaryl.

[0074] In another embodiment, X is CH2 and R is 3,5-difluorophenyl.

[0075] In another embodiment, R 1 , R 2 , and R 3 are independently selected from hydrogen, F, Cl, and OH.

[0076] In another embodiment, R 4 -Ar is selected from the moieties of Formulas A1, A2, A3, and A4:

[0077]

Chemical formula

[0078] In another embodiment, R 4 -Ar is of the formulas A1, A3, A3, and A4:

[0079]

Chemical formula

[0080] In another embodiment, R a is selected from H, (tetrahydro-2H-pyran-4-yl)amino, and 2-fluoroethylamino.

[0081] In another embodiment, R 4 is optionally substituted

[0082]

Chemical formula

[0083] In another embodiment, the TRK ligand has the formula 2:

[0084]

Chemical formula

[0085] In one embodiment, X 1 is selected from CR’ and N, where R’ is selected from hydrogen, F, Cl, CH3, CF3, and cyclopropyl.

[0086] In another embodiment, X 2 , X 3 , and X 4 are independently selected from C and N.

[0087] In another embodiment, X is selected from a single bond, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH, and CH2NCH3.

[0088] In another embodiment, R 1 and R 2 are each, upon each occurrence, independently selected from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3- to 6-membered heterocyclyl.

[0089] In another embodiment, X is CH2 and Ar 1 is 3-fluorophenyl.

[0090] In another embodiment, R 3 is directly connected to the linker portion of the divalent compound, and R 3 is null, a single bond, -OR 5 -, -SR 5 -, -NR 6 R 7 -, -COR 5 -, -CO2R 5 -, -CONR 6 R 7 -, -SOR 5 -, -SO2R 5 -, -SO2NR 6 R 7 -, -NR 5 COR 7 -, -NR 5 COR 7 -, -NR 5 C(O)NR 6 R 7 -, -NR 5 SOR 7 -, -NR 5 SO2R 7- C1-C8 alkylene optionally substituted, C1-C8 heteroalkylene optionally substituted, C1-C8 alkylene - O - C1-C8 alkylene optionally substituted, C1-C8 haloalkylene optionally substituted, C1-C8 hydroxyalkylene optionally substituted, C1-C8 alkylene - N(C1-C8 alkyl)-C1-C8 alkylene optionally substituted, C3-C8 carbocyclylene optionally substituted, 3- to 8-membered carbocyclyl optionally substituted, 3- to 8-membered heterocyclyl optionally substituted, C2-C8 alkenylene optionally substituted, C2-C8 alkynylene optionally substituted, aryl optionally substituted, and heteroaryl optionally substituted, where R 5 、R 6 、and R 7 are independently null, a single bond, hydrogen, C1-C8 alkyl optionally substituted, C1-C8 heteroalkyl optionally substituted, C2-C8 alkenyl optionally substituted, C2-C8 alkynyl optionally substituted, C3-C8 carbocyclyl optionally substituted, 3- to 8-membered heterocyclyl optionally substituted, heterocarbocyclyl optionally substituted, arylalkyl optionally substituted, heteroarylalkyl optionally substituted, C1-C8 alkylene optionally substituted, C1-C8 heteroalkylene optionally substituted, C1-C8 alkylene - O -, C1-C8 alkylene - N(C1-C8 alkyl)-, C1-C8 alkylene - O - alkylene optionally substituted, C1-C8 alkylene - N(C1-C8 alkyl)-C1-C8 alkylene optionally substituted, C3-C8 carbocyclyl optionally substituted, C3-C8 carbocyclyl - O - optionally substituted, 3- to 8-membered carbocyclyl optionally substituted, 3- to 8-membered heterocyclyl optionally substituted, aryl optionally substituted, and heteroaryl optionally substituted, or R 6 and R 7They combine with the atom to which they are attached to optionally form a 3- to 8-membered carbocyclic or heterocyclic ring.

[0091] In another embodiment, R 3 is attached to the linker portion of the bivalent compound via R 4 , and R 3 and R 4 are independently null, a single bond, -OR 5 -, -SR 5 -, -NR 6 R 7 -, -COR 5 -, -CO2R 5 -, -CONR 6 R 7 -, -SOR 5 -, -SO2R 5 -, -SO2NR 6 R 7 -, -NR 5 COR 7 -, -NR 5 C(O)NR 6 R 7 -, -NR 5 SOR 7 -, -NR 5 SO2R 7 -, and are selected from optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3- to 8-membered carbocyclic, optionally substituted 3- to 8-membered heterocyclic, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl, where R 5 , R 6 , and R 7is independently null, a single bond, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclic, optionally substituted 3- to 8-membered heterocyclic, optionally substituted heterocarbocyclic, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted C3-C8 carbocyclylene-O-, optionally substituted 3- to 8-membered carbocyclic, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or 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.

[0092] In another embodiment, Ar 1 is selected from C 6-10 aryl and C5-C 10 heteroaryl, each of which is F, Cl, CN, NO2, OR 10 , NR 11 R 12 , COR 10 , CO2R 10 , CONR 11 R 12 , SOR 10 , SO2R 10 , SO2NR 11 R 12 , NR 10 COR 12 , NR 10 C(O)NR11 R 12 、 NR 10 SOR 12 、 NR 10 SO2R 12 、 and independently selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino C1-C6 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3- to 7-membered heterocyclic, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, and optionally substituted C4-C5 heteroaryl, wherein R 10 、 R 11 、 and R 12 are each, upon each occurrence, independently selected from null, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3- to 7-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or R 11 and R 12 together with the atom to which they are attached form an optionally 3- to 8-membered carbocyclic or heterocyclic ring.

[0093] In another embodiment, Ar 2 is selected from C 6-10 aryl and C5-C 10 heteroaryl, each of which is independently F, Cl, CN, NO2, OR 13 、 NR 14 R 15 、 COR 13 、 CO2R 13 、 CONR 14 R 15 、 SOR 13, SO2R 13 , SO2NR 14 R 15 , NR 13 COR 14 , NR 13 C(O)NR 14 R 15 , NR 13 SOR 14 , NR 13 SO2R 14 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino C1-C6 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3- to 7-membered heterocyclic, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, and optionally substituted C4-C5 heteroaryl, wherein R 13 , R 14 , and R 15 are each, upon each occurrence, independently selected from null, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3- to 7-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or R 14 and R 15 together with the atom to which they are attached form an optionally 3- to 8-membered carbocyclic or heterocyclic ring.

[0094] In another embodiment, R 3 -Ar 2 is of formulas B1 and B2:

[0095]

Chemical formula

[0096] In another embodiment, R 3 -Ar 2 is of Formula B3:

[0097]

Chemical formula

[0098] In another embodiment, X 1 is N, X 2 is N, X 3 is C, X 4 is C, and X is CH2.

[0099] In another embodiment, Ar 1 is 3-fluorophenyl.

[0100] In another embodiment, Ar 2 is 2-pyridyl.

[0101] In another embodiment, R 3 is optionally substituted

[0102]

Chemical formula

[0103] In another embodiment, the TRK ligand is of Formula 3:

[0104]

Chemical formula

[0105] In one embodiment, X 1 and X 4 are selected from CR’ and N, and R’ is selected from hydrogen, F, Cl, CH3, CF3, and cyclopropyl.

[0106] In one embodiment, X 1 is N.

[0107] In one embodiment, X 4 is CH.

[0108] In another embodiment, X 2 and X 3 are independently selected from C and N.

[0109] In one embodiment, X 2 is C, and X 3 is N.

[0110] In one embodiment, X 3 is C, and X 2 is N.

[0111] In another embodiment, X is selected from a single bond, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH, and CH2NCH3.

[0112] In another embodiment, X is CH2.

[0113] In another embodiment, R 1 and R 2 are independently selected from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclyl.

[0114] In another embodiment, R 1 and R 2 are hydrogen.

[0115] In another embodiment, R 3 is selected from hydrogen, CH3, CH2CH3, propyl, isopropyl, cyclopropyl, CH2F, CHF2, and CF3.

[0116] In another embodiment, R 3 is selected from hydrogen.

[0117] In another embodiment, R 4 is directly connected to the linker portion of the divalent compound, and R 4is null, -OR 6 -, -SR 6 -, -N(R 7 )R 6 -, -COR 6 -, -CO2R 6 -, -CON(R 7 )R 6 -, -SOR 6 -, -SO2R 6 -, -SO2N(R 7 )R 6 -, -NR 8 COR 6 -, -N(R 8 )C(O)N(R 7 )R 6 -, -NR 8 SOR 6 -, -NR 8 SO2R 6 -, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl, selected from R 6is selected from null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclic, optionally substituted C3-C8 carbocyclic-O-, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, R 7 and R 8 are independently selected from null, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclic, optionally substituted heterocyclic, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3- to 8-membered carbocyclic, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or R 6 and R 7 together with the atom to which they are attached form an optionally 3- to 8-membered carbocyclic or heterocyclic ring.

[0118] In another embodiment, R 4 is connected via R 5 to the linker portion of the bivalent compound, and R 4 and R 5 are independently null, -OR 6 -, -SR 6 -, -N(R 7 )R 6 -, -COR 6 -, -CO2R 6 -, -CON(R 7 )R 6 -, -SOR6 -,-SO2R 6 -,-SO2N(R 7 )R 6 -,-NR 8 COR 6 -,-N(R 8 )C(O)N(R 7 )R 6 -,-NR 8 SOR 6 -,-NR 8 SO2R 6 -,-Optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl, selected from R 6 is null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, selected from R 7 and R 8is independently selected from null, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclic, optionally substituted heterocyclic, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclic, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or R 6 and R 7 together with the atom to which they are attached form an optionally 3-8 membered carbocyclic or heterocyclic ring.

[0119] In another embodiment, R 4 and R 5 are independently selected from null, optionally substituted

[0120]

Chemical formula

[0121] In another embodiment, R 4 and R 5 are independently selected from null, optionally substituted

[0122]

Chemical formula

[0123] In another embodiment, -R 4 -R 5 - is selected from null, optionally substituted

[0124]

Chemical formula

[0125] In another embodiment, -R 4 -R 5 - is optionally substituted

[0126]

Chemical Formula

[0127] In another embodiment, Ar is selected from aryl and heteroaryl, each of which is independently selected from F, Cl, CN, NO2, OR 10 , NR 11 R 12 , COR 10 , CO2R 10 , CONR 11 R 12 , SOR 10 , SO2R 10 , SO2NR 11 R 12 , NR 10 COR 12 , NR 10 C(O)NR 11 R 12 , NR 10 SOR 12 , NR 10 SO2R 12 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino C1-C6 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, and optionally substituted C4-C5 heteroaryl, wherein R 10 , R 11 , and R 12is independently selected from null, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or R 11 and R 12 together with the atom to which they are attached form an optionally 3-8 membered carbocyclic or heterocyclic ring.

