Troponin receptor kinase (TRK) degradation compounds and methods of use

Abstract

The present invention provides bivalent compounds, compositions comprising one or more of the bivalent compounds, and methods of using the bivalent compounds to treat certain diseases in a subject in need thereof. Methods of identifying such bivalent compounds are also provided.

Description

Background Technology

[0001] This disclosure relates to divalent compounds (e.g., bifunctional small molecule compounds), compositions comprising one or more of said divalent compounds, and methods of treating certain diseases in subjects in need using said divalent compounds. This disclosure also relates to methods for identifying such divalent compounds. Summary of the Invention

[0002] According to one aspect of this disclosure, the divalent compounds disclosed herein comprise a tropomyosin receptor kinase (TRK) ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof.

[0003] In one embodiment, the TRK ligand is capable of binding to a TRK protein comprising TRK, a TRK mutant, a TRK deletion, or a TRK fusion protein.

[0004] In another embodiment, the TRK ligand is a TRK kinase inhibitor or a portion thereof.

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

[0006] In another embodiment, the degradation tag binds to a ubiquitin ligase, or is a hydrophobic group or tag that causes the TRK protein to misfold.

[0007] In another embodiment, the ubiquitin ligase is an E3 ligase.

[0008] In another embodiment, the E3 ligase is selected from cereblon E3 ligase, VHL E3 ligase, MDM2 ligase, TRIM24 ligase, TRIM21 ligase, KEAP1 ligase, and IAP ligase.

[0009] In another embodiment, the degradation label 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, and the like.

[0010] In another embodiment, the TRK ligand is conjugated to the degradation tag via a linker portion.

[0011] In another embodiment, the TRK ligand comprises a portion of Formula 1.

[0012]

[0013] in

[0014] X is selected from CR'R", CO, O, S, SO, SO2, and NR', where

[0015] R' and R" are independently selected from hydrogen, halogen, OH, optionally substituted C1-C8 alkyl, optionally substituted C 1-8 Alkoxy, optionally substituted C1-C8 alkoxy, C1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylamino, C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C3-C 10 Cycloalkoxy groups and optionally substituted 3-10 membered heterocyclic groups; or

[0016] R' and R” together with the atoms they are attached to form optionally substituted 3-8 membered cycloalkyl or heterocyclic rings;

[0017] R is selected from optionally substituted C1-C8 alkyl groups, optionally substituted C3-C6 alkyl groups, etc. 10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups;

[0018] R 1 R 2 and R 3 Independently selected from hydrogen, halogen, CN, NO2, OR 5 SR6 NR 7 R 8 COR 5 CO2R 5 C(O)NR 7 R 8 SOR 5 SO2R 5 SO2NR 7 R 8 NR 7 C(O)R 8 NR 5 C(O)NR 7 R 8 NR 7 SOR 8 NR 7 SO2R 8 Optionally substituted C1-C8 alkyl, Optionally substituted C1-C8 alkoxy, Optionally substituted C1-C8 alkoxy-C1-C8 alkyl, Optionally substituted C1-C8 alkylamino-C1-C8 alkyl, Optionally substituted C3-C 10 cycloalkyl, optionally substituted C3-C 10 Cycloalkoxy, optionally substituted 3-10 membered heterocyclic groups, optionally substituted C2-C8 alkenyl groups, and optionally substituted C2-C8 alkynyl groups, wherein

[0019] R 5 R 6 R 7 and R 8 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic groups, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted aryl or optionally substituted heteroaryl, or

[0020] R 7 and R 8 Together with the atoms they are attached to, they form optionally substituted 4-8 membered heterocyclic rings;

[0021] R 4 The linker portion is connected to the divalent compound and is selected from bonds, OR 9 SR 9 NR 10 R 11 COR 9 CO2R 9 CONR 10 R 11SOR 9 SO2R 9 SO2NR 10 R 11 NR 10 COR 11 NR 9 CONR 10 R 11 NR 10 SOR 11 NR 10 SO2R 11 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic groups, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, aryl, and optionally substituted heteroaryl, wherein

[0022] R 9 R 10 and R 11 Independently selected from empty, bonded, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0023] R 10 and R 11 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings; and

[0024] Ar is selected from aryl and heteroaryl groups, each of which is optionally substituted by one or more substituents, which are independently selected from hydrogen, halogen, CN, NO2, OR. 12 SR 12 NR 13 R 14 COR 12 CO2R 12 CONR 13 R 14 SOR 12 SO2R 12 SO2NR 13 R 14 NR 13 COR 14 NR15 C(O)NR 13 R 14 NR 13 SOR 14 NR 13 SO2R 14 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic group, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0025] R 12 R 13 R 14 and R 15 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0026] R 13 and R 14 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0027] In one implementation, X is selected from CR'R", O, and NR'; wherein

[0028] R' and R" are independently selected from hydrogen, F, OH, optionally substituted C1-C3 alkyl and optionally substituted C1-C3 alkoxy; or

[0029] R' and R” together with the atoms they are attached to form optionally substituted 3-6 membered cycloalkyl or heterocyclic rings.

[0030] In another embodiment, X is selected from CH2, cyclopropylene, CHF, CF2, O, NH, NCH3, NCH2CH3 and N-isopropyl.

[0031] In another embodiment, R is selected from optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.

[0032] In another embodiment, R is selected from optionally substituted phenyl and optionally substituted heteroaryl groups.

[0033] In another embodiment, X is CH2; and R is 3,5-difluorophenyl.

[0034] In another implementation, R 1 R 2 and R 3 It is independently selected from hydrogen, F, Cl and OH.

[0035] In another implementation, R 4 -Ar is selected from parts of formulas A1, A2, A3, and A4:

[0036]

[0037] in

[0038] * indicates a connection to the linker portion of the divalent compound; and

[0039] R a Selected from hydrogen, halogens, CN, NO2, OR 12 SR 12 NR 13 R 14 COR 12 CO2R 12 CONR 13 R 14 SOR 12 SO2R 12 SO2NR 13 R 14 NR 13 COR 14 NR 15 C(O)NR 13 R 14 NR 13 SOR 14 NR 13 SO2R 14 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic group, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0040] R 12 R 13 R 14 and R15 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, aryl and optionally substituted heteroaryl, or

[0041] R 13 and R 14 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0042] In another implementation, R 4 -Ar is selected from parts of formulas A1, A3, A3, and A4:

[0043]

[0044] in

[0045] * indicates a connection to the linker portion of the divalent compound; and

[0046] R a Selected from hydrogen, halogen, NR 13 R 14 and NR 13 COR 14 ,in

[0047] R 13 and R 14 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, phenyl, and optionally substituted C5-C6 heteroaryl, or

[0048] R 13 and R 14 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0049] In another implementation, R a It is (tetrahydro-2H-pyran-4-yl)amino.

[0050] In another embodiment, the TRK ligand comprises a portion of formula 2:

[0051]

[0052] in

[0053] X 1 X 2 X 3 and X 4 Independently selected from C, CR' and N (preferably, X) 1 Selected from CR' and N, X 2 X 3 and X 4 (Independently selected from C and N), where

[0054] R' is selected from hydrogen, halogen, CN, NO2, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-6 membered heterocyclic groups;

[0055] X is selected from empty, key, C(R) 2 )2、C(R 2 )2C(R 2 )2, CO, C(R) 2 )2CO、CONR 2 C(R) 2 )2O、C(R 2 )2NR 2 and CH2NR 2 ;

[0056] R 1 and R 2 Each time it appears, it is independently selected from hydrogen, halogen, OH, NH2, CN, NO2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 alkoxyalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkylaminoC1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclic groups;

[0057] n is between 1 and 4;

[0058] R 3 Directly or through R 4 The linker portion connected to the divalent compound;

[0059] R 3 and R 4 Independently selected from empty, key, OR 5 SR 5 NR 6 R 7 COR 5 CO2R5 CONR 6 R 7 SOR 5 SO2R 5 SO2NR 6 R 7 NR 6 COR 7 NR 5 C(O)NR 6 R 7 NR 6 SOR 7 NR 6 SO2R 7 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 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 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein...

[0060] R 5 R 6 and R 7 Independently selected from empty, bonded, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0061] R 6 and R 7 Together with the atoms they are attached to, they form 3-8 membered cycloalkyl or 4-8 membered heterocyclic rings; and

[0062] Ar 1 and Ar 2 Independently selected from aryl and heteroaryl groups, wherein each is optionally substituted by one or more substituents, which are independently selected from halogens, CN, NO2, OR 10 SR 10 NR 11 R 12 COR 10 CO2R 10 CONR 11 R 12 SOR 10 SO2R 10 SO2NR11 R 12 NR 11 COR 12 NR 10 C(O)NR 11 R 12 NR 11 SOR 12 NR 11 SO2R 12 Optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0063] R 10 R 11 and R 12 Independently selected from empty, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0064] R 11 and R 12 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0065] In one implementation, X 1 It is selected from CR' and N, where R' is selected from hydrogen, F, Cl, CH3, CF3 and cyclopropyl.

[0066] In another implementation, X 2 X 3 and X 4 Selected independently from C and N.

[0067] In another embodiment, X is selected from bonds, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH and CH2NCH3.

[0068] In another implementation, R 1 and R 2Each time it appears, it is independently selected from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclic groups.

[0069] In another implementation, X is CH2; and Ar 1 It is 3-fluorophenyl.

[0070] In another implementation, R 3 The linker portion is directly connected to the divalent compound, and

[0071] R 3 Selected from empty, key, OR 5 SR 5 NR 6 R 7 COR 5 CO2R 5 CONR 6 R 7 SOR 5 SO2R 5 SO2NR 6 R 7 NR 6 COR 7 NR 5 C(O)NR 6 R 7 NR 6 SOR 7 NR 6 SO2R 7 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 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 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein...

[0072] R 5 R 6 and R 7 Independently selected from empty, bonded, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0073] R 6 and R 7 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0074] In another implementation, R 3 Through R 4 The linker portion connected to the divalent compound, and

[0075] R 3 and R 4 Independently selected from empty, key, OR 5 SR 5 NR 6 R 7 COR 5 CO2R 5 CONR 6 R 7 SOR 5 SO2R 5 SO2NR 6 R 7 NR 6 COR 7 NR 5 C(O)NR 6 R 7 NR 6 SOR 7 NR 6 SO2R 7 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 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 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein...

[0076] R 5 R 6 and R 7 Independently selected from empty, bonded, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0077] R 6 and R 7Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0078] In another implementation scheme,

[0079] Ar 1 Selected from C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein each is optionally substituted by one or more substituents, which are 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 11 COR 12 NR 10 C(O)NR 11 R 12 NR 11 SOR 12 NR 11 SO2R 12 Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, 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...

[0080] R 10 R 11 and R 12 Independently selected from empty, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0081] R 11 and R 12 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0082] In another implementation scheme,

[0083] Ar 2 Selected from C6-C10 Aryl and C5-C 10 Heteroaryl groups, wherein each is optionally substituted by one or more substituents, which are 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 11 COR 12 NR 10 C(O)NR 11 R 12 NR 11 SOR 12 NR 11 SO2R 12 Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, 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...

[0084] R 10 R 11 and R 12 Independently selected from empty, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0085] R 11 and R 12 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0086] In another implementation, R 3 -Ar 2 Selected from formulas B1 and B2:

[0087]

[0088] in

[0089] * indicates a connection to the linker portion of the divalent compound;

[0090] Y 1 Y 2 Y 3 and Y 4 Independently selected from CH and N, provided that Y 1 Y 2 Y 3 and Y 4 At most 3 of them are N;

[0091] Each R a Independently selected from hydrogen, halogen, CN, NO2, OR 12 SR 12 NR 13 R 14 COR 12 CO2R 12 CONR 13 R 14 SOR 12 SO2R 12 SO2NR 13 R 14 NR 13 COR 14 NR 15 C(O)NR 13 R 14 NR 13 SOR 14 NR 13 SO2R 14 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic group, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0092] R 12 R 13 R 14 and R 15 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0093] R13 and R 14 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings;

[0094] m is between 0 and 4; and

[0095] R 3 Same as defined in Equation 2.

[0096] In another implementation, R 3 -Ar 2 Selected from the portion of formula B3:

[0097]

[0098] in

[0099] * indicates a connection to the linker portion of the divalent compound;

[0100] Y 1 Y 2 Y 3 and Y 4 Independently selected from CR a N, O, and S, with the condition that Y 1 Y 2 Y 3 and Y 4 At most 3 of them are N;

[0101] Each R a Independently selected from hydrogen, halogen, CN, NO2, OR 12 SR 12 NR 13 R 14 COR 12 CO2R 12 CONR 13 R 14 SOR 12 SO2R 12 SO2NR 13 R 14 NR 13 COR 14 NR 15 C(O)NR 13 R 14 NR 13 SOR 14 NR 13 SO2R 14Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic group, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0102] R 12 R 13 R 14 and R 15 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0103] R 13 and R 14 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings;

[0104] m is between 0 and 4; and

[0105] R 3 Same as defined in Equation 2.

[0106] In another implementation, X 1 For N; X 2 For N; X 3 For C; X 4 C; X is CH2; Ar 1 It is 3-fluorophenyl; and Ar 2 It is 2-pyridyl.

[0107] In another embodiment, the TRK ligand comprises a portion of formula 3:

[0108]

[0109] in

[0110] X 1 X 2 X 3 and X 4 Independently selected from C, CR' and N (preferably, X) 1 and X 4 Independently selected from CR' and N;X 2and X 3 (Independently selected from C and N), where

[0111] R' is selected from hydrogen, halogen, CN, NO2 and optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic groups;

[0112] X is selected from empty, key, C(R) 2 )2、C(R 2 )2C(R 2 )2, CO, C(R) 2 )2CO、NR 2 CO, OC(R) 2 )2 and NR 2 C(R 2 )2;

[0113] R 1 and each R 2 Independently selected from hydrogen, halogen, OH, NH2, CN, NO2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 alkoxyalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkylaminoC1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclic groups; n is 1 to 4;

[0114] R 3 Selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-6 membered heterocyclic, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl and optionally substituted C1-C6 alkylaminoC1-C6 alkyl.

[0115] R 4 Directly or through R 5 The linker portion connected to the divalent compound, wherein R 4 and R 5 Independently selected from empty, OR 6 SR 6 NR 7 R 8 COR 6 CO2R 6 CONR 7 R 8 SOR 6 SO2R 6 SO2NR 7 R 8 NR 7COR 8 NR 9 C(O)NR 7 R 8 NR 7 SOR 8 NR 7 SO2R 8 Optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein...

[0116] R 6 R 7 R 8 and R 9 Independently selected from empty, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0117] R 7 and R 8 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings; Ar is selected from aryl and heteroaryl groups, each of which is optionally substituted by one or more substituents, which are independently selected from halogens, CN, NO2, OR 10 SR 10 NR 11 R 12 COR 10 CO2R 10 CONR 11 R 12 SOR 10 SO2R 10 SO2NR 11 R 12 NR 11 COR 12 NR 10 C(O)NR 11 R 12 NR 11 SOR 12 NR 11 SO2R 12Optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0118] R 10 R 11 and R 12 Independently selected from empty, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0119] R 11 and R 12 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0120] In one implementation, X 1 and X 4 It is selected from CR' and N, and R' is selected from hydrogen, F, Cl, CH3, CF3 and cyclopropyl.

[0121] In another implementation, X 2 and X 3 Selected independently from C and N.

[0122] In another embodiment, X is selected from bonds, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH and CH2NCH3.

[0123] In another implementation, R 1 and each R 2 Independently selected from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclic groups.

[0124] In another implementation, R 3 Selected from hydrogen, CH3, CH2CH3, propyl, isopropyl, cyclopropyl, CH2F, CHF2, and CF3.

[0125] In another implementation scheme,

[0126] R4 The linker portion is directly connected to the divalent compound, and

[0127] R 4 Select from empty, OR 6 SR 6 NR 7 R 8 COR 6 CO2R 6 CONR 7 R 8 SOR 6 SO2R 6 SO2NR 7 R 8 NR 7 COR 8 NR 9 C(O)NR 7 R 8 NR 7 SOR 8 NR 7 SO2R 8 Optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein...

[0128] R 6 R 7 R 8 and R 9 Independently selected from empty, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted arylalkyl, heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0129] R 7 and R 8 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0130] In another implementation scheme,

[0131] R 4 Through R 5 The linker portion connected to the divalent compound, and

[0132] R4 and R 5 Independently selected from empty, OR 6 SR 6 NR 7 R 8 COR 6 CO2R 6 CONR 7 R 8 SOR 6 SO2R 6 SO2NR 7 R 8 NR 7 COR 8 NR 9 C(O)NR 7 R 8 NR 7 SOR 8 NR 7 SO2R 8 Optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein...

[0133] R 6 R 7 R 8 and R 9 Independently selected from empty, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0134] R 7 and R 8 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0135] In another implementation scheme,

[0136] Ar is selected from aryl and heteroaryl groups, each of which is optionally substituted by one or more substituents, which are independently selected from F, Cl, CN, NO2, OR. 10 NR 11 R 12 COR 10CO2R 10 CONR 11 R 12 SOR 10 SO2R 10 SO2NR 11 R 12 NR 11 COR 12 NR 10 C(O)NR 11 R 12 NR 11 SOR 12 NR 11 SO2R 12 Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, 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...

[0137] R 10 R 11 and R 12 Independently selected from empty, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0138] R 11 and R 12 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0139] In another embodiment, the TRK ligand is derived from any of the following:

[0140]

[0141] In another embodiment, the TRK ligand is derived from the following TRK kinase inhibitors: DS-6051b, F 1775 2. PLX 748 6. AZD-6918, ASP7962, VM902A, PF- 062 73340 and ONO- 447 4.

[0142] In another embodiment, the TRK ligand is selected from:

[0143]

[0144] In some embodiments, the degradation label is selected from formulas 5A, 5B, 5C, and 5D:

[0145]

[0146] in

[0147] V, W, and X are independently selected from CR 2 and N;

[0148] Y is selected from CO and CR. 3 R 4 And N = N;

[0149] Z is selected from empty, CO, CR 5 R 6 NR 5 O, optional substitution of C1-C 10 Alkylene, optionally substituted C1-C 10 alkenyl, optionally substituted C1-C 10 Alynyl group, optionally substituted 3-10 membered carbocyclic group, optionally substituted 4-10 membered heterocyclic group, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from empty, CH2, CH=CH, C≡C, NH, and O;

[0150] R 1 and R 2 Independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbon cycloyl and optionally substituted 4- to 6-membered heterocyclic groups;

[0151] R 3 and R 4 Independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclic and optionally substituted 4- to 6-membered heterocyclic groups; or R 3 and R 4 Together with the atoms they are attached to, they form 3-6 membered carbon cyclic groups or 4-6 membered heterocyclic groups; and

[0152] R 5 and R 6Independently selected from empty, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbon cyclic group and optionally substituted 4- to 6-membered heterocyclic group; or R 5 and R 6 Together with the atoms they are attached to, they form 3-6 membered carbon cyclic groups or 4-6 membered heterocyclic groups.

[0153] In some embodiments, the degradation label is selected from formulas 5A, 5B, 5C, and 5D:

[0154]

[0155] in

[0156] V, W, and X are independently selected from CR 2 and N;

[0157] Y is selected from CO and CH2;

[0158] Z is selected from CH2, NH and O;

[0159] R 1 Selected from hydrogen, C1-C5 alkyl groups, and halogens; and

[0160] R 2 It is selected from hydrogen, halogens and C1-C5 alkyl groups.

[0161] In some embodiments, the degradation label is a part selected from formulas 5E, 5F, 5G, 5H, and 5I:

[0162]

[0163]

[0164] in

[0165] U, V, W, and X are independently selected from CR 2 and N;

[0166] Y is selected from CR 3 R 4 NR 3 And O; preferably, Y is selected from CH2, NH, NCH3 and O;

[0167] Z is selected from empty, CO, CR 5 R 6 NR 5 O, optional substitution of C1-C 10 Alkylene, optionally substituted C1-C 10 alkenyl, optionally substituted C1-C 10Alynyl group, optionally substituted 3-10 membered carbocyclic group, optionally substituted 4-10 membered heterocyclic group, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from empty, CH2, CH=CH, C≡C, NH, and O;

[0168] R 1 and R 2 Independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbon cycloyl and optionally substituted 4- to 6-membered heterocyclic groups;

[0169] R 3 and R 4 Independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclic and optionally substituted 4- to 6-membered heterocyclic groups; or R 3 and R 4 Together with the atoms they are attached to, they form 3-6 membered carbon cyclic groups or 4-6 membered heterocyclic groups; and

[0170] R 5 and R 6 Independently selected from empty, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbon cyclic group and optionally substituted 4- to 6-membered heterocyclic group; or R 5 and R 6 Together with the atoms they are attached to, they form 3-6 membered carbon cyclic groups or 4-6 membered heterocyclic groups.

[0171] In one implementation, the degradation label is a part of Formula 6A:

[0172]

[0173] in

[0174] R 1 and R 2Independently selected from hydrogen, optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; and

[0175] R 3 Hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)C3-C7 cycloalkyl, optionally substituted C(O)(3- 7-membered heterocyclic group), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)OC3-C7 cycloalkyl, optionally substituted C(O)O (3-7 membered heterocyclic), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally Optionally substituted C(O)NC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)NC3-C7 cycloalkyl, optionally substituted C(O)N (3-7 membered heterocyclic), 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.

[0176] In one embodiment, the degradation label is a portion selected from formulas 6B, 6C, 6D, 6E, and 6F:

[0177]

[0178]

[0179] in

[0180] R 1 and R 2 Independently selected from hydrogen, halogen, OH, NH2, CN, optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; (preferably, R 1 Selected from isopropyl or tert-butyl; and R 2 Selected from hydrogen or methyl);

[0181] R 3 Hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)C3-C7 cycloalkyl, optionally substituted C(O)(3- 7-membered heterocyclic group), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)OC3-C7 cycloalkyl, optionally substituted C(O)O (3-7 membered heterocyclic), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally The optional substituted C(O)NC1-C8 alkylamino C1-C8 alkyl, the optional substituted C(O)NC3-C7 cycloalkyl, the optional substituted C(O)N (3-7 membered heterocyclic), the optional substituted C(O)NC2-C8 alkenyl, the optional substituted C(O)NC2-C8 alkynyl, the optional substituted P(O)(OH)2, the optional substituted P(O)(OC1-C8 alkyl)2, and the optional substituted P(O)(OC1-C8 aryl)2; and

[0182] R 4 and R5 Independently selected from hydrogen, COR 6 CO2R 6 CONR 6 R 7 SOR 6 SO2R 6 SO2NR 6 R 7 Optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy C1-C8 alkyl groups, optionally substituted C1-C8 alkylamino C1-C8 alkyl groups, optionally substituted 3-8 membered cycloalkyl groups, optionally substituted 3-8 membered heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, wherein...

[0183] R 6 and R 7 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0184] R 4 and R 5 ;R 6 and R 7 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings;

[0185] Ar is selected from aryl and heteroaryl groups, each of which is optionally substituted by one or more substituents, which are independently selected from F, Cl, CN, NO2, OR. 8 NR 8 R 9 COR 8 CO2R 8 CONR 8 R 9 SOR 8 SO2R 8 SO2NR 9 R 10 NR 9 COR 10 NR 8 C(O)NR 9 R 10 NR 9 SOR 10 NR 9 SO2R 10Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, 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...

[0186] R 8 R 9 and R 10 Independently selected from empty, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0187] R 8 and R 9 ;R 9 and R 10 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0188] In another embodiment, the degradation label is a part of Formula 7A:

[0189]

[0190] in

[0191] V, W, X, and Z are independently selected from CR 4 and N.

[0192] R 1 R 2 R 3 and R 4 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl.

[0193] In another embodiment, the degradation label is a part of Formula 7B:

[0194]

[0195] in

[0196] R 1 R 2 and R 3Independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl;

[0197] R 4 and R 5 Independently selected from hydrogen, COR 6 CO2R 6 CONR 6 R 7 SOR 6 SO2R 6 SO2NR 6 R 7 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted aryl-C1-C8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0198] R 6 and R 7 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, or

[0199] R 6 and R 7 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0200] In another embodiment, the degradation label is derived from any of the following:

[0201]

[0202] In another embodiment, the degradation label is selected from:

[0203]

[0204]

[0205] In some embodiments, the connector portion is the connector portion of Formula 9:

[0206]

[0207] in

[0208] A, W, and B are independently selected from either the empty or divalent portion each time they appear, and the divalent portion is selected from R'-R", R'COR", R'CO2R", and R'C(O)N(R). 1 )R”、R'C(S)N(R 1 )R", R'OR", R'OC(O)R", R'OC(O)OR", R'OCON(R 1 )R", R'SR", R'SOR", R'SO2R", R'SO2N(R 1 )R”、R'N(R 1 )R”、R'NR 1 COR”, R'NR 1 C(O)OR”、R'NR 1 CON(R 2 )R”、R'NR 1 C(S)R”、R'NR 1 S(O)R”、R'NR 1 S(O)2R” and R'NR 1 S(O)2N(R 2 )R", where

[0209] R' and R" are independently selected from empty, arbitrarily substituted R. r -(C1-C8 alkyl) or a portion containing the following groups: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10-membered carbocyclic group, optionally substituted 4-10-membered heterocyclic group, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0210] R r Selected from optionally substituted 3-10 membered carbocyclic groups, optionally substituted 4-10 membered heterocyclic groups, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0211] R 1 and R 2 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 4-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;

[0212] R' and R”, R 1 and R 2 , R' and R 1 , R' and R 2 "R" and R 1 "R" and R 2 Together with the atoms they are attached to, they form 3-20 membered cycloalkyl or 4-20 membered heterocyclic rings; and

[0213] m ranges from 0 to 15.

