Compounds and methods for treating cancer

Abstract

The present disclosure relates to GSPT1 degrader compounds (e.g., small molecule compounds), compositions comprising one or more of the compounds, and methods of using the compounds to treat certain diseases in a subject in need thereof. The present disclosure also relates to methods for identifying such compounds.

Description

[0001] Cross-referencing

[0002] This application claims the benefit of PCT application No. PCT / CN2020 / 119834, filed on October 7, 2020, which is incorporated herein by reference in its entirety. Background Technology

[0003] There is a need in the art for compounds, compositions, and methods of using said compounds for treating diseases in patients with need. Summary of the Invention

[0004] This disclosure relates to compounds (e.g., small molecule compounds), compositions comprising one or more of said compounds, and methods of using said compounds to treat certain diseases in a subject of need. This disclosure also relates to methods for identifying or preparing such compounds.

[0005] In some embodiments, the treatment method comprises administering to a subject in need a first compound comprising a GSPT1 degrader and a second compound comprising an FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or activator.

[0006] In some embodiments, this document provides compounds having the structure of Formula 1 or pharmaceutically acceptable salts or solvates thereof:

[0007]

[0008] Where R 1 It is a divalent group attached to the joint portion, and is either absent or selected from R'-R”, R'OR”, R'SR”, R'N(R 3 )R", R'OC(O)R", R'OC(O)OR", R'OCON(R 3 )R", R'C(O)R", R'C(O)OR", R'CON(R 3 )R", R'S(O)R", R'S(O)2R", R'SO2N(R 3 )R”、R'NR 4 C(O)OR”、R'NR 4 C(O)R”、R'NR 4 C(O)N(R 3 )R”、R'NR 4 S(O)R”、R'NR 4 S(O)2R” and R'NR 4 S(O)2NR 3R”, ​​where R’ and R” are each a divalent group, the divalent group being either absent independently or selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyne, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-10-membered heterocyclic, optionally substituted 4-13-membered fused carbocyclic, optionally substituted 5-13-membered fused heterocyclic, optionally substituted 5-13-membered bridged carbocyclic, optionally substituted 5-13-membered bridged heterocyclic, optionally substituted 5-13-membered spirocarbocyclic, optionally substituted 5-13-membered spiroheterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; R 3 and R 4 Independently selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; or R' and R”, R 3 and R 4 , R' and R 3 , R' and R 4 "R" and R 3 or R” and R 4 Together with the atoms they are attached to, they form 3-20 membered carbon rings or 3-20 membered heterocyclic rings; R 2 Selected from hydrogen, halogen, oxo group, CN, NO2, OR 5 SR 5 、N(R 5 )R 6 OCOR 5 OCO2R 5 OCON(R) 5 )R 6 COR 5 CO2R 5 CON(R) 5 )R 6 SOR 5 SO2R 5 SO2N(R) 5 )R 6 NR 7 CO2R 5 NR 7 COR 5 NR 7 C(O)N(R 5 )R 6 NR 7 SOR 5NR 7 SO2R 5 NR 7 SO2N(R 5 )R 6 Optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered heterocyclic C1-C8 alkyl, optionally substituted 3-10 membered carbocyclic C1-C8 alkyl, optionally substituted 3-10 membered carbocyclic, optionally substituted 3-10 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, wherein each R 5 R 6 and R 7 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic C1-C8 alkyl, optionally substituted 3-10-membered heterocyclic C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; or R 5 and R 6 Or R 5 and R 7 Together with the atoms they are attached to, they form 3-20 membered heterocyclic groups or 5-6 membered heteroaryl groups; X is absent or selected from divalent groups, including CR. 8 R 9 CO, CO2, CONR 8 NR 8 NR 8 CO, NR 8 CO2, NR 8 C(O)NR 9 NR 8 SO, NR 8 SO2, NR 8 SO2NR 9 O, OC(O), OCO2, OCONR 8 S, SO, SO2 and SO2NR 8Optionally substituted C1-C8 alkylene groups, optionally substituted C2-C8 alkenyl groups, optionally substituted C2-C8 alkyne groups, optionally substituted 3-10-membered carbocyclic groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, wherein each R 8 and R 9 Independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclic, optionally substituted 3-10 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; or R 8 and R 9 Together with the atoms they are attached to, they form 3-20 membered carbon cyclic groups or 3-20 membered heterocyclic groups; and ring A and Ring B Each of the following is independently nonexistent or selected from optionally substituted 3-10 membered carbocyclic groups, optionally substituted 3-10 membered heterocyclic groups, optionally substituted 4-13 membered fused carbocyclic groups, optionally substituted 5-13 membered fused heterocyclic groups, optionally substituted 5-13 membered bridging carbocyclic groups, optionally substituted 5-13 membered bridging heterocyclic groups, optionally substituted 5-13 membered spirocarbocyclic groups, optionally substituted 5-13 membered spiroheterocyclic groups, optionally substituted aryl groups, optionally substituted bicyclic fused aryl groups, optionally substituted tricyclic fused aryl groups, and optionally substituted heteroaryl groups, optionally substituted bicyclic fused heteroaryl groups, and optionally substituted tricyclic fused heteroaryl groups.

[0009] In some embodiments, this document provides compounds having the structure of Formula 1 or pharmaceutically acceptable salts or solvates thereof:

[0010]

[0011] Wherein ring A is absent or optionally substituted 3-10 membered carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl group, optionally substituted bicyclic aryl group, optionally substituted heteroaryl group, or optionally substituted bicyclic heteroaryl group; ring B is absent or optionally substituted 3-10 membered carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl group, or optionally substituted heteroaryl group; R 1 It does not exist; R 2 It is hydrogen, halogen, CN, NO2, OR 5 SR5 、N(R 5 )R 6 C(O)R 5 C(O)OR 5 C(O)N(R) 5 )R 6 SO2R 5 SO2N(R) 5 )R 6 NR 7 C(O)OR 5 NR 7 C(O)R 5 NR 7 C(O)N(R 5 )R 6 NR 7 SOR 5 NR 7 SO2R 5 NR 7 SO2N(R 5 )R 6 Optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy or optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclic or optionally substituted 3-10 membered heterocyclic; X is absent, -O- or NR. 8 ; Each R 5 R 6 and R 7 Independently, it is hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic C1-C8 alkyl, optionally substituted 3-10-membered heterocyclic C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-10-membered heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl; or R 5 and R 6 Together with the atoms they are attached to, they optionally form 3-20 membered heterocyclic groups or 5-6 membered heteroaryl rings; R 8 It is hydrogen or C1-C8 alkyl; and the connector is the connecting portion that attaches the degradation label to ring B.

[0012] In some embodiments, this document provides pharmaceutical compositions comprising the compounds described herein and pharmaceutically acceptable excipients.

[0013] Incorporation

[0014] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent or patent application had been specifically and individually indicated to be incorporated herein by reference. Attached Figure Description

[0015] The novel features of this disclosure are specifically set forth in the appended claims. A fuller understanding of the features and advantages of this disclosure will be obtained by referring to the following detailed description, along with the accompanying drawings, which illustrate illustrative embodiments utilizing the principles of this disclosure, in which:

[0016] Figure 1A Images of Western blots of GSPT1 after MV4;11 cells were treated with GS-001 or GS-002.

[0017] Figure 1B Images of Western blots of GSPT1 after MV4;11 cells were treated with GS-004, GS-005 or GS-006.

[0018] Figure 1C Images of Western blots of GSPT1 after MV4;11 cells were treated with GS-007, GS-008, GS-009, GS-010, GS-011, GS-012 or GS-013.

[0019] Figure 1D Images of Western blots of GSPT1 after MV4;11 cells were treated with GS-017, GS-018, or GS-019.

[0020] Figure 1E Images of Western blots of GSPT1 after MV4;11 cells were treated with GS-020, GS-021, GS-022, GS-060, GS-062, GS-063, or GS-064.

[0021] Figure 2A This is a graph showing the cell viability of MOML-13 cells treated with different doses of GS-002 with or without 20 nM gilteritinib.

[0022] Figure 2B This is a graph showing the cell viability of MOML-13 cells treated with different doses of GS-005 with or without 20 nM giretinib.

[0023] Figure 2C This is a graph showing the cell viability of MOML-13 cells treated with different doses of GS-006 with or without 20 nM giretinib. Detailed Implementation

[0024] Translation termination is a GTP-dependent process regulated by two key proteins, eRF1 and eRF3. The translation termination factor eRF3a (also known as the eukaryotic peptide chain release factor GTP-binding subunit ERF3A or "GSPT1") is a GTPase that interacts with eRF1 to promote stop codon recognition and the release of nascent peptides from the ribosome (Chauvin, Salhi et al. 2005). GSPT1 activates eRF1 in a GTP-dependent manner, and its GTPase activity requires a complex with eRF1 and the ribosome (Frolova, Le Goff et al. 1996). GTP-bound GSPT1 and eRF1 together with the ribosome form a functional translation termination complex (Zhouravleva, Frolova et al. 1995). By regulating translation, GSPT1 plays a variety of important roles in cell physiology. Increased expression of GSPT1 has been reported in human malignancies, including lung and gastric cancer (Malta-Vacas, Aires et al. 2005; Tian, ​​Tian et al. 2018; Sun, Zhang et al. 2019; Zhang, Zou et al. 2019). Therefore, GSPT1 is considered a novel cancer target through which active translation contributing to the malignant phenotype of cancer cells can be impaired. Recently, Matyskiela and colleagues reported that the phthalimide-derived molecule CC-885 led to cereblon-dependent degradation of GSPT1 and other targets such as IKZF1 and IKZF3 (Matyskiela, Lu et al. 2016). Ishoey et al. also reported that GSPT1 was degraded by a partial heterobifunctional compound derived from phthalimide (Ishoey, Chorn et al. 2018). CC-885 induced significant toxicity in the vast majority of tested cell lines, presumably due to the degradation of GSPT1 and many other proteins (Matyskiela, Lu et al. 2016). Therefore, despite its broad and potent anticancer activity, CC-885 exhibits unacceptable toxicity, which has prevented further development (Hansen, Correa et al. 2020).

[0025] In some embodiments, compounds are disclosed herein. In some embodiments, the compounds include the chemical structures or formulas disclosed herein. The compounds may be or include GSPT1 degraders. GSPT1 degraders are characterized by their ability to degrade GSPT1 or reduce cellular protein levels of GSPT1. Some embodiments relate to a composition comprising the compounds. Some embodiments relate to methods of preparing the compounds. Some embodiments relate to methods of using the compounds or pharmaceutical compositions of the compounds. For example, the compounds may be used to treat a condition or disease. In some cases, the compounds are used to treat cancer.

[0026] This disclosure includes all stereoisomers, geometric isomers, tautomers, and isotopes of the compounds with structures described and named herein. This disclosure also includes the compounds described herein, regardless of how they are prepared, for example, synthetically, through biological processes (e.g., metabolism or enzymatic conversion), or in combination thereof.

[0027] This disclosure includes pharmaceutically acceptable salts of the compounds with the structures described herein and those named herein.

[0028] One or more constituent atoms of the compounds provided herein may be replaced or substituted by isotopes of said atoms at natural or non-natural abundances. In some embodiments, the compound comprises at least one deuterium atom. In some embodiments, the compound comprises two or more deuterium atoms. In some embodiments, the compound comprises 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound may be replaced or substituted by deuterium atoms. In some embodiments, the compound comprises at least one fluorine atom. In some embodiments, the compound comprises two or more fluorine atoms. In some embodiments, the compound comprises 1-2, 1-3, 1-4, 1-5, or 1-6 fluorine atoms. In some embodiments, all hydrogen atoms in the compound may be replaced or substituted by fluorine atoms.

[0029] I. Compounds

[0030] In some embodiments, compounds are disclosed herein. In some embodiments, the compounds contain a degradation tag disclosed herein. In some embodiments, the compounds contain a cereblon-binding moiety. In some embodiments, the degradation tag contains a cereblon-binding moiety. In some embodiments, the compounds include a GSPT1 degrader. For example, the compounds can cause GSPT1 degradation. The compounds can degrade GSPT1 due to cereblon modulation by the degradation tag. The compounds can bind to or modulate GSPT1 or cereblon. In some embodiments, the compounds include heterobifunctional compounds. In some embodiments, the compounds include molecular glues. In some embodiments, the compounds can be used as molecular glues. In some embodiments, the compounds contain a linker. In some embodiments, the compounds contain a truncated Janus kinase (JAK) binding moiety.

[0031] In some embodiments, the compounds disclosed herein include Formula 1, or a pharmaceutically acceptable salt or solvate thereof:

[0032]

[0033] Where R 1 It is a divalent group attached to the joint portion, and is either absent or selected from R'-R”, R'OR”, R'SR”, R'N(R 3 )R", R'OC(O)R", R'OC(O)OR", R'OCON(R 3 )R", R'C(O)R", R'C(O)OR", R'CON(R 3 )R", R'S(O)R", R'S(O)2R", R'SO2N(R 3 )R”、R'NR 4 C(O)OR”、R'NR 4 C(O)R”、R'NR 4 C(O)N(R 3 )R”、R'NR 4 S(O)R”、R'NR 4 S(O)2R” and R'NR 4 S(O)2NR 3R”, ​​where R’ and R” are each a divalent group, the divalent group being either absent independently or selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyne, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-10-membered heterocyclic, optionally substituted 4-13-membered fused carbocyclic, optionally substituted 5-13-membered fused heterocyclic, optionally substituted 5-13-membered bridged carbocyclic, optionally substituted 5-13-membered bridged heterocyclic, optionally substituted 5-13-membered spirocarbocyclic, optionally substituted 5-13-membered spiroheterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; R 3 and R 4 Independently selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; or R' and R”, R 3 and R 4 , R' and R 3 , R' and R 4 "R" and R 3 or R” and R 4 Together with the atoms they are attached to, they form 3-20 membered carbon rings or 3-20 membered heterocyclic rings; R 2 Selected from hydrogen, halogen, oxo group, CN, NO2, OR 5 SR 5 、N(R 5 )R 6 OCOR 5 OCO2R 5 OCON(R) 5 )R 6 COR 5 CO2R 5 CON(R) 5 )R 6 SOR 5 SO2R 5 SO2N(R) 5 )R 6 NR 7 CO2R 5 NR 7 COR 5 NR 7 C(O)N(R 5 )R 6 NR 7 SOR 5NR 7 SO2R 5 NR 7 SO2N(R 5 )R 6 Optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered heterocyclic C1-C8 alkyl, optionally substituted 3-10 membered carbocyclic C1-C8 alkyl, optionally substituted 3-10 membered carbocyclic, optionally substituted 3-10 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, wherein each R 5 R 6 and R 7 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 ynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic C1-C8 alkyl, optionally substituted 3-10-membered heterocyclic C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; or R 5 and R 6 Or R 5 and R 7 Together with the atoms they are attached to, they form 3-20 membered heterocyclic groups or 5-6 membered heteroaryl groups; X is absent or selected from divalent groups, including CR. 8 R 9 CO, CO2, CONR 8 NR 8 NR 8 CO, NR 8 CO2, NR 8 C(O)NR 9 NR 8 SO, NR 8 SO2, NR 8 SO2NR 9 O, OC(O), OCO2, OCONR 8 S, SO, SO2 and SO2NR 8Optionally substituted C1-C8 alkylene groups, optionally substituted C2-C8 alkenyl groups, optionally substituted C2-C8 alkyne groups, optionally substituted 3-10-membered carbocyclic groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, wherein each R 8 and R 9 Independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclic, optionally substituted 3-10 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; or R 8 and R 9 Together with the atoms they are attached to, they form 3-20 membered carbon cyclic groups or 3-20 membered heterocyclic groups; and ring A and Ring B Each of the following is independently nonexistent or selected from optionally substituted 3-10 membered carbocyclic groups, optionally substituted 3-10 membered heterocyclic groups, optionally substituted 4-13 membered fused carbocyclic groups, optionally substituted 5-13 membered fused heterocyclic groups, optionally substituted 5-13 membered bridging carbocyclic groups, optionally substituted 5-13 membered bridging heterocyclic groups, optionally substituted 5-13 membered spirocarbocyclic groups, optionally substituted 5-13 membered spiroheterocyclic groups, optionally substituted aryl groups, optionally substituted bicyclic fused aryl groups, optionally substituted tricyclic fused aryl groups, and optionally substituted heteroaryl groups, optionally substituted bicyclic fused heteroaryl groups, and optionally substituted tricyclic fused heteroaryl groups.

[0034] Some embodiments include a degradation tag. In some embodiments, the degradation tag includes a cereblon-binding moiety. The degradation tag can bind to cereblon. Without wishing to be bound by any particular theory, it is contemplated herein that, in some embodiments, linking pomalidomide to any part of the molecule can recruit cereblon E3 ligases. The degradation tag may include pomalidomide or a functional fragment thereof. In some embodiments, the degradation tag is optional.