[0128] In another embodiment, Ar is aryl and the aryl is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, and NO2.

[0129] In another embodiment, Ar is

[0130]

Chemical formula

[0131] In another embodiment, the TRK ligand is of formula 3A:

[0132]

Chemical formula

[0133] In one embodiment, X 1 and X 3 are selected from CR’ and N, and R’ is selected from hydrogen, F, Cl, CH3, CF3, and cyclopropyl.

[0134] In one embodiment, X 1 is N.

[0135] In one embodiment, X 1 is CR’, and R’ is selected from hydrogen, F, Cl, CH3, CF3, and cyclopropyl.

[0136] In one embodiment, X 2 is C, and X 3 is N.

[0137] In one embodiment, X 3 is C, and X 2 is N.

[0138] In another embodiment, X is selected from a single bond, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH, and CH2NCH3.

[0139] In another embodiment, X is CH2.

[0140] In another embodiment, R 1 and each R 2 are independently selected from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclyl.

[0141] In another embodiment, R 1 and R 2 are hydrogen.

[0142] In another embodiment, R 3 is selected from hydrogen, CH3, CH2CH3, propyl, isopropyl, cyclopropyl, CH2F, CHF2, and CF3.

[0143] In another embodiment, R 3 is selected from hydrogen.

[0144] In another embodiment, R 4 is directly connected to the linker portion of the divalent compound, and R 4 is null, -OR 6 -, -SR6 -,-N(R 7 )R 6 -,-COR 6 -,-CO2R 6 -,-CON(R 7 )R 6 -,-SOR 6 -,-SO2R 6 -,-SO2N(R 7 )R 6 -,-NR 8 COR 6 -,-N(R 8 )C(O)N(R 7 )R 6 -,-NR 8 SOR 6 -,-NR 8 SO2R 6 -,-optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl, selected from R 6is selected from null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl-O-, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, and R 7 and R 8 are independently selected from null, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3- to 8-membered carbocyclyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 6 and R 7 together with the atom to which they are attached form an optionally 3- to 8-membered carbocyclyl or heterocyclyl ring.

[0145] In another embodiment, R 4 is connected via R 5 to the linker portion of the bivalent compound, and R 4 and R 5 are independently null, -OR 6 -, -SR 6 -, -N(R 7 )R 6 -, -COR 6 -, -CO2R 6 -, -CON(R 7 )R 6-, -SOR 6 -, -SO2R 6 -, -SO2N(R 7 )R 6 -, -NR 8 COR 6 -, -N(R 8 )C(O)N(R 7 )R 6 -, -NR 8 SOR 6 -, -NR 8 SO2R 6 -, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted aryl, and optionally substituted heteroaryl, selected from R 6 is null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, selected from R 7 and R 8is independently selected from null, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclic, optionally substituted heterocyclic, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3- to 8-membered carbocyclic, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or R 6 and R 7 together with the atom to which they are attached form an optionally 3- to 8-membered carbocyclic ring or 3- to 8-membered heterocyclic ring.

[0146] In another embodiment, R 4 and R 5 are independently selected from null, optionally substituted

[0147]

Chemical formula

[0148] In another embodiment, R 4 and R 5 are independently selected from null, optionally substituted

[0149]

Chemical formula

[0150] In another embodiment, -R 4 -R 5 - is selected from null, optionally substituted

[0151]

Chemical formula

[0152] In another embodiment, -R 4 -R 5 - is optionally substituted

[0153]

Chemical Formula

[0154] In another embodiment, Ar is selected from aryl and heteroaryl, each of which is independently selected from F, Cl, CN, NO2, OR 10 , NR 11 R 12 , COR 10 , CO2R 10 , CONR 11 R 12 , SOR 10 , SO2R 10 , SO2NR 11 R 12 , NR 10 COR 12 , NR 10 C(O)NR 11 R 12 , NR 10 SOR 12 , NR 10 SO2R 12 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino C1-C6 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3- to 7-membered heterocyclic, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, and optionally substituted C4-C5 heteroaryl, where R 10 R 11 and R 12is independently selected from null, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclic ring, optionally substituted 3- to 7-membered heterocyclic ring, optionally substituted aryl, and optionally substituted heteroaryl, or R 11 and R 12 together with the atom to which they are attached form an optionally 3- to 8-membered carbocyclic or heterocyclic ring.

[0155] In another embodiment, Ar is aryl, and the aryl is optionally substituted by one or more substituents independently selected from F, Cl, Br, CN, and NO2.

[0156] In another embodiment, Ar is

[0157]

Chemical formula

[0158] In another embodiment, the TRK ligand is of formula 12-1 or formula 12-2:

[0159]

Chemical formula

[0160] In another embodiment, X is selected from CH, CF, and N.

[0161] In another embodiment, X is CH.

[0162] In another embodiment, X is CF.

[0163] In another embodiment, X is N.

[0164] In another embodiment, Y is selected from O and S.

[0165] In another embodiment, Y is O.

[0166] In another embodiment, Y is S.

[0167] In another embodiment, R 1 is selected from optionally substituted acyclic amino, optionally substituted cyclic amino, optionally substituted phenyl, and optionally substituted heteroaryl.

[0168] In another embodiment, R 1 is optionally substituted

[0169]

Chemical formula

[0170] In another embodiment, R 1’ is selected from null, optionally substituted acyclic amino, optionally substituted cyclic amino, optionally substituted phenyl, and optionally substituted heteroaryl.

[0171] In another embodiment, R 1’ is optionally substituted

[0172]

Chemical formula

[0173] In another embodiment, R 2 is null, -O-, -S-, -N(R 12 )-, -C(O)-, -CO2-, -CON(R 12 )-, -SO-, -SO2-, -SO2N(R 12 )-, -N(R 13 )CO-, -N(R 13 )C(O)N(R 12)-, -N(R 13 )SO-, -N(R 13 )SO2-, a C3-C8 carbocyclic group optionally substituted, and a C3-C8 heterocyclic group optionally substituted, where R 12 and R 13 are independently selected from hydrogen, a C1-C8 alkyl group optionally substituted, a C1-C8 heteroalkyl group optionally substituted, a C2-C8 alkenyl group optionally substituted, a C2-C8 alkynyl group optionally substituted, a C3-C8 carbocyclic group optionally substituted, a heterocarbocyclic group optionally substituted, an arylalkyl group optionally substituted, a heteroarylalkyl group optionally substituted, a 3- to 8-membered carbocyclic group optionally substituted, a 3- to 8-membered heterocyclic group optionally substituted, an aryl group optionally substituted, and a heteroaryl group optionally substituted.

[0174] In another embodiment, R 2 is null, -CONH-,

[0175]

Chemical formula

[0176] In another embodiment, R 3 is hydrogen, halogen, CN, NO2, OH, NH2, -CONH-,

[0177]

Chemical formula

[0178] In another embodiment, R 2 -R 3 is hydrogen, halogen, CN, NO2,

[0179]

Chemical formula

[0180] In another embodiment, R 4 is selected from hydrogen, halogen, CN, NO2, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 3- to 8-membered carbocyclyl-C1-C8 alkyl, optionally substituted 3- to 8-membered heterocyclyl-C1-C8 alkyl, optionally substituted 3- to 8-membered carbocyclyl, and optionally substituted 3- to 8-membered heterocyclyl, optionally substituted 3- to 8-membered carbocyclyl-C1-C8 alkyl, and optionally substituted 3- to 8-membered heterocyclyl-C1-C8 alkyl, optionally substituted 3- to 8-membered carbocyclyl-O-, optionally substituted 3- to 8-membered heterocyclyl-O-, optionally substituted 3- to 8-membered carbocyclyl-N(C1-C8 alkyl)-, and optionally substituted 3- to 8-membered heterocyclyl-N(C1-C8 alkyl)-.

[0181] In another embodiment, R 4 is selected from hydrogen, halogen, CN, NO2, OCH3,

[0182]

Chemical formula

[0183] In another embodiment, R 4’ is null, -O-, -S-, -N(R 12 ’)-, -C(O)-, -CO2-, -CON(R 12 ’)-, -SO-, -SO2-, -SO2N(R 12 ’)-, -N(R 12 ’)CO-, -N(R 13 ’)C(O)N(R 12 ’)-, -N(R 13 ’)SO-, -N(R13 ’)SO2-, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted C3-C8 carbocyclylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted 3-8 membered carbocyclyl-C1-C8 alkylene, and optionally substituted 3-8 membered heterocyclyl-C1-C8 alkylene, optionally substituted 3-8 membered carbocyclyl-O-, optionally substituted 3-8 membered heterocyclyl-O-, optionally substituted 3-8 membered carbocyclyl-N(C1-C8 alkyl)-, and optionally substituted 3-8 membered heterocyclyl-N(C1-C8 alkyl)-, wherein R 12 ’ and R 13 ’ are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 carbocyclylene, optionally substituted heterocarbocyclylene, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0184] In another embodiment, R 4’is selected from null, -O-, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkylene-O-C1-C8 alkylene, optionally substituted C1-C8 alkylene-N(C1-C8 alkyl)-C1-C8 alkylene, optionally substituted 3- to 8-membered carbocyclic, optionally substituted 3- to 8-membered heterocyclic, optionally substituted 3- to 8-membered carbocyclic-C1-C8 alkylene, and optionally substituted 3- to 8-membered heterocyclic-C1-C8 alkylene, optionally selected 3- to 8-membered carbocyclic-O-, optionally substituted 3- to 8-membered heterocyclic-O-, optionally substituted 3- to 8-membered carbocyclic-N(C1-C8 alkyl)-, and optionally substituted 3- to 8-membered heterocyclic-N(C1-C8 alkyl)-.

[0185] In another embodiment, R 4’ is null, -O-,

[0186]

Chemical formula

[0187] In another embodiment, the TRK ligand is of Formula 13:

[0188]

Chemical formula

[0189] In another embodiment, the TRK ligand is of formula 13-1:

[0190]

Chemical formula

[0191] In another embodiment, the TRK ligand is of formula 13-2:

[0192]

Chemical formula

[0193] In another embodiment, X is selected from CH, CF, and N.

[0194] In another embodiment, X is N.

[0195] In another embodiment, Y is selected from -O-, -CH2-, and -NH-.

[0196] In another embodiment, Y is -O-.