[0214] In one embodiment, the connector portion is the connector portion of Formula 9:

[0215]

[0216] in

[0217] A, W, and B are independently selected from empty, CO, CO2, and C(O)NR each time they appear. 1 C(S)NR 1 O, S, SO, SO2, SO2NR 1 NR 1 NR 1 CO, NR 1 CONR 2 NR 1C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl and optionally substituted C3-C 13 Spiroherocyclic groups, in which

[0218] R 1 and R 2 Independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino, and optionally substituted C1-C6 alkylaminoC1-C6 alkyl; and

[0219] m ranges from 0 to 15.

[0220] In one embodiment, the connector portion is the connector portion of Formula 9A:

[0221]

[0222] in

[0223] R 1 R 2 R 3 and R 4Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino and optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-8-membered cycloalkoxy, optionally substituted 3-10-membered carbocyclic amino, optionally substituted 4-8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, or

[0224] R 1 and R 2 R 3 and R 4 Together with the atoms they are attached to, they form 3-20 membered cycloalkyl or 4-20 membered heterocyclic rings;

[0225] A, W, and B are independently selected from either the empty or divalent portion each time they appear, and the divalent portion is selected from R'-R", R'COR", R'CO2R", and R'C(O)N(R). 5 )R”、R'C(S)N(R 5 )R", R'OR", R'OC(O)R", R'OC(O)OR", R'OCONR 5 R", R'SR", R'SOR", R'SO2R", R'SO2N(R 5 )R”、R'N(R 5 )R”、R'NR 5 COR”, R'NR 5 C(O)OR”、R'NR 5 CON(R 6 )R”、R'NR 5 C(S)R”、R'NR 5 S(O)R”、R'NR 5 S(O)2R” and R'NR 5 S(O)2N(R 6 )R", where

[0226] R' and R" are independently selected from empty, arbitrarily substituted R. r-(C1-C8 alkyl) or a portion containing the following groups: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10-membered carbocyclic group, optionally substituted 4-10-membered heterocyclic group, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0227] R r Selected from optionally substituted 3-10 membered carbocyclic groups, optionally substituted 4-10 membered heterocyclic groups, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0228] R 5 and R 6 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 4-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;

[0229] R' and R”, R 5 and R 6 , R' and R5 , R' and R 6 "R" and R 5 "R" and R 6 Together with the atoms they are attached to, they form 3-20 membered cycloalkyl or 4-20 membered heterocyclic rings;

[0230] m is between 0 and 15;

[0231] n is between 0 and 15 each time it appears; and

[0232] o ranges from 0 to 15.

[0233] In one embodiment, the connector portion is a connector portion of type 9A.

[0234]

[0235] in

[0236] R 1 R 2 R 3 and R 4 Each time it appears, it is independently selected from hydrogen, halogen, CN, OH, NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic group, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino and optionally substituted C1-C6 alkylaminoC1-C6 alkyl;

[0237] A, W, and B are independently selected from empty, CO, CO2, and C(O)NR each time they appear. 5 C(S)NR 5 O, S, SO, SO2, SO2NR 5 NR 5 NR 5 CO, NR 5 CONR 6 NR 5 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl and optionally substituted C3-C 13 Spiroherocyclic groups, in which

[0238] R 5 and R 6 Independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted C3-

[0239] C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino and optionally substituted C1-C6 alkylaminoC1-C6 alkyl;

[0240] m is between 0 and 15;

[0241] Each n is between 0 and 15; and

[0242] o ranges from 0 to 15.

[0243] In another embodiment, the connector portion is a Type 9B connector portion:

[0244]

[0245] in

[0246] R 1 and R 2 Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, 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 alkylamino-C1-C8 alkyl, optionally substituted 3-10 membered carbocyclic, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclic amino, optionally substituted 4-10 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0247] R 1 and R 2 Together with the atoms they are attached to, they form 3-20 membered cycloalkyl or 4-20 membered heterocyclic rings;

[0248] A and B are independently selected from either the empty or divalent portion each time they appear, and the divalent portion is selected from R'-R”, R'COR”, R'CO2R”, R'C(O)NR”. 3 R”、R'C(S)NR 3 R", R'OR", R'OC(O)R", R'OC(O)OR", R'OCON(R 3 )R", R'SR", R'SOR", R'SO2R", R'SO2N(R 3 )R”、R'N(R 3 )R”、R'NR 3 COR”, R'NR 3 C(O)OR”、R'NR 3 CON(R 4 )R'、R'NR 3 C(S)R”、R'NR 3 S(O)R”、R'NR 3 S(O)2R” and R'NR 3 S(O)2N(R 4 )R", where

[0249] R' and R" are independently selected from empty, arbitrarily substituted R. r -(C1-C8 alkyl) or a portion containing the following groups: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10-membered carbocyclic group, optionally substituted 4-10-membered heterocyclic group, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0250] R rSelected from optionally substituted 3-10 membered carbocyclic groups, optionally substituted 4-10 membered heterocyclic groups, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0251] R 3 and R 4 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 4-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;

[0252] R' and R”, R 3 and R 4 , R' and R 3 , R' and R 4 "R" and R 3 "R" and R 4 Together with the atoms they are attached to, they form 3-20 membered cycloalkyl or 4-20 membered heterocyclic rings;

[0253] Each m is between 0 and 15; and

[0254] n is between 0 and 15.

[0255] In another embodiment, the connector portion is the connector portion of Formula 9B.

[0256]

[0257] in,

[0258] Each R 1 and each R 2Independently selected from hydrogen, halogen, CN, OH, NH2 and optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino or C1-C6 alkylaminoC1-C6 alkyl;

[0259] Each A and each B are independently selected from empty, CO, CO2, C(O)NR 3 C(S)NR 3 O, S, SO, SO2, SO2NR 3 NR 3 NR 3 CO, NR 3 CONR 4 NR 3 C(S) and optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl or C3-C 13 Spiroherocyclic groups, in which

[0260] R 3 and R 4 Independently selected from hydrogen and optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino or C1-C6 alkylaminoC1-C6 alkyl;

[0261] Each m is between 0 and 15; and

[0262] n is between 0 and 15.

[0263] In another implementation, in Equation 9B, m is 1 to 15.

[0264] In another implementation, n is 1 in Equation 9B.

[0265] In another implementation, in formula 9B, R 1 and R 2 Independently selected from hydrogen and optionally substituted C1-C8 alkyl groups.

[0266] In another embodiment, the connector portion is the connector portion of Formula 9C:

[0267]

[0268] in

[0269] X is selected from O, NH, and NR. 7 ;

[0270] R 1 R 2 R 3 R 4 R 5 and R 6 Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-8-membered cycloalkoxy, optionally substituted 4-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.

[0271] A and B are independently selected from empty or divalent portions, wherein the divalent portion is selected from R'-R”, R'COR”, R'CO2R”, R'C(O)N(R) 8 )R”、R'C(S)N(R 8 )R", R'OR", R'OC(O)R", R'OC(O)OR", R'OCON(R 8 )R", R'SR", R'SOR", R'SO2R", R'SO2N(R 8 )R”、R'N(R 8 )R”、R'NR 8 COR”, R'NR 8 C(O)OR”、R'NR 8 CON(R 9)R”、R'NR 8 C(S)R”、R'NR 8 S(O)R”、R'NR 8 S(O)2R” and R'NR 8 S(O)2N(R 9 )R", where

[0272] R' and R" are independently selected from empty, arbitrarily substituted R. r -(C1-C8 alkyl) or a portion containing the following groups: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10-membered carbocyclic group, optionally substituted 4-10-membered heterocyclic group, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0273] R r Selected from optionally substituted 3-10 membered carbocyclic groups, optionally substituted 4-10 membered heterocyclic groups, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0274] R 7 R 8 and R 9Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 4-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;

[0275] R' and R”, R 8 and R 9 , R' and R 8 , R' and R 9 "R" and R 8 "R" and R 9 Together with the atoms they are attached to, they form 3-20 membered cycloalkyl or 4-20 membered heterocyclic rings;

[0276] m ranges from 0 to 15 each time it appears;

[0277] n is between 0 and 15 each time it appears;

[0278] o is between 0 and 15; and

[0279] p ranges from 0 to 15.

[0280] In another embodiment, the connector portion is a connector portion of type 9C.

[0281]

[0282] in,

[0283] X is selected from O, NH, and NR. 7 ;

[0284] R 1 R 2 R 3 R 4 R 5 and R 6 Each time it appears, it is independently selected from hydrogen, halogen, CN, OH, NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic group, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino and optionally substituted C1-C6 alkylaminoC1-C6 alkyl;

[0285] A and B are independently selected from empty, CO, CO2, and C(O)NR each time they appear. 7C(S)NR 7 O, S, SO, SO2, SO2NR 7 NR 7 NR 7 CO, NR 7 CONR 8 NR 7 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl and optionally substituted C3-C 13 Spiroherocyclic groups, in which

[0286] R 7 and R 8 Independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino and optionally substituted C1-C6 alkylaminoC1-C6 alkyl;

[0287] Each m ranges from 0 to 15;

[0288] Each n is between 0 and 15;

[0289] o is between 0 and 15; and

[0290] p ranges from 0 to 15.

[0291] In one implementation, in Equation 9C, m and n are 1, and p is 1 to 15;

[0292] In one implementation, in formula 9C, X is selected from O and NH;

[0293] In one implementation, in formula 9C, R 1 R 2 R3 R 4 R 5 and R 6 Independently selected from hydrogen, or optionally substituted C1-C6 alkyl groups.

[0294] In another embodiment, the connector portion includes a ring selected from 3- to 13-membered rings, 3- to 13-membered fused rings, 3- to 13-membered bridge rings, and 3- to 13-membered spiral rings.

[0295] In another embodiment, the connector portion includes a ring selected from formulas C1, C2, C3, C4, and C5:

[0296]

[0297] In one implementation, A, B, and W are independently selected from empty, CO, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH2-NH-CH2-NH-CO, NH-CO-CH2-NH-CH2, CO-NH-CH2-NH-CH2, CH2-NH-CH2, R, each time they appear. r -CO、R r -NH、R r -NH-CO, R r -CO-NH,R r -CH2-NH-CO, R r -CH2-CO-NH, R r -NH-CO-CH2, R r -CO-NH-CH2, R r -CH2-NH-CH2-CO-NH, R r -CH2-NH-CH2-NH-CO, R r -NH-CO-CH2-NH-CH2, R r -CO-NH-CH2-NH-CH2, R r -CH2-NH-CH2.

[0298] In one implementation, R r It can be C1, C2, C3, C4 or C5.

[0299] In one implementation, R r Selected from

[0300] In another embodiment, the length of the linker is 0 to 40 straight-chain atoms.

[0301] In another embodiment, the length of the linker is 0 to 20 straight-chain atoms.

[0302] In another embodiment, the length of the connector is 0 to 8 straight-chain atoms.

[0303] In another embodiment, the connector is selected from -(CO)-(CH2). 1-8 -、-(CH2) 1-9 -、-(CH2) 1-2 -(CO)-NH-(CH2) 2-9 -、-(CH2) 1-2 -(CO)-NH-(CH2) 1-3 -(OCH2CH2) 1-7 -、-(CH2) 0-1 -(CO)-(CH2) 1-3 -(OCH2CH2) 1-7 -、-(CO)-(CH2) 0-3 -(alkenyl)-(CH2) 0-3 -、-(CO)-(CH2) 0-3 -(ethynyl)-(CH2) 0-3 -、-(CO)-(CH2) 0-3 -(3-8 membered carbon cycloyl)-(CH2) 0-3 -、-(CO)-(CH2) 0-3 -(3-8 membered heterocyclic carbonyl group)-(CH2) 0-3 -、-(CH2) 0-3 -(alkenyl)-(CH2) 0-3 -、-(CH2) 0-3 -(ethynyl)-(CH2) 0-3 -、-(CH2) 0-3 -(3-8 membered carbon cycloyl)-(CH2) 0-3 - and -(CH2) 0-3 -(3-8 membered heterocyclic carbonyl group)-(CH2) 0-3 -;

[0304] R r -(CO)-(CH2) 1-8 -、R r -(CH2) 1-9 -、R r -(CH2) 1-2 -(CO)-NH-(CH2) 2-9 -、R r -(CH2) 1-2 -(CO)-NH-(CH2) 1-3 -(OCH2CH2)1-7 -、R r -(CH2) 0-1 -(CO)-(CH2) 1-3 -(OCH2CH2) 1-7 -、R r -(CO)-(CH2) 0-3 -(alkenyl)-(CH2) 0-3 -、R r -(CO)-(CH2) 0-3 -(ethynyl)-(CH2) 0-3 -、R r -(CO)-(CH2) 0-3 -(3-8 membered carbon cycloyl)-(CH2) 0-3 -、R r -(CO)-(CH2) 0-3 -(3-8 membered heterocyclic carbonyl group)-(CH2) 0-3 -、R r -(CH2) 0-3 -(alkenyl)-(CH2) 0-3 -、R r -(CH2) 0-3 -(ethynyl)-(CH2) 0-3 -、R r -(CH2) 0-3 -(3-8 membered carbon cycloyl)-(CH2) 0-3 -and R r -(CH2) 0-3 -(3-8 membered heterocyclic carbonyl group)-(CH2) 0-3 -

[0305] In some embodiments, the divalent compound is selected from CPD-001 to CPD-206, or a pharmaceutically acceptable salt or analogue thereof.

[0306] In some embodiments, the divalent compound is selected from CPD-009, CPD-010, CPD-013, CPD-014, CPD-015, CPD-021, CPD-022, CPD-023, CPD-024, CPD-025, CPD-026, CPD-027, CPD-028, CPD-029, CPD-030, CPD-031, and CPD-03. 2. 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, and pharmaceutically acceptable salts or analogs thereof.

[0307] In some embodiments, the divalent compound is selected from 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... 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-184, TR-186, TR-189, TR-190, TR-191, TR-194, TR-196, TR-198, and their pharmaceutically acceptable salts or analogues.

[0308] In some embodiments, the divalent compound is selected from TR-106, TR-108, TR-109, TR-113, TR-115, TR-116, TR-117, TR-119, TR-121, TR-122, TR-123, TR-124, TR-125, TR-127, TR-128, TR-129, TR-130, TR-131, TR-132, TR-135, TR-137, TR-140, TR-141, TR-142, TR-143, TR-144, and TR-14. 5. 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-186, TR-189, TR-190, TR-191, TR-194, TR-196, TR-198, and their pharmaceutically acceptable salts or analogues.

[0309] In some embodiments, the divalent compound is selected from TR-123, TR-172, TR-173, TR-181, TR-185, TR-186, TR-191, TR-196, TR-198, and pharmaceutically acceptable salts or analogs thereof.

[0310] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-4-((7-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-7-oxohepyl)amino)isoindoline-1,3-dione (CPD-009).

[0311] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione (CPD-010).

[0312] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-4-((4-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4-oxobutyl)amino)isoindoline-1,3-dione (CPD-013).

[0313] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-4-((5-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione (CPD-014).

[0314] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-4-((5-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione (CPD-015).

[0315] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-4-((15-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecanyl)amino)isoindoline-1,3-dione (CPD-021).

[0316] In some embodiments, the divalent compound is (2S,4R)-1-((S)-2-(11-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-11-oxoundecanoamide)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-022).

[0317] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-4-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione (CPD-023).

[0318] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-4-((8-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-8-oxooctyl)amino)isoindoline-1,3-dione (CPD-024).

[0319] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-4-((18-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentoxaoctadecyl)amino)isoindoline-1,3-dione (CPD-025).

[0320] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-4-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione (CPD-026).

[0321] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-4-((2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)isoindoline-1,3-dione (CPD-027).

[0322] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione (CPD-028).

[0323] In some embodiments, the divalent compound is (2S,4R)-1-((S)-2-(8-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-8-oxooctamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-029).

[0324] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazole-3-yl)-4-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)propionyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-030).

[0325] 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-dioxoisoindoline-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-acyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-031).

[0326] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazole-3-yl)-4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)ethoxy)propionyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-032).

[0327] In some embodiments, the divalent compound is (2S,4R)-1-((S)-2-(8-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazole-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-8-oxooctamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-033).

[0328] In some embodiments, the divalent compound is (2S,4R)-1-((S)-2-(6-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazole-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-6-oxohexamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-044).

[0329] In some embodiments, the divalent compound is (2S,4R)-1-((S)-2-(7-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazole-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-7-oxoheptamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-047).

[0330] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazole-3-yl)-4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)heptanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-049).

[0331] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazole-3-yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)valeryl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-050).

[0332] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazole-3-yl)-4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propionyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-051).

[0333] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazole-3-yl)-4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)octanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-052).

[0334] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazole-3-yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyryl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-053).

[0335] 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-dioxoisoindoline-4-yl)amino)-3,6,9,12,15-pentaoctadecane-18-acyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-054).

[0336] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazole-3-yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)glycyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-055).

[0337] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazole-3-yl)-4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-056).

[0338] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazole-3-yl)-4-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)ethoxy)ethoxy)propionyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-057).

[0339] In some embodiments, the divalent compound is N-(2-(2-(2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)ethoxy)-ethoxy)ethyl)-2-(4-(6-(6-(((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (CPD-059).

[0340] In some embodiments, the divalent compound is N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethyl)-2-(4-(6-(6-(((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (CPD-060).

[0341] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazole-3-yl)-4-(4-(2-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-062).

[0342] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)-2-oxo-6,9,12-trioxa-3-azatetradecyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-064).

[0343] In some embodiments, the divalent compound is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)-2-oxo-6,9,12,15,18-penta-3-azaeicosyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-065).

[0344] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione (TR-123).

[0345] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)isoindoline-1,3-dione (TR-172).

[0346] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)isoindoline-1,3-dione (TR-173).

[0347] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)isoindoline-1,3-dione (TR-181).

[0348] In some embodiments, the divalent compound is 3-(6-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (TR-185).

[0349] In some embodiments, the divalent compound is 3-(5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (TR-186).

[0350] In some embodiments, the divalent compound is 3-(5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (TR-191).

[0351] In some embodiments, the divalent compound is 3-(6-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (TR-196).

[0352] In some embodiments, the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-(((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)isoindoline-1,3-dione (TR-198).

[0353] According to one aspect of this disclosure, the compositions disclosed herein comprise the divalent compound or a pharmaceutically acceptable salt or analogue thereof.

[0354] According to one aspect of this disclosure, the method of treating tropomyosin receptor kinase (TRK)-mediated diseases disclosed herein includes administering the divalent compound or a pharmaceutically acceptable salt or analogue thereof to a subject suffering from a TRK-mediated disease.

[0355] In one implementation, the TRK-mediated disease is caused by TRK expression, mutation, or fusion.

[0356] In one implementation, the TRK function of the subject suffering from the TRK-mediated disease is elevated relative to that of a healthy subject not suffering from the TRK-mediated disease.

[0357] In one embodiment, the divalent compound is selected from CPD-001 to CPD-206, or the like.

[0358] In one embodiment, the divalent compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally. In one embodiment, the method further includes administering an additional treatment regimen for cancer treatment to the subject.

[0359] In one implementation, the additional treatment options are selected from surgery, chemotherapy, radiotherapy, hormone therapy, and immunotherapy.

[0360] In one implementation, the TRK-mediated diseases are selected from non-small cell lung cancer, colorectal cancer, gastric cancer, liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, bladder cancer, endometrial cancer, prostate cancer, low-grade glioma, glioblastoma, spitzoid carcinoma, soft tissue sarcoma, papillary thyroid carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesodermal nephroma, secretory breast cancer, breast analog secretory carcinoma, acute myeloid leukemia, ductal carcinoma, pulmonary neuroendocrine tumor, pheochromocytoma, and Wilms' tumor.

[0361] In one implementation, the TRK-mediated diseases or conditions include cancer, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, and other diseases, including but not limited to neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric cancer, lung cancer, liver cancer, uterine cancer, adrenal cancer, biliary tract cancer, colorectal cancer, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, breast cancer, esophageal cancer, bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secretory breast cancer, secretory type breast cancer, salivary gland cancer, papillary thyroid carcinoma, ductal carcinoma, and adult myeloid leukemia. Diseases, acute myeloid leukemia, large cell neuroendocrine tumors, pulmonary neuroendocrine tumors, sarcomas, pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenital mesodermal nephroma, secretory breast cancer, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system vegetations, osteosarcoma, synovial sarcoma, liposarcoma, soft tissue alveolar sarcoma, Spitzoid carcinoma, Wilms' tumor, lymphomas (e.g., including Hodgkin's lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma), inflammation Inflammatory lung diseases (e.g., asthma), inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's disease), inflammatory skin diseases (e.g., atopic dermatitis, eczema, and psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, osteoarthritis pain, chronic low back pain, osteoporotic low back pain, fracture pain, rheumatoid arthritis pain, postherpetic neuralgia, diabetic neuropathy pain, fibromyalgia, pancreatitis pain, interstitial cystitis pain, endometriosis pain, irritable bowel syndrome pain, migraine, pulpitis pain, interstitial cystitis pain, bladder pain syndrome, central pain syndrome, postoperative pain syndrome, bone And joint pain, recurrent motion pain, toothache, myofascial pain, perioperative pain, dysmenorrhea, myofascial pain, angina pectoris, headache, primary hyperalgesia, secondary hyperalgesia, primary anomalous pain, secondary anomalous pain, other pain caused by central sensitization, generalized pruritus, localized pruritus, senile pruritus, pruritus gravidarum, anal pruritus, vulvar pruritus, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic disease, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelinating diseases, and myelination disorders. In some embodiments, the disease or condition is a relapsing disease.

[0362] In one implementation, the TRK-mediated disease is recurrent cancer.

[0363] In one implementation, the TRK-mediated disease is refractory to one or more prior treatments.

[0364] According to one aspect of this disclosure, a method for identifying divalent compounds that mediate TRK degradation or reduction is disclosed. The method includes:

[0365] Provide heterobifunctional test compounds containing TRK ligands conjugated to degradation tags via linkers;

[0366] The heterobifunctional test compound is brought into contact with cells containing ubiquitin ligase and TRK;

[0367] Determine whether TRK levels in the cells are decreased; and

[0368] The heterobifunctional test compounds were identified as divalent compounds that mediate TRK degradation or reduction.

[0369] In one implementation, the cell is a cancer cell.

[0370] In one implementation, the cancer cells are TRK-mediated cancer cells.

[0371] Incorporated by reference

[0372] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually cited and incorporated herein by reference. Attached Figure Description

[0373] The novel features of the invention are specifically set forth in the appended claims. A better understanding of the features and advantages of the invention will be gained by referring to the following detailed description of illustrative embodiments utilizing the principles of the invention, along with the accompanying drawings, in which:

[0374] Figure 1 A shows an immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with entrectinib or the divalent compounds CPD-001–CPD-022.

[0375] Figure 1 B shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with entrectinib or the divalent compound CPD-023–CPD-044.

[0376] Figure 1C shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with entrectinib or the divalent compounds CPD-045–CPD-065.

[0377] Figure 2 The immunoblots show the expression of TPM3-TRKA fusion protein in KM12 cells at different time points after treatment with entrectinib or the divalent compounds CPD-027, CPD-053, and CPD-060.

[0378] Figure 3 Immunoblots show the expression of TPM3-TRKA fusion protein in KM12 cells from subcutaneous xenograft tumors after treatment with CPD-027, CPD-053, and CPD-060 at specific dose ranges.

[0379] Figure 4 Figure A shows the relationship between KM12 cell viability and the concentrations of divalent compounds CPD-010, CPD-053, and CPD-057.

[0380] Figure 4 B shows the cell viability of KM12 and H358 cells in relation to the concentration of the divalent compound CPD-053.

[0381] Figure 5 A shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with GNF-8625, LOXO101, or the divalent compound TR-104–TR-129.

[0382] Figure 5 B shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of TR-115, TR-116, TR-119, TR-123, TR-124, TR-127, or TR-129.

[0383] Figure 5 C shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of TR-130, TR-131, TR-132, TR-140, TR-146, TR-150 or TR-168.

[0384] Figure 6 A shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of TR-171, TR-172, TR-173, or TR-176.

[0385] Figure 6B shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-177, TR-181, TR-182, or GNF-8625.

[0386] Figure 6 C shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of TR-186, TR-188, TR-189, or TR-190.

[0387] Figure 6 D shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-191, TR-194, TR-196, TR198, or GNF-8625.

[0388] Figure 7 The immunoblot shows the TPM3-TRKA, AGBL4-TRKB, and ETV6-TRKC fusion proteins overexpressed in KM12 cells after treatment with TR-123 at a certain dose range.

[0389] Figure 8 A shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of the compound TR-123 or TR-123-neg (TR-123-neg).

[0390] Figure 8 B shows the immunoblot of wild-type TRKA protein expressed in HEL cells after treatment with a specific dose range of the compound TR-123 or TR-123-neg.

[0391] Figure 9 A shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a single dose of TR-123 or in combination with MG-132, bortezomib, or MLN4924.

[0392] Figure 9 B shows the immunoblot of wild-type TRKA protein expressed in HEL cells after treatment with a single dose of TR-123 or in combination with MG-132, bortezomib, MLN4924 or pomalidomide.

[0393] Figure 10 A shows the immunoblot of the TPM3-TRKA fusion protein in subcutaneous KM12 xenograft tumors after treatment with a range of TR-123 doses.

[0394] Figure 10B shows the immunoblot of TPM3-TRKA fusion protein expressed in subcutaneous KM12 xenograft tumors after treatment with TR-171, TR-172, TR-173, TR-177, or TR-181.

[0395] Figure 11 The graph shows the relationship between plasma concentration of TR-123 and time points after administration.

[0396] Figure 12 A shows the relationship between the volume of a subcutaneous KM12 xenograft tumor and the number of days after treatment with a certain dose range of CPD-060.