[0035] In some implementations, the degradation label is a part of structural formula 5, and wherein the degradation label is transmitted via Z. E Connect to the connector part;

[0036]

[0037]

[0038] Z E It is a divalent group -(R E z ) nE -; where n E It is 0, 1, 2, 3, 4, 5, or 6; R E Z It is R independently each time it appears. E r Or R E w ;where R E w Each time it appears, it is a key or selected from -C(O)-, -CR E 5 R E 6 -、-NR E 5 -、-O-、Optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 alkenyl, optionally substituted C1-C 10 etymynyl; and R E r Each time it appears, it is a bond or selected from optionally substituted 3-10 membered carbocyclic groups (such as 3-8 membered carbocyclic groups), optionally substituted 3-10 membered heterocyclic groups, optionally substituted C3-C 13 Fused carbocyclic group, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridging carbocyclic groups, optionally substituted C3-C 13 Bridging heterocyclic groups, optionally substituted C3-C 13 Spirocarbocyclic group, optionally substituted C3-C 13 Spiroheterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group; condition is -R E z -R E z -Not-OO-;R E 5 and R E 6 Each time it appears, it is independently selected from hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted 3- to 8-membered carbocyclic and optionally substituted 3- to 8-membered heterocyclic; or R E 5 and RE 6 Together with the atoms they are attached to, they form optionally substituted 3-8 membered carbocyclic or heterocyclic rings; R E 1 Selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted 3-8 membered carbocyclic and optionally substituted 3-8 membered heterocyclic; L E It is a divalent group, wherein the divalent group is selected from those that do not exist, -L E 1 -and-L E 1 -L E 2 -; where L E 1 and L E 2 Independently selected from -CO-, -O-, -CR E 10 R E 11 -and-NR E 10 -, the condition is -L E 1 -L E 2 -Not –OO-; where R E 10 and R E 11 Independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C6 alkoxy, and optionally substituted C1-C6 alkylamino; and cyclic A E It is selected from formula A E 1. A E 2. A E 3. A E 4 and A E 5's divalent group:

[0039]

[0040] Where * indicates that it is related to L E Connection or when L E When there is no ring A E The connection, and Z E Connected to ring A E Any possible location on it; Indicates a single or double bond; VE 1 V E 2 V E 3 V E 4 and V E 5 Each time it appears, it is independently selected from key, C, CR. E 2 S, N and NR E 2 ; or V E 1 and V E 2 V E 2 and V E 3 V E 3 and V E 4 or V E 4 and V E 5 The atoms to which they are attached combine to optionally form a 6-membered aryl or a 5, 6, or 7-membered heteroaryl ring; R E 2 Each time it appears, it is independently selected from the absence of, hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-8 membered carbocyclic and optionally substituted 3-8 membered heterocyclic; or R E 2 And another R E 2 Together with the atoms to which they are attached, they form optionally substituted 3-8 membered carbocyclic groups, optionally substituted 3-8 membered heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; W E 1 W E 2 W E 3 and W E 4 Each is independently selected from -N=, -C≡, and -CR. E 3 =、-CO-、-O-、-CR E 3 RE 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 - and -N = N-; or W E 1 and W E 2 W E 2 and W E 3 or W E 3 and W E 4 The atoms to which they are attached combine to optionally form a 6-membered aryl or a 5, 6, or 7-membered heteroaryl ring; and R E 3 and R E 4 Each time it appears, it is independently selected from the absence of, hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted 3- to 8-membered carbocyclic group, and optionally substituted 3- to 8-membered heterocyclic group; or R on the same atom or on adjacent atoms. E 3 and R E 4 Together with the atoms they are attached to, they form optionally substituted 3- to 8-membered carbon cyclic or heterocyclic rings.

[0041] In some embodiments, the compound is a compound of formula I, wherein ring A is absent or optionally substituted with a 3-10 membered carbocyclic group, optionally substituted with a 3-10 membered heterocyclic group, optionally substituted with an aryl group, optionally substituted with a bicyclic aryl group, optionally substituted with a heteroaryl group, or optionally substituted with a bicyclic heteroaryl group; ring B is absent or optionally substituted with a 3-10 membered carbocyclic group, optionally substituted with a 3-10 membered heterocyclic group, optionally substituted with an aryl group, or optionally substituted with a heteroaryl group; R 1 It does not exist; R 2 It is hydrogen, halogen, CN, NO2, OR 5 SR 5 、N(R 5 )R 6 C(O)R 5 C(O)OR 5 C(O)N(R) 5 )R6 SO2R 5 SO2N(R) 5 )R 6 NR 7 C(O)OR 5 NR 7 C(O)R 5 NR 7 C(O)N(R 5 )R 6 NR 7 SOR 5 NR 7 SO2R 5 NR 7 SO2N(R 5 )R 6 Optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy or optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclic or optionally substituted 3-10 membered heterocyclic; X is absent, -O- or NR. 8 ; Each R 5 R 6 and R 7 Independently, it is hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic C1-C8 alkyl, optionally substituted 3-10-membered heterocyclic C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-10-membered heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl; or R 5 and R 6 Together with the atoms they are attached to, they optionally form 3-20 membered heterocyclic groups or 5-6 membered heteroaryl rings; R 8 It is hydrogen or C1-C8 alkyl; and the connector is the linker that attaches the degradation label to the ring B.

[0042] In some implementations, the degradation label is part of Formula 5, and the degradation label is transmitted via Z. E The connector portion attached to the divalent compound;

[0043]

[0044] Among them: Z E Yes - (R Ez ) nE - a divalent group; where the subscript n E = 0, 1, 2, 3, 4, 5 or 6; where R E Z It is R independently each time it appears. E r or R E w ;where R E w It is either absent or selected from -CO- or -CR each time it appears. E 5 R E 6 -、-NR E 5 -、-O-、Optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 alkenyl, optionally substituted C1-C 10 etymynyl; and R E r Each occurrence is either absent or selected from optionally substituted 3-10 membered carbocyclic groups such as 3-8 membered carbocyclic groups, optionally substituted 4-10 membered heterocyclic groups such as 3-8 membered heterocyclic groups, optionally substituted 4-13 membered fused carbocyclic groups, optionally substituted 5-13 membered fused heterocyclic groups, optionally substituted 5-13 membered bridging carbocyclic groups, optionally substituted 5-13 membered bridging heterocyclic groups, optionally substituted 5-13 membered spirocarbocyclic groups, optionally substituted 5-13 membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; the condition is -R E z -R E z -Not-OO-;R E 5 and R E 6 Each time it appears, it is independently selected from hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted 3- to 8-membered carbocyclic group, and optionally substituted 3- to 8-membered heterocyclic group; or R E 5 and R E 6 Together with the atoms they are attached to, they form optionally substituted 3-8 membered carbocyclic or heterocyclic rings; R E 1Selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 3-8 membered heterocyclic groups; L E It is a divalent group, wherein the divalent group is selected from those without (null) or -L E 1 -and-L E 1 -L E 2 -; where L E 1 and L E 2 Independently selected from -CO-, -O-, -CR E 10 R E 11 -and-NR E 10 -, the condition is -L E 1 -L E 2 -Not –OO-; where R E 10 and R E 11 Independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally substituted C1-C6 alkylamino; and cyclic A E It is selected from formula A E 1. A E 2. A E 3. A E 4 and A E 5's divalent group:

[0045]

[0046] Where * indicates and L E The connection, and Z E Connected to ring A E Any possible location on it; Indicates whether it is a single or double key; V E 1 V E 2 V E 3 V E 4 and V E 5 Each occurrence is independently selected from non-existent, C, and CR. E 2S, N and NR E 2 ; or V E 1 and V E 2 V E 2 and V E 3 V E 3 and V E 4 or V E 4 and V E 5 Combining them to optionally form a 6-membered aryl ring or a 5, 6, or 7-membered heteroaryl ring; R E 2 Each time it appears, it is independently selected from the absence of, hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-8 membered carbocyclic and optionally substituted 3-8 membered heterocyclic; or R E 2 And another R E 2 Together with the atoms to which they are attached, they form optionally substituted 3-8 membered carbocyclic groups, optionally substituted 3-8 membered heterocyclic rings, optionally substituted aryl groups, and optionally substituted heteroaryl groups; W E 1 W E 2 W E 3 and W E 4 Each is independently selected from -N=, -C≡, and -CR. E 3 =、-CO-、-O-、-CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 -and -N = N-; or W E 1 and W E 2 W E2 and W E 3 or W E 3 and W E 4 Combining them together to optionally form a 6-membered aryl ring or a 5, 6, or 7-membered heteroaryl ring; and R E 3 and R E 4 Each time it appears, it is independently selected from the absence of, hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted 3- to 8-membered carbocyclic group, and optionally substituted 3- to 8-membered heterocyclic group; or R on the same atom or on adjacent atoms. E 3 and R E 4 Together with the atoms they are attached to, they form optionally substituted 3- to 8-membered carbon cyclic or heterocyclic rings.

[0047] In some implementations, part of formula 5 has the structure of formula 5-1:

[0048]

[0049] in Indicates a single or double bond; R E 1 It is hydrogen; Z E It is non-existent, -CH2-, -NH-, or -O-; V E 1 V E 2 V E 3 and V E 4 Each is independent of the other, C and CR. E 2 Or N; W E 1 W E 2 and W E 3 Each is independently selected from -C(O)-, -N-, and -NR-. E 3 -or-CR E 3 R E 4 -; Each R E 2 It is hydrogen independently; and R E 3and R E 4 Each is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, or optionally substituted C1-C6 alkyl; or R E 3 and R E 4 Together with the atoms to which they are attached, they form optionally substituted 3-6 membered carbon cyclic groups or 3-6 membered heterocyclic groups.

[0050] In some implementations, the degradation label comprises structural formula 5-1, wherein Indicates a single or double bond; R E 1 It is hydrogen; Z E It is non-existent, -CH2-, -NH-, or -O-; V E 1 V E 2 V E 3 and V E 4 Each is independent of the other, C and CR. E 2 Or N; W E 1 W E 2 and W E 3 Each is independently selected from -C(O)-, -N-, and -NR-. E 3 -or-CR E 3 R E 4 -; Each CR E 2 It is hydrogen independently; and R E 3 and R E 4 Each is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, or optionally substituted C1-C6 alkyl groups. In some embodiments, W E 1 and W E 3 Each is independently C(O) or CH2; and W E 2 It is N. In some implementations, the degradation label has the following structure:

[0051]

[0052] Some implementations include a connector. In some implementations, the connector is optional. In some implementations, the connector portion includes structural formula 9:

[0053]

[0054] Where A L W L and B L Each time it appears, it is either not present independently or selected from the following divalent parts: R L d -R L e R L d COR L e R L d CO2R L e R L d C(O)N(R L 1 )R L e R L d C(S)N(R L 1 )R L e R L d OR L e R L d SR L e R L d SOR L e R L d SO2R L e R L d SO2N(R L 1 )R L e R L d N(R L 1 )R L e R L d N(R L 1 )CORL e R L d N(R L 1 CON(R) L 2 )R L e R L d N(R L 1 )C(S)R L e Optionally substituted C1-C8 alkylene groups, optionally substituted C2-C8 alkenyl groups, optionally substituted C2-C8 ynylene groups, optionally substituted C1-C8 alkoxy-C1-C8 alkylene groups, optionally substituted C1-C8 haloalkylene groups, optionally substituted C1-C8 heteroalkylene groups, optionally substituted C1-C8 hydroxyalkylene groups, optionally substituted 4-13 fused carbocyclic groups, Optionally substituted 5-13 fused heterocyclic groups, optionally substituted 5-13 bridging carbocyclic groups, optionally substituted 5-13 bridging heterocyclic groups, optionally substituted 5-13 spirocarbocyclic groups, optionally substituted 5-13 spiroheterocyclic groups, optionally substituted 3-10 bridging carbocyclic groups, optionally substituted 3-10 bridging heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, wherein R L d and R L e Individually absent or selected from the following divalent groups: optionally substituted (C1-C8 alkylene)-R L r R, which is arbitrarily replaced L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r-(C1-C8 alkylene), optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyneyl, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 haloalkylene Optionally substituted 3-10-membered carbocyclic groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted 4-13-membered fused carbocyclic groups, optionally substituted 5-13-membered fused heterocyclic groups, optionally substituted 5-13-membered bridging carbocyclic groups, optionally substituted 5-13-membered bridging heterocyclic groups, optionally substituted 5-13-membered spirocarbocyclic groups, optionally substituted 5-13-membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; R L r Selected from optionally substituted 3-10-membered carbocyclic groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted 4-13-membered fused carbocyclic groups, optionally substituted 5-13-membered fused heterocyclic groups, optionally substituted 5-13-membered bridged carbocyclic groups, optionally substituted 5-13-membered bridged heterocyclic groups, optionally substituted 5-13-membered spirocarbocyclic groups, optionally substituted 5-13-membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; R L 1 and R L 2 Each is 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 3-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; or R L d and R L e R L 1 and R L 2 R L d and R L 1 R L d and R L 2 R L e and RL 1 Or R L e and R L 2 Together with the atoms to which they are attached, they optionally form 3-20 membered carbocyclic or 4-20 membered heterocyclic rings; and m L It is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0055] In some implementations, the connector includes structure 9, wherein A L It is a optionally substituted 4-13 fused carbocyclic group, an optionally substituted 5-13 fused heterocyclic group, an optionally substituted 5-13 bridging carbocyclic group, an optionally substituted 5-13 bridging heterocyclic group, an optionally substituted 5-13 spirocarbocyclic group, an optionally substituted 5-13 spiroheterocyclic group, an optionally substituted 3-10 carbocyclic group, or an optionally substituted 3-10 heterocyclic group; W L and B L Each time it appears, it is either not present independently or selected from the following divalent parts: R L d -R L e R L d C(O)R L e R L d CO2R L e R L d C(O)N(R L 1 )R L e R L d OR L e R L d N(R L 1 )R L e R L d N(R L 1 COR L e R L d N(R L 1 CON(R) L 2)R L e Optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyneyl, optionally substituted C1-C8 alkoxy-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 4-13 fused carbocyclic, optionally substituted 5-13 fused heterocyclic, optionally substituted 5-13 bridged carbocyclic, optionally substituted 5-13 bridged heterocyclic, optionally substituted 5-13 spirocyclic, optionally substituted 5-13 spiroheterocyclic, optionally substituted 3-10 carbocyclic, optionally substituted 3-10 heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; R L d and R L e Individually absent or selected from the following divalent groups: optionally substituted (C1-C8 alkylene)-R L r R, which is arbitrarily replaced L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene), 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 alkylamino C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10-membered carbocyclic group, optionally substituted 3-10-membered heterocyclic group, optionally substituted 4-13-membered fused carbocyclic group, optionally substituted 5-13-membered fused heterocyclic group, optionally substituted 5-13-membered bridged carbocyclic group, optionally substituted 5-13-membered bridged heterocyclic group, optionally substituted 5-13-membered spirocarbocyclic group, optionally substituted 5-13-membered spiroheterocyclic group, optionally substituted aryl group and optionally substituted heteroaryl group; R L rSelected from optionally substituted aryl groups or optionally substituted heteroaryl groups; and m L It is 1, 2, or 3.

[0056] In some implementation schemes, A L It is a substituted 3-10 membered carbocyclic group or a substituted 3-10 membered heterocyclic group; W L and B L Each time it appears, it is either not present independently or selected from the following divalent parts: R L d -R L e R L d C(O)R L e R L d CO2R L e R L d C(O)N(R L 1 )R L e R L d OR L e R L d N(R L 1 )R L e and R L d N(R L 1 COR L e ;R L d and R L e Each of them independently does not exist or is selected from (C1-C8 alkylene)-R which are optionally substituted. L r R, which is arbitrarily replaced L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene), optionally substituted C1-C8 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R L r Selected from optionally substituted aryl groups and optionally substituted heteroaryl groups.

[0057] In some implementation schemes, A L It is a optionally substituted 4-13 fused carbocyclic group, an optionally substituted 5-13 fused heterocyclic group, an optionally substituted 5-13 bridging carbocyclic group, an optionally substituted 5-13 bridging heterocyclic group, an optionally substituted 5-13 spirocarbocyclic group, an optionally substituted 5-13 spiroheterocyclic group, an optionally substituted 3-10 carbocyclic group, or an optionally substituted 3-10 heterocyclic group; W L and B L Each time it appears, it is either not present independently or selected from the following divalent parts: R L d -R L e R L d C(O)R L e R L d CO2R L e R L d C(O)N(R L 1 )R L e R L d OR L e R L d N(R L 1 )R L e R L d N(R L 1 COR L e R L d N(R L 1 CON(R) L 2 )R L eOptionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyneyl, optionally substituted C1-C8 alkoxy-C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 4-13 fused carbocyclic, optionally substituted 5-13 fused heterocyclic, optionally substituted 5-13 bridged carbocyclic, optionally substituted 5-13 bridged heterocyclic, optionally substituted 5-13 spirocyclic, optionally substituted 5-13 spiroheterocyclic, optionally substituted 3-10 carbocyclic, optionally substituted 3-10 heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; R L d and R L e Individually absent or selected from the following divalent groups: optionally substituted (C1-C8 alkylene)-R L r R, which is arbitrarily replaced L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene), optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyneyl, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 haloalkylene Optionally substituted 3-10-membered carbocyclic groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted 4-13-membered fused carbocyclic groups, optionally substituted 5-13-membered fused heterocyclic groups, optionally substituted 5-13-membered bridging carbocyclic groups, optionally substituted 5-13-membered bridging heterocyclic groups, optionally substituted 5-13-membered spirocarbocyclic groups, optionally substituted 5-13-membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; R L r Selected from optionally substituted aryl groups and optionally substituted heteroaryl groups; and m L It is 1, 2, or 3.

[0058] In some implementation schemes, A LIt is a 5-13 spirocyclocyclic group, a 5-13 spiroheterocyclic group, a 3-10 spirocyclocyclic group, or a 3-10 spirocyclic group that is optionally substituted.

[0059] In some embodiments, ring A is a substituted 3-10 membered carbocyclic group, a substituted 3-10 membered heterocyclic group, a substituted aryl group, a substituted bicyclic aryl group, a substituted heteroaryl group, or a substituted bicyclic heteroaryl group; and ring B is a substituted 3-10 membered carbocyclic group, a substituted 3-10 membered heterocyclic group, a substituted aryl group, or a substituted heteroaryl group. In some embodiments, ring A is a substituted 3-10 membered carbocyclic group, a substituted 3-10 membered heterocyclic group, a substituted aryl group, a substituted bicyclic aryl group, a substituted heteroaryl group, or a substituted bicyclic heteroaryl group; and

[0060] Cycle B is a heteroaryl group that is absent or optionally substituted.

[0061] In some implementations, ring B is absent or contains a portion of structure B-1:

[0062]

[0063] Where X 4 It is CR 12 Or N; each R 12 Independently, it is hydrogen, halogen, CN, OR 5 、N(R 5 )R 6 C(O)R 5 C(O)OR 5 C(O)N(R) 5 )R 6 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted 3-10 membered carbocyclic or optionally substituted 3-10 membered heterocyclic; or two R on adjacent carbon atoms 12 They are joined together to form optionally substituted 3-7 membered carbocyclic groups, optionally substituted 4-7 membered heterocyclic groups, optionally substituted 6 membered aryl groups, or optionally substituted 5-6 membered heteroaryl rings; each R 5 and R 6Independently, it is hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic C1-C8 alkyl, optionally substituted 3-10-membered heterocyclic C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-10-membered heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl; or R 5 and R 6 Together with the atoms to which they are attached, they optionally form optional substituted 4-7 membered heterocyclic groups or optional substituted 5-6 membered heteroaryl rings; p1 is 0, 1, or 2; * indicates a connection to a linker portion; and ** indicates a connection to X and / or ring A; and ring A is a portion having the structure of formula A-1:

[0064]

[0065] Where X 1 X 2 and X 3 Each is CR independently 10 Or N; each R 10 Independently, hydrogen, halogen, CN, NO2, OR 5 SR 5 、N(R 5 )R 6 C(O)R 5 C(O)OR 5 C(O)N(R) 5 )R 6 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, or optionally substituted C1-C8 alkylamino; or two R atoms on adjacent carbon atoms. 10 They are joined together to form optionally substituted 3-7 membered carbocyclic groups, optionally substituted 4-7 membered heterocyclic groups, optionally substituted 6 membered aryl groups, or optionally substituted 5-6 membered heteroaryl rings; each R 5 and R 6Independently, it is hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic C1-C8 alkyl, optionally substituted 3-10-membered heterocyclic C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-10-membered heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl; or R 5 and R 6 Together with the atoms to which they are attached, they optionally form substituted 4-7 membered heterocyclic groups or substituted 5-6 membered heteroaryl rings; and p2 is 0, 1, 2, 3 or 4.