[0197] In another embodiment, R 1 is selected from hydrogen and NH2.

[0198] In another embodiment, R 1 is NH2.

[0199] In another embodiment, R 2 is selected from hydrogen, halogen, CN, NO2, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 carbocyclic, and optionally substituted C1-C8 alkoxy.

[0200] In another embodiment, R 2 is selected from H, F, Cl, Br, OCH3, OCF3, and OCHF2.

[0201] In another embodiment, R 2 is OCH3.

[0202] In another embodiment, R 3 , R 4 , R 5 , and R 6 are independently selected from H, F, CH3, cyclopropyl, and cyclobutyl.

[0203] In another embodiment, R 3 and R 4 , and / or R 5 and R 6They combine with the atom to which they are attached and optionally form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0204] In another embodiment, R 3 、R 4 、R 5 、and R 6 are H.

[0205] In another embodiment, R 7 is null, an optionally substituted 3- to 8-membered carbocyclic ring, an optionally substituted 3- to 8-membered heterocyclic ring, an optionally substituted C4-C 13 fused carbocyclic ring, an optionally substituted 5- to 13-membered fused heterocyclic ring, an optionally substituted C5-C 13 bridged carbocyclic ring, an optionally substituted 5- to 13-membered bridged heterocyclic ring, an optionally substituted C5-C 13 spirocarbocyclic ring, an optionally substituted 5- to 13-membered spiroheterocyclic ring, an optionally substituted aryl, and an optionally substituted heteroaryl.

[0206] In another embodiment, R 7 is null,

[0207]

Chemical formula

[0208] In another embodiment, R 8 is null, -C(O)-, -C(O)-NH-, an optionally substituted 3- to 8-membered carbocyclic ring, an optionally substituted 3- to 8-membered heterocyclic ring, an optionally substituted C4-C 13 fused carbocyclic ring, an optionally substituted 5- to 13-membered fused heterocyclic ring, an optionally substituted C5-C 13 bridged carbocyclic ring, an optionally substituted 5- to 13-membered bridged heterocyclic ring, an optionally substituted C5-C 13It is selected from spirocarbocyclyl, optionally substituted 5- to 13-membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0209] In another embodiment, R 8 is null, -C(O)-, -C(O)-NH-,

[0210]

Chemical formula

[0211] In another embodiment, R 7 -R 8 is null,

[0212]

Chemical formula

[0213] In another embodiment, Ar is selected from optionally substituted phenyl and optionally substituted pyridinyl.

[0214] In another embodiment, Ar is

[0215]

Chemical formula

[0216] In another embodiment, the TRK ligand is as follows:

[0217]

Chemical formula

[0218] In another embodiment, the TRK ligand is obtained from the following TRK kinase inhibitors: DS-6051b, F17752, PLX7486, AZD-6918, ASP7962, VM902A, PF-06273340, and ONO-4474.

[0219] In another embodiment, the TRK ligand is as follows:

[0220]

Chemical formula

[0221] In some embodiments, the cleavage tag is part selected from the group of formulas 5A, 5B, 5C, and 5D:

[0222]

Chemical formula

[0223] In some embodiments, the cleavage tag is of formula 5E, 5F, 5G, 5H, 5I, 5J, 5K, 5L, 5M, 5N, 5O, 5P, and 5Q:

[0224]

Chemical formula

[0225] In one embodiment, the cleavage tag is of formula 6A:

[0226] [Chemical formula] is the part where, in the formula, R 1 and R 2 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3- to 7-membered heterocyclic, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl, and R 3is hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxyC1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)C3-C7 carbocyclyl, optionally substituted C(O)(3-7 membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxyC1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)OC3-C7 carbocyclyl, optionally substituted C(O)O(3-7 membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxyC1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)NC3-C7 carbocyclyl, optionally substituted C(O)N(3-7 membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2, and optionally substituted P(O)(OC1-C8 aryl)2.

[0227] In one embodiment, the cleavage tag is of formula 6B, 6C, 6D, 6E, and 6F:

[0228] [Chemical] is a moiety selected from the group consisting of, wherein R 1 and R 2 are independently selected from hydrogen, halogen, OH, NH2, CN, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3- to 7-membered heterocyclic, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl, (preferably R 1 is selected from iso-propyl or tert-butyl, and R 2 is selected from hydrogen or methyl), R 3is hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxyC1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)C3-C7 carbocyclyl, optionally substituted C(O)(3-7 membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxyC1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)OC3-C7 carbocyclyl, optionally substituted C(O)O(3-7 membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxyC1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)NC3-C7 carbocyclyl, optionally substituted C(O)N(3-7 membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2, and optionally substituted P(O)(OC1-C8 aryl)2, and R 4 and R 5 are independently hydrogen, COR 6 , CO2R 6 , CONR6 R 7 、 SOR 6 、 SO2R 6 、 SO2NR 6 R 7 、 optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-8 membered carbocyclic, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 6 and R 7 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-8 membered carbocyclic, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or 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, Ar is selected from aryl and heteroaryl, each of which is independently F, Cl, CN, NO2, OR 8 、 NR 8 R 9 、 COR 8 、 CO2R 8 、 CONR 8 R 9 、 SOR 8 、 SO2R 8 、 SO2NR 8 R 9 、 NR 10 COR 8 、 NR 10 C(O)NR 8 R 9 、 NR10 SOR 8 、NR 10 SO2R 8 、 and one or more substituents independently selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino C1-C6 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, and optionally substituted C4-C5 heteroaryl, wherein R 8 、R 9 、 and R 10 are independently null, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or R 8 and R 9 together with the atoms to which they are attached form an optionally 3-8 membered carbocyclic or heterocyclic ring.

[0229] In another embodiment, the cleavage tag is the moiety of Formula 7A:

[0230]

Chemical formula

[0231] In another embodiment, the cleavage tag is of formula 7B:

[0232]

Chemical formula

[0233] In another embodiment, the cleavage tag is as follows:

[0234] [Chemical formula] obtained from any of.

[0235] In another embodiment, the cleavage tag is obtained from any of 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.

[0236] In another embodiment, the cleavage tag is as follows:

[0237] [Chemistry]

[0238] [Chemistry]

[0239] [Chemistry]

[0240] [Chemistry]

[0241] [Chemistry]

[0242] [Chemistry]

[0243] [Chemistry] is selected from the group consisting of.

[0244] In another embodiment, the cleavage tag is selected from the group consisting of: Formula 8A, 8B, 8C, 8D, 8E, 8F, 8G, 8H, 8I, 8J, 8K, 8L, 8M, 8O, 8P, 8Q, 8R, 8AQ, 8AR, 8AS, 8AT, 8AU, 8AV, 8AW, 8AX, 8AY, 8AZ, 8BA, 8BB, 8BC, 8BD, 8BE, 8BF, 8BG, 8BH, 8BI, 8BJ, 8BK, 8BL, 8BM, and 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.

[0245] In some embodiments, the linker moiety has the formula 9:

[0246]

Chemical Formula

[0247] In one embodiment, the linker moiety is of formula 9A:

[0248]

Chemical formula

[0249] In another embodiment, the linker moiety is of formula 9B:

[0250]

Chemical formula

[0251] In another embodiment, the linker moiety is of formula 9C:

[0252]

Chemical formula

[0253] In one embodiment, in Formula 9C, m and n are 0 or 1, and p is 0 to 15.

[0254] In one embodiment, in Formula 9C, X is selected from O and NH.

[0255] In one embodiment, in Formula 9C, R 1 , R 2 , R 3 , R 4 , R 5and R 6 is independently selected from hydrogen and optionally substituted C1-C6 alkyl.

[0256] In another embodiment, the linker moiety comprises one or more rings selected from the group consisting of 3- to 13-membered rings, 4- to 13-membered fused rings, 5- to 13-membered bridged rings, and 5- to 13-membered spiro rings.

[0257] In another embodiment, the linker moiety is of formula C1, C2, C3, C4, and C5:

[0258]

Chemical formula

[0259] In one embodiment, A, B, and W at each occurrence are independently null, optionally substituted -(CH2) 0-8 -, optionally substituted -(CH2) 0-8 -CO-(CH2) 0-8 -, optionally substituted -(CH2) 0-8 -NH-(CH2) 0-8 -, optionally substituted -(CH2) 0-8 -NH-CO(CH2) 0-8 -, optionally substituted -(CH2) 0-8 -CO-NH-(CH2) 0-8 -, optionally substituted -(CH2) 0-3-NH-(CH2) 0-3 -CO-NH-(CH2) 0-8 -,-(CH2) optionally substituted 0-3 -NH-(CH2) 1-3 -NH-CO-(CH2) 0-8 -,-(CH2) optionally substituted 0-8 -CO-NH-(CH2) 1-3 -NH-(CH2) 0-3 -,-(CH2) optionally substituted 0-8 -R r -(CH2) 0-8 -,-(CH2) optionally substituted 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 -,-(CH2) optionally substituted 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -,-(CH2) optionally substituted 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 -,-(CH2) optionally substituted 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 is selected from

[0260] In one embodiment, R r is of formula C1, C2, C3, C4, or C5

[0261] In one embodiment, R r is

[0262]

Chemical formula

[0263] In another embodiment, the length of the linker is from 0 to 40 atoms

[0264] In another embodiment, the length of the linker is from 0 to 20 atoms.

[0265] In another embodiment, the length of the linker is from 0 to 10 atoms.