[0397] Figure 12 B shows a graph depicting the relationship between body weight and the number of days following treatment with a given dose range of CPD-060.

[0398] Figure 13 A shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of TR-202, TR-203, or TR-204.

[0399] Figure 13 B shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of TR-208, TR-210, TR-211, or TR-214.

[0400] Figure 13 C shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-215, TR216, TR-217, TR218, TR-219, or TR-220.

[0401] Figure 13 D shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of doses of TR-221, TR-222, TR-223, TR-224, TR-225, TR-226, or TR-227.

[0402] Figure 13 E shows the immunoblot of TPM3-TRKA fusion protein expressed in KM12 cells after treatment with a range of TR-231, TR-232, TR-233, TR-234, or TR-235.

[0403] Figure 14 The graph shows the change in plasma concentration of TR-198 over time after administration via intravenous injection or oral feeding.

[0404] Figure 15A graph shows the change in subcutaneous KM12 xenograft tumor volume over the number of days following treatment with a range of TR-181 doses or a single dose of TR-198.

[0405] Figure 15 B shows a graph illustrating the change in body weight over the number of days following treatment with a range of TR-181 doses or a single dose of TR-198.

[0406] Figure 16 A shows a graph illustrating the percentage of body weight borne by the injured limb after treatment with a single dose of the mediator (Veh), TR-181, or ibuprofen (Ibu) in rats.

[0407] Figure 16 B shows a graph illustrating the percentage of body weight borne by the injured limb after treatment with a single dose of TR-181 or ibuprofen (Ibu) in guinea pigs. Detailed Implementation

[0408] This disclosure recognizes that the tropomyosin receptor kinase (TRK) receptor family comprises three members: TRKA, TRKB, and TRKC, encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. TRKs are receptor tyrosine kinases primarily involved in the development and function of neuronal tissues. Major ligands for TRKs include nerve growth factor (NGF) for TRKA, brain-derived growth factor (BDGF) for TRKB, and neurotrophic protein for TRKC (Vaishnavi et al., 2015). Ligand binding to the extracellular domain of TRK induces receptor dimerization and activation, thereby activating downstream signal transduction pathways such as the PI3K / AKT, RAF / MEK / ERK, and PLCγ pathways. These pathways have well-established roles in supporting cell proliferation, survival, and promoting tumorigenesis (Hanahan and Weinberg, 2011).

[0409] This further reveals that, like many other oncogenic receptor tyrosine kinases, TRK is aberrantly activated in a variety of human malignancies. Interestingly, the primary molecular mechanism for TRK activation in cancer is not point mutation, but rather fusion of the NTRK gene's reading frame (FFF) (Vaishnavi et al., 2015). Typically, the 3' region of the NTRK gene binds to the 5' region of the chaperone gene due to chromosomal rearrangement. The resulting chimeric protein consistently retains the kinase domain of the TRK protein, indicating that catalytic function is crucial for transformative activity. Deletion of the 5' region encoding the self-repressive domain in the NTRK gene endows these fusion kinases with constitutive activity. Furthermore, the expression of the chimeric protein is driven by the promoter of the fusion chaperone, often leading to overexpression. The most common TRK fusions include LMNA-TRKA, TPM3-TRKA, and ETV6-TRKC (Amatu et al., 2016). Thus, genetic events lead to the overexpression and constitutive activity of TRK fusion kinases. These fusions are carcinogenic, as demonstrated by their ability to transform mouse embryonic fibroblasts and normal epithelium (Russell et al., 2000; Vaishnavi et al., 2015).

[0410] TRK fusions were first reported in human colon cancer and were then named oncD (Martin-Zanca et al., 1986). Recent advances in high-throughput RNA sequencing have greatly improved the efficiency of identifying chromosomal rearrangement events in patient samples. Therefore, TRK fusions have been found in a wide variety of human malignancies, including but not limited to non-small cell lung cancer, colorectal cancer, gastric cancer, low-grade glioma, glioblastoma, spitzoid carcinoma, soft tissue sarcoma, papillary thyroid carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesodermal nephroma, secretory breast cancer, breast analogue secretory carcinoma, acute myeloid leukemia, and ductal carcinoma (Amatu et al., 2016; Khotskaya et al., 2017). The frequency of TRK fusions is relatively low. For example, approximately 0.5% to 2.7% of colon cancers are affected by TRK fusions (Creancier et al., 2015; Lee et al., 2015). However, TRK fusions are seen in the vast majority of cases in certain cancer types, such as secretory breast cancer (Tognon et al., 2002).

[0411] TRK mutations and deletions have been observed in other human diseases such as pulmonary neuroendocrine tumors, anhidrosis, obesity, congenital heart defects, and acute myeloid leukemia (Khotskaya et al., 2017). Furthermore, TRK amplification is associated with several human diseases, including liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, bladder cancer, endometrial cancer, pheochromocytoma, Wilms' tumor, and prostate cancer (Khotskaya et al., 2017).

[0412] The role of nerve growth factor (NGF) and its main receptor, tropomyosin receptor kinase A (TRKA), in central and peripheral pain has long been recognized (Denk et al., 2017). Nociceptive neurons express TRKA and mediate pain perception by transmitting pain signals to the central nervous system. Various NGF neutralizing antibodies, such as tanezumab, are being clinically evaluated in patients with osteoarthritis, low back pain, cancer pain, neuropathic pain, and other pain conditions (Miller et al., 2017). The efficacy of NGF antibodies in relieving pain has been clinically established. However, administration of NGF neutralizing antibodies has been shown to lead to rapidly progressive joint destruction in some patients, resulting in total joint replacement (Schnitzer and Marks, 2015). These adverse events may be associated with continued exposure to NGF antibodies. Targeting TRK represents another promising therapeutic strategy that blocks the NGF / TRK signaling pathway used for pain management. However, currently available pan-TRK kinase inhibitors may cause significant on-target adverse effects by modulating TRK family members in the central nervous system. Peripherally localized bifunctional TRK degradators are expected to selectively block the NGF / TRK pathway in peripheral nerves while preserving these targets in the central nervous system.

[0413] TRK is associated with the following diseases: cancer, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, and other diseases, including but not limited to neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric cancer, lung cancer, liver cancer, uterine cancer, adrenal cancer, biliary tract cancer, colorectal cancer, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, breast cancer, esophageal cancer, bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secretory breast cancer, salivary gland cancer, papillary thyroid carcinoma, ductal carcinoma, acute myeloid leukemia, and large cell neuroendocrine tumors. Pulmonary neuroendocrine tumors, sarcomas, pheochromocytomas, fibrosarcomas, congenital fibrosarcomas, congenital mesodermal nephromas, secretory breast cancer, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system vegetations, osteosarcoma, synovial sarcoma, liposarcoma, soft tissue alveolar sarcoma, Spitzoid carcinoma, Wilms' tumor, lymphomas (e.g., including Hodgkin's lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma), inflammatory lung diseases (e.g., asthma), inflammatory bowel disease. (e.g., ulcerative colitis, Crohn's disease), inflammatory skin diseases (e.g., atopic dermatitis, eczema, and psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, osteoarthritis pain, chronic low back pain, osteoporotic low back pain, fracture pain, rheumatoid arthritis pain, postherpetic neuralgia, diabetic neuropathy pain, fibromyalgia, pancreatitis pain, interstitial cystitis pain, endometriosis pain, irritable bowel syndrome pain, migraine, pulpitis pain, interstitial cystitis pain, bladder pain syndrome, central pain syndrome, postoperative pain syndrome, bone and joint pain, and more. Recurrent motor pain, toothache, myofascial pain, perioperative pain, dysmenorrhea, myofascial pain, angina pectoris, headache, primary hyperalgesia, secondary hyperalgesia, primary anomalous pain, secondary anomalous pain, other pain caused by central sensitization, generalized pruritus, localized pruritus, senile pruritus, pruritus gravidarum, anal pruritus, vulvar pruritus, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic diseases, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelinating diseases, and myelination disorders.

[0414] TRK kinase inhibitors are currently in clinical or preclinical development, including but not limited to 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), dovirtinib (TKI-258, CHIR-258) (Chong et al., 2017), entrectinib (RXDX-101) (Menichincheri et al., 2016), milkiclib (PHA-848125AC) (Brasca et al., 2009), belizatinib (TSR-011) (Ricciuti et al., 2017), GZ389988 (Bailey et al., 2017a, b), and pegcantratinib (Cranston et al., ...). 2017), AZD7451 (Tatematsu et al., 2014), larotrectinib (LOXO-101; ARRY-470) (Drilon et al., 2018), TPX-0005 (Cui et al., 2016), LOXO-195 (Blake et al., 2016), Regorafenib (Subbiah et al., 2017), DS-6051b (Fujiwara et al., 2018), F17752 (Ama The most advanced drugs used include entrectinib (2016), PLX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a,b), VM902A (Bailey et al., 2017a,b), ONO-4474 (Bailey et al., 2017a,b), PF-06273340 (Skerratt et al., 2016), and GNF-8625 (Choi et al., 2015). The most advanced are entrectinib and larotrectinib (Khotskaya et al., 2017). These agents were tested in basket trials recruiting patients based on TRK fusion assays rather than histology. Phase 2 results for larotrectinib showed that most patients (75%) responded to treatment, and 55% remained progression-free within 1 year (Drilon et al., 2018). In patients with TRK fusion tumors, phase 1 results for entrectinib also documented significant and durable responses (Drilon et al., 2017b). The remarkable efficacy of TRK inhibitors was independent of tumor type. These real-world results collectively highlight the role of TRK fusion bodies as the sole oncogenic driver in a subgroup of human malignancies, regardless of the tissue of origin.

[0415] The nonspecific side effects of TRK kinase inhibitors and the development of resistance remain challenges in developing effective treatments. Therefore, novel small molecule targeting TRK through inhibition and / or degradation would be very useful.

[0416] Not wishing to be bound by any theory, this disclosure is considered to be based at least in part on the finding that novel iso-divalent small molecules that degrade TRK, TRK fusion proteins, and / or TRK mutant proteins may be used to treat TRK-mediated diseases, particularly non-small cell lung cancer, colorectal cancer, gastric cancer, liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, bladder cancer, endometrial cancer, prostate cancer, low-grade glioma, glioblastoma, spitzoid carcinoma, soft tissue sarcoma, papillary thyroid carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesodermal nephroma, secretory breast cancer, breast analogue secretory carcinoma, acute myeloid leukemia, ductal carcinoma, pulmonary neuroendocrine tumor, pheochromocytoma, and Wilms' tumor (Amatu et al., 2016; Khotskaya et al., 2017).The disclosed novel bifunctional TRK degradants can be used to treat TRK-mediated cancers, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, and other diseases, including but not limited to neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric cancer, lung cancer, liver cancer, uterine cancer, adrenal cancer, biliary tract cancer, colorectal cancer, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, breast cancer, esophageal cancer, bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secretory breast cancer, secretory breast cancer, salivary gland cancer, papillary thyroid carcinoma, ductal carcinoma, and adult medullary thyroid carcinoma. Leukemia, acute myeloid leukemia, large cell neuroendocrine tumors, pulmonary neuroendocrine tumors, sarcomas, pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenital mesodermal nephroma, secretory breast cancer, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system vegetations, osteosarcoma, synovial sarcoma, liposarcoma, soft tissue alveolar sarcoma, Spitzoid carcinoma, Wilms' tumor, lymphomas (e.g., including Hodgkin's lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic 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, and psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, osteoarthritis pain, chronic low back pain, osteoporotic low back pain, fracture pain, rheumatoid arthritis pain, postherpetic neuralgia, diabetic neuropathy pain, fibromyalgia, pancreatitis pain, interstitial cystitis pain, endometriosis pain, irritable bowel syndrome pain, migraine, pulpitis pain, interstitial cystitis pain, bladder pain syndrome, central pain syndrome, postoperative pain syndrome, bone And joint pain, recurrent motion pain, toothache, myofascial pain, perioperative pain, dysmenorrhea, myofascial pain, angina pectoris, headache, primary hyperalgesia, secondary hyperalgesia, primary anomalous pain, secondary anomalous pain, other pain caused by central sensitization, generalized pruritus, localized pruritus, senile pruritus, pruritus gravidarum, anal pruritus, vulvar pruritus, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic diseases, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelinating diseases and myelination disorders.

[0417] Selective degradation of target proteins induced by small molecules can be achieved by recruiting E3 ubiquitin ligases and mimicking protein misfolding with hydrophobic tags (Buckley and Crews, 2014). Additionally, the small molecule possesses one portion that binds to the E3 ubiquitin ligase and another portion that binds to the target protein (Buckley and Crews, 2014). The induced proximity leads to ubiquitination of the target, followed by its degradation via proteasome-mediated proteolysis. Several types of high-affinity small-molecule E3 ligase ligands have been identified or developed. These include (1) immunomodulatory drugs (IMiDs), such as thalidomide and pomalidomide, which bind to cereblon (CRBN or CRL4CRBN) – a component of the cullin-RING ubiquitin ligase (CRL) complex (Bondeson et al., 2015; Chamberlain et al., 2014; Fischer et al., 2014; Ito et al., 2010; Winter et al., 2015); and (2) VHL-1 – a hydroxyproline-containing ligand that binds to vanHip (2) pel-Lindau protein (VHL or CRL2VHL) – another component of the CRL complex (Bondeson et al., 2015; Buckley et al., 2012a; Buckley et al., 2012b; Galdeano et al., 2014; Zengerle et al., 2015); (3) compound 7, which selectively binds KEAP1 – a component of the CRL3 complex (Davies et al., 2016); (4) AMG232, which selectively binds MDM2 – a heterodimeric RING E3 ligase (Sun et al., 2014); and (5) LCL161, which selectively binds IAP – a heterodimeric RING E3 ligase (Ohoka et al., 2017; Okuhira et al., 2011; Shibata et al., 2017). Bifunctional degrader techniques recruiting E3 ligases have been applied to degrade several 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). Additionally, hydrophobic labeling methods utilizing bulky and hydrophobic adamantyl groups have been developed to mimic protein misfolding, leading to proteasome degradation of target proteins (Buckley and Crews, 2014). This method has been applied to the selective degradation of the pseudokinase HER3 (Xie et al., 2014). The inventors have not seen any attempts to apply these methods to the degradation of TRK, TRK mutants, TRK deletions, or TRK fusion proteins.

[0418] Currently available small molecules targeting TRK focus on inhibiting TRK kinase activity. Numerous selective small-molecule TRK kinase inhibitors have been reported, such as 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), dovirtinib (TKI-258, CHIR-258) (Chong et al., 2017), entrectinib (RXDX-101) (Menichincheri et al., 2016), milkiclib (PHA-848125AC) (Brasca et al., 2009), belizatinib (TSR-011) (Ricciuti et al., 2017), GZ389988 (Bailey et al., 2017a, b), and pegcantratinib (Cranston et al., 2019). 7) AZD7451 (Tatematsu et al., 2014), larotrectinib (LOXO-101; ARRY-470) (Drilon et al., 2018), 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 Li et al., 2016), PLX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a, b), VM902A (Bailey et al., 2017a, b), ONO-4474 (Bailey et al., 2017a, b), PF-06273340 (Skerratt et al., 2016), and GNF-8625 (Choi et al., 2015).

[0419] This disclosure employs a novel approach: developing compounds that not only directly and selectively regulate the kinase activity of TRK, but also directly and selectively regulate its protein levels. Strategies for inducing protein degradation include recruiting E3 ubiquitin ligases, mimicking protein misfolding with hydrophobic tags, and inhibiting molecular chaperones. Compared to techniques such as gene knockout or short hairpin RNA-mediated (shRNA) knockdown, this approach based on the use of divalent small molecule compounds allows for more flexible modulation of protein levels both in vitro and in vivo. Unlike gene knockout or shRNA knockdown, the small molecule approach further provides opportunities to study dose- and time-dependent effects in disease models by modulating the route of administration, concentration, and frequency of administration of the corresponding small molecule.

[0420] Divalent compounds

[0421] For the purposes of this disclosure, the terms "bifunctional compound", "bifunctional degrader", "bifunctional TRK degrader", "divalent compound" and "heterobifunctional compound" are used interchangeably.

[0422] In some aspects, this disclosure provides divalent compounds, including TRK ligands conjugated to degradation tags, or pharmaceutically acceptable salts or analogs thereof. The TRK ligand can be conjugated to the degradation tag directly or via a linker portion. In some embodiments, the TRK ligand can be conjugated directly to the degradation tag. In some embodiments, the TRK ligand can be conjugated to the degradation tag via a linker portion.

[0423] As used herein, the terms "tropomyosin receptor kinase ligand" and "TRK ligand" or "TRK targeting moiety" should be understood to include any molecule, from small to large, that associates with or binds to a TRK protein. In some embodiments, the TRK ligand is capable of binding to a TRK protein comprising TRK, a TRK mutant, a TRK deletion, or a TRK fusion protein. The TRK ligand can be, for example, but not limited to, small molecule compounds (i.e., molecules with a molecular weight less than about 1.5 kilodaltons (kDa), peptides or polypeptides, nucleic acids or oligonucleotides, carbohydrates such as oligosaccharides, or antibodies or fragments thereof.

[0424] TRK ligands

[0425] The TRK ligand or targeting portion may be a TRK kinase inhibitor or a portion thereof. In some embodiments, the TRK kinase inhibitor includes one or more of the following (e.g., 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), dovirtinib (TKI-258, CHIR-258) (Chon...). G et al., 2017), entrectinib (RXDX-101) (Menichincheri et al., 2016), milkiclib (PHA-848125AC) (Brasca et al., 2009), belizatinib (TSR-011) (Ricciuti et al., 2017), GZ389988 (Bailey et al., 2017a,b), pegcantratinib (Cranston et al., 2017), AZD7 451 (Tatematsu et al., 2014), larotrectinib (LOXO-101; ARRY-470) (Drilon et al., 2018), 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), PLX74 86 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a, b), VM902A (Bailey et al., 2017a, b), ONO-4474 (Bailey et al., 2017a, b), PF-06273340 (Skerratt et al., 2016), and GNF-8625 (Choi et al., 2015), and their analogues, are capable of inhibiting TRK kinase activity. As used herein, “TRK kinase inhibitor” means an agent that limits, delays, or otherwise inhibits physiological, chemical, or enzymatic action or function, resulting in a reduction of binding by at least 5%. Inhibitors may also alternatively refer to drugs, compounds, or agents that prevent or reduce the expression, transcription, or translation of genes or proteins. Inhibitors may, for example, reduce or prevent protein function by binding to or activating / inactivating another protein or receptor.

[0426] In some embodiments, the TRK ligand is derived from a TRK kinase inhibitor, which includes:

[0427]

[0428] In some embodiments, the TRK ligands include, but are not limited to, DS-6051b (Fujiwara et al., 2018), F17752 (Amatu et al., 2016), PLX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a, b), VM902A (Bailey et al., 2017a, b), PF-06273340 (Skerratt et al., 2016), and ONO-4474 (Bailey et al., 2017a, b). In some embodiments, the TRK ligand is derived from any one or more of the following: DS-6051b (Fujiwara et al., 2018), F17752 (Amatu et al., 2016), PLX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a, b), VM902A (Bailey et al., 2017a, b), PF-06273340 (Skerratt et al., 2016), and ONO-4474 (Bailey et al., 2017a, b).

[0429] In another embodiment, the TRK ligand comprises a portion of Formula 1;

[0430]

[0431] in,

[0432] R 1 R 2 R 3 R 4 Ar and X are as defined above.

[0433] In another embodiment, the TRK ligand comprises a portion of Formula 1.

[0434]

[0435] in

[0436] X is selected from CR'R", CO, O, S, SO, SO2, and NR', where

[0437] R' and R" are independently selected from hydrogen, halogen, OH, optionally substituted C1-C8 alkyl, optionally substituted C 1-8Alkoxy, optionally substituted C1-C8 alkoxy, C1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylamino, C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C3-C 10 Cycloalkoxy groups and optionally substituted 3-10 membered heterocyclic groups; or

[0438] R' and R” together with the atoms they are attached to form optionally substituted 3-8 membered cycloalkyl or heterocyclic rings;

[0439] R is selected from optionally substituted C1-C8 alkyl groups, optionally substituted C3-C6 alkyl groups, etc. 10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups;

[0440] R 1 R 2 and R 3 Independently selected from hydrogen, halogen, CN, NO2, OR 5 SR 6 NR 7 R 8 COR 5 CO2R 5 C(O)NR 7 R 8 SOR 5 SO2R 5 SO2NR 7 R 8 NR 7 C(O)R 8 NR 5 C(O)NR 7 R 8 NR 7 SOR 8 NR 7 SO2R 8 Optionally substituted C1-C8 alkyl, Optionally substituted C1-C8 alkoxy, Optionally substituted C1-C8 alkoxy-C1-C8 alkyl, Optionally substituted C1-C8 alkylamino-C1-C8 alkyl, Optionally substituted C3-C 10 cycloalkyl, optionally substituted C3-C 10 Cycloalkoxy, optionally substituted 3-10 membered heterocyclic groups, optionally substituted C2-C8 alkenyl groups, and optionally substituted C2-C8 alkynyl groups, wherein

[0441] R 5 R 6 R 7 and R 8Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic groups, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted aryl or optionally substituted heteroaryl, or

[0442] R 7 and R 8 Together with the atoms they are attached to, they form optionally substituted 4-8 membered heterocyclic rings;

[0443] R 4 The linker portion connected to the divalent compound, and selected from bonds, OR 9 SR 9 NR 10 R 11 COR 9 CO2R 9 CONR 10 R 11 SOR 9 SO2R 9 SO2NR 10 R 11 NR 10 COR 11 NR 9 CONR 10 R 11 NR 10 SOR 11 NR 10 SO2R 11 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic groups, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, aryl, and optionally substituted heteroaryl, wherein

[0444] R 9 R 10 and R 11Independently selected from empty, bonded, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0445] R 10 and R 11 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings; and

[0446] Ar is selected from aryl and heteroaryl groups, each of which is optionally substituted by one or more substituents, which are independently selected from hydrogen, halogen, CN, NO2, OR. 12 SR 12 NR 13 R 14 COR 12 CO2R 12 CONR 13 R 14 SOR 12 SO2R 12 SO2NR 13 R 14 NR 13 COR 14 NR 15 C(O)NR 13 R 14 NR 13 SOR 14 NR 13 SO2R 14 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic group, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0447] R 12 R 13 R 14 and R 15Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0448] R 13 and R 14 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0449] In one implementation scheme

[0450] X is selected from CR'R", O, and NR', where

[0451] R' and R" are independently selected from hydrogen, F, OH, optionally substituted C1-C3 alkyl and optionally substituted C1-C3 alkoxy, or

[0452] R' and R” together with the atoms they are attached to form optionally substituted 3-6 membered cycloalkyl or heterocyclic rings.

[0453] In another embodiment, X is selected from CH2, cyclopropylene, CHF, CF2, O, NH, NCH3, NCH2CH3 and N-isopropyl.

[0454] In another embodiment, R is selected from optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.

[0455] In another embodiment, R is selected from optionally substituted phenyl and optionally substituted heteroaryl groups.

[0456] In another embodiment, X is CH2; and R is 3,5-difluorophenyl.

[0457] In another implementation, R 1 R 2 and R 3 It is independently selected from hydrogen, F, Cl and OH.

[0458] In another implementation, R 4 -Ar is selected from parts of formulas A1, A2, A3, and A4:

[0459]

[0460] in

[0461] * indicates a connection to the linker portion of the divalent compound; and

[0462] R a Selected from hydrogen, halogens, CN, NO2, OR 12 SR 12 NR 13 R 14 COR 12 CO2R 12 CONR 13 R 14 SOR 12 SO2R 12 SO2NR 13 R 14 NR 13 COR 14 NR 15 C(O)NR 13 R 14 NR 13 SOR 14 NR 13 SO2R 14 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic group, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0463] R 12 R 13 R 14 and R 15 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, aryl and optionally substituted heteroaryl, or

[0464] R 13 and R 14 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0465] In another implementation, R 4 -Ar is selected from parts of formulas A1, A3, A3, and A4:

[0466]

[0467] in

[0468] * indicates a connection to the linker portion of the divalent compound; and

[0469] R a Selected from hydrogen, halogen, NR 13 R 14 and NR 13 COR 14 ,in

[0470] R 13 and R 14 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, phenyl, and optionally substituted C5-C6 heteroaryl, or

[0471] R 13 and R 14 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0472] In another implementation, R a It is (tetrahydro-2H-pyran-4-yl)amino.

[0473] In another embodiment, the TRK ligand comprises a portion of formula 2;

[0474]

[0475] in,

[0476] R 1 R 2 R 3 R 4 Ar 1 Ar 2 X, X 1 X 2 X 3 X 4 And n is as defined above.

[0477] In another embodiment, the TRK ligand comprises a portion of formula 2:

[0478]

[0479] in

[0480] X 1 X 2 X 3 and X 4 Independently selected from C, CR' and N (preferably, X) 1 Selected from CR' and N, X 2 X 3 and X 4 (Independently selected from C and N), where

[0481] R' is selected from hydrogen, halogen, CN, NO2, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-6 membered heterocyclic groups;

[0482] X is selected from empty, key, C(R) 2 )2、C(R 2 )2C(R 2 )2, CO, C(R) 2 )2CO、CONR 2 C(R) 2 )2O、C(R 2 )2NR 2 and CH2NR 2 ;

[0483] R 1 and R 2 Each time it appears, it is independently selected from hydrogen, halogen, OH, NH2, CN, NO2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 alkoxyalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkylaminoC1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclic groups;

[0484] n is between 1 and 4;

[0485] R 3 Directly or through R 4 The linker portion connected to the divalent compound;

[0486] R 3 and R 4 Independently selected from empty, key, OR 5 SR 5 NR 6 R 7 COR 5 CO2R 5 CONR 6 R 7SOR 5 SO2R 5 SO2NR 6 R 7 NR 6 COR 7 NR 5 C(O)NR 6 R 7 NR 6 SOR 7 NR 6 SO2R 7 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 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 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein...