[0066] In some implementations, ring B includes structural formula B-2:

[0067]

[0068] In some implementation schemes, R 12 It is hydrogen, halogen, CN, OR 5 、N(R 5 )R 6 C(O)R 5 C(O)OR 5 C(O)N(R) 5 )R 6 Optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, optionally substituted C1-C8 alkylamino groups, optionally substituted C1-C8 haloalkyl groups, optionally substituted 3-10 membered carbocyclic groups, or optionally substituted 3-10 membered heterocyclic groups. In some embodiments, R 12 It can be hydrogen, halogen, CN, OH, CH3, -OCH3, CF3, CF2, cyclopropyl, cyclobutyl, or cyclopentyl.

[0069] In some implementations, ring A is a portion that includes structural formula A-2, structural formula A-3, or structural formula A-4:

[0070]

[0071] Where X 1 It is CR 10 Or N; X 2 It is CR 10 Or N; X 3 It is CR 10 Or N; R 10A and R10B Each is R independently 10 ; or R 10A and R 10B They bond together with the atoms to form optionally substituted 6-membered aryl or 5-6-membered heteroaryl rings; each R 10 Independently, H, halogen, CN, NO2, OR 5 SR 5 、N(R 5 )R 6 C(O)R 5 C(O)OR 5 C(O)N(R) 5 )R 6 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, or optionally substituted C1-C8 alkylamino; and each R 5 and R 6 Independently, it is hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic C1-C8 alkyl, optionally substituted 3-10-membered heterocyclic C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-10-membered heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl; or R 5 and R 6 Together with the atoms to which they are attached, they optionally form substituted 4-7 membered heterocyclic groups or substituted 5-6 membered heteroaryl rings.

[0072] In some implementations, ring A comprises structural formula A-5:

[0073]

[0074] Where R 11 It is hydrogen, halogen, CN, NO2, OR 5 SR 5 、N(R 5 )R 6 C(O)R 5 C(O)OR 5 C(O)N(R) 5 )R 6 SO2R 5 SO2N(R)5 )R 6 NR 7 C(O)OR 5 NR 7 C(O)R 5 NR 7 C(O)N(R 5 )R 6 NR 7 SOR 5 NR 7 SO2R 5 NR 7 SO2N(R 5 )R 6 Optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy or optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclic or optionally substituted 3-10 membered heterocyclic.

[0075] In some implementations, ring A comprises structural formula A-6:

[0076]

[0077] Where X 1 X 2 or X 3 At least one of them is N. In some implementations, X 3 It is N.

[0078] In some implementations, ring A includes structural formula A-7:

[0079]

[0080] Where R 11 It is hydrogen, halogen, CN, NO2, OR 5 SR 5 、N(R 5 )R 6 C(O)R 5 C(O)OR 5 C(O)N(R) 5 )R 6 SO2R 5 SO2N(R) 5 )R 6 NR 7 C(O)OR 5 NR 7 C(O)R 5 NR7 C(O)N(R 5 )R 6 NR 7 SOR 5 NR 7 SO2R 5 NR 7 SO2N(R 5 )R 6 Optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclic or optionally substituted 3-10 membered heterocyclic.

[0081] In some implementations, each R 10 Independently, hydrogen, halogen, CN, NO2, OR 5 、N(R 5 )R 6 C(O)R 5 C(O)OR 5 Optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted 3-10 membered carbocyclic or optionally substituted 3-10 membered heterocyclic.

[0082] In some implementation schemes, R 11 It is hydrogen, halogen, CN, NO2, OR 5 、N(R 5 )R 6 C(O)R 5 C(O)OR 5 C(O)N(R) 5 )R 6 Optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted 3-10 membered carbocyclic or optionally substituted 3-10 membered heterocyclic.

[0083] In one implementation, R 1 No. In another implementation, R 1 It includes divalent groups selected from the following groups: R'-R", R'OR", R'SR", R'N(R 3 )R", R'OC(O)R", R'OC(O)OR", R'OCON(R 3 )R", R'C(O)R", R'C(O)OR", R'CON(R 3)R", R'S(O)R", R'S(O)2R", R'SO2N(R 3 )R”、R'NR 4 C(O)OR”、R'NR 4 C(O)R”、R'NR 4 C(O)N(R 3 )R”、R'NR 4 S(O)R”、R'NR 4 S(O)2R” and R'NR 4 S(O)2NR 3 R”, ​​where R’ and R” are each a divalent group, the divalent group being independently selected from unsubstituted or optionally substituted C1-C8 alkylene groups, optionally substituted C2-C8 alkenyl groups, optionally substituted C2-C8 alkyne groups, optionally substituted 3-10-membered carbocyclic groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted 4-13-membered fused carbocyclic groups, optionally substituted 5-13-membered fused heterocyclic groups, optionally substituted 5-13-membered bridged carbocyclic groups, optionally substituted 5-13-membered bridged heterocyclic groups, optionally substituted 5-13-membered spirocyclic groups, optionally substituted 5-13-membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups. In another embodiment, R 1 It is R'C(O)R'. In another embodiment, R 1 It is R'C(O)OR". In another implementation, R 1 It is C(O).

[0084] In one implementation, R 2 Selected from hydrogen, halogen, oxo group, CN, NO2, OR 5 SR 5 、N(R 5 )R 6 OCOR 5 OCO2R 5 OCON(R) 5 )R 6 COR 5 CO2R 5 CON(R) 5 )R 6 SOR 5 SO2R 5 SO2N(R) 5 )R 6 NR 7 CO2R 5 NR 7 COR 5 NR 7 C(O)N(R 5)R 6 NR 7 SOR 5 NR 7 SO2R 5 NR 7 SO2N(R 5 )R 6 Optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered heterocyclic C1-C8 alkyl, optionally substituted 3-10 membered carbocyclic C1-C8 alkyl, optionally substituted 3-10 membered carbocyclic, optionally substituted 3-10 membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, wherein R 5 R 6 and R 7 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic C1-C8 alkyl, optionally substituted 3-10-membered heterocyclic C1-C8 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 3-10-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, or R 5 and R 6 R 5 and R 7 Together with the atoms they are attached to, they form 3-20 membered heterocyclic rings or 5-6 membered heteroaryl rings.

[0085] In another implementation, R 2 Selected from hydrogen, halogen, oxo group, CN, NO2, OR 5 SR 5 and N(R) 5 )R 6 In another implementation, R 2 It is a halogen. In another embodiment, R 2 Selected from chloro, bromo, fluorine, and iodine groups. In one embodiment, R 2It is optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered heterocyclic C1-C8 alkyl, optionally substituted 3-10 membered carbocyclic C1-C8 alkyl, optionally substituted 3-10 membered carbocyclic, optionally substituted 3-10 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl. In another embodiment, R 2 It is an optionally substituted C1-C8 alkyl group. In another embodiment, R 2 It is an optionally substituted C1-C8 heteroalkyl group. In another embodiment, R 2 It is methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, or hexyl. In another embodiment, R 2 Selected from OH, OCH3, NH2, SH, carbocyclic, heterocyclic, aryl, or heteroaryl groups. In another embodiment, R 2 It is a heterocyclic group. In one implementation, R 2 It is piperidine. In another embodiment, R 2 It is a piperidine substituted with a C1-C8 alkyl group. In another embodiment, R 2 It is furan. In another embodiment, R 2 It is pyran. In another embodiment, R 2 Selected from optionally substituted azacyclopropanes, pyrrolidines, piperidines, piperazines, morpholine, thiomorpholine, tetrahydrofuran, tetrahydrothiofuran, and tetrahydropyran.

[0086] In another embodiment, X is selected from the absence or divalent portion, wherein the divalent portion is selected from the absence, CR 8 R 9 CO, CO2, CONR 8 NR 8 NR 8 CO, NR 8 CO2, NR 8 C(O)NR 9 NR 8 SO, NR 8 SO2, NR 8 SO2NR 9 O, OC(O), OCO2, OCONR 8 S, SO, SO2 and SO2NR 8Optionally substituted C1-C8 alkylene groups, optionally substituted C2-C8 alkenyl groups, optionally substituted C2-C8 alkyne groups, optionally substituted 3-10-membered carbocyclic groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, wherein R 8 and R 9 Independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclic, optionally substituted 3-10 membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, or R 8 and R 9 Together with one or more atoms to which they are attached, they form a 3-20 membered carbon ring or a 3-20 membered hetero ring. In one embodiment, X is absent. In another embodiment, X is selected from CR. 8 R 9 CO, CO2, CONR 8 NR 8 NR 8 CO, NR 8 CO2, NR 8 C(O)NR 9 NR 8 SO, NR 8 SO2, NR 8 SO2NR 9 O, OC(O), OCO2, OCONR 8 S, SO, SO2 and SO2NR 8 In another embodiment, X is 0. In some embodiments, X does not exist. In another embodiment, X is NR. 8 , where R 8It is CH3. In another embodiment, X is a heteroaryl group that is optionally substituted. In another embodiment, the heteroaryl group is selected from pyrroloyl, furanyl, thiophene, pyridinyl, pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoyndolyl, benzofuranyl, benzothiophene, quinolinyl, 2-methylquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzotriazolyl, benzimidazolyl, benzothiazolyl , benzoisothiazolyl, benzoisoxazolyl, benzoxadiazolyl, benzoxazolyl, cenolinyl, 1H-inzolyl, 2H-inzolyl, indoleazinyl, isobenzofuranyl, naphridinyl, phthalazinyl, pteridinyl, purineyl, oxazolopyridinyl, thiazopyridinyl, imidazopyridinyl, furanopyridinyl, thienopyridinyl, pyridinopyrimidinyl, pyridinopyrazinyl, pyridinopyridazinyl, thienothiazolyl, thienooxazolyl and thienoimidazolyl.

[0087] In another embodiment, ring A and Ring B The group is independently selected from unsubstituted or optionally substituted 3-10 membered carbocyclic groups, optionally substituted 3-10 membered heterocyclic groups, optionally substituted 4-13 membered fused carbocyclic groups, optionally substituted 5-13 membered fused heterocyclic groups, optionally substituted 5-13 membered bridged carbocyclic groups, optionally substituted 5-13 membered bridged heterocyclic groups, optionally substituted 5-13 membered spirocyclic groups, optionally substituted 5-13 membered spirocyclic groups, optionally substituted aryl groups, optionally substituted bicyclic fused aryl groups, optionally substituted tricyclic fused aryl groups, and optionally substituted heteroaryl groups, optionally substituted bicyclic fused heteroaryl groups, and optionally substituted tricyclic fused heteroaryl groups. In one embodiment, ring A is a heterocyclic group. In one embodiment, ring A is piperidine. In another embodiment, ring A is piperidine substituted with a C1-C8 alkyl group. In another embodiment, ring A is furan. In another embodiment, ring A is pyran. In another embodiment, ring A is selected from optionally substituted azacyclic propanes, pyrrolidines, piperidines, piperazines, morpholine, thiomorpholine, tetrahydrofuran, tetrahydrothiofuran, and tetrahydropyran. In one embodiment, ring B is a heterocyclic group. In one embodiment, ring B is piperidine. In another embodiment, ring B is piperidine substituted with a C1-C8 alkyl group. In another embodiment, ring B is furan. In another embodiment, ring B is pyran. In another embodiment, ring B is selected from optionally substituted azacyclic propanes, pyrrolidines, pyrrolidines, piperidines, piperazines, morpholine, thiomorpholine, tetrahydrofuran, tetrahydrothiofuran, and tetrahydropyran.

[0088] In another embodiment, the degradation label is part of Formula 5, and wherein R E 2Each time it appears, it is independently selected from the absence of, hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl.

[0089] In another embodiment, the degradation label is part of Formula 5, and wherein V E 1 V E 2 V E 3 V E 4 and V E 5 Each occurrence is independently selected from non-existent, C, and CR. E 2 S, N and NR E 2 ; or V E 1 and V E 2 V E 2 and V E 3 V E 3 and V E 4 or V E 4 and V E 5 The combination can optionally form a 6-membered aryl ring or a 5, 6, or 7-membered heteroaryl ring.

[0090] In another embodiment, the degradation label is part of Formula 5, and wherein ring A E It is from formula A E A group consisting of 1, wherein V E 1 V E 2 V E 3 and V E 4 Each is independently selected from C and CR. E 2 S, N and NR E 2 .

[0091] In another embodiment, the degradation label is part of Formula 5, and wherein ring A E It is from formula A E 2 groups, and wherein V E 1 V E 2 V E 3 V E 4 and V E 5 Each time it appears, it is independently selected from C and C. E 2 S, N and NR E 2 .

[0092] In another embodiment, the degradation label is part of Formula 5, and wherein ring A E It is from formula A E 3 groups, and in which V E 1 V E 2 V E 3 V E 4 and V E 5 Each is independently selected from C and CR. E 2 S, N and NR E 2 ; or V E 1 and V E 2 V E 2 and V E 3 V E 3 and V E 4 or V E 4 and V E 5 They can be combined to optionally form a 6-membered aryl ring or a 5, 6, or 7-membered heteroaryl ring.

[0093] In another embodiment, the degradation label is part of Formula 5, and wherein ring A E It is from formula A E 4 groups, and in which It is a single key, and W E 1 W E2 W E 3 and W E 4 Each is independently selected from -N= and -CR. E 3 =、-CO-、-O-、-CR E 3 R E 4 -and-NR E 3 -

[0094] In another embodiment, the degradation label is part of Formula 5, and wherein ring A E It is from formula A E A group consisting of 5, wherein V E 1 V E 2 and V E 3 Each independently selected from CR E 2 S, N, with the condition V E 1 V E 2 and V E 3 At least one of them is S, N or NR E 2 ; or V E 1 and V E 2 V E 2 and V E 3 They can be combined to optionally form a 5-membered heteroaryl ring.

[0095] In another embodiment, the degradation label is part of Formula 5, and wherein R E 1 Selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 3-8 membered heterocyclic groups; preferably, R E 1 Selected from hydrogen, halogen, cyano, nitro and C1-C5 alkyl; more preferably, R E 1 Selected from H, CH3, or F.

[0096] In another embodiment, the degradation label is part of Formula 5, and wherein R E 2Selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3- to 8-membered carbocyclic groups, and optionally substituted 3- to 8-membered heterocyclic groups; preferably, R E 2 Selected from hydrogen, halogen, cyano, nitro, and C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3- to 8-membered carbocyclic groups, and optionally substituted 3- to 8-membered heterocyclic groups; more preferably, R E 2 Selected from H, F, OMe, O-iPr or O-cPr.

[0097] In another embodiment, the degradation label is part of Formula 5, and wherein R E 3 and R E 4 Independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered carbocyclic group and optionally substituted 3- to 8-membered heterocyclic group; or R E 3 and R E 4 Together with the atoms they are attached to, they form 3-8 membered carbon cyclic groups or 3-8 membered heterocyclic groups.

[0098] In another embodiment, the degradation label is part of Formula 5, and wherein R E r Selected from group R E And group R E It consists of the following:

[0099]

[0100]

[0101] In another embodiment, the degradation label is part of Formula 5, and wherein in Z E In the group, there are at most three R E Z It is R E r .

[0102] In another embodiment, the degradation label is part of Formula 5, and where n E = 0, 1, 2 or 3.

[0103] In another embodiment, the degradation label is part of Formula 5, and wherein Z E It is selected from -R Ew -、-(R E w )2-、-(R E w )3-、-R E r -、-R E w -R E r -R E w -、-R E r -R E w -and-R E r -(R E w )2- divalent group.

[0104] In another embodiment, the degradation label is part of Formula 5, and wherein R E 5 and R E 6 Each time it appears, it is independently selected from the absence of, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted 3- to 8-membered carbocyclic group, and optionally substituted 3- to 8-membered heterocyclic group; or R E 5 and R E 6 Together with the atoms they are attached to, they form 3-8 member carbon rings or heterocyclic rings.

[0105] In another embodiment, the degradation label is part of Formula 5, and wherein R E Z Selected from -CO-, -CR E 5 R E 6 -、-NR E 5 -、-O-、Optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 alkenyl, optionally substituted C1-C 10 Alynyl group, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group.

[0106] In another embodiment, the degradation label is part of Formula 5, and wherein Z E Selected from non-existent, CH2, CH=CH, C≡C, NH and O.

[0107] In another embodiment, the degradation label is part of Formula 5, and wherein ring A E Having formula A E 4, and L E It's not that it doesn't exist.

[0108] In another embodiment, the degradation label is part of Formula 5, and wherein ring A E Having formula A E 4, and L E Selected from -NH-, -N(C1-C4 alkyl)-, -CO-, -NH-CO-, -N(C1-C4 alkyl)-CO-, -CO-NH- and -CO-N(C1-C4 alkyl)-.

[0109] In another embodiment, the degradation label is selected from the parts of formulas 5-1, 5-2, 5-3, 5-4, 5-5, and 5-6, and the degradation label is transmitted via Z. E The divalent group is attached to the linker portion of the divalent compound;

[0110]

[0111] in

[0112] Z E R E 1 L E , V E 1 V E 2 V E 3 V E 4 V E 5 W E 1 W E 2 W E 3 and W E 4 As defined in Equation 5.

[0113] In another embodiment, the degradation label is selected from the portions of formulas 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, 5I, 5J, 5K, 5L, and 5M:

[0114]

[0115] in,

[0116] VE 6 V E 7 V E 8 and V E 9 Each is independently selected from non-existent, C, and CR. E 12 and N; or V E 1 and V E 2 V E 2 and V E 3 V E 3 and V E 4 or V E 4 and V E 5 They can be combined to optionally form a 6-membered aryl ring or a 5, 6, or 7-membered heteroaryl ring;

[0117] R E 12 Each time it appears, it is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-8 membered carbon cycloyl and optionally substituted 3-8 membered heterocyclic.

[0118] W E 6 and W E 7 Each independently selected from -CR E 2 = and -N=;

[0119] W E 1 W E 2 W E 3 W E 4 V E 1 V E 2 V E 3 V E 4 V E 5 RE 1 R E 3 and Z E As defined in Equation 5.

[0120] In another implementation, W E 1 Selected from -CO-, -O-, -CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 - and -N = N-.