[0266] In another embodiment, the linker is null, optionally substituted -(CO)-(CH2) 0-8 -, optionally substituted -(CH2) 0-9 -, optionally substituted -(CH2) 1-2 -(CO)-NH-(CH2) 0-9 -, optionally substituted -(CH2) 1-2 -(CO)-NH-(CH2) 1-3 -(OCH2CH2) 1-7 -, optionally substituted -(CH2) 0-1 -(CO)-(CH2) 1-3 -(OCH2CH2) 1-7 -, optionally substituted -(CO)-(CH2) 0-3 -(alkenylene)-(CH2) 0-3 -, optionally substituted -(CO)-(CH2) 0-3 -(alkynylene)-(CH2) 0-3 -, optionally substituted -(CO)-(CH2) 0-3 -(3- to 8-membered carbocyclic)-(CH2) 0-3 -, optionally substituted -(CO)-(CH2) 0-3 -(3- to 8-membered heterocyclic)-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -(alkynylene)-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -(alkynylene)-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -(3- to 8-membered carbocyclic)-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -(3- to 8-membered heterocyclic)-(CH2) 0-3 -, optionally substituted -(CH2) 0-8 -R r -(CH2)0-8 - (CH2) optionally substituted with - 0-8 - R r - (CO) - (CH2) 1-8 - (CH2) optionally substituted with - 0-8 - R r - (CH2) 1-2 - (CO) - NH - (CH2) 2-9 - (CH2) optionally substituted with - 0-8 - R r - (CH2) 1-2 - (CO) - NH - (CH2) 1-3 - (OCH2CH2) 1-7 - (CH2) optionally substituted with - 0-8 - R r - (CH2) 0-1 - (CO) - (CH2) 1-3 - (OCH2CH2) 1-7 - (CH2) optionally substituted with - 0-8 - R r - (CO) - (CH2) 0-3 - (alkenylene) - (CH2) 0-3 - (CH2) optionally substituted with - 0-8 - R r - (CO) - (CH2) 0-3 - (alkynylene) - (CH2) 0-3 - (CH2) optionally substituted with - 0-8 - R r - (CO) - (CH2) 0-3 - (3 - 8 membered carbocyclic) - (CH2) 0-3 - (CH2) optionally substituted with - 0-8 - R r - (CO) - (CH2) 0-3 - (3 - 8 membered heterocyclic) - (CH2) 0-3 - (CH2) optionally substituted with - 0-8 - R r - (CH2) 0-3 - (alkenylene) - (CH2) 0-3 - (CH2) optionally substituted with - 0-8 - R r - (CH2) 0-3 - (alkynylene) - (CH2) 0-3- (CH2) optionally substituted 0-8 -R r - (CH2) 0-3 - (3 - 8 membered carbocyclic)-(CH2) 0-3 - and (CH2) optionally substituted 0-8 -R r - (CH2) 0-3 - (3 - 8 membered heterocyclic)-(CH2) 0-3 - selected from

[0267] In one aspect of the present specification, a bivalent compound comprising a tropomyosin receptor kinase (TRK) ligand conjugated to a cleavage tag via a linker, or a pharmaceutically acceptable salt or analog thereof, wherein the linker and the cleavage tag are each independently selected from those disclosed herein, and the TRK ligand is R 4 connected to the linker via to formula 10:

[0268]

Chemical formula

[0269]

Chemical formula

[0270] In one aspect herein, a bivalent compound comprising a tropomyosin receptor kinase (TRK) ligand conjugated to a cleavage 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 cleavage tag is Z, or V 1 、V 2 、V 3 、V 4 、W 1 、W 2 、and W 3Connect to the linker through any of the following Formula 11:

[0271]

Chemical formula

[0272] In another aspect herein, a bivalent compound comprising a tropomyosin receptor kinase (TRK) ligand conjugated to a cleavage tag via a linker, or a pharmaceutically acceptable salt or analog thereof, wherein the TRK ligand and the cleavage tag are each independently selected from those disclosed herein, and the linker is of formula 9:

[0273]

Chemical formula

[0274] In another aspect herein, a bivalent compound, or a pharmaceutically acceptable salt or analog thereof, comprising a tropomyosin receptor kinase (TRK) ligand conjugated to a cleavage tag via a linker, wherein the TRK ligand is R 4 is connected to the linker via R to formula 10:

[0275]

Chemical formula

[0276]

Chemical formula

[0277]

Chemical Formula

[0278]

Chemical formula

[0279] In certain embodiments of the divalent compounds disclosed herein, U is selected from a single bond, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH, and CH2NCH3.

[0280] In certain embodiments of the divalent compounds disclosed herein, R 1 and R 2 are each, independently upon each occurrence, selected from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3- to 6-membered heterocyclyl.

[0281] In certain embodiments of the divalent compounds disclosed herein, R 1 and R 2 are each, independently upon each occurrence, selected from hydrogen, F, Cl, CH3, CF3, and cyclopropyl.

[0282] In certain embodiments of the divalent compounds disclosed herein, Ar 1 is optionally substituted C6-C 10 aryl and optionally substituted C5-C 10 heteroaryl.

[0283] In certain embodiments of the divalent compounds disclosed herein, Ar 1 is selected from 3-fluorophenyl, 3,5-difluorophenyl, and 2,5-difluorophenyl.

[0284] 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 via R 5 .

[0285] 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.

[0286] In certain embodiments of the valent compounds disclosed herein, R 4 is

[0287]

Chemical formula

[0288] In certain embodiments of the divalent compounds disclosed herein, L is Ar 2 and Ar 2 is optionally substituted C6-C 10 aryl and optionally substituted C5-C 10 heteroaryl selected from.

[0289] In certain embodiments of the divalent compounds disclosed herein, X-R, taken together,

[0290]

Chemical formula

[0291] 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, and X-R, taken together,

[0292] [Chemical formula] supports that U is CH2 and Ar 1 is 3-fluorophenyl and L is Ar 2 and Ar 2 is 2-pyridyl.

[0293] In a specific embodiment of the divalent compound disclosed herein, L is Ar 2 or NR 3 COAr 2 and Ar 2 -R 4 is selected from the moieties of formulas B1, B2, and B3:

[0294] [Chemical formula] wherein, * represents the connection part to the linker part of the divalent compound, Y 1 Y 2 Y 3 and Y 4 are independently selected from CRa and N, on the premise that at most 3 of Y 1 Y 2 Y 3 and Y 4 are N, and each R is independently hydrogen, halogen, CN, NO2, OR a NR 14 R 15 COR 16 CO2R 14 CONR 14 R 15 SOR 16 SO2R 14 SO2NR 14 R 15 NR 16 COR 14 NR 15 C(O)NR 14 R 15 NR 16 SOR 14 NR 15 NR 14SO2R 15 、 selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, and R 14 、 R 15 、 and R 16 are, at each occurrence, independently selected from null, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C6 carbocyclic, optionally substituted 3-8 membered heterocyclic, optionally substituted heterocarbocyclic, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 15 and R 16 together with the atoms to which they are attached form an optionally 3-8 membered carbocyclic ring or 3-8 membered heterocyclic ring.

[0295] 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 the moieties of formula B4:

[0296] [Chemical formula] wherein, * represents a connecting part to the linker portion of a divalent compound, Y 1’ Y 2’ Y 3’ and Y 4’ is Y 1’ Y 2’ Y 3’ and Y 4’ assuming that at most 3 of Y a are N, is independently selected from C, N, O, and S, each R a is independently hydrogen, halogen, CN, NO2, OR 14 NR 15 R 16 COR 14 CO2R 14 CONR 15 R 16 SOR 14 SO2R 14 SO2NR 15 R 16 NR 14 COR 15 NR 14 C(O)NR 15 R 16 NR 14 SOR 15 NR 14 SO2R 15 is selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, and R 14 R 15 and R 16At each occurrence, it is independently selected from null, hydrogen, C1-C8 alkyl optionally substituted, C1-C8 heteroalkyl optionally substituted, C2-C8 alkenyl optionally substituted, C2-C8 alkynyl optionally substituted, C3-C6 carbocyclic optionally substituted, 3- to 8-membered heterocyclic optionally substituted, heterocarbocyclic optionally substituted, arylalkyl optionally substituted, heteroarylalkyl optionally substituted, aryl optionally substituted, and heteroaryl optionally substituted, or R 15 and R 16 together with the atom to which they are attached form an optionally 3- to 8-membered carbocyclic ring or 3- to 8-membered heterocyclic ring.

[0297] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 CO, and R 3 is selected from hydrogen, CH3, CH2CH3, propyl, isopropyl, cyclopropyl, CH2F, CHF2, and CF3.

[0298] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 CO, and R 4 is directly connected to the linker portion of the divalent compound.

[0299] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 CO, and R 4 is, 5 connected to the linker portion of the divalent compound via R

[0300] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 where R 3 is selected from hydrogen, CH3, CH2CH3, propyl, isopropyl, cyclopropyl, CH2F, CHF2, and CF3, and Ar 2 is C6-C optionally substituted10 Selected from aryl and optionally substituted C5-C 10 heteroaryl.

[0301] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 wherein R 4 is directly connected to the linker portion of the divalent compound.

[0302] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 wherein R 4 is, through R 5 connected to the linker portion of the divalent compound.

[0303] In certain embodiments of the divalent compounds disclosed herein, L is Ar 2 NR 3 COAr 2 wherein Ar 2 -R 4 is selected from moieties of Formulas B1, B2, and B3.

[0304] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 wherein Ar 2 -R 4 is selected from the moiety of Formula B1, where Y 1 is CH or N.

[0305] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 wherein Ar 2 -R 4 is selected from the moiety of Formula B2, where Y 1 is CR a wherein R a is H,

[0306]

Chemical formula

[0307] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 wherein Ar 2 -R 4 is selected from the moiety of formula B3, where Y 2 is CR a and R a is

[0308]

Chemical formula

[0309] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 wherein X-R is X-Ar 1 It is.

[0310] In certain embodiments of the divalent compounds disclosed herein, L is NR 3 COAr 2 wherein X-R is X-Ar 1 wherein X is CH2 and Ar 1 is 3-fluorophenyl, 3,5-difluorophenyl, or 2,5-difluorophenyl.

[0311] In certain embodiments of the divalent compounds disclosed herein, V 1 , V 2 , V 3 , and V 4 are each independently CR 2’ It is.

[0312] In certain embodiments of the divalent compounds disclosed herein, W 1 , W 2 , and W 3 at least one of which is NR 5’ It is.

[0313] In certain embodiments of the divalent compounds disclosed herein, W1 , W 2 , and W 3 at least one of is NR 5’ , and R 5’ only one of is 2,6-dioxopiperidin-3-yl optionally substituted by R 1’ .

[0314] In certain embodiments of the divalent compounds disclosed herein, W 1 is CO.

[0315] In certain embodiments of the divalent compounds disclosed herein, W 2 is CO.

[0316] In certain embodiments of the divalent compounds disclosed herein, W 3 is CO.

[0317] In certain embodiments of the divalent compounds disclosed herein, W 1 and W 3 are both CO.

[0318] In certain embodiments of the divalent compounds disclosed herein, W 2 is CO, W 1 and W 3 are both NR 5’ , and R 5’ only one of is 2,6-dioxopiperidin-3-yl optionally substituted by R 1’ .

[0319] In certain embodiments of the divalent compounds disclosed herein, W, at each occurrence, is independently selected from the formulas C1, C2, C3, C4, and C5:

[0320]

Chemical formula

[0321] In certain embodiments of the divalent compounds disclosed herein, the linker length is from 3 to 40 atoms.

[0322] In certain embodiments of the divalent compounds disclosed herein, the linker length is from 3 to 20 atoms.

[0323] In certain embodiments of the divalent compounds disclosed herein, the linker length is from 3 to 10 atoms.