[0487] R 5 R 6 and R 7 Independently selected from empty, bonded, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0488] R 6 and R 7 Together with the atoms they are attached to, they form 3-8 membered cycloalkyl or 4-8 membered heterocyclic rings; and

[0489] Ar 1 and Ar 2 Independently selected from aryl and heteroaryl groups, wherein each is optionally substituted by one or more substituents, which are independently selected from halogens, CN, NO2, OR 10 SR 10 NR 11 R 12 COR 10 CO2R 10 CONR 11 R 12 SOR 10 SO2R 10 SO2NR 11 R 12 NR 11 COR12 NR 10 C(O)NR 11 R 12 NR 11 SOR 12 NR 11 SO2R 12 Optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0490] R 10 R 11 and R 12 Independently selected from empty, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0491] R 11 and R 12 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0492] In one implementation, X 1 It is selected from CR' and N, where R' is selected from hydrogen, F, Cl, CH3, CF3 and cyclopropyl.

[0493] In another implementation, X 2 X 3 and X 4 Selected independently from C and N.

[0494] In another embodiment, X is selected from bonds, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH and CH2NCH3.

[0495] In another implementation, R 1 and R 2 Each time it appears, it is independently selected from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclic groups.

[0496] In another implementation, X is CH2; and Ar 1 It is 3-fluorophenyl.

[0497] In another implementation, R 3 The linker portion is directly connected to the divalent compound, and

[0498] R 3 Selected from empty, key, OR 5 SR 5 NR 6 R 7 COR 5 CO2R 5 CONR 6 R 7 SOR 5 SO2R 5 SO2NR 6 R 7 NR 6 COR 7 NR 5 C(O)NR 6 R 7 NR 6 SOR 7 NR 6 SO2R 7 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 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 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein...

[0499] R 5 R 6 and R 7 Independently selected from empty, bonded, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0500] R 6 and R 7 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0501] In another implementation, R 3 Through R 4The linker portion connected to the divalent compound, and

[0502] R 3 and R 4 Independently selected from empty, key, OR 5 SR 5 NR 6 R 7 COR 5 CO2R 5 CONR 6 R 7 SOR 5 SO2R 5 SO2NR 6 R 7 NR 6 COR 7 NR 5 C(O)NR 6 R 7 NR 6 SOR 7 NR 6 SO2R 7 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 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 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein...

[0503] R 5 R 6 and R 7 Independently selected from empty, bonded, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0504] R 6 and R 7 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0505] In another implementation scheme,

[0506] Ar 1 Selected from C6-C 10 Aryl and C5-C 10Heteroaryl groups, wherein each is optionally substituted by one or more substituents, which are 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 11 COR 12 NR 10 C(O)NR 11 R 12 NR 11 SOR 12 NR 11 SO2R 12 Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, 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...

[0507] R 10 R 11 and R 12 Independently selected from empty, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0508] R 11 and R 12 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0509] In another implementation scheme,

[0510] Ar 2 Selected from C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein each is optionally substituted by one or more substituents, which are independently selected from F, Cl, CN, NO2, OR 10 NR 11 R 12 COR 10CO2R 10 CONR 11 R 12 SOR 10 SO2R 10 SO2NR 11 R 12 NR 11 COR 12 NR 10 C(O)NR 11 R 12 NR 11 SOR 12 NR 11 SO2R 12 Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, 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...

[0511] R 10 R 11 and R 12 Independently selected from empty, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0512] R 11 and R 12 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0513] In another implementation, R 3 -Ar 2 Selected from formulas B1 and B2:

[0514]

[0515] in

[0516] * indicates a connection to the linker portion of the divalent compound;

[0517] Y 1 Y 2 Y 3 and Y 4 Independently selected from CH and N, provided that Y 1 Y 2 Y 3and Y 4 At most 3 of them are N;

[0518] Each R a Independently selected from hydrogen, halogen, CN, NO2, OR 12 SR 12 NR 13 R 14 COR 12 CO2R 12 CONR 13 R 14 SOR 12 SO2R 12 SO2NR 13 R 14 NR 13 COR 14 NR 15 C(O)NR 13 R 14 NR 13 SOR 14 NR 13 SO2R 14 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic group, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0519] R 12 R 13 R 14 and R 15 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0520] R 13 and R 14 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings;

[0521] m is between 0 and 4; and

[0522] R 3 Same as defined in Equation 2.

[0523] In another implementation, R 3 -Ar 2 Selected from the portion of formula B3:

[0524]

[0525] in

[0526] * indicates a connection to the linker portion of the divalent compound;

[0527] Y 1 Y 2 Y 3 and Y 4 Independently selected from CR a N, O, and S, with the condition that Y 1 Y 2 Y 3 and Y 4 At most 3 of them are N;

[0528] Each R a Independently selected from hydrogen, halogen, CN, NO2, OR 12 SR 12 NR 13 R 14 COR 12 CO2R 12 CONR 13 R 14 SOR 12 SO2R 12 SO2NR 13 R 14 NR 13 COR 14 NR 15 C(O)NR 13 R 14 NR 13 SOR 14 NR 13 SO2R 14 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic group, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0529] R 12 R 13 R 14 and R15 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0530] R 13 and R 14 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings;

[0531] m is between 0 and 4; and

[0532] R 3 Same as defined in Equation 2.

[0533] In another implementation, X 1 For N; X 2 For N; X 3 For C; X 4 C; X is CH2; Ar 1 It is 3-fluorophenyl; and Ar 2 It is 2-pyridyl.

[0534] In another embodiment, the TRK ligand comprises a portion of formula 3;

[0535]

[0536] in,

[0537] R 1 R 2 R 3 R 4 Ar, X, X 1 X 2 X 3 X 4 And n is as defined above.

[0538] In another embodiment, the TRK ligand comprises a portion of formula 3:

[0539]

[0540] in

[0541] X 1 X 2 X 3 and X 4 Independently selected from C, CR' and N (preferably, X)1 and X 4 Independently selected from CR' and N;X 2 and X 3 (Independently selected from C and N), where

[0542] R' is selected from hydrogen, halogen, CN, NO2 and optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic groups;

[0543] X is selected from empty, key, C(R) 2 )2、C(R 2 )2C(R 2 )2, CO, C(R) 2 )2CO、NR 2 CO, OC(R) 2 )2 and NR 2 C(R 2 )2;

[0544] R 1 and each R 2 Independently selected from hydrogen, halogen, OH, NH2, CN, NO2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 alkoxyalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 alkylaminoC1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclic groups; n is 1 to 4;

[0545] R 3 Selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-6 membered heterocyclic, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl and optionally substituted C1-C6 alkylaminoC1-C6 alkyl.

[0546] R 4 Directly or through R 5 The linker portion connected to the divalent compound, wherein R 4 and R 5 Independently selected from empty, OR 6 SR 6 NR 7 R 8 COR 6 CO2R 6 CONR 7 R 8 SOR 6 SO2R6 SO2NR 7 R 8 NR 7 COR 8 NR 9 C(O)NR 7 R 8 NR 7 SOR 8 NR 7 SO2R 8 Optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein...

[0547] R 6 R 7 R 8 and R 9 Independently selected from empty, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0548] R 7 and R 8 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings; Ar is selected from aryl and heteroaryl groups, each of which is optionally substituted by one or more substituents, which are independently selected from halogens, CN, NO2, OR 10 SR 10 NR 11 R 12 COR 10 CO2R 10 CONR 11 R 12 SOR 10 SO2R 10 SO2NR 11 R 12 NR 11 COR 12 NR 10 C(O)NR 11 R 12 NR 11 SOR 12NR 11 SO2R 12 Optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0549] R 10 R 11 and R 12 Independently selected from empty, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0550] R 11 and R 12 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0551] In one implementation, X 1 and X 4 It is selected from CR' and N, and R' is selected from hydrogen, F, Cl, CH3, CF3 and cyclopropyl.

[0552] In another implementation, X 2 and X 3 Selected independently from C and N.

[0553] In another embodiment, X is selected from bonds, CH2, CH2CH2, CO, CH2CO, CONH, CONCH3, CH2O, CH2NH and CH2NCH3.

[0554] In another implementation, R 1 and each R 2 Independently selected from hydrogen, F, Cl, OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted C1-C4 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclic groups.

[0555] In another implementation, R 3 Selected from hydrogen, CH3, CH2CH3, propyl, isopropyl, cyclopropyl, CH2F, CHF2, and CF3.

[0556] In another implementation scheme,

[0557] R 4 The linker portion is directly connected to the divalent compound, and

[0558] R 4 Select from empty, OR 6 SR 6 NR 7 R 8 COR 6 CO2R 6 CONR 7 R 8 SOR 6 SO2R 6 SO2NR 7 R 8 NR 7 COR 8 NR 9 C(O)NR 7 R 8 NR 7 SOR 8 NR 7 SO2R 8 Optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein...

[0559] R 6 R 7 R 8 and R 9 Independently selected from empty, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted arylalkyl, heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0560] R 7 and R 8 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0561] In another implementation scheme,

[0562] R 4 Through R 5The linker portion connected to the divalent compound, and

[0563] R 4 and R 5 Independently selected from empty, OR 6 SR 6 NR 7 R 8 COR 6 CO2R 6 CONR 7 R 8 SOR 6 SO2R 6 SO2NR 7 R 8 NR 7 COR 8 NR 9 C(O)NR 7 R 8 NR 7 SOR 8 NR 7 SO2R 8 Optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein...

[0564] R 6 R 7 R 8 and R 9 Independently selected from empty, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0565] R 7 and R 8 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0566] In another implementation scheme,

[0567] Ar is selected from aryl and heteroaryl groups, each of which is optionally substituted by one or more substituents, which are independently selected from F, Cl, CN, NO2, OR. 10NR 11 R 12 COR 10 CO2R 10 CONR 11 R 12 SOR 10 SO2R 10 SO2NR 11 R 12 NR 11 COR 12 NR 10 C(O)NR 11 R 12 NR 11 SOR 12 NR 11 SO2R 12 Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, 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...

[0568] R 10 R 11 and R 12 Independently selected from empty, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0569] R 11 and R 12 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0570] In another embodiment, the TRK ligand is selected from:

[0571]

[0572] Degradable labels

[0573] As used herein, the term “degradation tag” refers to a compound that associates with or binds to ubiquitin ligases to recruit the corresponding ubiquitination mechanism to TRK, or a hydrophobic group or tag that causes TRK protein misfolding and subsequent degradation or loss of function at the proteasome.

[0574] In some embodiments, the degradation label is selected from formulas 5A, 5B, 5C, and 5D:

[0575]

[0576] in

[0577] V, W, and X are independently selected from CR 2 and N;

[0578] Y is selected from CO and CR. 3 R 4 And N = N;

[0579] Z is selected from empty, CO, CR 5 R 6 NR 5 O, optional substitution of C1-C 10 Alkylene, optionally substituted C1-C 10 alkenyl, optionally substituted C1-C 10 Alynyl group, optionally substituted 3-10 membered carbocyclic group, optionally substituted 4-10 membered heterocyclic group, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from empty, CH2, CH=CH, C≡C, NH, and O;

[0580] R 1 and R 2 Independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbon cycloyl and optionally substituted 4- to 6-membered heterocyclic groups;

[0581] R 3 and R 4 Independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclic and optionally substituted 4- to 6-membered heterocyclic groups; or R 3 and R 4 Together with the atoms they are attached to, they form 3-6 membered carbon cyclic groups or 4-6 membered heterocyclic groups; and

[0582] R 5 and R 6Independently selected from empty, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbon cyclic group and optionally substituted 4- to 6-membered heterocyclic group; or R 5 and R 6 Together with the atoms they are attached to, they form 3-6 membered carbon cyclic groups or 4-6 membered heterocyclic groups.

[0583] In some embodiments, the degradation label is selected from formulas 5A, 5B, 5C, and 5D:

[0584]

[0585] in,

[0586] V, W, and X are independently selected from CR 2 and N;

[0587] Y is selected from CO and CH2;

[0588] Z is selected from CH2, NH and O;

[0589] R 1 Selected from hydrogen, C1-C5 alkyl groups, and halogens; and

[0590] R 2 It is selected from hydrogen, halogens and C1-C5 alkyl groups.

[0591] In one embodiment, the degradation label is selected from Formula 5B and Formula 5C.

[0592] In some embodiments, the degradation label is a part selected from formulas 5E, 5F, 5G, 5H, and 5I:

[0593]

[0594] in

[0595] U, V, W, and X are independently selected from CR 2 and N;

[0596] Y is selected from CR 3 R 4 NR 3 And O; preferably, Y is selected from CH2, NH, NCH3 and O;

[0597] Z is selected from empty, CO, CR 5 R 6 NR 5 O, optional substitution of C1-C 10 Alkylene, optionally substituted C1-C 10 alkenyl, optionally substituted C1-C 10Alynyl group, optionally substituted 3-10 membered carbocyclic group, optionally substituted 4-10 membered heterocyclic group, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from empty, CH2, CH=CH, C≡C, NH, and O;

[0598] R 1 and R 2 Independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbon cycloyl and optionally substituted 4- to 6-membered heterocyclic groups;

[0599] R 3 and R 4 Independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclic and optionally substituted 4- to 6-membered heterocyclic groups; or R 3 and R 4 Together with the atoms they are attached to, they form 3-6 membered carbon cyclic groups or 4-6 membered heterocyclic groups; and

[0600] R 5 and R 6 Independently selected from empty, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbon cyclic group and optionally substituted 4- to 6-membered heterocyclic group; or R 5 and R 6 Together with the atoms they are attached to, they form 3-6 membered carbon cyclic groups or 4-6 membered heterocyclic groups.

[0601] In one implementation, the degradation label is a part of Formula 6A:

[0602]

[0603] in

[0604] R 1 and R 2Independently selected from hydrogen, optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; and

[0605] R 3 Hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)C3-C7 cycloalkyl, optionally substituted C(O)(3- 7-membered heterocyclic group), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)OC3-C7 cycloalkyl, optionally substituted C(O)O (3-7 membered heterocyclic), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally Optionally substituted C(O)NC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)NC3-C7 cycloalkyl, optionally substituted C(O)N (3-7 membered heterocyclic), 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.

[0606] In one embodiment, the degradation label is a portion selected from formulas 6B, 6C, 6D, 6E, and 6F:

[0607]

[0608] in

[0609] R1 and R 2 Independently selected from hydrogen, halogen, OH, NH2, CN, optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; (preferably, R 1 Selected from isopropyl or tert-butyl; and R 2 Selected from hydrogen or methyl);

[0610] R 3 Hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)C3-C7 cycloalkyl, optionally substituted C(O)(3- 7-membered heterocyclic group), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)OC3-C7 cycloalkyl, optionally substituted C(O)O (3-7 membered heterocyclic), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally The optional substituted C(O)NC1-C8 alkylamino C1-C8 alkyl, the optional substituted C(O)NC3-C7 cycloalkyl, the optional substituted C(O)N (3-7 membered heterocyclic), the optional substituted C(O)NC2-C8 alkenyl, the optional substituted C(O)NC2-C8 alkynyl, the optional substituted P(O)(OH)2, the optional substituted P(O)(OC1-C8 alkyl)2, and the optional substituted P(O)(OC1-C8 aryl)2; and

[0611] R 4 and R 5 Independently selected from hydrogen, COR 6CO2R 6 CONR 6 R 7 SOR 6 SO2R 6 SO2NR 6 R 7 Optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy C1-C8 alkyl groups, optionally substituted C1-C8 alkylamino C1-C8 alkyl groups, optionally substituted 3-8 membered cycloalkyl groups, optionally substituted 3-8 membered heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, wherein...

[0612] R 6 and R 7 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, 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 cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0613] R 4 and R 5 ;R 6 and R 7 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings;

[0614] Ar is selected from aryl and heteroaryl groups, each of which is optionally substituted by one or more substituents, which are independently selected from F, Cl, CN, NO2, OR. 8 NR 8 R 9 COR 8 CO2R 8 CONR 8 R 9 SOR 8 SO2R 8 SO2NR 9 R 10 NR 9 COR 10 NR 8 C(O)NR 9 R 10 NR 9 SOR 10 NR 9 SO2R 10Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, 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...

[0615] R 8 R 9 and R 10 Independently selected from empty, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0616] R 8 and R 9 ;R 9 and R 10 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0617] In another embodiment, the degradation label is a part of Formula 7A:

[0618]

[0619] V, W, X, and Z are independently selected from CR. 4 and N.

[0620] R 1 R 2 R 3 and R 4 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl.

[0621] In another embodiment, the degradation label is a part of Formula 7B:

[0622]

[0623] in

[0624] R 1 R 2 and R 3Independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl;

[0625] R 4 and R 5 Independently selected from hydrogen, COR 6 CO2R 6 CONR 6 R 7 SOR 6 SO2R 6 SO2NR 6 R 7 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted aryl-C1-C8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0626] R 6 and R 7 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, or

[0627] R 6 and R 7 Together with the atoms they are attached to, they form 4-8 membered cycloalkyl or heterocyclic rings.

[0628] In another embodiment, the degradation label is derived from any of the following:

[0629]

[0630] In some embodiments, the degradation tag is an E3 ligase. In some embodiments, the degradation tag comprises one or more of cereblon E3 ligase, VHL E3 ligase, MDM2 ligase, TRIM24 ligase, TRIM21 ligase, KEAP1 ligase, and IAP ligase. In some embodiments, the degradation labels of this disclosure include, for example, pomalidomide (Fischer et al., 2014), thalidomide (Fischer et al., 2014), lenalidomide (Fischer et al., 2014), VH032 (Galdeano et al., 2014; Maniaci et al., 2017), adamantane (Xie et al., 2014), 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane (E. Wakeling, 1995), nutlin-3a (Vassilev et al., 2004), RG7112 (Vu et al., 2013), RG7338, AMG 232 (Sun et al., 2014), AA-115 (Aguilar et al., 2017), phenbutazone (Hiroyuki) Suda et al., 1976), MV1 (Varfolomeev et al., 2007), LCL161 (Weisberg et al., 2010) and / or their analogues. In some embodiments, the degradation tag is derived from compounds comprising: pomalidomide (Fischer et al., 2014), thalidomide (Fischer et al., 2014), lenalidomide (Fischer et al., 2014), VH032 (Galdeano et al., 2014; Maniaci et al., 2017), adamantane (Xie et al., 2014), 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane (E. Wakeling, 1995), nutlin-3a (Vassilev et al., 2004), RG7112 (Vu et al., 2013), RG7338, AMG 232 (Sun et al., 2014), AA-115 (Aguilar et al., 2017), and phenbutazone (Hiroyuki). Suda et al., 1976), MV1 (Varfolomeev et al., 2007), LCL161 (Weisberg et al., 2010) and / or their analogues.

[0631] In another embodiment, the degradation label is selected from:

[0632]

[0633]

[0634] Connector part

[0635] As used herein, a “linker” or “linker moiety” is a bond, molecule, or group of molecules that binds two separate entities together. A linker provides the optimal spacing between the two entities. The term “linker” in some respects refers to any reagent or molecule that bridges a TRK ligand to a degradation tag. Those skilled in the art will recognize that sites located on the TRK ligand or degradation tag (which are not essential for the function of the degradation products of this disclosure) are ideal sites for attaching a linker, provided that the linker, once attached to the conjugate of this disclosure, does not interfere with the function of the TRK ligand, i.e., its ability to bind TRK, or the function of the degradation tag, i.e., its ability to recruit ubiquitin ligases.

[0636] The length of the linker for the divalent compound can be adjusted to minimize the molecular weight of the divalent compound, avoid conflicts between the TRK ligand or targeting moiety and the ubiquitin ligase, and / or induce TRK misfolding via a hydrophobic tag. In some embodiments, the linker comprises an acyclic or cyclic saturated or unsaturated carbon, ethylene glycol, amide, amino, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic, or carbonyl group. In some embodiments, the length of the linker is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more atoms.

[0637] In some embodiments, the connector portion is the connector portion of Formula 9:

[0638]

[0639] in

[0640] A, W, and B are independently selected from either the empty or divalent portion each time they appear, and the divalent portion is selected from R'-R", R'COR", R'CO2R", and R'C(O)N(R). 1 )R”、R'C(S)N(R 1 )R", R'OR", R'OC(O)R", R'OC(O)OR", R'OCON(R 1 )R", R'SR", R'SOR", R'SO2R", R'SO2N(R 1 )R”、R'N(R 1 )R”、R'NR 1 COR”, R'NR 1 C(O)OR”、R'NR 1 CON(R 2 )R”、R'NR 1 C(S)R”、R'NR 1 S(O)R”、R'NR1 S(O)2R” and R'NR 1 S(O)2N(R 2 )R", where

[0641] R' and R" are independently selected from empty, arbitrarily substituted R. r -(C1-C8 alkyl) or a portion containing the following groups: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10-membered carbocyclic group, optionally substituted 4-10-membered heterocyclic group, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0642] R r Selected from optionally substituted 3-10 membered carbocyclic groups, optionally substituted 4-10 membered heterocyclic groups, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0643] R 1 and R 2Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 4-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;

[0644] R' and R”, R 1 and R 2 , R' and R 1 , R' and R 2 "R" and R 1 "R" and R 2 Together with the atoms they are attached to, they form 3-20 membered cycloalkyl or 4-20 membered heterocyclic alkyl rings; and m is 0 to 15.

[0645] In some embodiments, the connector portion is the connector portion of Formula 9:

[0646]

[0647] in

[0648] A, W, and B are independently selected from empty, CO, CO2, and C(O)NR each time they appear. 1 C(S)NR 1 O, S, SO, SO2, SO2NR 1 NR 1 NR 1 CO, NR 1 CONR 2 NR 1 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl and optionally substituted C3-C 13 Spiroherocyclic groups, in which

[0649] R 1 and R 2 Independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino, and optionally substituted C1-C6 alkylaminoC1-C6 alkyl; and

[0650] m ranges from 0 to 15.

[0651] In one embodiment, the connector portion is the connector portion of Formula 9A:

[0652]

[0653] Where R 1 R 2 R 3 and R 4 Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino and optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-8-membered cycloalkoxy, optionally substituted 3-10-membered carbocyclic amino, optionally substituted 4-8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, or

[0654] R 1 and R 2 R 3 and R 4 Together with the atoms they are attached to, they form 3-20 membered cycloalkyl or 4-20 membered heterocyclic rings;

[0655] A, W, and B are independently selected from either the empty or divalent portion each time they appear, and the divalent portion is selected from R'-R", R'COR", R'CO2R", and R'C(O)N(R). 5 )R”、R'C(S)N(R 5 )R", R'OR", R'OC(O)R", R'OC(O)OR", R'OCONR 5 R", R'SR", R'SOR", R'SO2R", R'SO2N(R 5 )R”、R'N(R5 )R”、R'NR 5 COR”, R'NR 5 C(O)OR”、R'NR 5 CON(R 6 )R”、R'NR 5 C(S)R”、R'NR 5 S(O)R”、R'NR 5 S(O)2R” and R'NR 5 S(O)2N(R 6 )R", where

[0656] R' and R" are independently selected from empty, arbitrarily substituted R. r -(C1-C8 alkyl) or a portion containing the following groups: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10-membered carbocyclic group, optionally substituted 4-10-membered heterocyclic group, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0657] R r Selected from optionally substituted 3-10 membered carbocyclic groups, optionally substituted 4-10 membered heterocyclic groups, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0658] R 5 and R 6 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 4-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;

[0659] R' and R”, R 5 and R 6 , R' and R 5 , R' and R 6 "R" and R 5 "R" and R 6 Together with the atoms they are attached to, they form 3-20 membered cycloalkyl or 4-20 membered heterocyclic rings;

[0660] m is between 0 and 15;

[0661] n is between 0 and 15 each time it appears; and

[0662] o ranges from 0 to 15.

[0663] In one embodiment, the connector portion is the connector portion of Formula 9A:

[0664]

[0665] in

[0666] R 1 R 2 R 3 and R 4 Each time it appears, it is independently selected from hydrogen, halogen, CN, OH, NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic group, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino and optionally substituted C1-C6 alkylaminoC1-C6 alkyl;

[0667] A, W, and B are independently selected from empty, CO, CO2, and C(O)NR each time they appear. 5 C(S)NR 5 O, S, SO, SO2, SO2NR 5 NR 5 NR5 CO, NR 5 CONR 6 NR 5 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl and optionally substituted C3-C 13 Spiroherocyclic groups, in which

[0668] R 5 and R 6 Independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino and optionally substituted C1-C6 alkylaminoC1-C6 alkyl;

[0669] m is between 0 and 15;

[0670] Each n is between 0 and 15; and

[0671] o ranges from 0 to 15.

[0672] In another embodiment, the connector portion is the connector portion of Formula 9B:

[0673]

[0674] in

[0675] R 1 and R 2Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, 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 alkylamino-C1-C8 alkyl, optionally substituted 3-10 membered carbocyclic, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclic amino, optionally substituted 4-10 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0676] R 1 and R 2 Together with the atoms they are attached to, they form 3-20 membered cycloalkyl or 4-20 membered heterocyclic rings;

[0677] A and B are independently selected from either the empty or divalent portion each time they appear, and the divalent portion is selected from R'-R”, R'COR”, R'CO2R”, R'C(O)NR”. 3 R”、R'C(S)NR 3 R", R'OR", R'OC(O)R", R'OC(O)OR", R'OCON(R 3 )R", R'SR", R'SOR", R'SO2R", R'SO2N(R 3 )R”、R'N(R 3 )R”、R'NR 3 COR”, R'NR 3 C(O)OR”、R'NR 3 CON(R 4 )R'、R'NR 3 C(S)R”、R'NR 3 S(O)R”、R'NR 3 S(O)2R” and R'NR 3 S(O)2N(R 4 )R", where

[0678] R' and R" are independently selected from empty, arbitrarily substituted R. r-(C1-C8 alkyl) or a portion containing the following groups: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10-membered carbocyclic group, optionally substituted 4-10-membered heterocyclic group, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0679] R r Selected from optionally substituted 3-10 membered carbocyclic groups, optionally substituted 4-10 membered heterocyclic groups, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0680] R 3 and R 4 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 4-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;

[0681] R' and R”, R 3 and R 4 , R' and R3 , R' and R 4 "R" and R 3 "R" and R 4 Together with the atoms they are attached to, they form 3-20 membered cycloalkyl or 4-20 membered heterocyclic rings;

[0682] Each m is between 0 and 15; and

[0683] n is between 0 and 15.