[0121] In another embodiment, the degradation label is part of formula 5-1 or formula 5-3.

[0122]

[0123] in

[0124] V E 1 V E 2 V E 3 and V E 4 Each is independently selected from non-existent, C, and CR. E 2 and N; or V E 1 and V E 2 V E 2 and V E 3 or V E 3 and V E 4 They can be combined to optionally form a 6-membered aryl ring or a 5, 6, or 7-membered heteroaryl ring;

[0125] Indicates a single or double bond; where (i) when in W E 1 With W E 2 When there is a single bond (i.e., W) E 1 and

[0126] W E 2 Between Indicator key), W E 1 W E 2 and W E 3 Each is independently selected from –N=, -CR E 3 =、-CO-、-O-、-CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 - and -N = N-; or (ii) when W E 1 With W E 2 When there are double bonds (i.e., W) E 1 With W E 2 Between (Indicator double key), W E 1 and W E 2 Each is independently selected from -N=, -C≡ and -CR E 3 =; W E 3 Selected from -O-, -N=, -NR E 3 -、-C(O)NR E 3 -、-CR E 3 =CR E 4 -and-CR E 3 =N-;

[0127] Z E R E 2 R E 3 R E 4 and R E 1 As defined in Equation 5.

[0128] In another embodiment, the degradation label is a part of formula 5-1 or 5-3, and wherein V E 1 V E 2 V E 3 and V E 4 Each is independently selected from C, N, and CR. E 2 .

[0129] In another embodiment, the degradable label formula 5-1 is a part of formula 5A, 5B, 5E, 5F, or 5G:

[0130]

[0131] Among them W E 6 and W E 7 Each independently selected from -CR E 2 = and -N=; and V E 1 V E 2 V E 3 V E 4 W E 1 W E 3 Z E R E 3 and R E 1 As defined in Equation 5-1.

[0132] In another embodiment, the degradation label is a part of formula 5A, 5B, 5E, 5F, or 5G, and wherein V E 1 V E 2 V E 3 and V E 4 Each is independently selected from non-existent, C, and CR. E 2 and N (preferably C, CR) E 2 and N).

[0133] In another embodiment, the degradation label is a part of formula 5A, 5B, 5E, 5F, or 5G, and wherein W E1 and W E 3 Each is independently selected from -CO-, -O-, and -CR. E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 - and -N = N-; preferably, W E 1 and W E 3 Each is independently selected from -CO-, -O-, and -CR. E 3 R E 4 -and-NR E 3 -

[0134] In another embodiment, the degradation label formula 5-3 is a part of formula 5C:

[0135]

[0136] Among them W E 3 Is it N or CR? E 3 ;and V E 1 V E 2 V E 3 V E 4 Z E and R E 1 As defined in Formula 5-3. In another embodiment, the degradation label is a part of Formula 5C, wherein V E 1 V E 2 V E 3 and V E 4 Each is independently selected from non-existent CR E 2 and N.

[0137] In another embodiment, the degradation label is part of Formula 5-2.

[0138]

[0139] V E 1 V E 2 V E 3 V E 4 and V E 5 Each is independently selected from non-existent, C, and CR. E 2 and N; or V E 1 and V E 2 V E 2 and V E 3 V E 3 and V E 4 or V E 4 and V E 5 They can be combined to optionally form a 6-membered aryl ring or a 5, 6, or 7-membered heteroaryl ring;

[0140] Indicates a single or double bond; (i) when in W E 1 With W E 2 When there is a single bond (i.e., W) E 1 With W E 2 Between Indicator key), W E 1 and W E 4 Each is independently selected from -N= and -CR. E 3 =、-CO-、-O-、-CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 - and -N = N-, and W E 2 and W E3 Each is independently selected from -N= and -CR. E 3 =、-CO-、-O-、-CR E 3 R E 4 -and-NR E 3 -; or (ii) when in W E 1 With W E 2 When there are double bonds (i.e., W) E 1 With W E 2 Between (Indicator double key), W E 1 and W E 2 Each is independently selected from -N=, C and -CR E 2 =; W E 3 Selected from -N=, -CR E 3 =、-CO-、-O-、-CR E 3 R E 4 -and-NR E 3 -; and W E 4 Selected from -N=, -CR E 3 =、-CO-、-O-、-CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 -and -N = N-;

[0141] Z E R E 2 R E 3 R E 4 and R E 1 As defined in Equation 5.

[0142] In another embodiment, the degradation label is part of Formula 5-2, wherein V E 1 V E 2 V E 3 V E 4 and V E 5 Each is independently selected from non-existent, C, and CR. E 2 and N.

[0143] In another embodiment, the degradation label is part of Formula 5-2, wherein Indicates a single key.

[0144] In another embodiment, the degradation label is part of Formula 5-2, wherein Indicates a single key, W E 1 and W E 4 Each is independently selected from -CO-, -O-, and -CR. E 3 R E 4 -and-NR E 3 - and W E 2 and W E 3 Each is independently selected from -N= and -CR. E 3 =、-CO-、-O-、-CR E 3 R E 4 -and-NR E 3 -

[0145] In another embodiment, the degradable label formula 5-2 is a part of formula 5D.

[0146]

[0147] Where V E 1 V E 2 V E 3 V E 4 V E 5 W E 1 ZE and R E 1 As defined in Equation 5-2.

[0148] In another embodiment, the degradation label is part of formula 5D, wherein W E 1 Selected from -CO-, -O-, -CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 - and -N = N-; preferably, W E 1 Selected from -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -

[0149] In another embodiment, the degradation label is part of formula 5D, where V E 1 V E 2 V E 3 V E 4 and V E 5 Each is independently selected from non-existent, C, and CR. E 2 and N; or V E 1 and V E 2 V E 2 and V E 3 V E 3 and V E 4 or V E 4 and V E 5 Combined together, optionally forming a 6-membered aryl ring or a 5, 6, or 7-membered heteroaryl ring; preferably, V E 1 V E 2 VE 3 V E 4 and V E 5 Each is independently selected from non-existent, C, and CR. E 2 and N.

[0150] In another embodiment, the degradation label is part of Formula 5-4.

[0151]

[0152] Where V E 1 V E 2 V E 3 V E 4 V E 5 L E Z E and R E 1 As defined in Equation 5.

[0153] In another embodiment, the degradation label is part of Formula 5-4, and wherein L E It's not that it doesn't exist.

[0154] In another embodiment, the degradation label is part of Formula 5-4, and wherein L E Selected from -NH-, -N(C1-C4 alkyl)-, -CO-, -NH-CO-, -N(C1-C4 alkyl)-CO-, -CO-NH- and -CO-N(C1-C4 alkyl)-.

[0155] In another embodiment, the degradation label is part of Formula 5-4, and wherein V E 1 V E 2 V E 3 V E 4 and V E 5 Each time it appears, it is independently selected from C and C. E 2 and N; or

[0156] V E 1 and V E 2 V E 2and V E 3 V E 3 and V E 4 or V E 4 and V E 5 Combined together to form optional The ring, where V E 6 V E 7 V E 8 and V E 9 Each is independently selected from C and CR. E 12 and N;

[0157] R E 12 Each time it appears, it is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-8 membered carbocyclic and optionally substituted 3-8 membered heterocyclic.

[0158] In another embodiment, the degradation label is part of Formula 5-4, and wherein V E 6 V E 7 V E 8 and V E 9 Each independently selected from CR E 12 and N.

[0159] In another embodiment, the degradation label is part of Formula 5-4, and wherein R E 12 Each time it appears, it is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, and optionally substituted C1-C6 alkyl groups.

[0160] In another embodiment, the degradation label is part of Formula 5-4, and wherein

[0161] Selected from the following:

[0162]

[0163] in

[0164] V E 1 V E 2 V E 3 V E 4 and V E 5 Each is independently selected from C and CR. E 2 and N; and V E 6 V E 7 V E 8 and V E 9 Each independently selected from CR E 12 and N.

[0165] In another embodiment, the degradation label is part of Formula 5-4, and wherein Z E It does not contain -CH2-, -O-, or -NH-.

[0166] In another embodiment, the degradation label formula 5-4 is a part of formula 5H or 5I;

[0167]

[0168] Where V E 1 V E 2 V E 3 V E 4 V E 5 V E 6 V E 7 V E 8 and V E 9 Each is independently selected from non-existent, C, and CR. E 2 and N; and Z E and R E 1 As defined in Equation 5-4.

[0169] In another embodiment, the degradation label is part of Formula 5-5.

[0170]

[0171] in W E 1 W E 2 W E 3 W E 4 Z E and R E 1 As defined in Equation 5.

[0172] In another embodiment, the degradation label is part of Formula 5-5, and wherein W E 1 W E 2 W E 3 and W E 4 Each is independently selected from -N=, -C≡, and -CR. E 3 =、-CO-、-O-、-CR E 3 R E 4 -and-NR E 3 -

[0173] In another embodiment, the degradation label is part of Formula 5-5, and wherein W E 1 W E 2 W E 3 and W E 4 Each is independently selected from -N=, -C≡, -CH=, -CO-, -O-, -N-, -CH2- and -NH-.

[0174] In another embodiment, the degradable label formula 5-5 is a part of formula 5J, 5K, or 5L;

[0175]

[0176] Among them W E 1 W E 2 W E 3 W E 4 Z E R E 3 and RE 1 As defined in Equation 5-5.

[0177] In another embodiment, the degradation label is part of Formula 5-6.

[0178]

[0179] in

[0180] V E 1 V E 2 and V E 3 Each is independently selected from C and CR. E 2 S, N and NR E 2 ; or V E 1 and V E 2 or V E 2 and V E 3 They can be combined to optionally form a 5-membered heteroaryl ring;

[0181] Indicates a single or double bond; where (i) when in W E 1 With W E 2 When there is a single bond (i.e., W) E 1 With W E 2 Between Indicator key), W E 1 W E 2 and W E 3 Each is independently selected from –N=, -CR E 3 =、-CO-、-O-、-CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 - and -N = N-; or (ii) when W E1 With W E 2 When there are double bonds (i.e., W) E 1 With W E 2 Between (Indicator double key), W E 1 and W E 2 Each is independently selected from -N=, -C≡ and -CR E 3 =; W E 3 Selected from -O-, -N=, -NR E 3 -、-C(O)NR E 3 -、-CR E 3 =CR E 4 -and-CR E 3 =N-; and Z E R E 2 R E 3 R E 4 and R E 1 As defined in Equation 5.

[0182] In another embodiment, the degradation label is part of Formula 5-6, and wherein V E 1 V E 2 V E 3 and V E 4 Each is independently selected from C and CR. E 2 S, N and NR E 2 .

[0183] In another embodiment, the degradation label formula 5-6 is a part of formula 5M:

[0184]

[0185] Where V E 1 V E 2 V E 3 WE 1 Z E and R E 1 As defined in Equation 5-6.

[0186] In another embodiment, the degradation label is a part of Formula 5M, and wherein V E 1 V E 2 and V E 3 Each is independently selected from C and CR. E 2 S, N and NR E 2 (Preferably, V) E 1 V E 2 and V E 3 One of them is S).

[0187] In another embodiment, the degradation label is part of formula 5M, and wherein W E 1 Selected from -CO-, -O-, -CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 - and -N = N-; preferably, W E 1 Selected from -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -

[0188] In another embodiment, the degradation label is part of Formula 5-1.

[0189] In another embodiment, the degradation label is part of Formula 5-6.

[0190] In another embodiment, the degradation label is part of Formula 5A.

[0191] In another embodiment, the degradation label is part of Formula 5M.

[0192] In another embodiment, the degradation label is derived from any of the following:

[0193]

[0194] In another embodiment, the degradation label is derived from any one of thalidomide, pomalidomide, lenalidomide, CRBN-1, CRBN-2, CRBN-3, CRBN-4, CRBN-5, CRBN-6, CRBN-7, CRBN-8, CRBN-9, CRBN-10, CRBN-11, CRBN-12, CRBN-13, CRBN-14, CRBN-15, and CRBN-16.

[0195] In another embodiment, the degradation label is derived from any of the following formulas:

[0196]

[0197]

[0198]

[0199]

[0200] In some implementations, the connector portion has Formula 9:

[0201]

[0202] in

[0203] A L W L and B L Each occurrence is independently selected from either the absence or divalent portion, wherein the divalent portion is selected from R. L d -R L e R L d COR L e R L d CO2R L e R L d C(O)N(R L 1 )R L e R L d C(S)N(RL 1 )R L e 、R L d OR L e 、R L d SR L e 、R L d SOR L e 、R L d SO2R L e 、R L d SO2N(R L 1 )R L e 、R L d N(R L 1 )R L e 、R L d N(R L 1 )COR L e 、R L d N(R L 1 )CON(R L 2 )R L e 、R L d N(R L 1 )C(S)R L eOptionally substituted C1-C8 alkylene groups, optionally substituted C2-C8 alkenyl groups, optionally substituted C2-C8 ynylene groups, optionally substituted C1-C8 alkoxy-C1-C8 alkylene groups, optionally substituted C1-C8 haloalkylene groups, optionally substituted C1-C8 heteroalkylene groups, optionally substituted C1-C8 hydroxyalkylene groups, optionally substituted 4-13 fused carbocyclic groups, Optionally substituted 5-13 fused heterocyclic groups, optionally substituted 5-13 bridging carbocyclic groups, optionally substituted 5-13 bridging heterocyclic groups, optionally substituted 5-13 spirocarbocyclic groups, optionally substituted 5-13 spiroheterocyclic groups, optionally substituted 3-10 bridging carbocyclic groups, optionally substituted 3-10 bridging heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, wherein R L d and R L e Independently selected from (C1-C8 alkylene)-R L r (preferred is CH2-R) L r ), R which is arbitrarily replaced L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene) or comprising the following portions: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyneyl, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy-C1-C8 alkylene, optionally substituted C1-C8 alkylamino-C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 Haloalkylene, optionally substituted 3-10-membered carbocyclic group, optionally substituted 3-10-membered heterocyclic group, optionally substituted 4-13-membered fused carbocyclic group, optionally substituted 5-13-membered fused heterocyclic group, optionally substituted 5-13-membered bridged carbocyclic group, optionally substituted 5-13-membered bridged heterocyclic group, optionally substituted 5-13-membered spirocarbocyclic group, optionally substituted 5-13-membered spiroheterocyclic group, optionally substituted aryl group and optionally substituted heteroaryl group.

[0204] R L rSelected from optionally substituted 3-10-membered carbocyclic groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted 4-13-membered fused carbocyclic groups, optionally substituted 5-13-membered fused heterocyclic groups, optionally substituted 5-13-membered bridging carbocyclic groups, optionally substituted 5-13-membered bridging heterocyclic groups, optionally substituted 5-13-membered spirocarbocyclic groups, optionally substituted 5-13-membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups.

[0205] R L 1 and R L 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 3-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.

[0206] R L d and R L e R L 1 and R L 2 R L d and R L 1 R L d and R L 2 R L e and R L 1 R L e and R L 2 Together with the atoms they are attached to, they form 3-20 membered carbon rings or 4-20 membered heterocyclic rings; and m L It is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0207] In another implementation, W L and m L As defined above; and A L and B L Each occurrence is independently selected from either the absence or divalent portion, wherein the divalent portion is selected from R.L d -R L e 、R L d COR L e 、R L d CO2R L e 、R L d C(O)N(R L 1 )R L e 、R L d C(S)N(R L 1 )R L e 、R L d OR L e 、R L d SR L e 、R L d SOR L e 、R L d SO2R L e 、R L d SO2N(R L 1 )R L e 、R L d N(R L 1 )R L e 、R L d N(R L 1 )COR L e 、R L d N(R L 1 )CON(R L 2 )R L e 、R L d N(R L1 )C(S)R L e Optionally substituted C1-C8 alkylene groups, Optionally substituted C2-C8 alkenyl groups, Optionally substituted C2-C8 ynylene groups, Optionally substituted C1-C8 alkoxy-C1-C8 alkylene groups, Optionally substituted C1-C8 heteroalkylene groups, Optionally substituted C1-C8 haloalkylene groups, Optionally substituted C1-C8 hydroxyalkylene groups, Optionally substituted 4-13 fused carbocyclic groups, Optionally substituted 5-13 fused heterocyclic groups, optionally substituted 5-13 bridging carbocyclic groups, optionally substituted 5-13 bridging heterocyclic groups, optionally substituted 5-13 spirocarbocyclic groups, optionally substituted 5-13 spiroheterocyclic groups, optionally substituted 3-10 bridging carbocyclic groups, optionally substituted 3-10 bridging heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, wherein R L d and R L e Independently selected from (C1-C8 alkylene)-R L r (preferred is CH2-R) L r ), R which is arbitrarily replaced L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene) or comprising the following portions: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyneyl, 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 groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted 4-13-membered fused carbocyclic groups, optionally substituted 5-13-membered fused heterocyclic groups, optionally substituted 5-13-membered bridging carbocyclic groups, optionally substituted 5-13-membered bridging heterocyclic groups, optionally substituted 5-13-membered spirocarbocyclic groups, optionally substituted 5-13-membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups.

[0208] In one implementation, A L Selected from optionally substituted C1-C8 alkylene groups. In another embodiment, A L It is methylene. In another embodiment, A LIt is ethylene. In another embodiment, A L It is n-propylidene. In another embodiment, A L No. In another implementation, A L It is R L d COR L e , where R L d It is CH2, and R L e It is CH2. In another implementation, A L It is R L d COR L e , where R L d It is CH2CH2, and R L e It is CH2. In another implementation, A L It is R L d COR L e , where R L d It is CH2, and R L e It is CH2CH2. In one implementation, A L It is R L d COR L e , where R L d and R L e None of them exist. In another implementation, A L It is a n-propylidene group optionally substituted with at least one Cl, Br, I, F, OH, NH2, SH, or OCH3. In another embodiment, A L It is an aryl group. In another embodiment, A L It is a phenyl group optionally substituted with at least one of Cl, Br, I, F, OH, NH2, SH, or OCH3. In another embodiment, A L It is an optionally substituted heteroaryl group. In another embodiment, A L It is R L d COR L e , where R L d No, and R L eIt is CH2CH2CH2. In another embodiment, A L It is an optionally substituted heteroaryl group. In another embodiment, A L It is R L d COR L e , where R L d No, and R L e It is CH2CH2CH2CH2. In another embodiment, A L The substituted heteroaryl group is optionally selected from the following: pyrroloyl, furanyl, thiopheneyl, pyridinyl, pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiopheneyl, quinolinyl, 2-methylquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzotriazolyl, benzimidazolyl, benzothiazolyl Azolyl, benzoisothiazolyl, benzoisoxazolyl, benzoxadiazolyl, benzoxazolyl, cenolinyl, 1H-inzolyl, 2H-inzolyl, indoleazinyl, isobenzofuranyl, naphridinyl, phthalazinyl, pteridinyl, purineyl, oxazolopyridinyl, thiazopyridinyl, imidazopyridinyl, furanpyridinyl, thienopyridinyl, pyridinylpyrimidinyl, pyridinylpyrazinyl, pyridinylpyridazinyl, thienothiazolyl, thienooxazolyl, and thienoimidazolyl.