[0324] In certain embodiments of the divalent compounds disclosed herein, the linker is optionally substituted -(CO)-(CH2) 0-3 -W-(CH2) 0-3 -, -(CH2) 0-3 -W-(CH2) 0-3 -, optionally substituted -(CO)-(CH2) 0-8 -, optionally substituted -(CH2) 0-9 -, optionally substituted -(CH2) 1-2 -(CO)-NH-(CH2) 2-9 -, optionally substituted -(CH2) 1-2 -(CO)-NH-(CH2) 1-3 -(OCH2CH2) 1-7 -, optionally substituted -(CH2) 0-1 -(CO)-(CH2) 1-3 -(OCH2CH2) 1-7 -, optionally substituted -(CO)-(CH2) 0-3 -(alkenylene)-(CH2) 0-3 -, optionally substituted -(CO)-(CH2) 0-3 -(alkynylene)-(CH2) 0-3 -, optionally substituted -(CH2) 0-3 -(alkenylene)-(CH2) 0-3-, (CH2) optionally substituted 0-3 - (alkynylene) - (CH2) 0-3 -, -(CH2) optionally substituted 0-3 - (CO) - (CH2) 0-3 -W-(CH2) 0-3 -, -(CH2) optionally substituted 0-3 -O-(CH2) 0-3 -W-(CH2) 0-3 -, -(CH2) optionally substituted 0-3 -NH-(CH2) 0-3 -W-(CH2) 0-3 -, -(CH2) optionally substituted 0-3 -O-(CH2) 0-3 -W-(CH2) 0-3 -O-(CH2) 0-3 -, -(CH2) optionally substituted 0-3 -NH-(CH2) 0-3 -W-(CH2) 0-3 -NH-(CH2) 0-3 -, -(CH2) optionally substituted 0-3 -O-(CH2) 0-3 -W-(CH2) 0-3 -NH-(CH2) 0-3 selected from -, and W is optionally substituted 3- to 10-membered carbocyclylene, optionally substituted 3- to 10-membered heterocyclylene, optionally substituted C4-C 13 fused carbocyclylene, optionally substituted 5- to 13-membered fused heterocyclylene, optionally substituted C5-C 13 bridged carbocyclylene, optionally substituted 5- to 13-membered bridged heterocyclylene, optionally substituted C5-C 13 spirocarbocyclylene, optionally substituted 5- to 13-membered spiroheterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0325] In certain embodiments of the divalent compounds disclosed herein, the linker is optionally substituted -(CO)-(CH2) 0-3 - (3- to 8-membered carbocyclyl) - (CH2)0-3 - (CO)-(CH2) optionally substituted 0-3 -(3 - 8 membered heterocyclyl)-(CH2) 0-3 - (CH2) optionally substituted 0-3 -(3 - 8 membered carbocyclyl)-(CH2) 0-3 - and (CH2) optionally substituted 0-3 -(3 - 8 membered heterocyclyl)-(CH2) 0-3 - selected from

[0326] In certain embodiments of the divalent compounds disclosed herein, W is

[0327]

Chemical formula

[0328] In some embodiments, the divalent compound is selected from the group consisting of CPD - 001 to CPD - 516, or pharmaceutically acceptable salts or analogs thereof.

[0329] In some embodiments, the divalent compound is 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-267It is selected from the group consisting of 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 their pharmaceutically acceptable salts or analogs.,

[0330] In some embodiments, the divalent compound is 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,It is selected from the group consisting of CPD-481, CPD-482, CPD-483, CPD-484, CPD-499, CPD-500, CPD-501, and pharmaceutically acceptable salts or analogs thereof.

[0331] In some embodiments, the divalent compound is selected from the group consisting of 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 pharmaceutically acceptable salts or analogs thereof.

[0332] In some embodiments, the divalent compound is not any of CPD-001 to CPD-246.

[0333] In some embodiments, the divalent compound is selected from the group consisting of CPD-247 to CPD-516, or pharmaceutically acceptable salts or analogs thereof.

[0334] In some embodiments, the divalent compound is selected from the group consisting of 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.

[0335] In some embodiments, the divalent compound includes the 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.

[0336] 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).

[0337] 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).

[0338] 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).

[0339] 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).

[0340] 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).

[0341] 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).

[0342] 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).

[0343] 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).

[0344] 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).

[0345] 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).

[0346] 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).

[0347] 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).

[0348] In some embodiments, the divalent compound is 3-[5-[3-[4-[6-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]piperazin-1-yl]propylamino]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (TR-221).

[0349] In some embodiments, the divalent compound is 3-((S)-5-(4-(3-(4-(6-(6-((S)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione (TR-224).

[0350] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)isoindoline-1,3-dione (TR-225).

[0351] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (TR-226).

[0352] 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-piperidyl)-1,3-dioxoisoindolin-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (TR-231).

[0353] 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).

[0354] In some embodiments, the bivalent 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).

[0355] 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)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-249).

[0356] 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).

[0357] 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).

[0358] 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).

[0359] 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).

[0360] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)piperazin-1-yl)benzamide (TR-263).

[0361] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)benzamide (TR-264).

[0362] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzamide (TR-265).

[0363] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)-2-((2-fluoroethyl)amino)benzamide (TR-266).

[0364] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((2-fluoroethyl)amino)benzamide (TR-267).

[0365] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-270).

[0366] 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).

[0367] 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).

[0368] 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).

[0369] 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).

[0370] 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).

[0371] 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).

[0372] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-284).

[0373] 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).

[0374] 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).

[0375] 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).

[0376] 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).

[0377] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-6-azaspiro[3.4]octan-2-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-290).

[0378] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(1-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)azetidin-3-yl)isoindoline-1,3-dione (TR-292).

[0379] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(1-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)azetidin-3-yl)isoindoline-1,3-dione (TR-293).

[0380] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-301).

[0381] 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).

[0382] 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).

[0383] 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).

[0384] 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).

[0385] 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).

[0386] 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).

[0387] 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).

[0388] 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).

[0389] In some embodiments, the bivalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(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).

[0390] 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-5-yl)but-3-yn-1-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-319).

[0391] 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-5-yl)butyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-320).

[0392] In some embodiments, the bivalent 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).

[0393] 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).

[0394] 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).

[0395] In some embodiments, the divalent compound is 3-(5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-331).

[0396] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-332).

[0397] In some embodiments, the divalent compound is 3-(6-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-335).

[0398] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-336).

[0399] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)amino)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-337).

[0400] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-1-yl)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-338).

[0401] 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).

[0402] 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).

[0403] 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).

[0404] 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).

[0405] 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).

[0406] 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).

[0407] 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)picolinamide (CPD-470).

[0408] 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)picolinamide (CPD-471).

[0409] In some embodiments, the divalent compound is N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-6-((1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoyl)piperidin-4-yl)amino)picolinamide (CPD-472).

[0410] In some embodiments, the divalent compound is N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-6-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoyl)piperidin-4-yl)amino)picolinamide (CPD-473).

[0411] In some embodiments, the divalent compound is N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-6-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)picolinamide (CPD-474).

[0412] In some embodiments, the divalent compound is N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-6-((1-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)amino)picolinamide (CPD-475).

[0413] 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)picolinamide (CPD-476).

[0414] 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).

[0415] 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).

[0416] 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).

[0417] In some embodiments, the divalent compound is N-(2-(4-carbamoylpiperidin-1-yl)-4-((4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)methyl)phenyl)-2-morpholinooxazole-4-carboxamide (CPD-482).

[0418] In some embodiments, the divalent compound is N-(2-(4-carbamoylpiperidin-1-yl)-4-((4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)methyl)phenyl)-2-morpholinooxazole-4-carboxamide (CPD-483).

[0419] In some embodiments, the divalent compound is N-(2-(4-carbamoylpiperidin-1-yl)-4-((4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoyl)piperazin-1-yl)methyl)phenyl)-2-morpholinooxazole-4-carboxamide (CPD-484).

[0420] In some embodiments, the divalent compound is 2-(4-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)acetamide (CPD-499).

[0421] 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).

[0422] 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).

[0423] According to one aspect of the present disclosure, the compositions disclosed herein comprise a bivalent compound, or a pharmaceutically acceptable salt or analog thereof, and a pharmaceutically acceptable carrier or diluent.

[0424] 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 analog thereof.

[0425] In one embodiment, the TRK-mediated disease is due to the expression, mutation, or fusion of TRK.

[0426] In one embodiment, a subject having a TRK-mediated disease has higher TRK function compared to a healthy subject without the TRK-mediated disease.

[0427] In one embodiment, the bivalent compound is selected from the group consisting of CPD-001 to CPD-516, or analogs thereof.

[0428] In one embodiment, the bivalent compound is selected from the group consisting of CPD-247 to CPD-516, or analogs thereof.

[0429] In one embodiment, the bivalent compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.

[0430] In one embodiment, the method further comprises administering to the subject an additional treatment regimen for treating cancer.

[0431] In one embodiment, the additional treatment regimen is selected from the group consisting of surgery, chemotherapy, radiation therapy, hormone therapy, and immunotherapy.

[0432] In one embodiment, the TRK-mediated disease is selected from the group consisting of 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, lung neuroendocrine tumor, chromaffin cell tumor, and Wilms tumor.

[0433] In one embodiment, a TRK-mediated disease or disorder is cancer, an inflammatory disease, acute or chronic pain, itching, a bone-related disorder, a neurodegenerative disorder, an infectious disease, another disorder, such as, but not limited to, neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric cancer, lung cancer, liver cancer, uterine cancer, adrenal cancer, bile duct 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, secretory breast tumor, salivary gland carcinoma, papillary thyroid carcinoma, ductal carcinoma, adult myeloid leukemia, acute myeloid leukemia, large cell neuroendocrine tumor, pulmonary neuroendocrine tumor, sarcoma, chromaffin cell tumor, fibrosarcoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, malignant fibrous histiocytoma, fetal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system neoplasm, osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, Spitzoid carcinoma, Wilms tumor, lymphoma (e.g., including Hodgkin lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-cell large cell lymphoma, Burkitt lymphoma, T-cell undifferentiated 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, psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, postoperative pain, inflammatory pain, neuropathic pain, nociceptive pain, pain of osteoarthritis, chronic low back pain, low back pain of osteoporosis, pain of fracture, pain of rheumatoid arthritis, postherpetic neuralgia, pain of diabetic neuropathy, fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, pain of endometriosis, pain of irritable bowel syndrome, migraine, pain of pulpitis, pain of interstitial cystitis, painful bladder syndrome, central pain syndrome, postoperative pain syndrome, bone and joint pain, repetitive motion pain, toothache, myofascial pain, intraoperative pain, dysmenorrhea, myofascial pain, angina pain, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain caused by central sensitization, generalized cutaneous pruritus, local cutaneous pruritus, senile pruritus, pruritus gravidarum, anal pruritus, vulvar pruritus, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, bone metastasis, ankylosing spondylitis, Paget's disease, pyorrhea alveolaris, osteolytic disease, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia nervosa, demyelination, and hypomyelination.In one embodiment, the disease or disorder is a recurrent disease or disorder.