[0684] In another embodiment, the connector portion is the connector portion of Formula 9B:

[0685]

[0686] in

[0687] Each R 1 and each R 2 Independently selected from hydrogen, halogen, CN, OH, NH2 and optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino or C1-C6 alkylaminoC1-C6 alkyl;

[0688] Each A and each B are independently selected from empty, CO, CO2, C(O)NR 3 C(S)NR 3 O, S, SO, SO2, SO2NR 3 NR 3 NR 3 CO, NR 3 CONR 4 NR 3 C(S) and optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C13 Spirocycloalkyl or C3-C 13 Spiroherocyclic groups, in which

[0689] R 3 and R 4 Independently selected from hydrogen and optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino or C1-C6 alkylaminoC1-C6 alkyl;

[0690] Each m is between 0 and 15; and

[0691] n is between 0 and 15.

[0692] In another implementation, in Equation 9B, m is 1 to 15.

[0693] In another implementation, n is 1 in Equation 9B.

[0694] In another implementation, in formula 9B, R 1 and R 2 Independently selected from hydrogen and optionally substituted C1-C8 alkyl groups.

[0695] In another embodiment, the connector portion is the connector portion of Formula 9C:

[0696]

[0697] in

[0698] X is selected from O, NH, and NR. 7 ;

[0699] R 1 R 2 R 3 R 4 R 5 and R 6Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylamino-C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-8-membered cycloalkoxy, optionally substituted 4-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.

[0700] A and B are independently selected from empty or divalent portions, wherein the divalent portion is selected from R'-R”, R'COR”, R'CO2R”, R'C(O)N(R) 8 )R”、R'C(S)N(R 8 )R", R'OR", R'OC(O)R", R'OC(O)OR", R'OCON(R 8 )R", R'SR", R'SOR", R'SO2R", R'SO2N(R 8 )R”、R'N(R 8 )R”、R'NR 8 COR”, R'NR 8 C(O)OR”、R'NR 8 CON(R 9 )R”、R'NR 8 C(S)R”、R'NR 8 S(O)R”、R'NR 8 S(O)2R” and R'NR 8 S(O)2N(R 9 )R", where

[0701] R' and R" are independently selected from empty, arbitrarily substituted R. r-(C1-C8 alkyl) or a portion containing the following groups: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10-membered carbocyclic group, optionally substituted 4-10-membered heterocyclic group, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0702] R r Selected from optionally substituted 3-10 membered carbocyclic groups, optionally substituted 4-10 membered heterocyclic groups, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 Spirohexyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0703] R 7 R 8 and R 9 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 4-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;

[0704] R' and R”, R 8 and R 9, R' and R 8 , R' and R 9 "R" and R 8 "R" and R 9 Together with the atoms they are attached to, they form 3-20 membered cycloalkyl or 4-20 membered heterocyclic rings;

[0705] m ranges from 0 to 15 each time it appears;

[0706] n is between 0 and 15 each time it appears;

[0707] o is between 0 and 15; and

[0708] p ranges from 0 to 15.

[0709] In another embodiment, the connector portion is the connector portion of Formula 9C:

[0710]

[0711] in

[0712] X is selected from O, NH, and NR. 7 ;

[0713] R 1 R 2 R 3 R 4 R 5 and R 6 Each time it appears, it is independently selected from hydrogen, halogen, CN, OH, NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic group, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino and optionally substituted C1-C6 alkylaminoC1-C6 alkyl;

[0714] A and B are independently selected from empty, CO, CO2, and C(O)NR each time they appear. 7 C(S)NR 7 O, S, SO, SO2, SO2NR 7 NR 7 NR 7 CO, NR 7 CONR 8 NR 7C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl groups, optionally substituted C3-C 13 Fused heterocyclic groups, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic groups, optionally substituted C3-C 13 Spirocycloalkyl and optionally substituted C3-C 13 Spiroherocyclic groups, in which

[0715] R 7 and R 8 Independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, optionally substituted 3-6 membered heterocyclic, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylamino and optionally substituted C1-C6 alkylaminoC1-C6 alkyl;

[0716] Each m ranges from 0 to 15;

[0717] Each n is between 0 and 15;

[0718] o is between 0 and 15; and

[0719] p ranges from 0 to 15.

[0720] In one implementation, in Equation 9C, m and n are 1, and p is 1 to 15;

[0721] In one implementation, in formula 9C, X is selected from O and NH;

[0722] In one implementation, in formula 9C, R 1 R 2 R 3 R 4 R 5 and R 6 Independently selected from hydrogen, or optionally substituted C1-C6 alkyl groups.

[0723] In another embodiment, the connector portion includes a ring selected from 3- to 13-membered rings, 3- to 13-membered fused rings, 3- to 13-membered bridge rings, and 3- to 13-membered spiral rings.

[0724] In another embodiment, the connector portion includes a ring selected from formulas C1, C2, C3, C4, and C5:

[0725]

[0726]

[0727] In one implementation, A, B, and W are independently selected from empty, CO, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH2-NH-CH2-NH-CO, NH-CO-CH2-NH-CH2CO-NH-CH2-NH-CH2 and CH2-NH-CH2, R, each time they appear. r -CO、R r -NH、R r -NH-CO, R r -CO-NH,R r -CH2-NH-CO, R r -CH2-CO-NH, R r -NH-CO-CH2, R r -CO-NH-CH2, R r -CH2-NH-CH2-CO-NH, R r -CH2-NH-CH2-NH-CO, R r -NH-CO-CH2-NH-CH2, R r -CO-NH-CH2-NH-CH2, R r -CH2-NH-CH2。 .

[0728] In one implementation, R r It can be C1, C2, C3, C4 or C5.

[0729] In one implementation, R r Selected from

[0730] In another embodiment, the length of the connector is 0 to 40 straight-chain atoms.

[0731] In another embodiment, the length of the connector is 0 to 20 straight-chain atoms.

[0732] In another embodiment, the length of the connector is 0 to 8 straight-chain atoms.

[0733] In another embodiment, the connector is selected from -(CO)-(CH2). 1-8 -、-(CH2) 1-9 -、-(CH2) 1-2 -(CO)-NH-(CH2) 2-9 -、-(CH2) 1-2 -(CO)-NH-(CH2) 1-3 -(OCH2CH2) 1-7 -、-(CH2) 0-1 -(CO)-(CH2) 1-3 -(OCH2CH2) 1-7 -、-(CO)-(CH2) 0-3 -(alkenyl)-(CH2) 0-3 -、-(CO)-(CH2) 0-3 -(ethynyl)-(CH2) 0-3 -、-(CO)-(CH2) 0-3 -(3-8 membered carbon cycloyl)-(CH2) 0-3 -、-(CO)-(CH2) 0-3 -(3-8 membered heterocyclic carbonyl group)-(CH2) 0-3 -、-(CH2) 0-3 -(alkenyl)-(CH2) 0-3 -、-(CH2) 0-3 -(ethynyl)-(CH2) 0-3 -、-(CH2) 0-3 -(3-8 membered carbon cycloyl)-(CH2) 0-3 - and -(CH2) 0-3 -(3-8 membered heterocyclic carbonyl group)-(CH2) 0-3 -;

[0734] R r -(CO)-(CH2) 1-8 -、R r -(CH2) 1-9 -、R r -(CH2) 1-2 -(CO)-NH-(CH2) 2-9 -、R r -(CH2) 1-2 -(CO)-NH-(CH2) 1-3 -(OCH2CH2) 1-7 -、R r -(CH2) 0-1-(CO)-(CH2) 1-3 -(OCH2CH2) 1-7 -、R r -(CO)-(CH2) 0-3 -(alkenyl)-(CH2) 0-3 -、R r -(CO)-(CH2) 0-3 -(ethynyl)-(CH2) 0-3 -、R r -(CO)-(CH2) 0-3 -(3-8 membered carbon cycloyl)-(CH2) 0-3 -、R r -(CO)-(CH2) 0-3 -(3-8 membered heterocyclic carbonyl group)-(CH2) 0-3 -、R r -(CH2) 0-3 -(alkenyl)-(CH2) 0-3 -、R r -(CH2) 0-3 -(ethynyl)-(CH2) 0-3 -、R r -(CH2) 0-3 -(3-8 membered carbon cycloyl)-(CH2) 0-3 -and R r -(CH2) 0-3 -(3-8 membered heterocyclic carbonyl group)-(CH2) 0-3 -

[0735] Without being bound by any specific theory, it is envisioned here that, in some embodiments, attaching pomalidomide or VHL-1 to any part of the molecule may recruit cereblon E3 ligase 3 or VHL E3 ligase to TRK.

[0736] Compared to wild-type (WT) cells, the divalent compounds disclosed herein can selectively affect TRK-mediated disease cells (i.e., the divalent compounds can kill TRK-mediated disease cells or inhibit their growth, while also exhibiting a relatively low ability to lyse or inhibit the growth of WT cells), for example, GI in one or more TRK-mediated disease cells. 50 Compared to its GI against one or more WT cells (e.g., WT cells of the same species and tissue type as TRK-mediated disease cells). 50 More than 1.5 times lower, more than 2 times lower, more than 2.5 times lower, more than 3 times lower, more than 4 times lower, more than 5 times lower, more than 6 times lower, more than 7 times lower, more than 8 times lower, more than 9 times lower, more than 10 times lower, more than 15 times lower, or more than 20 times lower.

[0737] In some aspects, this document provides a method for identifying a bivalent compound that mediates TRK degradation or reduction, the method comprising: providing a heterobifunctional test compound comprising a TRK ligand conjugated to a degradation tag via a linker; contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and TRK; determining whether TRK levels in the cell are reduced; and identifying the heterobifunctional test compound as a bivalent compound that mediates TRK degradation or reduction. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is a TRK-mediated cancer cell.

[0738] Cross-reactivity with protein kinases

[0739] In some respects, TRK ligands can bind to TRK, TRK fusion proteins, and / or TRK mutant proteins. In some respects, TRK ligands can bind to ROS1, ROS1 fusion proteins, and / or ROS1 mutant proteins. In some respects, TRK ligands can bind to ALK, ALK fusion proteins, and / or ALK mutant proteins. In some respects, TRK ligands can bind to TRK, ROS1, or ALK. In some respects, TRK ligands can bind to TRK or ROS1. In some respects, TRK ligands can bind to TRK or ALK. In some respects, TRK ligands can bind to ROS1 or ALK.

[0740] Synthesis and Testing of Divalent Compounds

[0741] The binding affinity of novel synthetic divalent compounds can be assessed using standard biophysical assays known in the art, such as isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR). Cellular assays can then be used to assess the ability of the divalent compounds to induce TRK degradation and inhibit cancer cell proliferation. In addition to evaluating changes in protein levels of TRK, TRK mutants, or TRK fusion proteins induced by the divalent compounds, enzyme activity can also be assessed. Assays applicable to any or all of these steps are known in the art and include, for example, Western blotting, quantitative mass spectrometry (MS), flow cytometry, enzyme activity assays, ITC, SRT, cell growth inhibition, xenograft, and allotopic and patient-derived xenograft models. Cell lines applicable to any or all of these steps are known in the art and include cancer cell lines: 1) KM12, 2) CUTO3.29, 3) MO91, 4) HEL. Mouse models applicable to any or all of these steps are known in the art and include subcutaneous xenograft models, allotopic models, patient-derived xenograft models, and patient-derived allotopic models.

[0742] As a non-limiting example, detailed synthetic schemes are described in specific exemplary divalent compound embodiments.

[0743] Pharmaceutically acceptable isotopic variations of the compounds disclosed herein are considered, which can be synthesized using conventional methods known in the art or methods corresponding to those described in the examples (replacing suitable reagents with suitable isotopic variations of those reagents). Specifically, an isotopic variation is a compound in which at least one atom is replaced by an atom of the same atomic number but with a different atomic mass than those commonly found in nature. Useful isotopes are known in the art, for example, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. Thus, exemplary isotopes include, for example, 2 H, 3 H, 13 C 14 C 15 N、 17 O、 18 O、 32 P, 35 S, 18 F and 36 Cl.

[0744] Isotopic variations (e.g., containing) 2 Isotopic variations of H can offer therapeutic advantages due to increased metabolic stability, such as prolonged in vivo half-life or reduced dose requirements. Additionally, certain isotopic variations (especially those containing radioactive isotopes) can be used in drug or substrate tissue distribution studies. Given its ease of introduction and convenient detection, radioactive isotope tritium ( 3 H) and carbon-14 ( 14 C) This is especially useful for this purpose.

[0745] Pharmaceutically acceptable solvates of the compounds disclosed herein are considered. Solvates can be generated, for example, by replacing the solvent used to crystallize the compounds disclosed herein with an isotopic variation (e.g., replacing H2O with D2O, acetone with d6-acetone, or DMSO with d6-DMSO).

[0746] Pharmaceutically acceptable fluorination variants of the compounds disclosed herein are considered, which can be synthesized using conventional methods known in the art or methods corresponding to those described in the examples (substituting suitable reagents with suitable fluorination variants of those reagents). Specifically, a fluorination variant is a compound in which at least one hydrogen atom is replaced by a fluorine atom. Fluorination variants can provide therapeutic advantages resulting from greater metabolic stability, such as prolonged in vivo half-life or reduced dose requirements.

[0747] Pharmaceutically acceptable prodrugs of the compounds disclosed herein are considered, which can be synthesized using conventional methods known in the art or methods corresponding to those described in the examples (e.g., converting hydroxyl or carboxylic acid groups to ester groups). As used herein, "prodrug" refers to a compound that can be converted into a therapeutic agent by certain chemical or physiological processes (e.g., enzymatic processes and metabolic hydrolysis). Therefore, the term "prodrug" also refers to a precursor of a pharmaceutically acceptable biologically active compound. A prodrug may be inactive, i.e., an ester, when administered to a subject, but can be converted into an active compound in vivo, for example, by hydrolysis to a free carboxylic acid or a free hydroxyl group. Prodrug compounds generally offer advantages such as solubility, tissue compatibility, or delayed release in organisms. The term "prodrug" is also intended to include any covalently bonded carrier that releases the active compound in vivo when such a prodrug is administered to a subject. Prodrugs of active compounds can be prepared by modifying the functional groups present in the active compound in such a way that the modification is cleaved into the parent active compound in conventional procedures or in vivo. Prodrugs include compounds in which a hydroxyl, amino, or thiol group is bonded to any group, and when the prodrug of the active compound is administered to a subject, that group cleaves to form a free hydroxyl, free amino, or free thiol group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols in the active compound, or acetamide, formamide, and benzamide derivatives of amine functional groups in the active compound, etc.

[0748] Characterization of exemplary divalent compounds

[0749] Specific exemplary divalent compounds were characterized in KM12 cells. KM12 cells expressing the TPM3-TRKA fusion protein were treated for 16 hours with 100 nM entrec or the divalent compounds disclosed herein (CPD-001–CPD-065). Cells were collected, lysed, and analyzed by Western blot using TRK protein-specific antibodies. GAPDH was included as a loading control. DMSO was used as a negative control. After 16 hours of treatment with the various divalent compounds at 100 nM, the level of TPM3-TRKA in KM12 cells was significantly reduced. Figure 1 A-1C).

[0750] Taking CPD-027, CPD-053, and CPD-060 as examples, it was found that the bifunctional compounds were particularly effective in reducing TPM3-TRKA protein levels in KM12 cells. Figure 1 A-1C). Treatment with 100 nM CPD-027, CPD-053, or CPD-060 at various time points readily detected significant degradation of TPM3-TRKA in KM12 cells 15 minutes after the addition of the divalent compound. Figure 2In addition, a selected group of compounds showed the ability to induce significant degradation of TPM3-TRKA at concentrations below 10 nM. Figure 5 , 6 And 13). Besides TPM3-TRKA, other TRK fusion proteins such as AGBL4-TRKB and ETV6-TRKC also underwent degradation induced by the dual-specificity compound ( Figure 7 The interaction with cereblon is crucial for the ability of dual-specific compounds to induce TRK protein degradation, as chemical modifications that disrupt cereblon binding eliminate TRKA degradation induced by TR-123. Figure 8 Degradation also depends on the ubiquitin-proteasome system, as it can be neutralized by co-administration of the proteasome inhibitor MG-132 and bortezomib, the lagin E3 ligase inhibitor MLN4924, or high concentrations of the competitive cereblon-binding pomalidomide. Figure 9 These findings collectively demonstrate that bispecific compounds induce the degradation of TRK family proteins through a mechanism mediated by cereblon, hysteresis E3 ligase, and proteasome specificity.

[0751] In addition to cultured cells, athymic nude mice bearing KM12 subcutaneous xenograft tumors were treated intraperitoneally with 10, 20, or 50 mg / kg CPD-053, CPD-027, or CPD-060. Four hours after administration, animals were sacrificed, and immunoblotting analysis was performed on TPM3-TPKA in homogenized xenograft tumor masses. Labels "a" or "b" represent two different samples of the same xenograft tumor. Within 4 hours of single-dose administration, the divalent compounds CPD-027, CPD-053, and CPD-060 demonstrated a significant ability to reduce TPM3-TRKA protein levels in KM12 subcutaneous xenograft tumors. Other compounds, including TR-123, TR-171, TR-172, TR-173, TR-177, and TR-181, also showed activity in inducing TPM3-TRKA degradation in KM12 subcutaneous tumors via intraperitoneal or oral administration. Figure 10 ).

[0752] To investigate the pharmacokinetics of a bifunctional compound, exemplified by TR-123, a single intraperitoneal injection of 20 mg / kg was evaluated. Plasma concentrations of TR-123 reported at each time point represent averages obtained from three experimental animals. Our data demonstrate significant plasma exposure to TR-123 over 12 hours. Figure 11In addition, the oral bioavailability of TR-198 at a dose of 2 mg / kg administered intravenously and 20 mg / kg administered orally in mice was evaluated. Data showed that the oral bioavailability of TR-198 in mice was approximately 16%. Figure 14 ).

[0753] TRK kinase activity is known to play a crucial role in tumors expressing TRK fusion proteins, as TRK kinase inhibitors impair cell proliferation, survival, and induce significant clinical responses (Amatu et al., 2016; Drilon et al., 2018; Drilon et al., 2017; Khotskaya et al., 2017). KM12 cells seeded in 96-well plates were treated with 500 nM entrectinib or the divalent compounds CPD-010, CPD-053, and CPD-057 after a 12-fold serial dilution. Cell viability was determined three days post-treatment using the CellTiter-Glo kit according to the manufacturer's instructions. Cell viability was normalized relative to the mean of three replicates of untreated cells. Dose-dependent responses were analyzed using least-squares nonlinear regression with GraphPad Prism 5.0 software. Each data point in the figure represents the mean ± standard deviation of the three technical replicates. The divalent compound also dose-dependently inhibited the viability of KM12 cells expressing TPM3-TRKA, taking CPD-010, CPD-053, and CPD-057 as examples. Figure 4 A). More specifically, all IC50 values ​​in KM12 cells 50 Divalent compounds with values ​​less than 1000 nM all induce the degradation of TPM3-TRKA. Figure 1 (and Tables 2-4). In contrast, when KM12 or H358 cells were treated with 1000 nMCPD-053 after a 3-fold serial dilution at 8 points, taking CPD-053 as an example, the divalent compound did not affect the cell viability of KRAS mutant H358 cells. Figure 4 B). Finally, taking CPD-060, TR-181, and TR-198 as examples, the application of divalent compounds significantly inhibited the growth of KM12 subcutaneous xenograft tumors without inducing significant weight loss. Figure 12 and 15 In summary, these results indicate that the divalent compound impairs the proliferation, survival, and tumorigenic potential of KM12 cells by specifically inducing the degradation of TPM3-TRKA.

[0754] The role of NGF and its major receptor TRKA in pain sensation is well-recognized (Denk et al., 2017). Targeting TRKA represents a promising therapeutic strategy for chronic pain management. For example, the divalent compound TR-123 has shown the ability to induce significant degradation of full-length TRKA, similar to the TPM3-TRKA fusion. Figure 8 and 9 The analgesic activity of the divalent compound was evaluated using a widely used chronic pain model associated with osteoarthritis. Osteoarthritis was induced in the right knee of adult male rats or guinea pigs following injection of monoiodoacetate. One week later, the animals were treated with TR-181 as a positive control with ibuprofen. Pain sensation was assessed using a disuse instrument by weight distribution between the injured limb and the contralateral limb. The data showed that TR-181 had significant analgesic activity in the osteoarthritis models in rats and guinea pigs. Figure 16 ).

[0755] Definition of terminology

[0756] As used herein, the terms “comprising” and “including” are used in their open, non-restrictive sense.

[0757] "Alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms and without any degree of unsaturation. Alkyl groups can contain one, two, three, four, five, six, seven, eight, nine, ten, one, twelve, threeteen, fourteen, fifteen, or sixteen carbon atoms. In some embodiments, the alkyl group contains 1 to 15 carbon atoms (e.g., C1-C1). 15 Alkyl groups. In some embodiments, the alkyl group comprises 1 to 13 carbon atoms (e.g., C1-C1). 13 Alkyl group. In some embodiments, the alkyl group comprises 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises 5 to 15 carbon atoms (e.g., C5-C6 alkyl). 15 Alkyl group. In other embodiments, the alkyl group comprises 5 to 8 carbon atoms (e.g., C5-C8 alkyl). The alkyl group is attached to the rest of the molecule by a single bond, such as methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), pentyl, 3-methylhexyl, 2-methylhexyl, etc.

[0758] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms and containing at least one double bond. Alkenyl groups can contain two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms (e.g., C2-C). 12Alkenyl group. In some embodiments, the alkenyl group comprises 2 to 8 carbon atoms (e.g., C2-C8 alkenyl). In some embodiments, the alkenyl group comprises 2 to 6 carbon atoms (e.g., C2-C6 alkenyl). In other embodiments, the alkenyl group comprises 2 to 4 carbon atoms (e.g., C2-C4 alkenyl). The alkenyl group is connected to the rest of the molecule by a single bond, such as vinyl, propenyl (i.e., allyl), butenyl, pentenyl, pent-1,4-dienyl, etc.

[0759] As used in this article, the term "allyl" refers to the –CH2CH=CH2 group.

[0760] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms and containing at least one triple bond. The alkynyl group may contain two, three, four, five, six, seven, eight, nine, ten, one, twelve, threeteen, fourteen, fifteen, or sixteen carbon atoms. In some embodiments, the alkynyl group contains 2 to 12 carbon atoms (e.g., C2-C). 12 The alkynyl group (e.g., 2-C8 alkynyl). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (e.g., C2-C6 alkynyl). In other embodiments, the alkynyl group has 2 to 4 carbon atoms (e.g., C2-C4 alkynyl). The alkynyl group is attached to the rest of the molecule by a single bond. Examples of such groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, etc.

[0761] As used herein, the term "alkoxy" refers to an alkyl group as defined herein, which is attached to the rest of the molecule by an oxygen atom. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, etc.

[0762] As used herein, the term "aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms. An aryl group may contain 6 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to Hückel theory. In some embodiments, the aryl group contains 6 to 14 carbon atoms (i.e., C6-C6). 14 Aryl group). In some embodiments, the aryl group comprises 6 to 10 carbon atoms (i.e., C6-C1). 10 Aryl groups). Examples of such groups include, but are not limited to, phenyl, fluorenyl, and naphthyl groups. As used herein, the terms "Ph" and "phenyl" refer to the -C6H5 group.

[0763] The term "heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group comprising 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., it comprises a cyclic, delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryls include fused or bridged ring systems. In some embodiments, a heteroaryl refers to a group derived from a 3- to 10-membered aromatic ring group (3-10-membered heteroaryl). In some embodiments, a heteroaryl refers to a group derived from a 5- to 7-membered aromatic ring (5-7-membered heteroaryl). Heteroaryls include fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heteroaryl group is connected to the remainder of the molecule via any atom in the ring. Examples of such groups include, but are not limited to, pyridinyl, imidazole, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indoleyl, benzimidazolyl, benzofuranyl, cenolinyl, indazole, indazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindoleyl, pteridineyl, purineyl, oxadiazolyl, thiadiazolyl, furazonyl, benzofuranyl, benzothiophene, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphthidyl, furanylpyridinyl, etc. In some embodiments, the heteroaryl group is linked to the rest of the molecule via a ring carbon atom. In some embodiments, the heteroaryl group is linked to the rest of the molecule via a nitrogen atom (N-linked) or a carbon atom (C-linked). For example, the pyrrole-derived group can be pyrrole-1-yl (N-linked) or pyrrole-3-yl (C-linked). Similarly, the imidazole-derived group can be imidazole-1-yl (N-linked) or imidazole-3-yl (C-linked).