[0209] In one implementation, B L Selected from C1-C8 alkylene groups that may be optionally substituted. In another embodiment, B L It is methylene. In another embodiment, B L It is ethylene. In another embodiment, B L It is n-propylidene. In another embodiment, B L No. In another implementation, B L It is R L d COR L e , where R L d It is CH2, and R L e It is CH2. In another embodiment, B L It is R L d COR L e , where R L d It is CH2CH2, and R Le It is CH2. In another embodiment, B L It is R L d COR L e , where R L d It is CH2, and R L e It is CH2CH2. In one implementation, B L It is R L d COR L e , where R L d and R L e None of them exist. In another implementation, B L It is a n-propylidene group optionally substituted with at least one of Cl, Br, I, F, OH, NH2, SH, or OCH3. In another embodiment, B L It is an aryl group. In another embodiment, B L It is a phenyl group optionally substituted with at least one of Cl, Br, I, F, OH, NH2, SH, or OCH3. In another embodiment, B L It is an optionally substituted heteroaryl group. In another embodiment, B L It is R L d COR L e , where R L d No, and R L e It is CH2CH2CH2. In another embodiment, B L It is an optionally substituted heteroaryl group. In another embodiment, B L It is R L d COR L e , where R L d No, and R L e It is CH2CH2CH2CH2. In another embodiment, B LThe substituted heteroaryl group is optionally selected from the following: pyrroloyl, furanyl, thiopheneyl, pyridinyl, pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiopheneyl, quinolinyl, 2-methylquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzotriazolyl, benzimidazolyl, benzothiazolyl Azolyl, benzoisothiazolyl, benzoisoxazolyl, benzoxadiazolyl, benzoxazolyl, cenolinyl, 1H-inzolyl, 2H-inzolyl, indoleazinyl, isobenzofuranyl, naphridinyl, phthalazinyl, pteridinyl, purineyl, oxazolopyridinyl, thiazopyridinyl, imidazopyridinyl, furanpyridinyl, thienopyridinyl, pyridinylpyrimidinyl, pyridinylpyrazinyl, pyridinylpyridazinyl, thienothiazolyl, thienooxazolyl, and thienoimidazolyl.

[0210] In another implementation, R L r Selected from formulas C1, C2, C3, C4 and C5

[0211]

[0212] in

[0213] A L 1 B L 1 C L 1 and D L 1 Each occurrence is independently selected from none, O, CO, SO, SO2, NR. L b or CR L b R L c ;

[0214] X L 'and Y L 'Selected independently from N or CR each time it appears.' L b ;

[0215] A L 2 B L 2 C L 2 D L 2 and E L 2 Each occurrence is independently selected from N or CR. Lb A L 3 B L 3 C L 3 D L 3 and E L 3 Each occurrence is independently selected from N, O, S, NR. L b or CR L b ;

[0216] R L b and R L c 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, 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; and m L 1 n L 1 o L 1 and p L 1 Selected independently from 0, 1, 2, 3, 4 and 5.

[0217] In another implementation, R L r Selected from group R L And group R L It consists of the following:

[0218]

[0219]

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

[0221]

[0222] in

[0223] R L 1 R L 2 R L 3 and R L 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 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino and optionally substituted C1-C8 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 3-8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, or

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

[0225] A L W L and B L Each occurrence is independently selected from either the absence or divalent portion, wherein the divalent portion is selected from R. L d -R L e R L d COR L e R L d CO2R L e R L d C(O)N(R L 5 )R L e R L d C(S)N(R L5 )R L e 、R L d OR L e 、R L d SR L e 、R L d SOR L e 、R L d SO2R L e 、R L d SO2N(R L 5 )R L e 、R L d N(R L 5 )R L e 、R L d N(R L 5 )COR L e 、R L d N(R L 5 )CON(R L 6 )R L e 、R L d N(R L 5 )C(S)R L eOptionally substituted C1-C8 alkylene groups, Optionally substituted C2-C8 alkenyl groups, Optionally substituted C2-C8 ynylene groups, Optionally substituted C1-C8 alkoxy-C1-C8 alkylene groups, Optionally substituted C1-C8 heteroalkylene groups, Optionally substituted C1-C8 haloalkylene groups, Optionally substituted C1-C8 hydroxyalkylene groups, Optionally substituted 4-13 fused carbocyclic groups, Optionally substituted 5-13 fused heterocyclic groups, optionally substituted 5-13 bridging carbocyclic groups, optionally substituted 5-13 bridging heterocyclic groups, optionally substituted 5-13 spirocarbocyclic groups, optionally substituted 5-13 spiroheterocyclic groups, optionally substituted 3-10 bridging carbocyclic groups, optionally substituted 3-10 bridging heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, wherein R L d and R L e Independently selected from (C1-C8 alkyl)-R L r (preferred is CH2-R) L r ), R which is arbitrarily replaced L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene) or comprising the following portions: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyneyl, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy-C1-C8 alkylene, optionally substituted C1-C8 alkylamino-C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 Halogenated alkylene groups, optionally substituted 3-10-membered carbocyclic groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted 4-13-membered fused carbocyclic groups, optionally substituted 5-13-membered fused heterocyclic groups, optionally substituted 5-13-membered bridged carbocyclic groups, optionally substituted 5-13-membered bridged heterocyclic groups, optionally substituted 5-13-membered spirocarbocyclic groups, optionally substituted 5-13-membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups.

[0226] R L rSelected from optionally substituted 3-10-membered carbocyclic groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted 4-13-membered fused carbocyclic groups, optionally substituted 5-13-membered fused heterocyclic groups, optionally substituted 4-13-membered bridging carbocyclic groups, optionally substituted 5-13-membered bridging heterocyclic groups, optionally substituted 5-13-membered spirocarbocyclic groups, optionally substituted 5-13-membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups.

[0227] R L 5 and R L 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 heteroalkyl, 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 3-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.

[0228] R L d and R L e R L 5 and R L 6 R L d and R L 5 R L d and R L 6 R L e and R L 5 R L e and R L 6 Together with the atoms they are attached to, they form 3-20 membered carbon rings or 4-20 membered heterocyclic rings; m L It is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0229] n L Each time it appears, it is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and

[0230] oL It is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0231] In another implementation, A L W L and B L Each occurrence is independently selected from either the absence or divalent portion, wherein the divalent portion is selected from R. L d -R L e R L d COR L e R L d CO2R L e R L d C(O)N(R L 5 )R L e R L d C(S)N(R L 5 )R L e R L d OR L e R L d SR L e R L d SOR L e R L d SO2R L e R L d SO2N(R L 5 )R L e R L d N(R L 5 )R L e R L d N(R L 5 )COR L e RL d N(R L 5 CON(R) L 6 )R L e R L d N(R L 5 )C(S)R L e Optionally substituted C1-C8 alkylene, Optionally substituted C2-C8 alkenyl, Optionally substituted C2-C8 alkyne, Optionally substituted C1-C8 alkoxy-C1-C8 alkylene, Optionally substituted C1-C8 heteroalkylene, Optionally substituted C1-C8 haloalkylene, Optionally substituted C1-C8 hydroxyalkylene, Optionally substituted 4-13 fused carbocyclic, Optionally substituted 5-13 fused heterocyclic, Optionally substituted 5-13 bridged carbocyclic, Optionally substituted 5-13 bridged heterocyclic, Optionally substituted 5-13 spirocyclic, Optionally substituted 5-13 spiroheterocyclic, Optionally substituted 3-10 carbocyclic, Optionally substituted 3-10 heterocyclic, Optionally substituted aryl and Optionally substituted heteroaryl.

[0232] In another embodiment, the connector portion has Formula 9B:

[0233]

[0234] in

[0235] R L 1 and R L 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 heteroalkyl, 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 3-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or

[0236] R L 1 and R L2 Together with the atoms they are attached to, they form 3-20 membered carbon rings or 4-20 membered heterocyclic rings;

[0237] A L and B L Each occurrence is independently selected from either the absence or divalent portion, wherein the divalent portion is selected from R. L d -R L e R L d COR L e R L d CO2R L e R L d C(O)N(R L 3 )R L e R L d C(S)N(R L 3 )R L e R L d OR L e R L d SR L e R L d SOR L e R L d SO2R L e R L d SO2N(R L 3 )R L e R L d N(R L 3 )R L e R L d N(R L 3 COR L e R L d N(RL 3 CON(R) L 4 )R L e R L d N(R L 3 )C(S)R L e Optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyneyl, optionally substituted C1-C8 alkoxy-C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 4-13 fused carbocyclic, optionally substituted 5-13 fused heterocyclic, optionally substituted 5-13 bridged carbocyclic, optionally substituted 5-13 bridged heterocyclic, optionally substituted 5-13 spirocyclic, optionally substituted 5-13 spiroheterocyclic, optionally substituted 3-10 carbocyclic, optionally substituted 3-10 heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0238] R L d and R L e Independently selected from (C1-C8 alkylene)-R L r (preferred is CH2-R) L r ), R which is arbitrarily replaced L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r-(C1-C8 alkylene) or comprising the following portions: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyneyl, 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 groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted 4-13-membered fused carbocyclic groups, optionally substituted 5-13-membered fused heterocyclic groups, optionally substituted 5-13-membered bridging carbocyclic groups, optionally substituted 5-13-membered bridging heterocyclic groups, optionally substituted 5-13-membered spirocarbocyclic groups, optionally substituted 5-13-membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; R L r Selected from optionally substituted 3-10-membered carbocyclic groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted 4-13-membered fused carbocyclic groups, optionally substituted 5-13-membered fused heterocyclic groups, optionally substituted 5-13-membered bridged carbocyclic groups, optionally substituted 5-13-membered bridged heterocyclic groups, optionally substituted 5-13-membered spirocarbocyclic groups, optionally substituted 5-13-membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; R L 3 and R L 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 heteroalkyl, 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 3-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.

[0239] R L d and R L e R L 3 and R L 4 R L d and R L 3 R L d and R L 4R L e and R L 3 R L e and R L 4 Together with the atoms they are attached to, they form 3-20 membered carbon rings or 4-20 membered heterocyclic rings;

[0240] Each m L It is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and

[0241] n L It is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0242] In another implementation, A L and B L Each occurrence is independently selected from either the absence or divalent portion, wherein the divalent portion is selected from R. L d -R L e R L d COR L e R L d CO2R L e R L d C(O)N(R L 1 )R L e R L d C(S)N(R L 3 )R L e R L d OR L e R L d SR L e R L d SOR L e R L d SO2R L e R L dSO2N(R L 3 )R L e R L d N(R L 3 )R L e R L d N(R L 3 COR L e R L d N(R L 3 CON(R) L 4 )R L e R L d N(R L 3 )C(S)R L e Optionally substituted C1-C8 alkylene groups, Optionally substituted C2-C8 alkenyl groups, Optionally substituted C2-C8 ynylene groups, Optionally substituted C1-C8 alkoxy-C1-C8 alkylene groups, Optionally substituted C1-C8 heteroalkylene groups, Optionally substituted C1-C8 haloalkylene groups, Optionally substituted C1-C8 hydroxyalkylene groups, Optionally substituted 4-13 fused carbocyclic groups, Optionally substituted 5-13 fused heterocyclic groups, optionally substituted 5-13 bridging carbocyclic groups, optionally substituted 5-13 bridging heterocyclic groups, optionally substituted 5-13 spirocarbocyclic groups, optionally substituted 5-13 spiroheterocyclic groups, optionally substituted 3-10 bridging carbocyclic groups, optionally substituted 3-10 bridging heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, wherein R L d and R L e Independently selected from (C1-C8 alkylene)-R L r (preferred is CH2-R) L r ), R which is arbitrarily replaced L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r-(C1-C8 alkylene) or comprising the following portions: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyneyl, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy-C1-C8 alkylene, optionally substituted C1-C8 alkylamino-C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 Halogenated alkylene groups, optionally substituted 3-10-membered carbocyclic groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted 4-13-membered fused carbocyclic groups, optionally substituted 5-13-membered fused heterocyclic groups, optionally substituted 5-13-membered bridged carbocyclic groups, optionally substituted 5-13-membered bridged heterocyclic groups, optionally substituted 5-13-membered spirocarbocyclic groups, optionally substituted 5-13-membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups.

[0243] In one implementation, A L Selected from optionally substituted C1-C8 alkylene groups. In another embodiment, A L It is methylene. In another embodiment, A L It is ethylene. In another embodiment, A L It is n-propylidene. In another embodiment, A L No. In another implementation, A L It is R L d COR L e , where R L d It is CH2, and R L e It is CH2. In another implementation, A L It is R L d COR L e , where R L d It is CH2CH2, and R L e It is CH2. In another implementation, A L It is R L d COR L e , where R L d It is CH2, and R L e It is CH2CH2. In one implementation, A L It is R Ld COR L e , where R L d and R L e None of them exist. In another implementation, A L It is a n-propylidene group optionally substituted with at least one Cl, Br, I, F, OH, NH2, SH, or OCH3. In another embodiment, A L It is an aryl group. In another embodiment, A L It is a phenyl group optionally substituted with at least one of Cl, Br, I, F, OH, NH2, SH, or OCH3. In another embodiment, A L It is an optionally substituted heteroaryl group. In another embodiment, A L It is R L d COR L e , where R L d No, and R L e It is CH2CH2CH2. In another embodiment, A L It is an optionally substituted heteroaryl group. In another embodiment, A L It is R L d COR L e , where R L d No, and R L e It is CH2CH2CH2CH2. In another embodiment, A L The substituted heteroaryl group is optionally selected from the following: pyrroloyl, furanyl, thiopheneyl, pyridinyl, pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiopheneyl, quinolinyl, 2-methylquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzotriazolyl, benzimidazolyl, benzothiazolyl Azolyl, benzoisothiazolyl, benzoisoxazolyl, benzoxadiazolyl, benzoxazolyl, cenolinyl, 1H-inzolyl, 2H-inzolyl, indoleazinyl, isobenzofuranyl, naphridinyl, phthalazinyl, pteridinyl, purineyl, oxazolopyridinyl, thiazopyridinyl, imidazopyridinyl, furanpyridinyl, thienopyridinyl, pyridinylpyrimidinyl, pyridinylpyrazinyl, pyridinylpyridazinyl, thienothiazolyl, thienooxazolyl, and thienoimidazolyl.

[0244] In one implementation, B L Selected from C1-C8 alkylene groups that may be optionally substituted. In another embodiment, B L It is methylene. In another embodiment, B L It is ethylene. In another embodiment, B L It is n-propylidene. In another embodiment, B L No. In another implementation, B L It is R L d COR L e , where R L d It is CH2, and R L e It is CH2. In another embodiment, B L It is R L d COR L e , where R L d It is CH2CH2, and R L e It is CH2. In another embodiment, B L It is R L d COR L e , where R L d It is CH2, and R L e It is CH2CH2. In one implementation, B L It is R L d COR L e , where R L d and R L e None of them exist. In another implementation, B L It is a n-propylidene group optionally substituted with at least one Cl, Br, I, F, OH, NH2, SH, or OCH3. In another embodiment, B L It is an aryl group. In another embodiment, B L It is a phenyl group optionally substituted with at least one of Cl, Br, I, F, OH, NH2, SH, or OCH3. In another embodiment, B L It is an optionally substituted heteroaryl group. In another embodiment, B L It is R L d CORL e , where R L d No, and R L e It is CH2CH2CH2. In another embodiment, B L It is an optionally substituted heteroaryl group. In another embodiment, B L It is R L d COR L e , where R L d No, and R L e It is CH2CH2CH2CH2. In another embodiment, B L The substituted heteroaryl group is optionally selected from the following: pyrroloyl, furanyl, thiopheneyl, pyridinyl, pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiopheneyl, quinolinyl, 2-methylquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzotriazolyl, benzimidazolyl, benzothiazolyl Azolyl, benzoisothiazolyl, benzoisoxazolyl, benzoxadiazolyl, benzoxazolyl, cenolinyl, 1H-inzolyl, 2H-inzolyl, indoleazinyl, isobenzofuranyl, naphridinyl, phthalazinyl, pteridinyl, purineyl, oxazolopyridinyl, thiazopyridinyl, imidazopyridinyl, furanpyridinyl, thienopyridinyl, pyridinylpyrimidinyl, pyridinylpyrazinyl, pyridinylpyridazinyl, thienothiazolyl, thienooxazolyl, and thienoimidazolyl.

[0245] In another implementation, R L r Selected from group R L And group R L As defined in Equation 9.

[0246] In another embodiment, the connector portion has formula 9C:

[0247]

[0248] in

[0249] X L Selected from O and NR L 7 ;

[0250] R L 1 R L 2 RL 3 R L 4 R L 5 and R L 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 heteroalkyl, 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 3-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.

[0251] A L and B L Independently selected from the absence of or divalent portion, wherein the divalent portion is selected from R L d -R L e R L d COR L e R L d CO2R L e R L d C(O)N(R L 8 )R L e R L d C(S)N(R L 8 )R L e R L d OR L e R L d SR L e R L d SOR L e R L dSO2R L e R L d SO2N(R L 8 )R L e R L d N(R L 8 )R L e R L d N(R L 8 )COR L e R L d N(R L 8 CON(R) L 9 )R L e R L d N(R L 8 )C(S)R L e Optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyneyl, optionally substituted C1-C8 alkoxy-C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 4-13 fused carbocyclic, optionally substituted 5-13 fused heterocyclic, optionally substituted 5-13 bridged carbocyclic, optionally substituted 5-13 bridged heterocyclic, optionally substituted 5-13 spirocyclic, optionally substituted 5-13 spiroheterocyclic, optionally substituted 3-10 carbocyclic, optionally substituted 3-10 heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0252] R L d and R L e Independently selected from (C1-C8 alkylene)-R L r (preferred is CH2-R) L r ), R which is arbitrarily replaced L r-(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene) or comprising the following portions: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkyneyl, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy-C1-C8 alkylene, optionally substituted C1-C8 alkylamino-C1-C8 alkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 Haloalkylene, optionally substituted 3-10-membered carbocyclic group, optionally substituted 3-10-membered heterocyclic group, optionally substituted 4-13-membered fused carbocyclic group, optionally substituted 5-13-membered fused heterocyclic group, optionally substituted 5-13-membered bridged carbocyclic group, optionally substituted 5-13-membered bridged heterocyclic group, optionally substituted 5-13-membered spirocarbocyclic group, optionally substituted 5-13-membered spiroheterocyclic group, optionally substituted aryl group and optionally substituted heteroaryl group.