[0434] In one embodiment, the TRK-mediated disease or disorder is a recurrent cancer.

[0435] In one embodiment, the TRK-mediated disease or disorder is refractory to one or more existing treatments.

[0436] According to one aspect of the present disclosure, a method for identifying a bivalent compound that mediates the degradation or reduction of TRK is disclosed. The method comprises providing a heterobifunctional test compound comprising a TRK ligand conjugated to a degradation tag via a linker; contacting the heterobifunctional test compound with cells comprising a ubiquitin ligase and TRK; determining whether the TRK value in the cells decreases; identifying the heterobifunctional test compound as a bivalent compound that mediates the degradation or reduction of TRK; and comprises.

[0437] In one embodiment, the cells are cancer cells.

[0438] In one embodiment, the cancer cells are TRK-mediated cancer cells.

[0439] In one embodiment, the cells are neurons.

[0440] Citation by reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0441] The novel features of the present invention will be specifically described together with the appended claims. To better understand the features and advantages of the present invention, reference should be made to the following detailed description and the accompanying drawings, which illustrate exemplary embodiments in which the principles of the present invention are used.

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Mode for Carrying Out the Invention

[0442] In the present disclosure, it is recognized that the tropomyosin receptor kinase (TRK) receptor family includes TRKA, TRKB, and TRKC as three members respectively encoded by the genes of NTRK1, NTRK2, and NTRK3 (Khotskaya et al., 2017). TRK is a receptor tyrosine kinase mainly involved in 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). When a ligand binds to the extracellular domain of TRK, dimerization and activation of the receptor are induced, thereby activating downstream signaling pathways such as the PI3K / AKT, RAF / MEK / ERK, and PLCγ pathways. Such pathways have a well-established role in promoting tumor formation by supporting cell growth and survival (Hanahan and Weinberg, 2011).

[0443] Furthermore, in the present specification, like many other oncogenic receptor tyrosine kinases, it is recognized that TRK is abnormally activated in various human malignancies. Interestingly, the main molecular mechanism that activates TRK in cancer is not point mutation but in-frame fusion of the NTRK gene (Vaishnavi et al., 2015). Generally, the 3' region of the NTRK gene is connected to the 5' region of the partner gene by chromosomal rearrangement. The resulting chimeric protein always retains the kinase domain of the TRK protein, and thus the catalytic function is recognized as important for the transforming activity. When the 5' region of the NTRK gene encoding the autoinhibitory domain is lost, these fusion kinases become constitutively active. In addition, the expression of the chimeric protein is driven by the promoter of the fusion partner, often resulting in overexpression. The most frequently observed TRK fusions include LMNA-TRKA, TPM3-TRKA, and ETV6-TRKC (Amatu et al., 2016). Therefore, due to genetic events, overexpressed and constitutively active TRK fusion kinases are generated. As shown by the ability to transform mouse embryonic fibroblasts and normal epithelium, these fusions are oncogenic (Russell et al., 2000; Vaishnavi et al., 2015).

[0444] TRK fusions were first reported in human colon cancer and were named oncD at that time (Martin-Zanca et al., 1986). In recent years, the advancement of high-throughput RNA sequencing has greatly facilitated the efficiency of identifying chromosomal rearrangement events in patient samples. As a result, TRK fusions have been found across a diverse range of human malignancies, including but not limited to non-small cell lung cancer, colorectal cancer, gastric cancer, low-grade glioblastoma multiforme, Spitzoid carcinomas, soft tissue sarcomas, 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% - 2.7% of colorectal cancers are affected by TRK fusions (Creancier et al., 2015; Lee et al., 2015). However, in certain cancer types such as secretory breast carcinoma, TRK fusions can be found in the majority of cases (Tognon et al., 2002).

[0445] TRK mutations and deletions have been observed in additional human diseases such as pulmonary neuroendocrine tumors, anhidrotic ectodermal dysplasia, obesity, congenital heart disease, and acute myeloid leukemia (Khotskaya et al., 2017). In addition, TRK amplification has been associated with various human diseases including liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, bladder cancer, endometrial cancer, chromaffin cell tumors, Wilms tumors, and prostate cancer (Khotskaya et al., 2017).

[0446] For nerve growth factor (NGF) and its main receptor, tropomyosin receptor kinase A (TRKA), their roles in central and peripheral pain have been recognized (Denk et al., 2017). Nociceptive neurons express TRKA by transmitting pain signals to the central nervous system and mediate pain sensation. A number of NGF-neutralizing antibodies, such as tanezumab, have undergone clinical evaluation in patients with pain diseases such as osteoarthritis, low back pain, cancer pain, and neuropathic pain (Miller et al., 2017). The effectiveness of NGF antibodies for analgesia has been clearly documented in clinical settings. However, administration of NGF-neutralizing antibodies has been shown to result in rapid progression of joint destruction in some patients, necessitating total joint replacement (Schnitzer and Marks, 2015). These adverse events may be associated with persistent exposure to NGF antibodies. Targeting TRK represents another promising therapeutic approach for blocking the NGF / TRK signaling pathway for pain treatment. However, currently available pan-TRK kinase inhibitors may induce significant on-target adverse effects through the modulation of TRK family members in the central nervous system. Peripherally restricted TRK bifunctional degrading agents are expected to selectively inhibit the NGF / TRK pathway in peripheral nerves while leaving these targets intact in the central nervous system.

[0447] TRK is associated with cancer, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, and other diseases, such as, but not limited to, neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric cancer, lung cancer, liver cancer, uterine cancer, adrenal cancer, cholangiocarcinoma, intestinal cancer, colorectal cancer, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, breast cancer, esophageal cancer, bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secretory breast carcinoma, secretory carcinoma, salivary gland carcinoma, papillary thyroid carcinoma, ductal carcinoma, acute myeloid leukemia, large cell neuroendocrine tumor, pulmonary neuroendocrine tumor, sarcoma, chromaffin cell tumor, fibrosarcoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, malignant fibrous histiocytoma, fetal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system neoplasm, osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, Spitzoid carcinoma, Wilms tumor, lymphoma (including, for example, Hodgkin lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-cell large cell lymphoma, Burkitt lymphoma, T-cell undifferentiated large cell lymphoma), inflammatory lung disease (such as asthma), inflammatory bowel disease (such as ulcerative colitis, Crohn's disease), inflammatory skin disease (such as atopic dermatitis, eczema, psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, postoperative pain, inflammatory pain, neuropathic pain, nociceptive pain, pain of osteoarthritis, chronic low back pain, low back pain of osteoporosis, pain of fracture, pain of rheumatoid arthritis, postherpetic neuralgia, pain of diabetic neuropathy, fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, pain of endometriosis, pain of irritable bowel syndrome, migraine, pain of pulpitis, pain of interstitial cystitis, painful bladder syndrome, central pain syndrome, postoperative pain syndrome, bone and joint pain, repetitive motion pain, toothache, myofascial pain, intraoperative pain, dysmenorrhea, myofascial pain, angina pain, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain caused by central sensitization, generalized cutaneous pruritus, local cutaneous pruritus, senile cutaneous pruritus, pruritus of pregnancy, anal pruritus, vulvar pruritus, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, bone metastasis, ankylosing spondylitis, Paget's disease, pyorrhea alveolaris, osteolytic disease, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia nervosa, demyelination, and hypomyelination.

[0448] TRK kinase inhibitors are currently undergoing 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), altiractinib (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), mirvetuximab b (PHA-848125AC) (Brasca et al., 2009), belizatinib (TSR-011) (Ricciuti et al., 2017), GZ389988 (Bailey et al., 2017a, b), pegaptinib (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 ones are entrectinib and larotrectinib (Khotskaya et al., 2017). These agents are tested in basket trials that enroll patients according to the detection of TRK fusions instead of tissue histology. From the results of the phase 2 of larotrectinib, it has been observed that the majority of patients (75%) responded to the treatment and 55% of the patients remained progression-free at 1 year (Drilon et al., 2018). In the results of the phase 1 of entrectinib, significant durable responses have also been recorded in patients with TRK fusion tumors (Drilon et al., 2017b).The marked effects of TRK inhibitors were not tumor type-dependent. From these substantial results, overall, the role of TRK fusions as the only oncogenic driver in a subset of human malignancies is emphasized, regardless of the originating tissue.

[0449] Nonspecific side effects and the development of resistance to TRK kinase inhibitors remain challenges in the development of effective treatments. Therefore, new small molecule-targeted TRK functions via inhibition and / or degradation are highly useful.

[0450] Although not bound by any theory, the present disclosure is believed to be based at least in part on the usefulness of TRK, TRK fusion proteins, TRK splicing, and / or TRK mutant proteins in the treatment of TRK-mediated diseases, specifically 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, chromaffin cell tumor, and Wilms tumor (Amatu et al., 2016; Khotskaya et al., 2017).The disclosed novel bifunctional TRK degrader is useful for the treatment of TRK-mediated cancers, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, and other diseases, such as, but not limited to, neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric cancer, lung cancer, liver cancer, uterine cancer, adrenal cancer, cholangiocarcinoma, intestinal cancer, colorectal cancer, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, breast cancer, esophageal cancer, bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secretory breast carcinoma, secretory breast tumor, salivary gland carcinoma, papillary thyroid carcinoma, ductal carcinoma, adult myeloid leukemia, acute myeloid leukemia, large cell neuroendocrine tumor, pulmonary neuroendocrine tumor, sarcoma, chromaffin cell tumor, fibrosarcoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, malignant fibrous histiocytoma, fetal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system neoplasm, osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, Spitzoid carcinoma, Wilms tumor, lymphoma (e.g., including Hodgkin lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-cell large cell lymphoma, Burkitt lymphoma, T-cell undifferentiated large cell lymphoma), inflammatory lung diseases (e.g., asthma), inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's disease), inflammatory skin diseases (e.g., atopic dermatitis, eczema, psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, postoperative pain, inflammatory pain, neuropathic pain, nociceptive pain, pain of osteoarthritis, chronic low back pain, low back pain of osteoporosis, pain of fracture, pain of rheumatoid arthritis, postherpetic neuralgia, pain of diabetic neuropathy, fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, pain of endometriosis, pain of irritable bowel syndrome, migraine, pain of pulpitis, pain of interstitial cystitis, bladder pain syndrome, central pain syndrome, postoperative pain syndrome, bone and joint pain, repetitive motion pain, toothache, myofascial pain, intraoperative pain, dysmenorrhea, myofascial pain, angina pain, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain caused by central sensitization, generalized cutaneous pruritus, local cutaneous pruritus, senile cutaneous pruritus, pruritus gravidarum, anal pruritus, vulvar pruritus, metastatic bone diseases, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, bone metastasis, ankylosing spondylitis, Paget's disease, periodontitis, osteolytic diseases, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia nervosa, demyelination, and hypomyelination.