[0764] As used herein, the term "heterocyclic group" refers to a non-aromatic, monocyclic, bicyclic, tricyclic, or tetracyclic group having a total of 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 atoms in its ring system, and containing 3 to 12 carbon atoms and 1 to 4 heteroatoms, each independently selected from O, S, and N, provided that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms. Heterocyclic groups can include fused ring, bridged ring, or spirocyclic systems. In some embodiments, the heterocyclic group contains 3 to 10 ring atoms (3-10-membered heterocyclic group). In some embodiments, the heterocyclic group contains 3 to 8 ring atoms (3-8-membered heterocyclic group). In some embodiments, the heterocyclic group contains 4 to 8 ring atoms (4-8-membered heterocyclic group). In some embodiments, the heterocyclic group contains 3 to 6 ring atoms (3-6-membered heterocyclic group). Heterocyclic groups may contain oxygen substituents at any available atoms, which will result in a stable compound. For example, such a group may contain an oxygen atom at a available carbon or nitrogen atom. If chemically feasible, such a group may contain more than one oxygen substituent. Additionally, it should be understood that when such a heterocyclic group contains a sulfur atom, the sulfur atom may be oxidized by one or two oxygen atoms to yield a sulfoxide or sulfone. An example of a 4-membered heterocyclic group is an azirrobutylene (derived from azirrobutylane). An example of a 5-membered heterocyclic group is a pyrrolidinyl. An example of a 6-membered heterocyclic group is a piperidinyl. An example of a 9-membered heterocyclic group is an indoleyl. An example of a 10-membered heterocyclic group is a 4H-quinazinyl. Other examples of such heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholino, thiomorpholino, thiazolyl, piperazine, azacyclic butyl, oxacyclic butyl, thiocyclic butyl, high-piperidinyl, oxacyclic heptyl, thiepanyl, and oxacyclic heptyl. basalt, diazoxide Basic, sulfur-nitrogen The aryl group can be 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxacyclopentyl, pyrazolinyl, dithiohexyl, dithiohexyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, quinazinyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, and 1-oxo-2,8-diazaspiro[4.5]dec-8-yl. The heteroaryl group can be attached to the rest of the molecule via a carbon atom (C-linked) or a nitrogen atom (N-linked). For example, the groups derived from piperazine can be piperazine-1-yl (N-linked) or piperazine-2-yl (C-linked).

[0765] The term "cycloalkyl" refers to a saturated, monocyclic, bicyclic, tricyclic, or tetracyclic group having a total of 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms in its ring system. Cycloalkyl groups can be fused, bridged, or spirocyclic. In some embodiments, the cycloalkyl group comprises 3 to 8 carbon ring atoms (i.e., C3-C8 cycloalkyl). In some embodiments, the cycloalkyl group comprises 3 to 6 carbon ring atoms (i.e., C3-C6 cycloalkyl). Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, etc.

[0766] The term "cycloalkylene" refers to a bidentate group obtained by removing a hydrogen atom from a cycloalkyl ring as defined above. Examples of such groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, and cycloheptylene.

[0767] As used herein, the term "spirocyclic" has its conventional meaning, referring to any ring system comprising two or more rings, wherein the two rings share a common ring carbon. Each ring of a spirocyclic ring system as defined herein independently comprises 3 to 20 ring atoms. Preferably, they have 3 to 10 ring atoms. Non-limiting examples of spirocyclic systems include spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.

[0768] The term "cyano" refers to the -C≡N group.

[0769] The "aldehyde" group refers to the –C(O)H group.

[0770] "Alkoxy" refers to -O-alkyl as defined herein.

[0771] "Alkoxycarbonyl" refers to -C(O)-alkoxy group as defined in this article.

[0772] “alkylaminoalkyl” refers to -alkyl-NR-alkyl as defined herein.

[0773] "alkylsulfonyl" refers to -SO2 alkyl as defined herein.

[0774] "Amino" refers to the optional substitution of -NH2.

[0775] “Aminoalkyl” refers to -alkyl-amino as defined herein.

[0776] "Amino carbonyl" refers to -C(O)-amino as defined in this article.

[0777] "Arylalkyl" refers to -alkylaryl, where alkyl and aryl are as defined herein.

[0778] "Aryloxy group" refers to -O-aryl and -O-heteroaryl as defined herein.

[0779] "Aryloxycarbonyl" refers to -C(O)-aryloxy as defined in this article.

[0780] "Arylsulfonyl" refers to -SO2 aryl as defined in this article.

[0781] "Carbonyl" refers to the -C(O)- group as defined in this article.

[0782] The "carboxylic acid" group refers to the –C(O)OH group.

[0783] “Cycloalkoxy” refers to -O-cycloalkyl as defined herein.

[0784] The "halogenated" or "halogenated" group refers to fluorine, chlorine, bromine, or iodine.

[0785] "Halogenated alkyl" refers to an alkyl group that has been replaced by one or more halogen atoms.

[0786] "Hydroxy group" refers to the -OH group.

[0787] "Nitro" refers to the -NO2 group.

[0788] "Oxide" refers to the =O substituent.

[0789] "Trihaloalkyl" refers to a methyl group that has been replaced by three halogen atoms.

[0790] The term "substituted" means that the specified group or portion has one or more substituents, which are independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halogen, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo, -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C -4 alkyl), -CONH (C1-C4 alkyl), -CONH2, -NHC(O) (C1-C4 alkyl), -NHC(O) (phenyl), -N(C1-C4 alkyl)C(O) (C1-C4 alkyl), -N(C1-C4 alkyl)C(O) (phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2 (C1-C4 alkyl), -SO2 (phenyl), -SO2 (C1-C4 haloalkyl), -SO2NH2, -SO2NH (C1-C4 alkyl), -SO2NH (phenyl), -NHSO2 (C1-C4 alkyl), -NHSO2 (phenyl) and -NHSO2 (C1-C4 haloalkyl).

[0791] The term "empty" means that there are no atoms or parts present, but rather that there are bonds between adjacent atoms in the structure.

[0792] The term "optionally substituted" means that the specified group may be unsubstituted or substituted by one or more substituents as defined herein. It should be understood that in the compounds of this invention, when a group is referred to as "unsubstituted" or "substituted" by a group with fewer valence positions than those filling all the atoms in the compound, the remaining valence positions on such a group are filled with hydrogen. For example, if a C6 aryl group, also referred to herein as "phenyl," is substituted by another substituent, those skilled in the art will understand that such a group leaves four open positions on the carbon atoms of the C6 aryl ring (six initial positions, minus one position attached to the remainder of the compound and another substituent, leaving four open positions). In such a case, each of the remaining four carbon atoms bonds with a hydrogen atom to fill its valence position. Similarly, if a C6 aryl group in the compounds of this invention is referred to as "disubstituted," those skilled in the art will understand that this means that three carbon atoms of the C6 aryl group remain unsubstituted. Each of these three unsubstituted carbon atoms bonds with a hydrogen atom to fill its valence position.

[0793] As used in this paper, the same symbols in different general formulas represent different definitions. For example, the definition of R1 in Formula 1 is defined for Formula 1, while the definition of R1 in Formula 6 is defined for Formula 6.

[0794] As used in this article, when m (or n or o or p) is defined by a range, for example, "m is 0 to 15" or "m = 0-3" means that m is an integer from 0 to 15 (i.e., m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15), or m is an integer from 0 to 3 (i.e., m is 0, 1, 2 or 3), or any integer within the defined range.

[0795] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. A pharmaceutically acceptable salt of any of the divalent compounds described herein is intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0796] "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free base, are not biologically or otherwise undesirable, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid. It also includes salts formed from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Salts of amino acids such as arginine salts, gluconates, and galacturons are also involved (see, for example, Berge SM et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1–19 (1997), which is incorporated herein by reference in its entirety). Acid addition salts of basic compounds can be prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt, according to methods and techniques familiar to skilled technicians.

[0797] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the bioavailability and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts can be formed from metals or amines, such as alkali metals and alkaline earth metals, or organic amines. Salts derived from organic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases include, but are not limited to, salts of the following organic bases: primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucosamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., ibid.

[0798] Pharmaceutical Composition

[0799] In some respects, the compositions and methods described herein include pharmaceutical compositions comprising one or more of the divalent compounds disclosed herein, and the preparation and use of pharmaceuticals. This also includes the pharmaceutical compositions themselves.

[0800] In some aspects, the compositions disclosed herein may comprise other compounds, pharmaceuticals, or agents for treating cancer. For example, in some cases, the pharmaceutical compositions disclosed herein may be combined with one or more (e.g., one, two, three, four, five, or fewer than ten) compounds. Such additional compounds may include, for example, conventional chemotherapeutic agents or any other cancer treatments known in the art. When co-administered, the divalent compounds disclosed herein may be used synergistically with conventional chemotherapeutic agents or any other cancer treatments known in the art to produce mechanistically additive or synergistic therapeutic effects.

[0801] In some respects, the pH of the compositions disclosed herein can be adjusted using pharmaceutically acceptable acids, bases, or buffer solutions to enhance the stability of the divalent compound or its delivery form.

[0802] Pharmaceutical compositions typically comprise pharmaceutically acceptable excipients, adjuvants, or mediators. As used herein, the phrase "pharmaceutically acceptable" means a molecular entity or composition that is generally considered physiologically tolerable and, when administered to humans, generally does not produce allergic or similar adverse reactions such as stomach upset or dizziness. Pharmaceutically acceptable excipients, adjuvants, or mediators are substances that can be administered to a patient in conjunction with the compounds of the present invention without impairing their pharmacological activity and are non-toxic when administered in doses sufficient to deliver a therapeutic amount of the compound. Exemplary conventional non-toxic pharmaceutically acceptable excipients, adjuvants, and mediators include, but are not limited to, saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents compatible with drug administration.

[0803] In particular, pharmaceutically acceptable excipients, adjuvants, and mediators that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in the form of glycerides, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin. Cyclodextrins such as α-, β-, and γ-cyclodextrins can also be advantageously used to enhance the delivery of compounds of the general formula described herein.

[0804] Depending on the dosage form chosen to deliver the divalent compound disclosed herein, various pharmaceutically acceptable excipients, adjuvants, and mediators may be used. In the case of tablets for oral administration, pharmaceutically acceptable excipients, adjuvants, and mediators include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When administered orally as an aqueous suspension or emulsion, the active ingredient is suspended or dissolved in an oil phase in combination with an emulsifier or suspending agent. If desired, certain sweeteners, flavoring agents, or coloring agents may be added.

[0805] As used herein, the divalent compounds disclosed herein are defined as including their pharmaceutically acceptable derivatives or prodrugs. "Pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, solvate, or prodrug of the disclosed compounds or agents, such as carbamates, esters, phosphates, salts of esters, or other derivatives, which, upon administration to a recipient, can (directly or indirectly) provide the compound described herein or its active metabolites or residues. Particularly advantageous derivatives and prodrugs are those that, when administered to a subject, increase the bioavailability of such compounds relative to the parent species (e.g., by making orally administered compounds more readily absorbed into the bloodstream) or enhance the delivery of the parent compound to biological compartments (e.g., the brain or lymphatic system). Preferred prodrugs include derivatives in which groups enhancing water solubility or active transport via the intestinal membrane are attached to the general formula structure described herein. Such derivatives are recognized by those skilled in the art and require no extensive experimental work. Nevertheless, reference is made to the following teaching: Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Vol. 1: Principles and Practice, which is incorporated herein by reference to the extent that it teaches such derivatives.

[0806] The divalent compounds disclosed herein include pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, racemic diastereomers, mixtures of racemic diastereomers, and meso compounds, as well as pharmaceutically acceptable salts, solvates, morphological forms, or deuterated derivatives thereof.

[0807] In some aspects, the pharmaceutical compositions disclosed herein may comprise an effective amount of one or more divalent compounds. As used herein, the terms "effective amount" and "effective treatment" refer to the amount or concentration of one or more compounds or pharmaceutical compositions used for a period of time (including short-term or long-term administration, and periodic or continuous administration) that effectively induces the desired effect or physiological outcome (e.g., cell growth, cell proliferation, or treatment or prevention of cancer) within the scope of administration. In some aspects, the pharmaceutical composition may further comprise an amount of one or more additional compounds, drugs, or agents (e.g., conventional chemotherapeutic agents) for the treatment of cancer that effectively induce the desired effect or physiological outcome (e.g., cell growth, cell proliferation, or treatment or prevention of cancer).

[0808] In some respects, the pharmaceutical compositions disclosed herein can be formulated for sale in the United States, imported into the United States, or exported from the United States.

[0809] Administration of the pharmaceutical composition

[0810] The pharmaceutical compositions disclosed herein can be formulated or adapted for administration to subjects via any route, such as any route approved by the Food and Drug Administration (FDA). Exemplary methods are described in the FDA Data Standards Manual (DSM) (available at http: / / www.fda.gov / Drugs / DevelopmentApprovalProcess / FormsSubmissionRequirements / ElectronicSubmissions / DataStandardsManualmonographs). In particular, the pharmaceutical compositions can be formulated for administration via oral, parenteral, or transdermal delivery. As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0811] For example, the pharmaceutical compositions disclosed herein can be administered, for example, topically, rectally, nasally (e.g., by inhalation spray or nebulizer), buccally, vaginally, subcutaneously (e.g., by injection or by implanted reservoir) or ocularly.

[0812] For example, the pharmaceutical compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, emulsions, aqueous suspensions, dispersions, and solutions.

[0813] For example, the pharmaceutical compositions of the present invention can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus will melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0814] For example, the pharmaceutical compositions of the present invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the field of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons or other solubilizers or dispersants known in the art.

[0815] For example, the pharmaceutical compositions of the present invention can be administered by injection (e.g., as a solution or powder). Such compositions can be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable articles can also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injections, and naturally occurring, pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated forms, are also useful. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and / or suspensions, or carboxymethyl cellulose or similar dispersants. Other commonly used surfactants such as Tween, Spans, or other similar emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0816] In some aspects, the effective dosage of the pharmaceutical composition of the present invention may include, but is not limited to, for example, about 0.00001, 0.0001, 0.001, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2500, 5000 or 10000 mg / kg / day, or as required by the specific pharmaceutical composition.

[0817] When the pharmaceutical compositions disclosed herein comprise a combination of the divalent compound described herein with one or more adjunct compounds (e.g., one or more adjunct compounds, drugs, or agents for the treatment of cancer or any other condition or disease, including those known to be cancer-related or caused by cancer), the dose levels of both the divalent compound and the adjunct compound can be from about 1% to 100% of the dose typically administered in a monotherapy regimen, more preferably from about 5% to 95%. The adjunct agents may be administered separately from the compounds of the invention as part of a multi-dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds of the invention in a single composition.

[0818] In some respects, the pharmaceutical compositions disclosed herein may be included in containers, packages or dispensers together with instructions for use.

[0819] Treatment

[0820] The methods disclosed herein are intended to administer an effective amount of the compound or composition to achieve the desired or stated effect. Typically, the compounds or compositions of the invention will be administered about once to about six times daily, or alternatively or additionally, as a continuous infusion. Such administration can be used for chronic or acute therapy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific route of administration. Typical products will contain about 5% to about 95% (w / w) of the active compound. Alternatively, such products may contain about 20% to about 80% of the active compound.

[0821] In some respects, this article provides divalent compounds described herein for the prevention or treatment of diseases or conditions.

[0822] In some aspects, this document provides the divalent compounds described herein for the treatment or prevention of one or more diseases or conditions disclosed herein in a subject of need. In some embodiments, the disease or condition is a TRK-mediated disease or condition. In some embodiments, the disease or condition is caused by TRK expression, mutation, or fusion. In some embodiments, the disease or condition includes non-small cell lung cancer, colorectal cancer, gastric cancer, liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, bladder cancer, endometrial cancer, prostate cancer, low-grade glioma, glioblastoma, spitzoid carcinoma, soft tissue sarcoma, papillary thyroid carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesodermal nephroma, secretory breast cancer, breast analogue secretory carcinoma, acute myeloid leukemia, ductal carcinoma, pulmonary neuroendocrine tumor, pheochromocytoma, and Wilms' tumor.In some implementations, the disease or condition includes cancer, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, and other diseases, including but not limited to neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric cancer, lung cancer, liver cancer, uterine cancer, adrenal cancer, biliary tract cancer, colorectal cancer, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, breast cancer, esophageal cancer, bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secretory breast cancer, secretory type breast cancer, salivary gland cancer, papillary thyroid carcinoma, ductal carcinoma, adult myeloid leukemia, acute myeloid leukemia, etc. Leukemia, large cell neuroendocrine tumors, pulmonary neuroendocrine tumors, sarcomas, pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenital mesodermal nephroma, secretory breast cancer, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system vegetations, osteosarcoma, synovial sarcoma, liposarcoma, soft tissue alveolar sarcoma, Spitzoid carcinoma, Wilms' tumor, lymphomas (e.g., including Hodgkin's lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma), inflammatory lung diseases ( Examples of pain include asthma, inflammatory bowel diseases (such as ulcerative colitis and Crohn's disease), inflammatory skin diseases (such as atopic dermatitis, eczema, and psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, osteoarthritis pain, chronic low back pain, osteoporotic low back pain, fracture pain, rheumatoid arthritis pain, postherpetic neuralgia, diabetic neuropathy pain, fibromyalgia, pancreatitis pain, interstitial cystitis pain, endometriosis pain, irritable bowel syndrome pain, migraine, pulpitis pain, interstitial cystitis pain, bladder pain syndrome, central pain syndrome, postoperative pain syndrome, and bone and joint pain. Joint pain, recurrent movement pain, toothache, myofascial pain, perioperative pain, dysmenorrhea, myofascial pain, angina pectoris, headache, primary hyperalgesia, secondary hyperalgesia, primary anomalous pain, secondary anomalous pain, other pain caused by central sensitization, generalized pruritus, localized pruritus, senile pruritus, pruritus gravidarum, anal pruritus, vulvar pruritus, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic disease, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelinating diseases, and myelination disorders. In some implementations, the disease or condition is a recurrent disease. In some implementations, the disease or condition is recurrent cancer.In some implementations, the disease or condition is refractory to one or more prior treatments.

[0823] In some respects, this article provides the use of divalent compounds in the preparation of medicaments for the prevention or treatment of one or more of the diseases or conditions disclosed herein.

[0824] In some aspects, the disclosed methods include administering a therapeutically effective amount of one or more of the compounds or compositions described herein to a subject who requires or has been identified as requiring such treatment (e.g., a mammalian subject, such as a human subject). In some aspects, the disclosed methods include selecting a subject and administering an effective amount of one or more of the compounds or compositions described herein to that subject, and optionally repeating the administration as needed for the prevention or treatment of cancer.

[0825] In some aspects, subject selection may include obtaining a sample from a subject (e.g., a candidate subject) and testing that sample to indicate that the subject is suitable for selection. In some aspects, for example, a healthcare professional may identify or determine that a subject has previously had a condition or disease, has an elevated risk of having a condition or disease, or has a condition or disease. In some aspects, suitable subjects include, for example, subjects who have a condition or disease, or who have had a condition or disease but have resolved the disease or aspects thereof, exhibiting symptom relief (e.g., relative to other subjects with the same condition or disease (e.g., the majority of subjects)), or prolonged survival under the condition or disease (e.g., relative to other subjects with the same condition or disease (e.g., the majority of subjects)), for example, in an asymptomatic state (e.g., relative to other subjects with the same condition or disease (e.g., the majority of subjects)). In some aspects, a positive immune response against a condition or disease may be determined based on patient records, family history, or criteria for detecting a positive immune response. In some aspects, subject selection may involve multiple parties. For example, a first party may obtain a sample from a candidate subject, while a second party may test that sample. In some respects, subjects may be selected or recommended by medical practitioners (e.g., general practitioners). In some respects, subject selection may include obtaining samples from selected subjects and storing or using those samples in the methods disclosed herein. Samples may include, for example, cells or cell populations.

[0826] In some aspects, treatment methods may include single, multiple, and repeated administration of one or more of the compounds disclosed herein, as needed for the prevention or treatment of any of the diseases or conditions disclosed herein (e.g., TRK-mediated diseases). In some aspects, treatment methods may include assessing the subject's disease level before, during, or after treatment. In some aspects, treatment may continue until a reduction in the subject's disease level is detected.

[0827] As used herein, the term "subject" refers to any animal. In some cases, the subject is a mammal. In other cases, the term "subject" as used herein refers to a human being (e.g., a male, a female, or a child).

[0828] As used herein, the terms “application” or “administration” mean implantation, ingestion, injection, inhalation, or other absorption of a compound or composition, regardless of its form. For example, the methods disclosed herein include administering an effective amount of a compound or composition to achieve a desired or stated effect.

[0829] As used herein, the terms “treatment” or “treatment” mean to partially or completely alleviate, suppress, improve, or reduce a disease or condition suffered by a subject. This means any manner in which one or more symptoms of a disease or condition (e.g., cancer) are improved or otherwise beneficially altered. As used herein, improvement of symptoms of a particular condition (e.g., cancer) means any reduction attributable to or related to treatment by the divalent compounds, compositions, and methods of the present invention, whether permanent or temporary, continuous or transient. In some embodiments, treatment may promote or result in, for example, a reduction (e.g., in the number of tumor cells in the subject) relative to the number of tumor cells before treatment; a decrease (e.g., in the viability (e.g., mean viability) of tumor cells in the subject relative to the viability of tumor cells before treatment; a decrease in the growth rate of tumor cells; a decrease in the rate of local or distant tumor metastasis; or a reduction in one or more symptoms in the subject associated with one or more tumors relative to the symptoms in the subject before treatment.

[0830] As used herein, the terms “prevention” and “avoidance” refer to a reduction in the occurrence of disease or a decreased risk of disease or its associated symptoms in a subject. Prevention can be complete, e.g., the complete absence of disease or pathological cells in the subject. Prevention can also be partial, e.g., disease or pathological cells in the subject occur less frequently, later, or develop more slowly compared to situations where the present invention is not used. In some embodiments, the subject has an increased risk of developing one or more TRK-mediated diseases. Exemplary TRK-mediated diseases that can be treated with divalent compounds include, for example, non-small cell lung cancer, colorectal cancer, gastric cancer, liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, bladder cancer, endometrial cancer, prostate cancer, low-grade glioma, glioblastoma, spitzoid carcinoma, soft tissue sarcoma, papillary thyroid carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesodermal nephroma, secretory breast cancer, breast analogue secretory carcinoma, acute myeloid leukemia, ductal carcinoma, pulmonary neuroendocrine tumor, pheochromocytoma, and Wilms' tumor.Exemplary TRK-mediated diseases treatable with divalent compounds include, for example, cancer, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, and other diseases, including but not limited to neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric cancer, lung cancer, liver cancer, uterine cancer, adrenal cancer, biliary tract cancer, colorectal cancer, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, breast cancer, esophageal cancer, bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secretory breast cancer, secretory type breast cancer, salivary gland cancer, papillary thyroid carcinoma, ductal carcinoma, and adult medullary thyroid carcinoma. Leukemia, acute myeloid leukemia, large cell neuroendocrine tumors, pulmonary neuroendocrine tumors, sarcomas, pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenital mesodermal nephroma, secretory breast cancer, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomyosarcoma, neurofibrosarcoma, central nervous system vegetations, osteosarcoma, synovial sarcoma, liposarcoma, soft tissue alveolar sarcoma, Spitzoid carcinoma, Wilms' tumor, lymphomas (e.g., including Hodgkin's lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic 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, and psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, osteoarthritis pain, chronic low back pain, osteoporotic low back pain, fracture pain, rheumatoid arthritis pain, postherpetic neuralgia, diabetic neuropathy pain, fibromyalgia, pancreatitis pain, interstitial cystitis pain, endometriosis pain, irritable bowel syndrome pain, migraine, pulpitis pain, interstitial cystitis pain, bladder pain syndrome, central pain syndrome, postoperative pain syndrome, bone And joint pain, recurrent motion pain, toothache, myofascial pain, perioperative pain, dysmenorrhea, myofascial pain, angina pectoris, headache, primary hyperalgesia, secondary hyperalgesia, primary anomalous pain, secondary anomalous pain, other pain caused by central sensitization, generalized pruritus, localized pruritus, senile pruritus, pruritus gravidarum, anal pruritus, vulvar pruritus, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic diseases, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelinating diseases and myelination disorders.

[0831] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health status, sex, diet, timing of administration, excretion rate, combination of drugs, disease, severity and duration of the condition or symptoms, the patient’s predisposition to the disease, condition or symptoms, and the judgment of the attending physician.

[0832] An effective amount can be administered by single or multiple doses, application, or dosage. The therapeutically effective amount (i.e., effective dose) of a therapeutic compound depends on the selected therapeutic compound. Furthermore, treatment of a subject with a therapeutically effective amount of the compound or composition described herein may comprise a single treatment or a series of treatments. For example, an effective amount may be administered at least once. The composition may be administered from once or more daily to once or more weekly; including every other day. Those skilled in the art will understand that certain factors can influence the dosage and timing required for effective treatment of a subject, including but not limited to the severity of the disease or condition, prior treatment, the subject's general health or age, and any other pre-existing conditions.

[0833] After administration, the subject can be evaluated to detect, assess, or determine their disease level. In some cases, treatment may continue until a change in the subject's disease level (e.g., a decrease) is detected. Once the patient's condition improves (e.g., the subject's disease level changes (e.g., a decrease)), a maintenance dose of the disclosed compound or composition may be administered if necessary. Subsequently, the dosage or frequency, or both, may be reduced to a level where the improved condition is maintained, for example, based on symptoms. However, in the event of any recurrence of disease symptoms, the patient may require long-term intermittent treatment.

[0834] This disclosure is also described and demonstrated through the following embodiments. However, the use of these and other embodiments anywhere in the specification is merely illustrative and is in no way intended to limit the scope and meaning of the invention or any of the illustrative terms. Similarly, the invention is not limited to any particular preferred embodiment or aspect described herein. In fact, many modifications and variations will become apparent to those skilled in the art upon reading this specification, and such changes can be made without departing from the spirit or scope of the invention. Therefore, the invention is limited only by the items of the appended claims and the full scope of their equivalents.