[0253] R L r Selected from optionally substituted 3-10-membered carbocyclic groups, optionally substituted 3-10-membered heterocyclic groups, optionally substituted 4-13-membered fused carbocyclic groups, optionally substituted 5-13-membered fused heterocyclic groups, optionally substituted 5-13-membered bridging carbocyclic groups, optionally substituted 5-13-membered bridging heterocyclic groups, optionally substituted 5-13-membered spirocarbocyclic groups, optionally substituted 5-13-membered spiroheterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups.

[0254] R L 7 R L 8 and R L 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 heteroalkyl, 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 3-10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.

[0255] R L d and R L e R L8 and R L 9 R L d and R L 8 R L d and R L 9 R L e and R L 8 R L e and R L 9 Together with the atoms they are attached to, they form 3-20 membered carbon rings or 4-20 membered heterocyclic rings;

[0256] m L Each time it appears, it is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0257] n L Each time it appears, it is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0258] o L It is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and

[0259] p L It is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0260] In some embodiments, the length of the joint is 0 chain atoms. In some embodiments, the length of the joint is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 chain atoms, or a range of chain atoms defined by any two or more of the mentioned chain atom numbers. In another improvement, the length of the joint is 0 to 40 chain atoms. In another improvement, the length of the joint is 1 to 20 chain atoms. In yet another improvement, the length of the joint is 2 to 12 chain atoms. In some embodiments, the connector is –(3-10-membered carbocyclic)-(C1-C8 alkylene)- or –(3-10-membered heterocyclic)-(C1-C8 alkylene)-.

[0261] In another implementation, Rr The terms are selected from the above-defined formulas C1a, C2a, C3a, C4a, C5a, C1, C2, C3, C4 and C5.

[0262] In another implementation, R r Selected from group R.

[0263] In some embodiments, the compound is selected from Table 1, Table 2 or Table 3, wherein the compound is not CC-90009 and gilteritinib, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is GS-025, GS-031, GS-034, GS-035, GS-036, GS-043, GS-044, GS-045, GS-048, GS-049, GS-050, GS-051, GS-052, GS-053, GS-054, GS-060, GS-066, GS-068, GS-069, GS-070, GS-076, GS-077, GS-078, GS-087, GS-090, GS-093, GS-096, GS-097, GS-098, GS-101, GS-102, GS-105, GS-110, GS-113, GS-115, GS-116, GS-118, GS-120, GS-122, GS-123, GS-132, GS-134, GS-145, GS-150, GS-151, GS-156, GS-163, GS-166, GS-167, GS-171, GS-173, GS-174, GS-175, GS-181, GS-182, GS-188, GS-191, GS-194, GS-195, GS-196, GS-198, GS-199, GS-202, GS-204, GS-205, GS-207, GS-210, GS-211, GS-213, GS-215, GS-217, GS-221, GS-223, GS-224, GS-227, GS-228, GS-229, GS-230, GS-231, GS-240, GS-243, GS-247, GS-253, GS-254, GS-255, GS-256, GS-257, GS-259, GS-261, GS-262, GS-264, GS-266, GS-267, GS-272, GS-276, GS-277, GS-278, GS-280, GS-281, GS-282, GS-284, GS-285, GS-286, GS-287, GS-289, GS-299, GS-305, GS-308, GS-309, GS-311, GS-314, GS-315, GS-323, GS-339, GS-341, GS-348, GS-350, GS-351, GS-362, GS-366, GS-368, GS-GS-405, GS-406, GS-409, GS-410, GS-411, GS-418, GS-419, GS-421, GS-422, GS-426, GS-427, GS-428, GS-429, GS-431, GS-434, GS-442, GS-444, GS-447, GS-458, GS-463, GS-464, GS-467, GS-470, GS-476, GS-477, GS-478, GS-479, GS-480, GS-481, GS-482, GS-483, GS-486, GS-487, GS-488, GS-489, GS-490, GS-491, GS-493, GS-494, GS-495, GS-497, GS-500, GS-501, GS-503, GS-505, GS-509, GS-510, GS-511, GS-512, GS-513, GS-514, GS-518, GS-520, GS-522, GS-525, GS-526, GS-528, GS-529, GS-530, GS-531, GS-532, GS-534, GS-535, GS-541, GS-542, GS-543, GS-544, GS-548, GS-549, GS-552, GS-555, GS-557, GS-559, GS-562, GS-564, GS-567, GS-568, GS-569, GS-570, GS-571, GS-572, GS-573, GS-574, GS-575, GS-576, GS-579, GS-580, GS-581, GS-583, GS-584, GS-585, GS-586, GS-587, GS-589, GS-592, GS-593, GS-594, GS-598, GS-602, GS-603, GS-604, GS-609, GS-610, GS-611, GS-612, GS-613, GS-614, GS-615, GS-616, GS-618, GS-620, GS-621, GS-622, GS-623, GS-625, GS-630, GS-633, GS-634, GS-635 or GS-637; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is GS-060, GS-066, GS-105, GS-171, GS-173, GS-181, GS-182, GS-227, GS-243, GS-255, GS-261, GS-262, GS-264, GS-272, GS-286, GS-287, GS-305, GS-309,GS-314, GS-315, GS-339, GS-348, GS-418, GS-442, GS-444, GS-490, GS-510, GS-552, GS-568, GS-570, GS-579, GS-589, GS-613, or GS-614; or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the compound is GS-171, GS-243, GS-255, GS-264, GS-286, GS-305, GS-442, GS-444, GS-568, GS-579, GS-589, GS-613, or GS-614; or pharmaceutically acceptable salts or solvates thereof.

[0264] In some embodiments, the compound is selected from GS-001 to GS064, or pharmaceutically acceptable salts or analogs thereof. In some embodiments, the compound is selected from GS-002, GS-004, GS-005, GS-006, GS-007, or pharmaceutically acceptable salts or analogs thereof.

[0265] In one embodiment, the compound is 5-((6-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxoperidin-3-yl)isoindoline-1,3-dione (GS-002). In some embodiments, the compound comprises GS-002 or a pharmaceutically acceptable salt thereof.

[0266] In one embodiment, the compound is 2-(3-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-N-((2-(2,6-dioxoperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2,2-difluoroacetamide (GS-004). In some embodiments, the compound comprises GS-004 or a pharmaceutically acceptable salt thereof.

[0267] In one embodiment, the compound is 2-(2,6-dioxopiperidin-3-yl)-5-((6-oxo-6-(4-(4-(quinolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)hexyl)amino)isoindoline-1,3-dione (GS-006). In some embodiments, the compound comprises GS-006 or a pharmaceutically acceptable salt thereof.

[0268] In one embodiment, the compound is 5-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-((2-(2,6-dioxoperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2,2-difluoro-5-oxopentamide (GS-007). In some embodiments, the compound comprises GS-007 or a pharmaceutically acceptable salt thereof.

[0269] According to one aspect of this disclosure, the compositions disclosed herein comprise a compound or a pharmaceutically acceptable salt or analogue thereof.

[0270] In one embodiment, the compound is 2-(2,6-dioxopiperidin-3-yl)-5-((6-oxo-6-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)hexyl)amino)isoindoline-1,3-dione (GS-005). In some embodiments, the compound comprises GS-005 or a pharmaceutically acceptable salt thereof.

[0271] This document discloses GSPT1 degraders. In some embodiments, the compounds degrade GSPT1. In some embodiments, the compounds reduce cellular GSPT1 protein levels. In some embodiments, the compounds bind cereblon. In some embodiments, the compounds regulate cereblon. In some embodiments, the compounds degrade GSPT1 as a downstream effect of cereblon binding and regulation. Some examples of GSPT1 degraders are shown in Tables 1, 2, and 3.

[0272] In some embodiments, the compound is in IC50 at concentrations below 50 nM. 50 The compound inhibits cell growth. In some embodiments, the compound is expressed at an IC50 value below 25 nM. 50 The compound inhibits cell growth. In some embodiments, the compound is expressed at an IC50 value below 10 nM. 50 The compound inhibits cell growth. In some embodiments, the compound is expressed at an IC50 concentration of less than 8 nM. 50 The compound inhibits cell growth. In some embodiments, the compound is expressed at an IC50 concentration of less than 2 nM. 50 The value inhibits cell growth. In some embodiments, the cells include MV4;11 or MOLM-13 cells. In some embodiments, the cells are MV4;11 cells. In some embodiments, the cells are MOLM-13 cells.

[0273] In some embodiments, the compound is selected from compounds GS-001 to GS-639, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof. In some embodiments, the compound is selected from compounds GS-001 to GS-064, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof. In some embodiments, the compound is selected from compounds GS-064 to GS-639, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof. In some embodiments, the compound is selected from compounds GS-001 to GS-639, or pharmaceutically acceptable salts thereof. In some embodiments, the compound is selected from compounds GS-001 to GS-639.

[0274] In some embodiments, the compound comprises one of the following or a pharmaceutically acceptable salt thereof: GS-025, GS-031, GS-034, GS-035, GS-036, GS-043, GS-044, GS-045, GS-048, GS-049, GS-050, GS-051, GS-052, GS-053, GS-054, GS-060, GS-066, GS-068, GS-069, GS-070, GS-076, GS-077, GS-078, GS-087, GS-090, GS-093, GS-096, GS-097, GS-098, GS-101, GS-102, GS-105, GS-110, GS-113, GS-115, GS-116, GS-118, GS-120, GS-122, GS-123, GS-132, GS-134, GS-145, GS-150, GS-151, GS-156, GS-163, GS-166, GS-167, GS-171, GS-173, GS-174, GS-175, GS-181, GS-182, GS-188, GS-191, GS-194, GS-195, GS-196, GS-198, GS-199, GS-202, GS-204, GS-205, GS-207, GS-210, GS-211, GS-213, GS-215, GS-217, GS-221, GS-223, GS-224, GS-227, GS-228, GS-229, GS-230, GS-231, GS-240, GS-243, GS-247, GS-253, GS-254, GS-255, GS-256, GS-257, GS-259, GS-261, GS-262, GS-264, GS-266, GS-267, GS-272, GS-276, GS-277, GS-278, GS-280, GS-281, GS-282, GS-284, GS-285, GS-286, GS-287, GS-289, GS-299, GS-305, GS-308, GS-309, GS-311, GS-314, GS-315, GS-323, GS-339, GS-341, GS-348, GS-350, GS-351, GS-362, GS-366, GS-368, GS-370, GS-372, GS-377, GS-378, GS-386, GS-387, GS-396, GS-397, GS-399, GS-401, GS-404, GS-405, GS-406, GS-409, GS-410, GS-411, GS-418GS-419, GS-421, GS-422, GS-426, GS-427, GS-428, GS-429, GS-431, GS-434, GS-442, GS-444, GS-447, GS-458, GS-463, GS-464, GS-467, GS-470, GS-476, GS-477, GS-478, GS-479, GS-480, GS-481, GS-482, GS-483, GS-486, GS-487, GS-488, GS-489, GS-490, GS-491, GS-493, GS-494, GS-495, GS-497, GS-500, GS-501, GS-503, GS-505, GS-509, GS-510, GS-511, GS-512, GS-513, GS-514, GS-518, GS-520, GS-522, GS-525, GS-526, GS-528, GS-529, GS-530, GS-531, GS-532, GS-534, GS-535, GS-541, GS-542, GS-543, GS-544, GS-548, GS-549, GS-552, GS-555, GS-557, GS-559, GS-562, GS-564, GS-567, GS-568, GS-569, GS-570, GS-571, GS-572, GS-573, GS-574, GS-575, GS-576, GS-579, GS-580, GS-581, GS-583, GS-584, GS-585, GS-586, GS-587, GS-589, GS-592, GS-593, GS-594, GS-598, GS-602, GS-603, GS-604, GS-609, GS-610, GS-611, GS-612, GS-613, GS-614, GS-615, GS-616, GS-618, GS-620, GS-621, GS-622, GS-623, GS-625, GS-630, GS-633, GS-634, GS-635 or GS-637.

[0275] In some embodiments, the compound comprises one of the following or a pharmaceutically acceptable salt thereof: GS-060, GS-066, GS-105, GS-171, GS-173, GS-181, GS-182, GS-227, GS-243, GS-255, GS-261, GS-262, GS-264, GS-272, GS-286, GS-287, GS-305, GS-309, GS-314, GS-315, GS-339, GS-348, GS-418, GS-442, GS-444, GS-490, GS-510, GS-552, GS-568, GS-570, GS-579, GS-589, GS-613, or GS-614.

[0276] In some embodiments, the compound includes one of the following or a pharmaceutically acceptable salt thereof: GS-171, GS-243, GS-255, GS-264, GS-286, GS-305, GS-442, GS-444, GS-568, GS-579, GS-589, GS-613 or GS-614.

[0277] II. Synthesis and Testing of Compounds

[0278] The binding affinity of the novel synthetic compounds described herein 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 compounds' ability to induce GSPT1 degradation and inhibit cancer cell proliferation. Furthermore, changes in GSPT1 protein levels induced by the compounds are assessed. Assays suitable for any or all of these steps are known in the art and include, for example, Western blot, quantitative mass spectrometry (MS) analysis, flow cytometry, enzyme activity assays, ITC, SPR, cell growth inhibition, xenograft models, orthotopic models, and patient-derived xenograft models. Suitable cell lines for any or all of these steps are known in the art and include HEL, RS4;11, MV4;11, MOLT-4, CCRF-CEM, Kasumi-1, MM.1S, HL-60, WSU-DLCL2, Pfeiffer, and SU-DHL-1 cancer cell lines. Suitable mouse models for any or all of these steps are known in the art and include subcutaneous xenograft models, orthotopic models, patient-derived xenograft models, and patient-derived orthotopic models.

[0279] By way of non-limiting example, detailed synthetic schemes are described in the examples of specific exemplary compounds.

[0280] Pharmaceutically acceptable isotopic variations of the compounds disclosed herein are considered, and these compounds can be synthesized using conventional methods known in the art or methods corresponding to those described in the examples (replacing these reagents with appropriate isotopic variations of suitable reagents). Specifically, an isotopic variation is a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass than that commonly found in nature. Useful isotopes are known in the art and include, for example, 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.

[0281] Isotopic variations (e.g., containing) 2 Isotopic variations of H can provide therapeutic advantages due to greater metabolic stability, such as increased half-life or reduced dose requirements.

[0282] Furthermore, certain isotopic variations (especially those containing radioactive isotopes) can be used in studies of drug or substrate tissue distribution. Given the radioactive isotope tritium ( 3 H) and carbon-14 ( 14 C) They are easy to incorporate and have readily available detection methods, which are particularly useful for this purpose.

[0283] Pharmaceutically acceptable solvates of the compounds disclosed herein are considered. Solvates may be generated, for example, by replacing the solvent used to crystallize the compounds disclosed herein with an isotopic variation (e.g., D₂O instead of H₂O, d₆-acetone instead of acetone, or d₆-DMSO instead of DMSO).

[0284] Pharmaceutically acceptable fluorination variants of the compounds disclosed herein are considered, and these can be synthesized using conventional methods known in the art or methods corresponding to those described in the examples (replacing these reagents with appropriate fluorination variants of suitable 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 due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirement.

[0285] Pharmaceutically acceptable prodrugs of the compounds disclosed herein are considered, and these 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 into ester groups). As used herein, "prodrug" refers to a compound that can be converted into a therapeutic agent by some chemical or physiological process (e.g., enzymatic processes and metabolic hydrolysis). Therefore, the term "prodrug" also refers to a pharmaceutically acceptable precursor of a bioactive compound. When administered to a subject, a prodrug may be inactive, i.e., an ester, but is converted in vivo into an active compound, for example by hydrolysis to produce a free carboxylic acid or a free hydroxyl group. Prodrug compounds typically offer advantages in 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 upon administration of the prodrug to a subject. Prodrugs of active compounds can be prepared by modifying functional groups present in an active compound in such a manner that the modification is performed in conventional operations or cleaved in vivo to obtain the parent active compound. Prodrugs include compounds in which a hydroxyl, amino, or thiol group is bonded to any group that, upon application of the active compound to a subject, 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 with amine functional groups.

[0286] In some aspects, this document provides a method for identifying compounds that mediate the degradation or reduction of GSPT1, the method comprising: providing a compound comprising a CRBN binder; contacting the compound with cells comprising a ubiquitin ligase and GSPT1; determining whether the GSPT1 level in the cells is reduced; and identifying the compound as a compound that mediates the degradation or reduction of GSPT1. In some embodiments, the cells are cancer cells. In some embodiments, the cancer cells are GSPT1-mediated cancer cells.

[0287] III. Characterization of Exemplary Compounds

[0288] The specific exemplary compounds were first characterized using a cell viability assay (see Example 24). In the assay, MV4;11 and MOLM-13 cells were treated with the compounds for three days. 50 The value ranges from 1 nM to over 10 μM.

[0289] When combined with the FLT3 inhibitor gipritinib, the potency of some compounds is synergistically increased. In particular, the efficacy of the GSPT1 degraders GS-002, GS-005, and GS-006, when combined with gipritinib, is significantly improved, as indicated by inhibition of MOLM-13 cell growth. These experimental results demonstrate that GSPT1 degraders can be used in combination therapy with second compounds such as FLT3 pathway inhibitors.

[0290] IV. Pharmaceutical Compositions

[0291] In some aspects, the compositions and methods described herein include the manufacture and use of pharmaceutical compositions and medicaments comprising one or more compounds as disclosed herein (e.g., heterobifunctional compounds). The pharmaceutical composition itself is also included. In some embodiments, the pharmaceutical composition comprises the compounds described herein and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises compounds described herein, such as GSPT1 degraders. In some embodiments, the pharmaceutical composition comprises a second compound, such as an FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or activator. The second compound may be an FLT3 pathway inhibitor or an FLT3 inhibitor such as giretinib.

[0292] In some aspects, the compositions disclosed herein may include 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 administered together, the compounds disclosed herein may act in combination with conventional chemotherapeutic agents or any other cancer treatments known in the art to produce a mechanistically additive or synergistic therapeutic effect.

[0293] In some respects, the pH of the compositions disclosed herein can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the compound or its delivery form.