[0451] The selective degradation of target proteins induced by small molecules may be achieved by recruiting E3 ubiquitin ligases to mimic protein misfolding with hydrophobic tags (Buckley and Crews, 2014). In addition, this small molecule has one part that binds to the E3 ubiquitin ligase and another part that binds to the target protein target (Buckley and Crews, 2014). Target ubiquitination occurs by induced proximity, followed by degradation of the target via proteasome-mediated proteolysis. Various types of high-affinity small molecule E3 ligase ligands have been identified and developed. Examples of these include (1) immunomodulatory drugs (IMiDs) such as thalidomide and pomalidomide that 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 von Hippel-Lindau protein (VHL or CRL2VHL), a component of another CRL complex (Bondeson et al., 2015; Buckley et al., 2012a; Buckley et al., 2012b; Galdeano et al., 2014; Zengerle et al., 2015); (3) compound 7 that selectively binds to KEAP1, a component of the CRL3 complex (Davies et al., 2016); (4) AMG232 that selectively binds to MDM2, a heterodimeric RING E3 ligase (Sun et al., 2014); (5) LCL161 that selectively binds to IAP, a homodimeric RING E3 ligase (Ohoka et al., 2017; Okuhira et al., 2011; Shibata et al., 2017). The technique of E3 ligases that mobilize bifunctional degraders has been applied to the degradation of various 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, hydrophobic tagging approaches utilize bulky hydrophobic adamantyl groups and have been developed to mimic protein misfolding and result in proteasome-mediated degradation of target proteins (Buckley and Crews, 2014). This approach has been applied to the selective degradation of the pseudokinase HER3 (Xie et al., 2014). The inventors have not yet confirmed attempts to apply any of such approaches to the degradation of TRK, TRK mutants, TRK deletions, TRK splicing, or TRK fusion proteins.

[0452] Currently available small molecules targeting TRK focus on inhibiting the kinase activity of TRK. Many selective small molecule TRK kinase inhibitors, such as entrectinib (RXDX-101) (Menichincheri et al., 2016), GNF-8625 (Choi et al., 2015), larotrectinib (LOXO-101; ARRY-470) (Drilon et al., 2018), altiratinib (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), mirvetuximab b (PHA-848125AC) (Brasca et al., 2009), belizatinib (TSR-011) (Ricciuti et al., 2017), GZ389988 (Bailey et al., 2017a, b), pegaptanib (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) have been reported.

[0453] In the present disclosure, a novel approach is obtained for developing compounds that directly and selectively modulate not only the kinase activity of TRK but also its protein levels. Strategies for inducing proteolysis include recruitment of E3 ubiquitin ligases, mimicking protein misfolding with hydrophobic tags, and inhibition of chaperones. Such approaches are based on the use of bivalent small molecule compounds and enable modulation of protein levels in vitro and in vivo with a high degree of flexibility compared to techniques such as gene knockout and short hairpin RNA-mediated (shRNA) knockdown. Unlike gene knockout and shRNA knockdown, the small molecule approach further provides an opportunity to test dose and time dependencies in disease models by modulating the administration route, concentration, and dosing frequency of the corresponding small molecule.

[0454] Bivalent compound For the purposes of the present disclosure, the terms "bifunctional compound", "bifunctional degrader", "bifunctional TRK degrader", "bivalent compound", and "heterobifunctional compound" are used interchangeably.

[0455] In some embodiments, the present disclosure provides a bivalent compound comprising a TRK ligand conjugated to a degron, or a pharmaceutically acceptable salt or analog thereof. This TRK ligand may be conjugated directly to the degron or via a linker moiety. In certain embodiments, the TRK ligand may be conjugated directly to the degron. In certain embodiments, the TRK ligand may be conjugated to the degron via a linker moiety.

[0456] As used herein, the terms “tropomyosin receptor kinase ligand” and “TRK ligand,” or “TRK targeting moiety,” should be construed to include any molecule ranging from small molecules to large proteins that associates with or binds to a TRK protein. In certain embodiments, a TRK ligand is capable of binding to a TRK protein, including a TRK, a TRK mutation, a TRK deletion, a TRK splicing, or a TRK fusion protein. A TRK ligand can be, for example, but not limited to, a small molecule compound (i.e., a molecule having a molecular weight of less than about 1.5 kilodaltons (kDa)), a peptide or polypeptide, a nucleic acid or oligonucleotide, a carbohydrate such as an oligosaccharide, or an antibody or fragment thereof.

[0457] TRK ligand The TRK ligand or targeting moiety can be a TRK kinase inhibitor or a part thereof. In certain embodiments, the TRK kinase inhibitor includes (e.g., entrectinib (RXDX-101) (Menichincheri et al., 2016), GNF-8625 (Choi et al., 2015), larotrectinib (LOXO-101; ARRY-470) (Drilon et al., 2018), altiratinib (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), milciclib b (PHA-848125AC) (Brasca et al., 2009), belizatinib (TSR-011) (Ricciuti et al., 2017), GZ389988 (Bailey et al., 2017a, b), pegaptanib (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), and one or more of their analogs, thereby enabling inhibition of the kinase activity of TRK. As used herein, a "TRK kinase inhibitor" represents an agent that causes, by suppressing, delaying, or otherwise, inhibition of a physiological, chemical, or enzymatic action or function, and reduces the binding by at least 5%. The inhibitor can further or alternatively represent a drug, compound, or agent that prevents or reduces the expression, transcription, or translation of a gene or protein.The inhibitor can reduce or prevent the function of a protein, for example, by binding to or activating / inactivating other proteins or receptors.

[0458] In certain embodiments, the TRK ligand is as follows:

[0459]

Chemical formula

[0460] In certain embodiments, examples of the TRK ligand 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), ONO-4474 (Bailey et al., 2017a, b). In certain embodiments, the TRK ligand is obtained 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), ONO-4474 (Bailey et al., 2017a, b).

[0461] In one aspect herein, a compound of Formula I:

[0462]

Chemical formula

[0463]

Chemical formula

[0464] [Chem.] There is provided a compound, or a pharmaceutically acceptable salt thereof, which is:

[0465] In some embodiments, X 1 and X 2 are each N.

[0466] 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

[0467] and X 3 and X 4 are both C(O). In some embodiments, X 3 and X 4 are both CR 4 R 5 In some embodiments, R

[0468] is -NR 1 R 2 R 3 In some embodiments, R 1 is

[0469] [Chem.] is:

[0470] In one aspect herein, a compound of formula Ia:

[0471] [Chem.] or a pharmaceutically acceptable salt thereof, wherein in the formula, X 1 and X2 is independently selected from CH and N, X 3 and X 4 is independently selected from C(O), CR 4 R 5 , and NR 6 ; R 1 is H, -NR 2 R 3 , halogen, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C 3-10 carbocyclic, optionally substituted 3- to 10-membered heterocyclic, 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; R 2 , R 3 , R 4 , R 5 , and R 6 are independently H, halogen, optionally substituted C 1-6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C 3-10 carbocyclic, optionally substituted 3- to 10-membered heterocyclic, 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; L is a single bond, R'-R", R'COR", R'CO2R", R'C(O)N(R 7 )R", R'C(S)N(R 7 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 7 )R", R'N(R 7 )R", R"N(R 7)COR”, R’N(R 7 )CON(R 8 )R”, R’N(R 7 )C(S)R”, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C4-C 13 fused carbocyclic, optionally substituted 5- to 13-membered fused heterocyclic, optionally substituted C5-C 13 bridged carbocyclic, optionally substituted 5- to 13-membered bridged heterocyclic, optionally substituted C5-C 13 spirocarbocyclic, optionally substituted 5- to 13-membered spiroheterocyclic, optionally substituted 3- to 10-membered carbocyclic, optionally substituted 3- to 10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, selected from wherein L is optionally X 3 or X 4 and is bonded to R' and R” are independently null, optionally substituted C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3- to 10-membered carbocyclic, optionally substituted 3- to 10-membered heterocyclic, optionally substituted C4-C13 A fused carbocyclic ring, an optionally substituted 5- to 13-membered fused heterocyclic ring, an optionally substituted C5-C 13 A bridged carbocyclic ring, an optionally substituted 5- to 13-membered bridged heterocyclic ring, an optionally substituted C5-C 13 Selected from a spirocarbocyclic ring, an optionally substituted 5- to 13-membered spiroheterocyclic ring, an optionally substituted aryl, and an optionally substituted heteroaryl, and R 7 and R 8 are independently selected from hydrogen, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 heteroalkyl, an optionally substituted C1-C8 heteroalkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C1-C8 alkoxy-C1-C8 alkyl, an optionally substituted C1-C8 haloalkyl, an optionally substituted C1-C8 hydroxyalkyl, an optionally substituted C1-C8 aminoalkyl, an optionally substituted C1-C8 alkylamino C1-C8 alkyl, an optionally substituted 3- to 10-membered carbocyclic ring, an optionally substituted 3- to 10-membered heterocyclic ring, an optionally substituted aryl, and an optionally substituted heteroaryl, or R’ and R”, R 7 and R 8 , R’ and R 7 , R’ and R 8 , R” and R 7 , R” and R 8 together with the atoms to which they are attached form an optionally substituted 3- to 20-membered carbocyclic ring or 3- to 20-membered heterocyclic ring, A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0472] In some embodiments, L is

[0473]

Chemical formula

[0474] In some embodiments, X 1 and X 2 are each N.

[0475] In some embodiments, X 3 and X 4 at least one of which is NR 6 . In some embodiments, X 3 and X 4 are both NR 6 .

[0476] In some embodiments, X 3 or X 4 is -N-(2,6-dioxopiperidin-3-yl).

[0477] In some embodiments, R 1 is -NR 2 R 3 . In some embodiments, R 1 is

[0478]

Chemical formula

[0479] In some embodiments, L is connected to X 3 . In some embodiments, L is connected to X 4 .