[0835] Example

[0836] Example 1: 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (linker 1)

[0837]

[0838] A solution of 2-(2,6-dioxadiazine-3-yl)-4-fluoroisoindoline-1,3-dione (1.66 g, 6.0 mmol), tert-butyl (2-aminoethyl)carbamate (1.25 g, 6.6 mmol), and N,N-diisopropylethylamine (2.32 g, 18 mmol) in DMF (12 mL) was heated to 85 °C for 50 min in a microwave reactor. The three batches were combined and diluted with EtOAc (200 mL). The reaction mixture was washed with water and brine. The separated organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with hexane / EtOAc = 1:1) to give tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethyl)carbamate (1.3 g, yield: 16%) as a yellow solid. MS (ESI) m / z = 317.1 [M-100+H] + A solution of (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethyl)tert-butyl carbamate (2.0 g, 4.5 mmol) in DCM (10 mL) and TFA (5 mL) was stirred at room temperature for 2 h. The reaction was concentrated and ground together with EtOAc. The solid precipitate was filtered off. The solid was washed with MTBE and dried to give a yellow solid of 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (linker 1) (1.3 g, yield: 98%). 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),7.85(s,3H),7.45(t,J=7.2Hz,1H),7.19(d,J=7.2Hz,1H),7.10(d,J=7.2Hz,1H),6.84(t,J=6. 4Hz, 1H), 5.07 (dd, J = 5.2, 12.8Hz, 1H), 3.58 (q, J = 6.4Hz, 2H), 3.00 (s, 2H), 2.94-2.85 (m, 1H), 2.62-2.50 (m, 2H), 2.05-2.00 (m, 1H). MS(ESI)m / z=317.1[M+H] + .

[0839] Example 2: 4-((3-aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (linker 2)

[0840]

[0841] Linker 2 was synthesized according to the same procedure as linker 1 described in Example 1. (1.2 g, yield: 11% after two steps). 1 H NMR (400MHz, DMSO-d6)11.11(s,1H),7.74(s,3H),7.62–7.58(m,1H),7.15(d,J=8.4Hz,1H),7.05(d,J=7.2Hz,1H),6.78–6.7 5(m,1H),5.08–5.04(m,1H),3.43–3.36(m,2H),2.90–2.86(m,3H),2.62–2.51(m,2H),2.08–2.01(m,1H),1.86–1.80(m,2H). MS(ESI)m / z=331.1[M+H] + .

[0842] Example 3: 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (linker 3)

[0843]

[0844] Linker 3 was synthesized according to the same procedure as linker 1 described in Example 1. (1.4 g, yield: 15% after two steps). 1 H NMR (400MHz, DMSO-d6)11.11(s,1H),7.84(s,3H),7.62-7.57(m,1H),7.13(d,J=8.4Hz,1H),7.04(d,J=6.8Hz,1H),6.6 2(s,1H),5.08-5.04(m,1H),3.34(s,2H),2.90-2.83(m,3H),2.62-2.51(m,2H),2.06-2.01(m,1H),1.65-1.60(m,4H). MS(ESI)m / z=345.1[M+H]+.

[0845] Example 4: 4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (linker 4)

[0846]

[0847] Linker 4 was synthesized according to the same procedure as linker 1 described in Example 1. (2.3 g, yield: 26% after two steps). 1H NMR (400MHz, DMSO-d6) δ11.14(s,1H),7.72(s,3H),7.61–7.57(m,1H),7.10(d,J=8.4Hz,1H),7.03(d,J=7.2Hz,1H),6.56–6.53(m,1H) ,5.07–5.03(m,1H),3.32–3.28(m,2H),2.90–2.78(m,3H),2.62–2.51(m,2H),2.05–1.90(m,1H),1.62–1.54(m,4H),1.41–1.37(m,2H). MS(ESI)m / z=359.1[M+H] + .

[0848] Example 5: 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (linker 5)

[0849]

[0850] Linker 5 was synthesized according to the same procedure as linker 1 described in Example 1. (1.8 g, yield: 20% after two steps). 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),7.76(s,3H),7.58(t,J=7.2Hz,1H),7.10(d,J=8.4Hz,1H),7.03(d,J=7.2Hz,1H),6.54(t,J=6.0Hz, 1H),5.07–5.03(m,1H),3.37–3.27(m,2H),2.88–2.78(m,3H),2.61–2 .50(m,2H),2.04–2.01(m,1H),1.57–1.52(m,4H),1.40–1.30(m,4H). MS(ESI)m / z=373.1[M+H] + .

[0851] Example 6: 4-((7-aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (linker 6)

[0852]

[0853] Linker 6 was synthesized according to the same procedure as linker 1 described in Example 1. (2.0 g, yield: 25% after two steps). 1H NMR (400MHz, DMSO-d6) δ11.05(br,1H),7.94–7.56(m,4H),7.10–7.02(m,2H),6.52(t,J=6.0Hz,1H),5.07–5.02(m,1H),3.32–3 .27(m,2H),2.88–2.77(m,1H),2.75–2.61(m,2H),2.60–2.50(m,2H),2.04–2.02(m,1H),1.59–1.50(m,4H),1.35–1.30(m,6H). MS(ESI)m / z=387.2[M+H] + .

[0854] Example 7: 4-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (linker 7)

[0855]

[0856] Linker 7 was synthesized according to the same procedure as linker 1 described in Example 1. (1.1 g, yield: 18% after two steps). 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),7.69–7.56(m,4H),7.09(d,J=8.4Hz,1H),7.03(d,J=6.8Hz,1H),6.52(t,J=6.0Hz,1H),5.07–5.03 (m,1H),3.34–3.26(m,2H),2.89–2.85(m,1H),2.76(s,2H),2.61–2.56(m,2H),2.04–2.00(m,1H),1.59–1.49(m,4H),1.35–1.27(m,8H). MS(ESI)m / z=401.2[M+H] + .

[0857] Example 8: 4-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (linker 8)

[0858]

[0859] Linker 8 was synthesized according to the same procedure as linker 1 described in Example 1. (2.0 g, yield: 23% after two steps). 1H NMR (400MHz, DMSO-d6) δ10.10(s,1H),7.88(s,3H),7.60(t,J=8.0Hz,1H),7.17(d,J=8.4Hz,1H),7.06(d,J=6.8Hz,1H),6.40(d,J=5.6Hz,1H), 5.05(dd,J=5.2,12.8Hz,1H),3.67–3.62(m,4H),3.54–3.50(m,2H),3. 00(s,2H),2.90–2.85(m,1H),2.62–2.50(m,2H),2.03(t,J=7.6Hz,1H). MS(ESI)m / z=361.1[M+H] + .

[0860] Example 9: 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (linker 9)

[0861]

[0862] Linker 9 was synthesized according to the same procedure as linker 1 described in Example 1. (1.1 g, yield: 17% after two steps). 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.84(s,3H),7.62–7.58(m,1H),7.15(d,J=8.8Hz,1H),7.05(d,J=6.8Hz,1H),6.62–6. 59(m,1H),5.08–5.04(m,1H),3.65–3.59(m,8H),3.50–3.46(m,2H),2.97–2.86(m,3H),2.62–2.51(m,2H),2.05–1.99(m,1H). MS(ESI)m / z=405.2[M+H] + .

[0863] Example 10: 4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (linker 10)

[0864]

[0865] Linker 10 was synthesized according to the same procedure as linker 1 described in Example 1. (1.3 g, yield: 17% after two steps). 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.83(s,3H),7.61–7.57(m,1H),7.15(d,J=8.8Hz,1H),7.05(d,J=6.8Hz,1H), 6.62–6.59(m,1H),5.08–5.04(m,1H),3.64–3.45(m,14H),2.97–2.86(m,3H),2.62–2.51(m,2H),2.08–2.01(m,1H). MS(ESI)m / z=449.2[M+H] + .

[0866] Example 11: 4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (linker 11)

[0867]

[0868] Linker 11 was synthesized according to the same procedure as linker 1 described in Example 1. (1.2 g, yield: 16% after two steps). 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.84(s,3H),7.61–7.57(m,1H),7.15(d,J=8.8Hz,1H),7.05(d,J=6.8Hz,1 H),6.61(s,1H),5.08–5.04(m,1H),3.64–3.47(m,18H),2.99–2.86(m,3H),2.62–2.51(m,2H),2.08–2.01(m,1H). MS(ESI)m / z=493.2[M+H] + .

[0869] Example 12: 4-((17-amino-3,6,9,12,15-pentaheptadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (linker 12)

[0870]

[0871] Linker 12 was synthesized according to the same procedure as linker 1 described in Example 1. (1.2 g, yield: 15% after two steps). 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.82(s,3H),7.61–7.57(m,1H),7.15(d,J=8.4Hz,1H),7.05(d,J=7.2Hz,1H), 6.61–6.59(m,1H),5.08–5.03(m,1H),3.64–3.47(m,22H),3.00–2.86(m,3H),2.62–2.51(m,2H),2.05–2.02(m,1H). MS(ESI)m / z=537.2[M+H] + .

[0872] Example 13: (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)glycine (linker 13)

[0873]

[0874] Linker 13 was synthesized according to the same procedure as linker 1 described in Example 1. (840 mg, yield: 16% via two steps). 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),7.52(t,J=7.6Hz,1H),6.99–6.88(m,3H),5.04(dd,J= 5.2, 12.8Hz, 1H), 3.73 (s, 2H), 2.93–2.83 (m, 1H), 2.61–2.50 (m, 2H), 2.02 (t, J = 5.6Hz, 1H). MS(ESI)m / z=330.1[MH] - .

[0875] Example 14: 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propionic acid (linker 14)

[0876]

[0877] Linker 14 was synthesized according to the same procedure as linker 1 described in Example 1. (1.42 g, yield: 24% after two steps). 1H NMR (400MHz, DMSO-d6) δ11.61(br,1H),11.08(s,1H),7.58(dd,J=7.2,8.8Hz,1H),7.15(d,J=8.8Hz,1H),7.04(d,J=7.2Hz,1H ), 6.64(s,1H),5.05(dd,J=5.2,12.8Hz,1H),3.53(t,J=6.4Hz,2H),2.92–2.83(m,1H),2.61–2.50(m,4H),2.05–2.00(m,1H). MS(ESI)m / z=346.1[M+H] + .

[0878] Example 15: 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyric acid (linker 15)

[0879]

[0880] Linker 15 was synthesized according to the same procedure as linker 1 described in Example 1. (1.27 g, yield: 13% after two steps). 1 H NMR (400MHz, DMSO-d6) δ12.12(br,1H),11.08(s,1H),7.58(dd,J=7.2,8.8Hz,1H),7.13(d,J=8.8Hz,1H),7.03(d,J=7.2Hz,1H),6.64(t,J=6.0Hz,1H), 5.05(dd,J=5.6,12.8Hz,1H),3.33(q,J=6.8Hz,2H),2.93–2.83(m,1H),2.6 1–2.50(m,2H),2.31(t,J=6.8Hz,2H),2.07–2.00(m,1H),1.83–1.75(m,2H). MS(ESI)m / z=360.1[M+H] + .

[0881] Example 16: 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)valeric acid (linker 16)

[0882]

[0883] Linker 16 was synthesized according to the same procedure as linker 1 described in Example 1. (1.4 g, yield: 15% after two steps). 1H NMR (400MHz, DMSO-d6) δ12.02(br,1H),11.08(s,1H),7.58(dd,J=8.8,7.2Hz,1H),7.10(d,J=8.4Hz,1H),7.02(d,J=7.2Hz,1H),6.64(t,J=5.6 Hz,1H),5.07-5.03(m,1H),3.32–3.02(m,2H),2.93–2.84(m,1H),2.61 –2.54(m,2H),2.28–2.25(m,2H),2.05–2.01(m,1H),1.60–1.51(m,4H). MS(ESI)m / z=374.1[M+H] + .

[0884] Example 17: 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexanoic acid (linker 17)

[0885]

[0886] Linker 17 was synthesized according to the same procedure as linker 1 described in Example 1. (1.43 g, yield: 18% after two steps). 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),11.08(s,1H),7.57(dd,J=7.2,8.8Hz,1H) ,7.08(d,J=8.8Hz,1H),7.02(d,J=7.2Hz,1H),6.52(t,J=6.0Hz,1H),5.05(dd,J =5.6,12.8Hz,1H),3.30(q,J=6.8Hz,2H),2.93–2.83(m,1H),2.61–2.50(m,2H), 2.32(t,J=7.2Hz,2H),2.07–2.00(m,1H),1.61–1.50(m,4H),1.39–1.33(m,2H). MS(ESI)m / z = 388.1[M+H] + .

[0887] Example 18: 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)heptanoic acid (linker 18)

[0888]

[0889] Linker 18 was synthesized according to the same procedure as linker 1 described in Example 1. (2.3 g, yield: 24% after two steps). 1H NMR (400MHz, DMSO-d6) δ11.92(br,1H),11.08(s,1H),7.57(t,J=8.0Hz,1H),7. 13(d,J=8.8Hz,1H),7.03(d,J=6.8Hz,1H),6.52(t,J=5.6Hz,1H),5.05(dd,J=5 .6,12.8Hz,1H),3.30(q,J=6.4Hz,2H),2.93–2.83(m,1H),2.61–2.50(m,2H),2 .31(t,J=7.2Hz,2H),2.07–2.00(m,1H),1.58–1.48(m,4H),1.34–1.31(m,4H). MS(ESI)m / z = 402.1[M+H] + .

[0890] Example 19: 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)octanoic acid (linker 19)

[0891]

[0892] Linker 19 was synthesized according to the same procedure as linker 1 described in Example 1. (1.14 g, yield: 35% after two steps). 1 H NMR (400MHz, DMSO-d6) δ11.94(s,1H),11.08(s,1H),7.57(t,J=8.0Hz,1H),7. 08(d,J=8.4Hz,1H),7.02(d,J=6.8Hz,1H),6.52(t,J=5.6Hz,1H),5.05(dd,J= 5.6,12.8Hz,1H),3.31–3.26(m,2H),2.93–2.83(m,1H),2.61–2.50(m,2H),2. 19(t,J=7.2Hz,2H),2.05–2.00(m,1H),1.58–1.47(m,4H),1.35–1.25(s,6H). MS(ESI)m / z = 416.1[M+H] + .

[0893] Example 20: 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)propionic acid (linker 20)

[0894]

[0895] Linker 20 was synthesized according to the same procedure as linker 1 described in Example 1. (3.5 g, yield: 18% after two steps). 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),11.08(s,1H),7.58(dd,J=7.2Hz,8.8Hz,1H),7.13(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.58(t,J=5.6Hz 1H),5.05(dd,J=6.4Hz,12.8Hz,1H),3.67–3.58(m,4H),3.47–3.43(m,2H),2.93–2.84(m,1H),2.61–2.45(m,4H),2.07–2.01(m,1H). MS(ESI)m / z=390.1[M+H] + .

[0896] Example 21: 3-(2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)ethoxy)propionic acid (linker 21)

[0897]

[0898] Linker 21 was synthesized according to the same procedure as linker 1 described in Example 1. (2.0 g, yield: 24% after two steps). 1 H NMR (400MHz, DMSO-d6) δ12.13(s,1H),11.08(s,1H),7.58(dd,J=7.2Hz,8.4Hz,1H),7.14(d,J=8.4Hz,1H),7.04(d,J=6.8Hz,1H),6.60(t,J=6.0Hz 1H),5.05(dd,J=5.2Hz,12.4Hz,1H),3.63–3.44(m,10H),2.88–2.85(m,1H),2.61–2.49(m,2H),2.44–2.41(m,2H),2.04–2.01(m,1H). MS(ESI)m / z=434.1[M+H] + .

[0899] Example 22: 3-(2-(2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)ethoxy)ethoxy)propionic acid (linker 22)

[0900]

[0901] Linker 22 was synthesized according to the same procedure as linker 1 described in Example 1. (3.2 g, yield: 42% after two steps). 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),11.08(s,1H),7.58(dd,J=7.2Hz,8.4Hz,1H),7.14(d,J=8.8Hz,1H),7.04(d,J=6.8Hz,1H),6.60(t,J= 6.0Hz,1H),5.05(dd,J=5.2Hz,12.8Hz,1H),3.63–3.45(m,14H),2.88–2.85(m,1H),2.61–2.49(m,2H),2.44–2.40(m,2H),2.04–2.01(m,1H). MS(ESI)m / z=478.2[M+H] + .

[0902] Example 23: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-acid (linker 23)

[0903]

[0904] Linker 23 was synthesized according to the same procedure as linker 1 described in Example 1. (2.3 g, yield: 31% after two steps). 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),11.08(s,1H),7.58(dd,J=7.2Hz,8.8Hz,1H),7.14(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.60(t,J=6 .0Hz,1H),5.05(dd,J=5.2Hz,12.8Hz,1H),3.63–3.48(m,18H),2.898–2.85(m,1H),2.61–2.49(m,2H),2.44–2.41(m,2H),2.04–2.01(m,1H). MS(ESI)m / z=522.2[M+H] + .

[0905] Example 24: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)-3,6,9,12,15-pentaoctadecane-18-acid (linker 24)

[0906]

[0907] Linker 24 was synthesized according to the same procedure as linker 1 described in Example 1. (2.4 g, yield: 36% after two steps). 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),7.58(dd,J=7.2,8.4Hz,1H),7.13(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.60(t,J=5.6Hz,1H ), 5.05(dd,J=5.6,12.8Hz,1H),3.64–3.46(m,22H),2.93–2.83(m,1H),2.61–2.50(m,2H),2.44–2.40(m,2H),2.02(t,J=6.4Hz,1H). MS(ESI)m / z=566.2[M+H] + .

[0908] Example 25: (2S,4R)-1-((S)-2-(2-aminoacetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 25)

[0909]

[0910] Step 1: At 0°C, add EDCI (1.07 g, 5.60 mmol), HOBt (756 mg, 5.60 mmol) to a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (2.00 g, 4.67 mmol), 2-((tert-butoxycarbonyl)amino)acetic acid (900 mg, 5.14 mmol), and triethylamine (TEA) (3.2 mL, 23.35 mmol) in DCM / DMF (225 mL / 11 mL). Stir the mixture at room temperature for 16 hours. Pour the mixture into water and extract with DCM. The combined organic layers were concentrated, and the residue was purified by chromatography on a silica gel column (DCM / MeOH = 20 / 1, v / v) to give the desired product (tert-butyl 2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-2-oxoethyl)carbamate (1.5 g, yield: 55%). MS (ESI) m / z = 588.2 [M+H) + .

[0911] Step 2: Add HCl / EtOAc (100 mL) to a solution of (2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazolyl-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-2-oxoethyl)tert-butyl carbamate (1.50 g, 2.56 mmol) in ethyl acetate (EtOAc) (30 mL). The mixture was stirred at room temperature for 3 hours and filtered to obtain the desired product, which was dissolved in water (100 mL) and lyophilized to give (2S,4R)-1-((S)-2-(2-aminoacetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (linker 25) (1.07 g, yield: 80%). 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),8.72(s,1H),8.56(d,J=9.2Hz,1H),8.26(s,3H),7.38–7.47(m,4H),4.61(d,J=9.2Hz,1 H),4.36–4.47(m,3H),4.20–4.25(m,1H),3.60–3.70(m,4H),2.46(s,3H),2.10–2.05(m,1H),1.97–1.89(m,1H),0.95(s,9H). MS(ESI)m / z=488.3[M+H] + .

[0912] Example 26: (2S,4R)-1-((S)-2-(3-aminopropionamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 26)

[0913]

[0914] Linker 26 was synthesized according to the same procedure as linker 25 described in Example 25. (1.38 g, yield: 37% after two steps). 1H NMR(400MHz, DMSO-d6)δ9.36(s,1H),8.68(s,1H),8.26(d,J=9.2Hz,1H),8.16(s,3H),7.49–7.39(m,4H),4.53(d,J=9.2Hz,1H),4.47–4.35(m,3H) ,4.24–4.19(m,1H),3.69–3.60(m,2H),2.94–2.93(m,2H),2.64(t,J=7.2 Hz,2H),2.48(s,3H),2.06–2.01(m,1H),1.92–1.85(m,1H),0.95(s,9H). MS(ESI)m / z=502.3[M+H] + .

[0915] Example 27: (2S,4R)-1-((S)-2-(4-aminobutyramido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 27)

[0916]

[0917] Linker 27 was synthesized according to the same procedure as linker 25 described in Example 25. (1.38 g, yield: 46% after two steps). 1 H NMR(400MHz, DMSO-d6)δ9.66(s,1H),8.74(t,J=6.0,1H),8.25(s,3H),8.03(d,J=9.2Hz,1H),7.49–7.41(m,4H),4.53(d,J=9.2Hz,1H),4.51–4.35( m,3H),4.29–4.24(m,1H),3.71–3.65(m,2H),2.79–2.77(m,2H),2.52(s,3 H),2.45–2.27(m,2H),2.12–2.07(m,1H),1.94–1.80(m,3H),0.94(s,9H). MS(ESI)m / z=516.0[M+H] + .

[0918] Example 28: (2S,4R)-1-((S)-2-(5-aminopentamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 28)

[0919]

[0920] Linker 28 was synthesized according to the same procedure as linker 25 described in Example 25. (1.50 g, yield: 57% after two steps). 1 H NMR(400MHz, DMSO-d6)δ9.52(s,1H),8.73(t,J=11.6Hz,1H),8.20(s,3H),7.95(d,J= 9.6Hz,1H),7.43–7.50(m,4H),4.55(d,J=9.2Hz,1H),4.38–4.50(m,3H),4.23–4.29( m,1H),3.64–3.71(m,2H),2.74–2.78(m,2H),2.51(s,3H),2.30–2.35(m,1H),2.18–2 .23(m,1H),2.07–2.12(m,1H),1.88–1.95(m,1H),1.58(d,J=4.4Hz,4H),0.96(s,9H). MS(ESI)m / z=530.1[M+H] + .

[0921] Example 29: (2S,4R)-1-((S)-2-(6-aminohexanoamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 29)

[0922]

[0923] Linker 29 was synthesized according to the same procedure as linker 25 described in Example 25. (2.70 g, yield: 87% after two steps). 1 H NMR (400MHz, DMSO-d6): δ9.36(s,1H),8.69(t,J=6.4Hz,1H),8.12(brs,3H),7.92(d,J=9.6Hz,1H),7 .44(dd,J=13.6,8.4Hz,4H),4.54(d,J=9.6Hz,1H),4.48–4.39(m,2H),4.36(brs,1H),4.28–4.19(m,1 H),3.72–3.60(m,2H),2.79–2.67(m,2H),2.49(s,3H),2.31–2.21(m,1H),2.20–2.12(m,1H),2.10–2 .01(m,1H),1.94–1.85(m,1H),1.62–1.54(m,2H),1.53–1.44(m,2H),1.34–1.22(m,2H),0.94(s,9H). MS(ESI)m / z=544.3[M+H] + .

[0924] Example 30: (2S,4R)-1-((S)-2-(7-aminoheptamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 30)

[0925]

[0926] Linker 30 was synthesized according to the same procedure as linker 25 described in Example 25. (2.13 g, yield: 76% after two steps). 1 H NMR (400MHz, DMSO-d6): δ9.45(s,1H),8.70(t,J=6.0Hz,1H),8.14(brs,3H),7.86(d,J=9.2Hz,1 H),7.44(dd,J=12.8,8.4Hz,4H),4.54(d,J=9.2Hz,1H),4.49–4.40(m,2H),4.36(brs,1H),4.29– 4.20(m,1H),3.71–3.61(m,2H),2.78–2.67(m,2H),2.50(s,3H),2.31–2.22(m,1H),2.21–2.13( m,1H),2.11–2.03(m,1H),1.95–1.85(m,1H),1.60–1.44(m,4H),1.35–1.18(m,4H),0.94(s,9H). MS(ESI)m / z=558.3[M+H] + .

[0927] Example 31: (2S,4R)-1-((S)-2-(8-aminooctamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 31)

[0928]

[0929] Linker 31 was synthesized according to the same procedure as linker 25 described in Example 25. (1.81 g, yield: 65% after two steps). 1H NMR (400MHz, DMSO-d6): δ9.35(s,1H),8.69(t,J=6.0Hz,1H),8.11(brs,3H),7.88(d,J=9.2Hz,1 H),7.44(dd,J=14.0,8.4Hz,4H),4.54(d,J=9.6Hz,1H),4.48–4.39(m,2H),4.36(brs,1H),4.27– 4.20(m,1H),3.71–3.60(m,2H),2.78–2.68(m,2H),2.49(s,3H),2.31–2.22(m,1H),2.18–2.11( m,1H),2.09–2.01(m,1H),1.94–1.85(m,1H),1.58–1.44(m,4H),1.32–1.19(m,6H),0.94(s,9H). MS(ESI)m / z=572.3[M+H] + .

[0930] Example 32: (2S,4R)-1-((S)-2-(9-aminononamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 32)

[0931]

[0932] Linker 32 was synthesized according to the same procedure as linker 25 described in Example 25. (2.32 g, yield: 80% after two steps). 1 H NMR (400MHz, DMSO-d6): δ9.30(s,1H),8.67(t,J=6.4Hz,1H),8.10(brs,3H),7.88(d,J=9.2Hz,1 H),7.43(dd,J=14.0,8.8Hz,4H),4.55(d,J=9.2Hz,1H),4.48–4.39(m,2H),4.35(brs,1H),4.28– 4.19(m,1H),3.71–3.60(m,2H),2.77–2.67(m,2H),2.48(s,3H),2.31–2.22(m,1H),2.17–2.10( m,1H),2.09–2.01(m,1H),1.94–1.85(m,1H),1.60–1.40(m,4H),1.33–1.19(m,8H),0.94(s,9H). MS(ESI)m / z=586.3[M+H] + .