[0294] Pharmaceutical compositions typically include pharmaceutically acceptable excipients, excipients, or carriers. As used herein, the phrase "pharmaceutically acceptable" means that, when administered to a human, the molecular entity and composition are generally considered physiologically tolerable and generally do not produce anaphylactic or similar adverse reactions, such as stomach upset, dizziness, etc. Pharmaceutically acceptable excipients, excipients, or carriers are substances that can be administered to a patient together with the compounds of this disclosure 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, excipients, and carriers include, but are not limited to, saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonics, and absorption delay agents that are compatible with drug administration.

[0295] In particular, pharmaceutically acceptable excipients, excipients, and mediators that can be used in the pharmaceutical compositions of this disclosure 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 for pharmaceutical dosage forms such as Tween or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffering 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, dipotassium 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-cyclodextrin, β-cyclodextrin and γ-cyclodextrin can also be advantageously used to enhance the delivery of compounds of the formulas described herein.

[0296] Depending on the dosage form chosen to deliver the compounds disclosed herein, various pharmaceutically acceptable excipients, excipients, and mediators may be used. In the case of tablets for oral administration, pharmaceutically acceptable excipients, excipients, and mediators include lactose and corn starch. Lubricants, such as magnesium stearate, are often also 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 may be 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.

[0297] As used herein, the compounds disclosed herein are defined as including pharmaceutically acceptable derivatives or prodrugs thereof. "Pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, solvate, or prodrug of the compounds or agents disclosed herein, such as carbamates, esters, phosphates, salts of esters, or other derivatives, which, upon administration to a recipient, can provide (directly or indirectly) the compound described herein or its active metabolites or residues. Particularly advantageous derivatives and prodrugs are those that increase the bioavailability of such compounds when administered to a subject (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) relative to the parent species. Preferred prodrugs include derivatives in which groups enhancing water solubility or active transport via the intestinal membrane are attached to a structure of the formula described herein. Such derivatives will be recognized by those skilled in the art without excessive experimentation. Nevertheless, the reference to the teachings of Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Volume 1: Principles and Practice is incorporated herein by reference to the extent that it teaches about such derivatives.

[0298] The compounds disclosed herein include pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemics, mixtures of diastereomeric racemics and mesoforms, as well as pharmaceutically acceptable salts, solvent complexes, morphological forms or deuterated derivatives thereof.

[0299] In some respects, the pharmaceutical compositions disclosed herein may include effective amounts of one or more 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 described herein that is used over a sustained period of time (including acute or chronic administration and periodic or continuous administration) and that, in the case of its administration, effectively leads to the intended effect or physiological outcome (e.g., treatment or prevention of cell growth, cell proliferation, or cancer).

[0300] In some respects, the pharmaceutical composition may also effectively result in the amount of the intended effect or physiological outcome (e.g., treatment or prevention of cell growth, cell proliferation, or cancer) including one or more additional compounds, drugs, or agents (e.g., conventional chemotherapeutic agents) used to treat cancer.

[0301] In one embodiment, this disclosure relates to a pharmaceutical formulation comprising: (a) a compound of formula 1 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof; and (b) a second therapeutic agent.

[0302] In one embodiment, this disclosure relates to a pharmaceutical formulation comprising: (a) a compound of formula 1 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof; and (b) one or more therapeutic agents.

[0303] In one embodiment, this disclosure relates to a pharmaceutical formulation comprising a therapeutically effective amount of: (a) a compound of formula 1 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof; and (b) one or more therapeutic agents.

[0304] In one embodiment, this disclosure relates to a combination comprising a therapeutically effective amount of (a) a compound of formula 1 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof; and (b) a second therapeutic agent.

[0305] In one embodiment, this disclosure relates to a combination comprising a therapeutically effective amount of (a) a compound selected from compounds GS-001 to GS-639, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof; and (b) a second therapeutic agent.

[0306] In one embodiment, this disclosure relates to a combination comprising a therapeutically effective amount of (a) a compound selected from compounds GS-001 to GS-639, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof; and (b) one or more therapeutic agents.

[0307] In one embodiment, this disclosure relates to a combination comprising a therapeutically effective amount of (a) a compound selected from compounds GS-001 to GS-639, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof; (b) a second therapeutic agent; and (c) a pharmaceutically acceptable carrier or excipient.

[0308] In one embodiment, this disclosure relates to a combination comprising a therapeutically effective amount of (a) a compound selected from compounds GS-001 to GS-639, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof; (b) one or more therapeutic agents; and (c) a pharmaceutically acceptable carrier or excipient.

[0309] In one embodiment, this disclosure relates to a pharmaceutical formulation comprising a therapeutically effective amount of (a) a compound selected from compounds GS-001 to GS-639, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof; and (b) a second therapeutic agent.

[0310] In one embodiment, this disclosure relates to a pharmaceutical formulation comprising a therapeutically effective amount of (a) a compound selected from compounds GS-001 to GS-639, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof; and (b) one or more therapeutic agents.

[0311] In one embodiment, this disclosure relates to a pharmaceutical formulation comprising a therapeutically effective amount of (a) a compound selected from compounds GS-001 to GS-639, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof; (b) one or more therapeutic agents; and (c) a pharmaceutically acceptable carrier or excipient.

[0312] In one embodiment, the second or more therapeutic agents are anticancer drugs. In one embodiment, the second or more therapeutic agents are antiproliferative agents. In one embodiment, the second or more therapeutic agents are immunomodulators. In one embodiment, the second or more therapeutic agents are kinase inhibitors or activators. In one embodiment, the second or more therapeutic agents are kinase inhibitors.

[0313] In one embodiment, a second or more therapeutic agents inhibit the FMS-like tyrosine kinase 3 (FLT3) gene pathway. In some embodiments, the second compound is an FLT3 pathway inhibitor. The second compound may be gipretinib.

[0314] In one embodiment, the second or more therapeutic agents inhibit the PI3K / AKT / mTOR pathway. In one embodiment, the second or more therapeutic agents inhibit PI3K. In one embodiment, the second or more therapeutic agents inhibit AKT. In one embodiment, the second or more therapeutic agents inhibit mTOR. In some embodiments, the second compound is a PI3K-AKT-mTOR pathway inhibitor or activator.

[0315] In one embodiment, a second or more therapeutic agents inhibit the MAPK pathway. In one embodiment, a second or more therapeutic agents inhibit the RAS / RAF / MEK / ERK pathway. In one embodiment, a second or more therapeutic agents inhibit RAS. In one embodiment, a second or more therapeutic agents inhibit RAF. In one embodiment, a second or more therapeutic agents inhibit MEK. In one embodiment, a second or more therapeutic agents inhibit ERK. In some embodiments, the second compound is a RAS-RAF-MEK-ERK pathway inhibitor.

[0316] V. Administration of the pharmaceutical composition

[0317] The pharmaceutical compositions disclosed herein can be formulated or adapted for administration to a subject 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 www.fda.gov / Drugs / DevelopmentApprovalProcess / FormsSubmissionRequirements / ElectronicSubmissions / DataStandardsManualmonographs). In particular, the pharmaceutical compositions can be formulated for oral, parenteral, or percutaneous delivery and administered via oral, parenteral, or percutaneous 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.

[0318] The pharmaceutical compositions disclosed herein may be administered, for example, via the surface, rectum, nose (e.g., by inhalation spray or nebulizer), cheek, vagina, subcutaneously (e.g., by injection or by implanted reservoir) or eye.

[0319] In some embodiments, the pharmaceutical compositions of this disclosure are administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, emulsions, aqueous suspensions, dispersions, and solutions.

[0320] In some embodiments, the pharmaceutical compositions of this disclosure are administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients that are solid at room temperature (rt) but liquid at rectal temperature, and thus melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0321] In some embodiments, the pharmaceutical compositions of this disclosure are administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, or other solubilizers or dispersants known in the art.

[0322] In some embodiments, the pharmaceutical compositions of this disclosure are administered by injection (e.g., in solution or powder form). Such compositions can be formulated using suitable dispersants or wetting agents (such as Tween 80) and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic parenteral diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, 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 glycerol derivatives can be used to prepare injectable formulations, as can natural, pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. Other commonly used surfactants such as Tween, Span, or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0323] In some aspects, the effective dosage of the pharmaceutical composition disclosed herein 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 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 a specific pharmaceutical composition.

[0324] When the pharmaceutical compositions disclosed herein comprise a combination of the compounds described herein and one or more additional compounds (e.g., one or more additional compounds, drugs, or agents for treating cancer or any other disease or ailment, including those known to be cancer-related or caused by cancer), both the compound and the additional compound may be present at a dose level between about 1% and 100% of the dose typically administered in a monotherapy regimen, and more preferably between about 5% and 95%. The additional agents may be administered separately from the compounds disclosed herein as part of a multi-dose regimen. Alternatively, these agents may be part of a single dosage form and mixed together with the compounds disclosed in a single composition.

[0325] In some respects, the pharmaceutical compositions disclosed herein may be included in a container, package, or dispenser together with instructions for use.

[0326] VI. Treatment methods

[0327] In some embodiments, methods of administering the compositions described herein to a subject are disclosed. Some embodiments relate to using the compositions described herein, such as administering the compositions to a subject. Some embodiments relate to a method of treating a condition in a subject in need. Some embodiments relate to the use of the compositions described herein in a treatment method. In some embodiments, the treatment method includes administering to a subject in need a first compound comprising a GSPT1 degrader and a second compound comprising an FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, or a PI3K-AKT-mTOR pathway inhibitor or activator. Some embodiments include administering the compositions described herein to a subject suffering from a condition. In some embodiments, the treatment is applied to treat the subject's condition. In some embodiments, the composition treats the subject's condition. In some embodiments, the treatment includes preventing, inhibiting, or reversing the subject's condition. In some embodiments, the subject suffers from cancer.

[0328] According to one aspect of this disclosure, the method of treating GSPT1-mediated diseases disclosed herein includes administering a compound or a pharmaceutically acceptable salt or analogue thereof to a subject suffering from a GSPT1-mediated disease.

[0329] The compound may be a compound described herein, such as a compound of Formula 1. In some embodiments, the compound is a GSPT1 degrader. In one embodiment, the compound is selected from GS-001 to GS-639, or analogs thereof. In some embodiments, the first compound is a pharmaceutically acceptable salt or solvate of a compound disclosed in Tables 1, 2, or 3. The compound may be included in the pharmaceutical composition described herein. In some embodiments, the first compound and / or the second compound are administered to the subject in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0330] The methods disclosed herein contemplate administering an effective amount of a compound or composition to achieve the desired or stated effect. Typically, the compounds or compositions disclosed herein are administered about 1 to about 6 times daily, or alternatively or additionally, in the form of a continuous infusion. This administration can be used as a 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 administration modality. Typical formulations will contain about 5% to about 95% (w / w) of the active compound. Alternatively, such formulations may contain about 20% to about 80% of the active compound. In some embodiments, the first compound and the second compound are administered together to the subject. In some embodiments, the first compound and the second compound are administered separately to the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0331] In some aspects, this document provides a compound described herein for the prevention or treatment of a disease or ailment. In other aspects, this document provides a heterobifunctional compound described herein for the prevention or treatment of a disease or ailment.

[0332] In some aspects, this document provides a compound described herein for the treatment or prevention of one or more diseases or disorders disclosed herein in a subject of need. In some embodiments, the disease or disorder is a GSPT1-mediated disease or disorder. In some embodiments, the disease or disorder is cancer, inflammation, autoimmune disease, viral infection, and immune disease. In one implementation, GSPT1-mediated cancers are selected from brain cancer, gastric cancer, gastrointestinal cancer, liver cancer, biliary tract cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, lung cancer, pancreatic cancer, thyroid cancer, adenocarcinoma, bladder cancer, kidney cancer, muscle cancer, bone cancer, hematopoietic system cancers, myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin's lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, eosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, and myeloma. In some implementations, the disease or condition includes cancer. In some implementations, the disease or condition includes GSPT1-mediated cancer.

[0333] In one implementation, GSPT1-mediated cancers are selected from mesothelioma, leukemia, and lymphomas such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphomas associated with human T-lymphotropic virus (HTLV) such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphoma and multiple myeloma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute Myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma, myelodysplastic syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors and soft tissue sarcomas, common adult solid tumors such as head and neck cancers (e.g., oral, laryngeal, and nasopharyngeal cancers), esophageal cancer, urinary tract cancers (e.g., prostate, bladder, kidney, uterine, ovarian, and testicular cancers), lung cancers (e.g., small cell lung cancer and non-small cell lung cancer), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, and Gorlin's syndrome. Tumors associated with syndrome (e.g., medulloblastoma, meningioma, etc.), liver cancer, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid and gastrointestinal stromal tumors (GIST), skeletal muscle or smooth muscle cancer, gastric cancer, small bowel cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0334] In one implementation, GSPT1-mediated disease is recurrent cancer.

[0335] In one implementation, the GSPT1-mediated disease is one or more diseases that are difficult to treat with previous treatments.

[0336] In some aspects, this document provides for the use of the compounds in the manufacture of medicaments for the prevention or treatment of one or more of the diseases or ailments disclosed herein. Medicaments may include the compounds described herein. Medicaments may include the pharmaceutical compositions described herein.

[0337] 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 needs or has been determined to need 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 said subject, and optionally repeating the administration as needed to prevent or treat cancer.

[0338] In some aspects, subject selection may include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample to obtain indications that the subject is suitable for selection. In some aspects, a subject may be identified or determined by a healthcare professional as having a disease or illness, having an increased risk of having a disease or illness, or having a disease or illness. In some aspects, suitable subjects include, for example, those who have or have had a disease or illness but have experienced remission of the disease or aspects thereof, exhibiting reduced symptoms of the disease (e.g., relative to other subjects with the same disease or illness (e.g., most subjects)), or those who have survived an extended period with the disease or illness (e.g., relative to other subjects with the same disease or illness (e.g., most subjects)), such as those who are asymptomatic (e.g., relative to other subjects with the same disease or illness (e.g., most subjects)). In some aspects, a positive immune response to a disease or illness may be indicated from patient records, family history, or indicators of a positive immune response. In some aspects, subject selection may include multiple parties. For example, a first party may obtain a sample from a candidate subject, and a second party may test the sample. In some aspects, subjects may be selected or submitted by a practicing physician (e.g., a general practitioner). In some aspects, subject selection may include obtaining a sample from the selected subject and storing the sample or using the sample in the methods disclosed herein. The sample may include, for example, cells or cell populations.

[0339] In some aspects, the treatment methods may include single, multiple, and repeated administration of one or more of the compounds disclosed herein to prevent or treat the diseases or disorders disclosed herein (e.g., GSPT1-mediated diseases). In some aspects, the 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.

[0340] As used herein, the term "object" refers to any animal. In some cases, the object is a mammal. In other cases, the term "object" as used herein refers to a person (e.g., a man, woman, or child).

[0341] As used herein, the term "application" means implantation, ingestion, injection, inhalation, or other absorption of a compound or composition, regardless of the form. For example, the methods disclosed herein include applying an effective amount of a compound or composition to achieve the desired or stated effect.

[0342] As used herein, the term "treatment" means to partially or completely alleviate, suppress, improve, or reduce a disease or ailment that a subject is suffering from. This means any method employed to improve or otherwise beneficially alter one or more symptoms of a disease or condition (e.g., cancer). As used herein, improvement of symptoms of a particular condition (e.g., cancer) means any relief attributable to or related to treatment performed using the compounds, compositions, and methods of this disclosure, whether permanent or temporary, lasting or transient. In some embodiments, treatment may promote or result in, for example, a reduction in the number of tumor cells (e.g., in the subject) relative to the number of tumor cells prior to treatment; a reduction in the viability (e.g., average / mean viability) of tumor cells (e.g., in the subject) relative to the viability of tumor cells prior to treatment; a reduction in the growth rate of tumor cells; a reduction in the rate of local or distant tumor metastasis; or a reduction in one or more symptoms of the subject associated with one or more tumors relative to the subject's symptoms prior to treatment.

[0343] As used herein, the term "prevention" refers to reducing the occurrence of disease in a subject or reducing the risk of the subject acquiring disease or its associated symptoms. Prevention can be complete, such as the safe absence of disease or pathological cells in the subject. Prevention can also be partial, such that the occurrence of disease or pathological cells in the subject is less, occurs later, or develops more slowly compared to what would occur without this disclosure. In some embodiments, the subject has an increased risk of exhibiting one or more GSPT1-mediated diseases. Exemplary GSPT1-mediated diseases that can be treated with compounds include, for example, brain cancer, stomach cancer, gastrointestinal cancer, liver cancer, biliary tract cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, lung cancer, pancreatic cancer, thyroid cancer, adenocarcinoma, bladder cancer, kidney cancer, muscle cancer, bone cancer, and hematopoietic system cancers, such as myeloproliferative neoplasms, including essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin's lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, eosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, myeloma, and other hematologic malignancies.

[0344] In some embodiments, the compound is more effective in treating diseases such as cancer than existing drugs. For example, the compound may be effective at lower doses compared to existing drugs. In some embodiments, the compound is more effective than known cereblon modulators. In some embodiments, the compound is more effective than CC-90009. In some embodiments, the compound is more effective in reducing cell viability than known drugs. For example, the compound may be more effective in reducing cancer cell viability than CC-90009. Some of these embodiments are included in Tables 2 and 3.

[0345] In some embodiments, the combination of the compound with a second compound, such as an FLT3 pathway inhibitor, RAS-RAF-MEK-ERK pathway inhibitor, PI3K-AKT-mTOR pathway inhibitor, or activator, is more effective than existing drugs in treating diseases such as cancer. The second compound may be an FLT3 pathway inhibitor or an FLT3 inhibitor. In some embodiments, the second compound includes an FLT3 pathway inhibitor. In some embodiments, the second compound includes an FLT3 inhibitor. In some embodiments, the FLT3 inhibitor includes gipretinib, midostaurin, sorafenib, sunitinib, or lettaurtinib. In some embodiments, the FLT3 inhibitor includes gipretinib. In some embodiments, the combination of the compound with the second compound is effective at lower doses compared to existing drugs. In some embodiments, the combination of the compound with the second compound is more effective than known cereblon modulators. In some embodiments, the combination of the compound with the second compound is more effective than CC-90009. In some embodiments, the combination of the compound and the second compound is more effective in reducing cell viability than a known drug. For example, the combination of the compound and the second compound may be more effective in reducing cancer cell viability than CC-90009. Some such embodiments are included in Tables 2 and 3. In some embodiments, increased efficacy of the combination of the compound and the second compound is achieved compared to another drug.