[0480] In one aspect herein, Formula II:

[0481]

Chemical formula

[0482]

Chem.

[0483]

Chem.

[0484] In some embodiments, X 1 and X 2 are each N.

[0485] In one aspect herein, Formula III:

[0486]

Chem.

[0487] In some embodiments, L is

[0488]

Chemical formula

[0489] In some embodiments, R 4 , R 5 , and R 6 are each hydrogen.

[0490] In some embodiments, Y is CR 8 R 9 is. In some embodiments, Y is CH2.

[0491] In some embodiments, R7 is optionally substituted C 6-10 aryl. In some embodiments, R 7 is

[0492]

Chemical Structure

[0493] In some embodiments, Ar is NR 18 R 19 substituted C 6-10 aryl. In some embodiments, Ar is

[0494]

Chemical Structure

[0495] In some embodiments, R 3 is an optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, R 3 is

[0496]

Chemical Structure

[0497] In some embodiments, X 1 is CR 1 and X 2 is CH, and X 3 is NR 1 . In some embodiments, X 1 is NR 1 and X 2 is CH, and X 3 is CR 1 . In some embodiments, X 1 is CR 1 and X 2 is N, and X 3 is NR 1 . In some embodiments, X 1 is NR 1and X 2 is N and X 3 is CR 1 is. In some embodiments, X 1 is NR 1 and X 2 is CH and X 3 is N. In some embodiments, X 1 is N and X 2 is CH and X 3 is NR 1 is. In some embodiments, X 1 is CR 1 R 2 and X 2 is CO and X 3 is NR 1 is. In some embodiments, X 1 is NR 1 and X 2 is CO and X 3 is NR 1 is. In some embodiments, X 1 is O and X 2 is CO and X 3 is NR 1 is. In some embodiments, X 1 is CR 1 and X 2 is CO and X 3 is NR 1 is. In some embodiments, X 1 is N and X 2 is CO and X 3 is NR 1 is. In some embodiments, R 1 is

[0498]

Chemical formula

[0499] In one aspect of the present specification, Formula IV:

[0500]

Chemical formula

[0501] In some embodiments, L is

[0502]

Chemical formula

[0503] In some embodiments, Y 1 is N, Y 2 is N, Y 3 is C, Y 4 is C.

[0504] In some embodiments, Ar 1 is C 6-10 aryl optionally substituted with halogen. In some embodiments, Ar 1 is

[0505]

Chemical formula

[0506] In some embodiments, Ar 2 is C 11 aryl optionally substituted with NR 12 R 6-10 In some embodiments, Ar 2 is

[0507]

Chemical formula

[0508] In some embodiments, R 3 is an optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, R 3 is

[0509]

Chemical formula

[0510] In some embodiments, R 4 is hydrogen.

[0511] In some embodiments, Z is C(R 5 )2. In some embodiments, Z is CH2.

[0512] In some embodiments, n is 0.

[0513] 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, and X2 is CH, and X 3 is NR 1 is.

[0514] In some embodiments, R 1 is methyl. In some embodiments, R 1 is

[0515]

Chemical formula

[0516] In another embodiment, the TRK ligand is of Formula 1:

[0517]

Chemical formula

[0518] In another embodiment, the TRK ligand is of Formula 1:

[0519]

Chemical formula

[0520] In one embodiment, X is selected from CR’R”, O, and NR’, where R’ and R” are independently selected from hydrogen, F, OH, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, and optionally substituted C1-C3 alkoxy, or R’ and R” together with the atom to which they are attached form an optionally substituted 3- to 6-membered carbocyclic or heterocyclic ring.

[0521] In another embodiment, X is selected from CH2, cyclopropylene, CHF, CF2, O, NH, NCH3, NCH2CH3, and N-isopropyl.

[0522] In another embodiment, R is selected from optionally substituted C3-C8 carbocyclic, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.

[0523] In another embodiment, R is selected from optionally substituted phenyl and optionally substituted heteroaryl.

[0524] In another embodiment, X is CH2 and R is 3,5-difluorophenyl.

[0525] In another embodiment, R 1 , R 2 , and R 3 are independently selected from hydrogen, F, Cl, and OH.

[0526] In another embodiment, R 4 -Ar is of the formulas A1, A2, A3, and A4:

[0527]

Chemical formula

[0528] In another embodiment, R 4 -Ar is selected from the moieties of formulas A1, A3, A3, and A4:

[0529]

Chemical formula

[0530] In another embodiment, R ais selected from H, (tetrahydro-2H-pyran-4-yl)amino, and (2-fluoroethyl)amino.

[0531] In another embodiment, R 4 is

[0532]

Chemical formula

[0533] In another embodiment, the TRK ligand is of formula 2:

[0534]

Chemical formula

[0535] In another embodiment, the TRK ligand is of formula 2:

[0536]

Chemical formula

[0537] In one embodiment, X 1 is selected from CR’ and N, where R’ is selected from hydrogen, F, Cl, CH3, CF3, and cyclopropyl.

[0538] In another embodiment, X 2 , X 3 , and X 4 are independently selected from C and N.

[0539] In another embodiment, X is selected from a single bond, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH, and CH2NCH3.

[0540] In another embodiment, R 1 and R 2 are, each occurrence, independently selected from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclyl.

[0541] In another embodiment, X is CH2 and Ar 1 is 3-fluorophenyl.

[0542] In another embodiment, R 3 is directly connected to the linker portion of the divalent compound, and R 3 is null, a single bond, -OR 5 -, -SR 5 -, -NR 6 R 7 -, -COR 5 -, -CO2R 5 -, -CONR 6 R 7 -, -SOR 5 -, -SO2R 5 -, -SO2NR 6R 7 、 -NR 5 COR 7 --NR 5 C(O)NR 6 R 7 -、 -NR 5 SOR 7 -、 -NR 5 SO2R 7 -、 optionally substituted C1-C8 alkyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C1-C8 alkoxyC 1-8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 5 、 R 6 、 and R 7 are independently selected from null, a single bond, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted heterocarbocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 6 and R 7 together with the atoms to which they are attached form an optionally 3- to 8-membered carbocyclyl or heterocyclyl ring.

[0543] In another embodiment, R 3 is connected via R 4 to the linker portion of a bivalent compound, and R 3 and R4 is independently null, a single bond, -OR 5 -, -SR 5 -, -NR 6 R 7 -, -COR 5 -, -CO2R 5 -, -CONR 6 R 7 -, -SOR 5 -, -SO2R 5 -, -SO2NR 6 R 7 -, -NR 5 COR 7 -, -NR 5 C(O)NR 6 R 7 -, -NR 5 SOR 7 -, -NR 5 SO2R 7 -, optionally substituted C1-C8 alkyl, optionally substituted C 1-8 heteroalkyl, optionally substituted C1-C8 alkoxyC 1-8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 carbocyclic, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 5 、R 6 、and R 7is independently selected from null, single bond, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C6 carbocyclic, optionally substituted 3- to 8-membered heterocyclic, optionally substituted heterocarbocyclic, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 6 and R 7 together with the atoms to which they are attached form an optionally 3- to 8-membered carbocyclic or heterocyclic ring.

[0544] In another embodiment, Ar 1 is selected from C 6-10 aryl and C5-C 10 heteroaryl, each of which is F, Cl, CN, NO2, OR 10 , NR 11 R 12 , COR 10 , CO2R 10 , CONR 11 R 12 , SOR 10 , SO2R 10 , SO2NR 11 R 12 , NR 10 COR 12 , NR 10 C(O)NR 11 R 12 , NR 10 SOR 12 , NR 10 SO2R 12, selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino C1-C6 alkyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, and optionally substituted C4-C5 heteroaryl, where R 10 , R 11 , and R 12 are, each time they appear, independently null, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclic, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or R 11 and R 12 together with the atom to which they are attached form an optionally 3-8 membered carbocyclic or heterocyclic ring.

[0545] In another embodiment, Ar 2 is selected from C 6-10 aryl and C5-C 10 heteroaryl, each of whic...

Claims

1. Formula I: 【Chemical 1】 a compound of or a pharmaceutically acceptable salt thereof, wherein X １ and X ２ are independently selected from CH and N, X ３ and X ４ are independently selected from C(O) and CR ４ R ５ is selected from, R １ is 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, optionally substituted 3- to 10-membered heterocyclic, 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, R ２ R ３ R ４ and R ５ are independently H, optionally substituted C １－６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted C ３－１０ carbocyclic, optionally substituted 3- to 10-membered heterocyclic, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C １－６ heteroalkyl, optionally substituted C １－６ haloalkyl, and optionally substituted C １－６ alkoxy, and L is a single bond, 【Chemical 2】 selected from, or X ３ and X ４ wherein one of them is C(O) and the other is CR ４ R ５ and L is 【Chemical Formula 3】 a compound or a pharmaceutically acceptable salt thereof.

2. said X １ and said X ２ are each N, the compound or a pharmaceutically acceptable salt thereof according to claim 1.

3. said R １ is -NR ２ R ３ the compound or a pharmaceutically acceptable salt thereof according to claim 1.

4. said R １ is 【Chemical Formula 4】 the compound or a pharmaceutically acceptable salt thereof according to claim 3.

5. N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)piperazin-1-yl)benzamide, 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, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)-2-((2-fluoroethyl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((2-fluoroethyl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)morpholin-2-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)pyrrolidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-6-azaspiro[3.4]octan-2-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(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, 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, 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, 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, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(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, 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, 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, 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, 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, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)amino)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-1-yl)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-1-yl)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)piperidin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, (S)-N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, (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, (S)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, and (R)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide A divalent compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

6. (S)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, and (R)-N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide The divalent compound according to claim 5, selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

7. The bivalent compound according to claim 6, which 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, or a pharmaceutically acceptable salt thereof.

8. The bivalent compound according to claim 6, which 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, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a bivalent compound according to any one of claims 5 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

10. A composition for use in the treatment of tropomyosin receptor kinase (TRK)-mediated diseases, comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a bivalent compound according to any one of claims 5 to 8 or a pharmaceutically acceptable salt thereof.

11. The composition according to claim 10, wherein the TRK-mediated disease results from the expression, mutation, splicing, or fusion of TRK.

12. The composition according to claim 10, wherein the TRK-mediated disease is cancer, an inflammatory disease, acute pain, chronic pain, or pruritus.

13. The composition according to claim 12, wherein the TRK-mediated disease is cancer.

14. The composition according to claim 12, wherein the TRK-mediated disease is acute pain.

15. The composition according to claim 12, wherein the TRK-mediated disease is chronic pain.

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