[0933] Example 33: (2S,4R)-1-((S)-2-(10-aminodecanoyl)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 33)

[0934]

[0935] Linker 33 was synthesized according to the same procedure as linker 25 described in Example 25 (2.29 g, yield: 77% after two steps). 1 H NMR (400MHz, DMSO-d6): δ9.41(s,1H),8.67(t,J=6.0Hz,1H),8.14(brs,3H),7.85(d,J=8.8Hz,1 H),7.44(dd,J=13.6,8.8Hz,4H),4.54(d,J=8.8Hz,1H),4.48–4.39(m,2H),4.36(brs,1H),4.29– 4.20(m,1H),3.71–3.60(m,2H),2.78–2.67(m,2H),2.49(s,3H),2.32–2.22(m,1H),2.17–2.11(m ,1H),2.10–2.01(m,1H),1.95–1.86(m,1H),1.62–1.40(m,4H),1.34–1.16(m,10H),0.94(s,9H). MS(ESI)m / z=600.4[M+H] + .

[0936] Example 34: (2S,4R)-1-((S)-2-(11-aminoundecanoamide)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 34)

[0937]

[0938] Linker 34 was synthesized according to the same procedure as linker 25 described in Example 25. (1.10 g, yield: 37% after two steps). 1H NMR (400MHz, DMSO-d6): δ8.99(s,1H),8.61(t,J=6.4Hz,1H),7.87(d,J=8.8Hz,1H),7.41(dd,J=1 7.6,8.0Hz,4H),4.55(d,J=9.6Hz,1H),4.49–4.40(m,2H),4.36(brs,1H),4.26–4.17(m,1H),3.70 –3.64(m,2H),2.59–2.52(m,2H),2.45(s,3H),2.31–2.22(m,1H),2.16–2.08(m,1H),2.06–1.99( m,1H),1.96–1.86(m,1H),1.56–1.42(m,2H),1.39–1.30(m,2H),1.28–1.19(m,12H),0.94(s,9H). MS(ESI)m / z=614.4[M+H] + .

[0939] Example 35: (2S,4R)-1-((S)-2-(2-(2-aminoethoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 35)

[0940]

[0941] Linker 35 was synthesized according to the same procedure as linker 25 described in Example 25. (1.35 g, yield: 55% after two steps). 1 H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.70(t,J=6.0Hz,1H),8.35–8.14(m,3 H),7.78(d,J=9.6Hz,1H),7.47–7.38(m,4H),4.61(d,J=9.6Hz,1H),4.49–4. 34(m,3H),4.30–4.21(m,1H),4.09–3.99(m,2H),3.75–3.58(m,4H),3.06–2 .94(m,2H),2.48(s,3H),2.13–2.03(m,1H),1.95–1.85(m,1H),0.95(s,9H). MS(ESI)m / z = 532.0 [M+H] + .

[0942] Example 36: (2S,4R)-1-((S)-2-(3-(2-aminoethoxy)propamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 36)

[0943]

[0944] Linker 36 was synthesized according to the same procedure as linker 25 described in Example 25. (1.32 g, yield: 49% after two steps). 1 H NMR (400MHz, DMSO-d6) δ8.99 (s, 1H), 8.57 (t, J = 6.0Hz, 1H), 8.03 (d, J = 8Hz, 1H),7.85(s,3H),7.43–7.37(m,4H),4.57(d,J=9.2Hz,1H),4.46–4.31(m,3 H),4.26–4.20(m,1H),3.69–3.55(m,6H),3.99–2.95(m,2H),2.60–2.56(m, 1H),2.46–2.42(m,4H),2.05–2.03(m,1H),1.93–1.92(m,1H),0.95(s,9H). MS(ESI)m / z = 546.0 [M+H] + .

[0945] Example 37: (2S,4R)-1-((S)-2-(2-(2-(2-aminoethoxy)ethoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 37)

[0946]

[0947] Linker 37 was synthesized according to the same procedure as linker 25 described in Example 25. (1.2 g, yield: 49% after two steps). 1H NMR (400MHz, DMSO-d6) δ9.38(s,1H),8.78(t,J=6.0Hz,1H),8.18(s,3H),7.59–7.37(m,5H),4.58(d,J=9.6Hz,1H),4.49(t,J=8.2Hz,1H),4 .42–4.26(m,3H),4.09–3.95(m,2H),3.72–3.55(m,8H),2.99–2.92(m ,2H),2.49(s,3H),2.15–2.04(m,1H),1.95–1.85(m,1H),0.95(s,9H). MS(ESI)m / z=576.1[M+H] + .

[0948] Example 38: (2S,4R)-1-((S)-2-(3-(2-(2-aminoethoxy)ethoxy)propamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 38)

[0949]

[0950] Linker 38 was synthesized according to the same procedure as linker 25 described in Example 25. (1.34 g, yield: 49% after two steps). 1 H NMR (400MHz, DMSO-d6) δ9.02 (s, 1H), 8.58 (t, J = 6.0Hz, 1H), 7.94 (d, J = 8Hz, 1H) ,7.82(s,3H),7.42–7.30(m,4H),4.58(d,J=9.2Hz,1H),4.60–4.37(m,3H),4.2 5–4.31(m,1H),3.70–3.50(m,10H),3.00–2.96(m,2H),2.57–2.55(m,1H),2.45 (s,3H),2.41–2.38(m,1H),2.06–2.04(m,1H),1.95–1.93(m,1H),0.95(s,9H). MS(ESI)m / z = 590.1 [M+H] + .

[0951] Example 39: (2S,4R)-1-((S)-14-amino-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazo-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 39)

[0952]

[0953] Linker 39 was synthesized according to the same procedure as linker 25 described in Example 25. (1.53 g, yield: 56% after two steps). 1 H NMR(400MHz, DMSO-d6)δ9.01(s,1H),8.59(t,J=6.0Hz,1H),7.81(s,3H),7.48–7.41(m,5H),4.58(d,J=9.6Hz,1H),4.47–4.2 6(m,4H),3.99(s,2H),3.70–3.58(m,12H),3.0–2.96(m,2H),2.46(s,3H),2.11–2.06(m,1H),1.95–1.88(m,1H),0.96(s,9H). MS(ESI)m / z=621.1[M+H] + .

[0954] Example 40: (2S,4R)-1-((S)-1-amino-14-(tert-butyl)-12-oxo-3,6,9-trioxa-13-azapentadecan-15-acyl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 40)

[0955]

[0956] Linker 40 was synthesized according to the same procedure as linker 25 described in Example 25. (1.52 g, yield: 51% after two steps). 1 H NMR (400MHz, DMSO-d6) δ9.01 (s, 1H), 8.57 (t, J = 6.0Hz, 1H), 7.91 (d, J = 9.2Hz, 1H),7.81(s,3H),7.44–7.38(m,4H),4.58–4.55(m,1H),4.45–4.36(m,3H),4.2 5–4.21(m,1H),3.70–3.48(m,14H),3.00–2.97(m,2H),2.59-2.52(m,1H),2.46 (s,3H),2.39–2.34(m,1H),2.08–2.03(m,1H),1.95–1.88(m,1H),0.94(s,9H). MS(ESI)m / z = 633.8[M+H] + .

[0957] Example 41: (2S,4R)-1-((S)-1-amino-17-(tert-butyl)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecane-18-acyl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 41)

[0958]

[0959] Linker 41 was synthesized according to the same procedure as linker 25 described in Example 25. (1.12 g, yield: 37% after two steps). 1 H NMR(400MHz, DMSO-d6)δ8.98(s,1H),8.58(t,J=5.6Hz,1H),7.92(d,J=9.2Hz,1H),7.44–7.3 8(m,4H),4.56(d,J=9.2Hz,1H),4.47–4.41(m,2H),4.38–4.34(m,1H),4.26–4.19(m,1H),3. 70–3.55(m,5H),3.53–3.45(m,14H),3.35(t,J=5.6Hz,2H),2.64(t,J=5.6Hz,2H),2.58–2.5 0(m,1H),2.45(s,3H),2.40–2.35(m,1H),2.08–2.00(m,1H),1.94–1.91(m,1H),0.94(s,9H). MS(ESI)m / z=678.1[M+H] + .

[0960] Example 42: (2S,4R)-1-((S)-1-amino-20-(tert-butyl)-18-oxo-3,6,9,12,15-pentaoxa-19-azacotetradecane-21-acyl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (linker 42)

[0961]

[0962] Linker 42 was synthesized according to the same procedure as linker 25 described in Example 25 (1.1 g, 1.52 mmol, yield: 32% after two steps). 1H NMR(400MHz, DMSO-d6)δ9.38(s,1H),8.67(t,J=16Hz,1H),8.14(br,3H),7.91(d,J= 9.2Hz,1H),7.39–7.48(m,4H),4.53(d,J=9.2Hz,1H),4.39–4.46(m,2H),4.36–4.34( m,1H),4.20–4.25(m,1H),3.45–3.68(m,22H),2.91–2.95(m,2H),2.52–2.58(m,1H) ,2.47(s,3H),2.32–2.39(m,1H),2.03–2.08(m,1H),1.85–1.92(m,1H),0.92(s,9H). MS(ESI)m / z=722.4[M+H] + .

[0963] Example 43: 4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazolyl-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-4-oxobutyric acid (linker 43)

[0964]

[0965] A mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (1.0 g, 2.3 mmol) and succinic anhydride (465 mg, 4.65 mmol) in pyridine (5 mL) was stirred overnight at room temperature. The mixture was concentrated. The residue was purified by rapid chromatography (reversed phase, MeCN / H2O) to give the title compound linker 43 (1.05 g, yield: 86%). 1 H NMR (400MHz, DMSO-d6): δ12.02(s,1H),8.99(s,1H),8.58(t,J=6.0Hz,1H),7.96( d,J=9.2Hz,1H),7.43–7.37(m,4H),5.13(d,J=3.6Hz,1H),4.53(d,J=9.2Hz,1H),4 .46–4.40(m,2H),4.34(s,1H),4.21(dd,J=16.0,5.2Hz,1H),3.69–3.60(m,2H),2 .45(s,3H),2.44–2.33(m,4H),2.06–2.01(m,1H),1.93–1.87(m,1H),0.93(s,9H). 13C NMR (100MHz, DMSO-d6): δ173.83,171.92,170.86,169.56,151.41,147.70,139.48,131.15,129.6 3,128.62,127.41,68.87,58.70,56.44,56.34,41.65,37.91,35.35,29.74,29.25,26.35,15.92. MS(ESI)m / z=531.2[M+H] + .

[0966] Example 44: 5-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazolyl-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-5-oxovaleric acid (linker 44)

[0967]

[0968] Linker 44 was synthesized according to the same procedure as linker 43 described in Example 43. (1.5 g, yield: 79%) 1 H NMR (400MHz, DMSO-d6): δ8.99(s,1H),8.59(t,J=6.0Hz,1H),7.91(d,J=9.2Hz,1 H),7.44–7.37(m,4H),5.16(brs,1H),4.54(d,J=9.2Hz,1H),4.47–4.42(m,2H),4 .36(s,1H),4.21(dd,J=16.0,5.2Hz,1H),3.7–3.64(m,2H),2.45(s,3H),2.31–2. 14(m,4H),2.07–2.02(m,1H),1.94–1.81(m,1H),1.74–1.68(m,2H),0.94(s,9H). 13 C NMR (100MHz, DMSO-d6): δ174.18,171.94,171.63,169.66,151.41,147.70,139.46,131.15,129.6 1,128.62,127.41,68.86,58.69,56.38,41.65,37.91,35.16,34.03,33.10,26.35,20.89,15.92. MS(ESI)m / z=543.2[MH] - .

[0969] Example 45: 6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazo-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-6-oxohexanoic acid (linker 45)

[0970]

[0971] Linker 45 was synthesized according to the same procedure as linker 25 described in Example 25. (1.2 g, yield: 55% after two steps). 1 H NMR (400MHz, CDCl3) δ8.68(s,1H),7.75(s,1H),7.32–7.27(m,5H),4.64–4.57(m,3H),4.56–4.50(m,1H),4.28–4. 25(m,1H),4.02–3.99(m,1H),3.71–3.68(m,1H),2.47(s,3H),2.24–2.18(m,6H),1.59–1.48(m,4H),0.96(s,9H). MS(ESI)m / z=559.3[M+H] + .

[0972] Example 46: 7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazolyl-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-7-oxoheptanoic acid (linker 46)

[0973]

[0974] Linker 46 was synthesized according to the same procedure as linker 45 described in Example 45. (1.1 g, yield: 33% after two steps). 1 H NMR (400MHz, CDCl3) δ8.67(s,1H),7.56–7.55(m,1H),7.34–7.30(m,5H),4.68–4.59(m,3H),4.59–4.51(m,1H),4.25(dd,J=4.8Hz,15 .2Hz,1H),4.06–4.03(m,1H),3.70–3.68(m,1H),2.46(s,3H),2.31–2.11(m,6H),1.55–1.51(m,4H),1.29–1.24(m,2H),0.94(s,9H). MS(ESI)m / z=573.1[M+H] + .

[0975] Example 47: 8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazolyl-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-8-oxooctanoic acid (linker 47)

[0976]

[0977] Linker 47 was synthesized according to the same procedure as linker 45 described in Example 45. (1.08 g, yield: 52% after two steps). 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.55(t,J=2.4Hz,1H),7.83(d,J=9.2Hz,1H),7.44–7.38(m,4H),4.55(d,J=9.6Hz,1H),4.52–4.41(m, 2H),4.36(s,1H),4.25–4.21(m,1H),3.67–3.66(m,2H),2.45(s,3H), 2.30–1.91(m,6H),1.49–1.47(m,4H),1.26–1.24(m,4H),0.92(s,9H). MS(ESI)m / z=587.3[M+H] + .

[0978] Example 48: 9-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazolyl-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-9-oxononanoic acid (linker 48)

[0979]

[0980] Linker 48 was synthesized according to the same procedure as linker 45 described in Example 45. (1.16 g, yield: 44% after two steps). 1 H NMR(400MHz, CDCl3)δ8.70(s,1H),7.55(s,1H),7.33–7.27(m,4H),7.08(d,J=8.0Hz,1H),4.68–4.52(m,4H),4.31–4.27(m,1 H),4.08–4.05(m,1H),3.69–3.67(m,1H),2.48(s,3H),2.33–2.11(m,6H),1.60–1.47(m,4H),1.29–1.20(m,6H),0.96(s,9H). MS(ESI)m / z=601.1[M+H] + .

[0981] Example 49: 10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazo-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-10-oxodecanoic acid (linker 49)

[0982]

[0983] Linker 49 was synthesized according to the same procedure as linker 45 described in Example 45. (1.1 g, yield: 35%) 1 H NMR (400MHz, DMSO-d6): δ8.99(s,1H),8.58(t,J=6.0Hz,1H),7.85(d,J=9.2Hz, 1H),7.43–7.37(m,4H),4.54(d,J=9.2Hz,1H),4.47–4.41(m,2H),4.35(s,1H), 4.21(dd,J=16.0,5.6Hz,1H),3.69–3.63(m,2H),2.45(s,3H),2.29–2.09(m,4H ),2.03–2.01(m,1H),1.94–1.88(m,1H),1.47(m,4H),1.24(b,8H),0.94(s,9H). 13 CNMR (100MHz, DMSO-d6): δ172.07,171.92,169.69,151.41,147.70,139.48,131.14,129.62,128. 61,127.40,68.84,58.67,56.32,56.26,41.64,37.93,35.18,34.85,28.62,26.36,25.39,15.93. MS(ESI)m / z=615.3[M+H] + .

[0984] Example 50: 11-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazo-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-11-oxoundecanoic acid (linker 50)

[0985]

[0986] Linker 50 was synthesized according to the same procedure as linker 45 described in Example 45. (1.1 g, yield: 50%) 1H NMR (400MHz, DMSO-d6): δ8.99(s,1H),8.58(t,J=6.0Hz,1H),7.85(t,J=9.2Hz,1H),7.37–7.43(m,4H),4.56–4 .19(m,5H),3.70–3.60(m,2H),2.45(s,3H),2.27–1.90(m,6H),1.49–1.45(m,4H),1.23(m,10H),0.93(s,9H). 13 C NMR (100MHz, DMSO-d6): δ174.59,172.07,171.92,169.69,151.42,147.70,139.49,131.14,129.62,128.61,127.41,68.84 ,58.67,56.32,56.25,41.64,37.93,35.19,34.85,33.80,28.82,28.70,28.68,28.62,28.55,26.37,25.42,24.55,15.93. MS(ESI)m / z=629.4[M+H] + .

[0987] Example 51: 3-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazolyl-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-3-oxopropoxy)propionic acid (linker 51)

[0988]

[0989] Linker 51 was synthesized according to the same procedure as linker 45 described in Example 45. (1.1 g, yield: 42%) 1 H NMR (400MHz, DMSO-d6) δ8.98 (s, 1H), 8.55 (t, J = 6.0Hz, 1H), 7.91 (d, J = 9.2 Hz,1H),7.43–7.37(m,4H),4.55–4.53(m,1H),4.45–4.40(m,2H),4.35(s,1 H),4.24–4.19(m,1H),3.68–3.52(m,6H),2.54–2.56(m,1H),2.45–2.37(m, 5H),2.34–2.30(m,1H),2.05–2.00(m,1H),1.93–1.86(m,1H),0.93(s,9H). MS(ESI)m / z=575[M+H] + .

[0990] Example 52: 2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazo-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-2-oxoethoxy)acetic acid (linker 52)

[0991]

[0992] Linker 52 was synthesized according to the same procedure as linker 43 described in Example 43. (1.2 g, yield: 63%) 1 H NMR(400MHz,DMSO-d6)δ12.81(br s,1H),8.98(s,1H),8.58(t,J=6.0Hz,1H),7.60(d,J=9.6Hz,1H),7.45–7.35(m,4H),5.14(br,1H),4.58–4.55(m,1H),4.46–4.36(m, 3H),4.28–4.26(m,1H),4.14(s,2H),4.04(s,2H),3.69–3.60(m,2H),2.44(s,3H),2.08–2.03(m,1H),1.93–1.87(m,1H),0.95(s,9H). MS(ESI)m / z=547[M+H] + .

[0993] Example 53: 3-(2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazolyl-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-3-oxopropoxy)ethoxy)propionic acid (linker 53)

[0994]

[0995] Linker 53 was synthesized according to the same procedure as linker 45 described in Example 45. (1.4 g, yield: 23% after two steps). 1H NMR (400MHz, DMSO-d6): δ8.98(s,1H),8.56(t,J=6.0Hz,1H),7.91(d,J=9.2Hz,1H), 7.43–7.37(m,4H),4.55(d,J=9.6Hz,1H),4.46–4.41(m,2H),4.35(s,1H),4.29–4.20 (m,1H),3.70–3.57(m,7H),3.50–3.45(m,5H),2.57–2.55(m,1H),2.45(s,3H),2.43 –2.41(m,1H),2.37–2.32(m,1H),2.09–2.01(m,1H),1.94–1.87(m,1H),0.94(s,9H). MS(ESI)m / z=619.3[M+H] + .

[0996] Example 54: 2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazo-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-2-oxoethoxy)ethoxy)acetic acid (linker 54)

[0997]

[0998] Linker 54 was synthesized according to the same procedure as linker 53 described in Example 53. (1.13 g, yield: 20% after two steps). 1 H NMR (400MHz, DMSO-d6): δ8.98(s,1H),8.60(t,J=6.0Hz,1H),7.49(d,J=9.2Hz,1H),7.40(s,4H),4.57(d,J=9.2Hz,1H),4.47–4.36 (m,3H),4.28–4.23(m,1H),4.05–3.93(m,4H),3.69–3.61(m,6H),2.45(s,3H),2.08–2.03(m,1H),1.94–1.87(m,1H),0.94(s,9H). MS(ESI)m / z=591.2[M+H] + .

[0999] Example 55: (S)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazolyl-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-16,16-dimethyl-13-oxo-4,7,10-trioxa-14-azaheptadecanoic acid (linker 55)

[1000]

[1001] Linker 55 was synthesized according to the same procedure as linker 45 described in Example 45 (1.7 g, yield 37%). 1 H NMR (400MHz, DMSO-d6): δ8.99(s,1H),8.56(t,J=6.0Hz,1H),7.91(d,J=9.6Hz,1 H),7.44–7.38(m,4H),4.56(d,J=9.2Hz,1H),4.47–4.42(m,2H),4.36(s,1H),4.2 5–4.20(m,1H),3.70–3.55(m,6H),3.50–3.46(m,8H),2.58–2.51(m,3H),2.45–2. 42(m,5H),2.40–2.33(m,1H),2.07–2.02(m,1H),1.94–1.88(m,1H),0.94(s,9H). LCMS(ESI)m / z=661.0[MH] - .

[1002] Example 56: (S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazolyl-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecanoic acid (linker 56)

[1003]

[1004] Linker 56 was synthesized according to the same procedure as linker 45 described in Example 45. (1.21 g, yield: 31% after two steps). 1 H NMR (400MHz, CDCl3): δ8.68(s,1H),7.80–7.71(m,11H),7.41–7.33(m,5H),4.71–7.65(m,1H),4.61–4.50(m,3H),4.37 –4.33(m,1H),4.07–3.94(m,5H),3.77–3.58(m,10H),2.51(s,3H),2.38–2.30(m,1H),2.24–2.19(m,1H),0.98(s,9H). LCMS(ESI)m / z=635.0[M+H] + .

[1005] Example 57: (S)-18-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazolyl-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-19,19-dimethyl-16-oxo-4,7,10,13-tetraoxa-17-azaeicosanoic acid (linker 57)

[1006]

[1007] Linker 57 was synthesized according to the same procedure as linker 45 described in Example 45 (1.6 g, yield 43%). 1 H NMR (400MHz, CDCl3): δ8.69(s,1H),7.55–7.52(m,1H),7.47–7.45(m,1H),7.36(s,4H),4.70–4.66(m,1H),4.62–4.57(m,2H),4.50(s, 1H),4.34–4.29(m,1H),4.12–4.09(m,1H),3.75–3.48(m,18H),2.56–2.47(m,7H),2.40–2.33(m,1H),2.23–2.18(m,1H),0.96(s,9H). MS(ESI)m / z=707.1[M+H] + .

[1008] Example 58: (S)-21-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazolyl-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-22,22-dimethyl-19-oxo-4,7,10,13,16-pentaoxa-20-azatriocanoic acid (linker 58)

[1009]

[1010] Linker 58 was synthesized according to the same procedure as linker 45 described in Example 45. (1.2 g, yield: 23%) 1H NMR(400MHz, DMSO-d6)δ8.98(s,1H),8.57(t,J=6.0Hz,1H),7.91(d,J=9.6H z,1H),7.43–7.31(m,4H),4.56–4.53(m,1H),4.45–4.35(m,3H),4.24–4.19 (m,1H),3.69–3.55(m,6H),3.49–3.47(m,16H),2.57–2.53(m,1H),2.45(s, 3H),2.39–2.32(m,3H),2.06–2.01(m,1H),1.93–1.86(m,1H),0.95(s,9H). MS(ESI)m / z=751[M+H] + .

[1011] Example 59: (S)-19-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazolyl-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-20,20-dimethyl-17-oxo-3,6,9,12,15-pentaoxa-18-azaeicosanoic acid (linker 59)

[1012]

[1013] Linker 59 was synthesized according to the same procedure as linker 45 described in Example 45. (1.3 g, yield: 39%) 1 H NMR(400MHz, DMSO-d6)δ8.98(s,1H),8.69(t...

Claims

1. Divalent compounds, selected from: 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidone-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione (TR-123) 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b (Pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)propyl)isoindoline-1,3-dione (TR-172) 2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b (Pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)ethoxy)isoindoline-1,3-dione (TR-173) 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b ]pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)ethyl)amino)isoindoline-1,3-dione (TR-181), 3-(5-(3-(4-(6-(6-( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b (TR-186) pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)propyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione 3-(5-((2-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b (TR-191)pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)ethyl)amino)-1-oxoisoindololin-2-yl)piperidine-2,6-dione 3-(5-(3-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b (TR-203)pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)-3-oxoprop-1-yn-1-yl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione 2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b [[1,2-b]pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)ethyl)isoindoline-1,3-dione (TR-204), 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)isoindoline-1,3-dione (TR-225) N -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-233), and their pharmaceutically acceptable salts.

2. The divalent compound according to claim 1, wherein the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione (TR-123) or a pharmaceutically acceptable salt thereof.

3. The divalent compound according to claim 1, wherein the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b [[pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)propyl)isoindoline-1,3-dione (TR-172) or a pharmaceutically acceptable salt thereof.] 4. The divalent compound according to claim 1, wherein the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(6-( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b [[pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)ethoxy)isoindoline-1,3-dione (TR-173) or a pharmaceutically acceptable salt thereof.] 5. The divalent compound according to claim 1, wherein the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b [[Pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)ethyl)amino)isoindoline-1,3-dione (TR-181) or a pharmaceutically acceptable salt thereof.] 6. The divalent compound according to claim 1, wherein the divalent compound is 3-(5-(3-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b ]pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)propyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (TR-186) or a pharmaceutically acceptable salt thereof.

7. The divalent compound according to claim 1, wherein the divalent compound is 3-(5-((2-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b [[Pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)ethyl)amino)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (TR-191) or a pharmaceutically acceptable salt thereof.] 8. The divalent compound according to claim 1, wherein the divalent compound is 3-(5-(3-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b ]pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)-3-oxoprop-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (TR-203) or a pharmaceutically acceptable salt thereof.

9. The divalent compound according to claim 1, wherein the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(6-(( R )-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2- b [[pyridazine-3-yl)pyridin-2-yl)piperazine-1-yl)ethyl)isoindoline-1,3-dione (TR-204) or a pharmaceutically acceptable salt thereof.] 10. The divalent compound according to claim 1, wherein the divalent compound is 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidine-1-yl)isoindoline-1,3-dione (TR-225) or a pharmaceutically acceptable salt thereof.

11. The divalent compound according to claim 1, wherein the divalent compound is... N -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-233) or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a divalent compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, and a pharmaceutically acceptable excipient.

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