[0346] In some embodiments, the second compound comprises a RAS-RAF-MEK-ERK pathway inhibitor. In some embodiments, the RAS-RAF-MEK-ERK pathway inhibitor includes vemurafenib, dabrafenib, encorafenib, SB590885, PLX4720, XL281, RAF265, trametinib, binimetinib, cobimetinib, selumetinib, CI-1040, or PD0325901. In some embodiments, the second compound comprises a PI3K-AKT-mTOR pathway inhibitor or activator. In some implementations, PI3K-AKT-mTOR pathway inhibitors or activators include Apolisib, Idelalisib, Copanlisib, Duvelisib, MK-2206, ARQ-092, gedatolisib, Apolisib, VQD-002, Perifosine, AZD5363, Ipatasertib, Rapamycin, and Tescisib. Temsirolimus, everolimus, ridaforolimus, rapamycin analogues, sirolimus, dactolisib, BGT226, SF1126, PKI-587, NVPBE235, sapanisertib, AZD8055 and AZD2014, Wortmannin, LY294002, hibiscone C, taselisib, perifoxetine, buparlisib, umbralisib, PX-866, dactolisib, CUDC-907, voxtalisib, bisper oxovanadium, or Sarcopoterium.

[0347] In some implementations, the compounds disclosed herein can selectively affect GSPT1-mediated disease cells compared to WT (wild-type) cells (i.e., heterobifunctional compounds can kill or inhibit the growth of GSPT1-mediated disease cells while having a relatively low ability to lyse or inhibit the growth of WT cells), for example, targeting one or more GSPT1-mediated disease cells with GI 50 It targets one or more WT cells, such as WT cells belonging to the same species and tissue type as GSPT1-mediated disease cells. 50 Less than 1 / 1.5, less than 1 / 2, less than 1 / 2.5, less than 1 / 3, less than 1 / 4, less than 1 / 5, less than 1 / 6, less than 1 / 7, less than 1 / 8, less than 1 / 9, less than 1 / 10, less than 1 / 15, or less than 1 / 20.

[0348] In some implementations, the compound has an IC50 in cells. 50 ICs below CC-90009 50 In some embodiments, the cells include cell lines. In some cases, the cell lines include MV4;11 cells. In some cases, the cell lines include MOLM-13 cells. In some cases, the IC50 of the compound... 50 The assay is based on treating cells with a single compound. In some cases, the IC50 of the compound... 50 Below 100 nM. In some cases, the IC50 of the compound... 50 Below 100 nM. In some cases, the IC50 of the compound... 50 Below 75 nM. In some cases, the IC50 of the compound... 50 Below 50 nM. In some cases, the IC50 of the compound... 50 Below 25 nM. In some cases, the IC50 of the compound... 50 Below 10 nM. In some cases, the IC50 of the compound... 50 Below 9 nM. In some cases, the IC50 of the compound... 50 Below 8 nM. In some cases, the IC50 of the compound... 50 Below 7 nM. In some cases, the IC50 of the compound... 50 Below 6 nM. In some cases, the IC50 of the compound... 50 Below 5 nM. In some cases, the IC50 of the compound... 50 Below 4 nM. In some cases, the IC50 of the compound... 50 Below 3 nM. In some cases, the IC50 of the compound... 50 Below 2 nM. In some cases, the IC50 of the compound... 50 Below 1 nM. In some cases, the IC50 of the compound...50 Below 0.5 nM. In some cases, the IC50 of the compound... 50 Below 0.25 nM. In some cases, the IC50 of the compound... 50 Above 100 nM. In some cases, the IC50 of the compound... 50 Above 100 nM. In some cases, the IC50 of the compound... 50 Above 75 nM. In some cases, the IC50 of the compound... 50 Above 50 nM. In some cases, the IC50 of the compound... 50 Above 25 nM. In some cases, the IC50 of the compound... 50 Above 10 nM. In some cases, the IC50 of the compound... 50 Above 9 nM. In some cases, the IC50 of the compound... 50 Above 8 nM. In some cases, the IC50 of the compound... 50 Above 7 nM. In some cases, the IC50 of the compound... 50 Above 6 nM. In some cases, the IC50 of the compound... 50 Above 5 nM. In some cases, the IC50 of the compound... 50 Above 4 nM. In some cases, the IC50 of the compound... 50 Above 3 nM. In some cases, the IC50 of the compound... 50 Above 2 nM. In some cases, the IC50 of the compound... 50 Above 1 nM. In some cases, the IC50 of the compound... 50 Above 0.5 nM. In some cases, the IC50 of the compound... 50 Above 0.5 nM. In some cases, the IC50 of the compound... 50 Above 0.25 nM. Some examples of IC50 values ​​and ranges for compounds are shown in Table 2 and / or Table 3.

[0349] In some embodiments, in cells, the combination of the compound with a second compound such as an FLT3 pathway inhibitor, RAS-RAF-MEK-ERK pathway inhibitor, PI3K-AKT-mTOR pathway inhibitor, or activator has an IC50. 50 ICs below CC-90009 50 The second compound may be an FLT3 pathway inhibitor or an FLT3 inhibitor such as giretinib. In some embodiments, the cells include cell lines. In some cases, the cell lines include MV4;11 cells. In some cases, the cell lines include MOLM-13 cells. In some cases, IC50... 50 The assay is based on cell treatment with a combination of the compound and a second compound (e.g., giretinib). In some cases, the IC50 of the combination of the compound and the second compound is...50 Below 100 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 100 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 75 nM. In some cases, the IC50 of the compound combined with the second compound... 50 Below 50 nM. In some cases, the IC50 of the compound combined with the second compound... 50 Below 25 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 10 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 9 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 8 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 7 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 6 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 5 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 4 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 3 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 2 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 1 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 0.5 nM. In some cases, the IC50 of the combination of the compound and the second compound is... 50 Below 0.25 nM. In some cases, the IC50 of the compound... 50 Above 100 nM. In some cases, the IC50 of the compound... 50 Above 100 nM. In some cases, the IC50 of the compound... 50 Above 75 nM. In some cases, the IC50 of the compound... 50 Above 50 nM. In some cases, the IC50 of the compound... 50 Above 25 nM. In some cases, the IC50 of the compound... 50 Above 10 nM. In some cases, the IC50 of the compound... 50 Above 9 nM. In some cases, the IC50 of the compound... 50 Above 8 nM. In some cases, the IC50 of the compound... 50 Above 7 nM. In some cases, the IC50 of the compound...50 Above 6 nM. In some cases, the IC50 of the compound... 50 Above 5 nM. In some cases, the IC50 of the compound... 50 Above 4 nM. In some cases, the IC50 of the compound... 50 Above 3 nM. In some cases, the IC50 of the compound... 50 Above 2 nM. In some cases, the IC50 of the compound... 50 Above 1 nM. In some cases, the IC50 of the compound... 50 Above 0.5 nM. In some cases, the IC50 of the compound... 50 Above 0.5 nM. In some cases, the IC50 of the compound... 50 Above 0.25 nM. IC50 of the combination of the compound and the second compound. 50 Some examples of the values ​​are shown in Tables 2 and 3.

[0350] The specific dosage and treatment regimen for any particular patient will depend on a number of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, rate of excretion, combination of drugs, severity and duration of the disease, ailment or symptoms, the patient’s predisposition to the disease, ailment or symptoms, and the judgment of the treating physician.

[0351] An effective amount may be administered, applied, or dosed once or multiple times. The therapeutically effective amount (i.e., the 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 include a single treatment or a series of treatments. For example, an effective amount may be administered at least once. The composition may be administered once or multiple times daily to once or multiple times weekly; including every other day. Those skilled in the art will understand that certain factors can influence the choice of 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 overall health or age, and any other pre-existing conditions.

[0352] Following administration, the subject may be assessed to detect, evaluate, 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. After the patient's condition improves (e.g., a change in the subject's disease level (e.g., a decrease)), a maintenance dose of the compounds or compositions disclosed herein may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced to a level that maintains the improved condition, for example, depending on the symptoms. However, after any recurrence of disease symptoms, the patient may require long-term intermittent treatment.

[0353] Methods may include administering the compound to a subject via any of the routes of administration described herein. In one embodiment, the compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.

[0354] In one implementation, the method further includes administering to the subject an additional treatment regimen for treating cancer, inflammatory conditions, or autoimmune diseases.

[0355] In one implementation, the additional treatment options are selected from surgery, chemotherapy, radiation therapy, hormone therapy, targeted therapy, and immunotherapy.

[0356] Some implementation schemes include the administration of additional compounds. Such additional compounds may preferably be kinase inhibitors, particularly FLT3 pathway inhibitors (e.g., giretinib, midotulin, sorafenib, sunitinib, or letatinib), MAPK pathway inhibitors, RAS-RAF-MEK-ERK pathway inhibitors (e.g., vemurafenib, dabrafenib; encofenib, SB590885, PLX4720, XL281, RAF265, trametinib, bemetinib, cobimetinib, selumetinib, CI-1040, or PD0325901), or PI3K-AKT-mTOR pathway inhibitors or activators (e.g., apitolisib, ederalipix, curpannicine, duvelixib, MK- 2206, ARQ-092, Gidarisox, Apolisib, VQD-002, Perifoxine, AZD5363, Patashote, Rapamycin, Tesirolimus, Everolimus, Desfolimus, Rapamycin Analog, Sirolimus, Dacilex, BGT226, SF1126, PKI-587, NVPBE235, Salpasotex, AZD8055 and AZD2014, Wolmanpem, LY294002, Hibiscus C, Taselisib, Perifoxine, Buppanisib, Upalis, PX-866, Dacilex, CUDC-907, Voxtalisib, Vanadyl or Sanguisorba officinalis).

[0357] Some embodiments include administering a first compound to a subject in need. In some embodiments, the first compound is a GSPT1 degrader. In some embodiments, the first compound is a compound of Formula 1. In some embodiments, the first compound includes any of the compounds in Tables 1, 2, or 3. In some embodiments, the first compound is selected from GS-001 to GS-639, or a pharmaceutically acceptable salt thereof. In some embodiments, the first compound includes GS-002, or a pharmaceutically acceptable salt thereof. In some embodiments, the first compound includes GS-005, or a pharmaceutically acceptable salt thereof. In some embodiments, the first compound includes GS-006, or a pharmaceutically acceptable salt thereof. In some embodiments, the first compound does not bind JAK. In some embodiments, the first compound includes a truncated JAK-binding moiety. In some embodiments, the first compound does not include a JAK-binding moiety. Some embodiments include administering a second compound to a subject, including an FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, a PI3K-AKT-mTOR pathway inhibitor, or an activator. In some embodiments, the second compound includes an FLT3 pathway inhibitor. In some embodiments, the second compound comprises a RAS-RAF-MEK-ERK pathway inhibitor. In some embodiments, the second compound comprises a PI3K-AKT-mTOR pathway inhibitor or activator. Some embodiments include a treatment method comprising administering to a subject in need a first compound comprising a GSPT1 degrader and a second compound comprising an FLT3 pathway inhibitor, a RAS-RAF-MEK-ERK pathway inhibitor, a PI3K-AKT-mTOR pathway inhibitor, or an activator. In some embodiments, the first compound and / or the second compound are administered to the subject in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. In some embodiments, the first compound and the second compound are administered to the subject co-administered. In some embodiments, the first compound and the second compound are administered to the subject separately.

[0358] Some implementations include a method for treating or preventing cancer, the method comprising administering to a patient in need a combination of a compound having degradative activity against GSPT1 and one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from inhibitors of inhibitory molecules, activators of co-stimulatory molecules, chemotherapeutic agents, targeted anticancer therapies, oncolytic drugs, cytotoxic agents, or combinations thereof.

[0359] In one embodiment, this disclosure relates to a method of treating or preventing cancer, the method comprising administering to a patient in need a combination comprising (a) a compound of formula 1 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof; and (b) a second therapeutic agent.

[0360] In one embodiment, this disclosure relates to a method of treating or preventing cancer, the method comprising administering to a patient in need a compound comprising (a) a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof; and (b) a combination of one or more therapeutic agents.

[0361] In one embodiment, this disclosure relates to a method of treating or preventing cancer, the method comprising administering to a patient in need a combination comprising (a) a compound selected from compounds GS-001 to GS-639, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof; and (b) a second therapeutic agent.

[0362] In one embodiment, this disclosure relates to a method of treating or preventing cancer, the method comprising administering to a patient in need a compound comprising (a) a compound selected from compounds GS-001 to GS-639, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof; and (b) a combination of one or more therapeutic agents.

[0363] In some embodiments, a second or more therapeutic agents inhibit the FMS-like tyrosine kinase 3 (FLT3) gene pathway. In one embodiment, a second or more therapeutic agents inhibit FLT3. Examples of FLT3 inhibitors include gipretinib, midotulin, sorafenib, sunitinib, or letatinib. In some embodiments, the FLT3 inhibitor includes gipretinib. In some embodiments, the second compound includes an FLT3 pathway inhibitor (e.g., gipretinib).

[0364] In some embodiments, a second or more therapeutic agents inhibit the PI3K / AKT / mTOR pathway. In one embodiment, a second or more therapeutic agents inhibit PI3K. In one embodiment, a second or more therapeutic agents inhibit AKT. In one embodiment, a second or more therapeutic agents inhibit mTOR. In some embodiments, the second compound comprises a PI3K-AKT-mTOR pathway inhibitor or activator. Examples of RAS-RAF-MEK-ERK pathway inhibitors include vemurafenib, dabrafenib; encofenib, SB590885, PLX4720, XL281, RAF265, trametinib, bemetinib, cobimetinib, selumetinib, CI-1040, or PD0325901. In some embodiments, the second compound comprises a RAS-RAF-MEK-ERK pathway inhibitor.

[0365] In some embodiments, a second or more therapeutic agents inhibit the MAPK pathway. In one embodiment, a second or more therapeutic agents inhibit the RAS / RAF / MEK / ERK pathway. In one embodiment, a second or more therapeutic agents inhibit RAS. In one embodiment, a second or more therapeutic agents inhibit RAF. In one embodiment, a second or more therapeutic agents inhibit MEK. In one embodiment, a second or more therapeutic agents inhibit ERK. In some embodiments, the second compound comprises a RAS-RAF-MEK-ERK pathway inhibitor. Examples of PI3K-AKT-mTOR pathway inhibitors or activators include Apolisib, Adelaolisib, Cupanixin, Duveliximab, MK-2206, ARQ-092, Gidarisoxetine, Apolisib, VQD-002, Perifoxetine, AZD5363, Patashote, Rapamycin, Tesirolimus, Everolimus, Desfolimus, Rapamycin analogs, Sirolimus, Dacrysipelu, BGT226, SF1126, PKI-587, NVPBE235, Salpasipelu, AZD8055 and AZD2014, Wolmanpem, LY294002, Hibiscus ketone C, Taselisib, Perifoxetine, Buppanixin, Upalis, PX-866, Dacrysipelu, CUDC-907, Voxtalisib, Vanadyl peroxide, and Sanguisorba officinalis. In some embodiments, the second compound includes a PI3K-AKT-mTOR pathway inhibitor. In some embodiments, the second compound includes a PI3K-AKT-mTOR pathway activator.

[0366] VII. Definition of Terms

[0367] As used herein, the terms “contains” and “includes” are used in their open, non-restrictive sense.

[0368] "Alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms and without any unsaturated carbon atoms. Alkyl groups can contain one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In some embodiments, alkyl groups contain one to fifteen carbon atoms (e.g., C1-C1). 15 Alkyl groups. In some embodiments, the alkyl group comprises one to thirteen carbon atoms (e.g., C1-C1). 13 Alkyl group. In some embodiments, the alkyl group comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (e.g., C5-C6 alkyl). 15Alkyl group). In other embodiments, the alkyl group comprises five to eight 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.

[0369] "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 two to twelve carbon atoms (e.g., C2-C). 12 Alkenyl groups. In some embodiments, the alkenyl group comprises two to eight carbon atoms (e.g., C2-C8 alkenyl). In some embodiments, the alkenyl group comprises two to six carbon atoms (e.g., C2-C6 alkenyl). In other embodiments, the alkenyl group comprises two to four carbon atoms (e.g., C2-C4 alkenyl). The alkenyl group is attached to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pent-1,4-dienyl, etc.

[0370] As used in this article, the term "allyl" refers to the –CH2CH=CH2 group.

[0371] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group consisting only of carbon and hydrogen atoms and containing at least one triple bond. An alkynyl group can contain two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In some embodiments, the alkynyl group contains two to twelve carbon atoms (e.g., C2-C). 12 The alkynyl group (e.g., C2-C8 alkynyl). In other embodiments, the alkynyl group has two to six carbon atoms (e.g., C2-C6 alkynyl). In still other embodiments, the alkynyl group has two to four 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.

[0372] 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, pentyloxy, hexyloxy, etc.

[0373] 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 six to eighteen 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 conforming to Hückel's theory. In some embodiments, the aryl group contains six to fourteen carbon atoms (C6-C4). 14 Aryl or 6-14 aryl groups. In some embodiments, the aryl group comprises six to ten carbon atoms (C6-C14). 10 Aryl or 6-10 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.

[0374] The term "heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group (i.e., 3-18-membered heteroaryl) containing two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in said ring system is fully unsaturated, i.e., it contains a cyclic delocalized (4n+2)π electron system conforming to Hückel's theory. 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 bridging ring systems. One or more heteroatoms in the heteroaryl are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heteroaryl is attached to the remainder of the molecule by any atom of one or more rings. 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, indoleazinyl, 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 remainder of the molecule via a ring carbon atom. In some embodiments, the heteroaryl group is linked to the remainder 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).

[0375] As used herein, the term "heterocyclic group" means 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 may include fused, bridged, or spirocyclic ring 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 10 ring atoms (4-10 membered heterocyclic group). In some embodiments, the heterocyclic group contains 4 to 8 ring atoms (4-8 membered heterocyclic group). Heterocyclic groups may contain oxo-substituents at any available atom that will produce a stable compound. For example, such a group may contain an oxo group at a usable carbon or nitrogen atom. If chemically feasible, such a group may contain more than one oxo substituent. Furthermore, 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 provide a sulfoxide or sulfone. An example of a 4-membered heterocyclic group is an azirrobutyl (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 indololinyl. 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, morpholinyl, thiomorpholinyl, thiazolyl, piperazine, azacyclic butyl, oxacyclic butyl, thiocyclic butyl, high-piperidinyl, oxacyclic heptyl, thiocyclic heptyl, and oxacyclic azacyclic... basalt, diazoxide Basic, sulfur-nitrogen The aryl groups include 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).

[0376] The term "cycloalkyl" or "carbocyclic" 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. The carbocyclic group can be fused, bridged, or spirocyclic. In some embodiments, the carbocyclic group comprises 3 to 8 carbon ring atoms (3-8 membered carbocyclic group). In some embodiments, the carbocyclic group comprises 3 to 10 carbon ring atoms (3-10 membered carbocyclic group). Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, etc.

[0377] 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.

[0378] As used herein, the term "spirocyclic" has its conventional meaning, referring to any ring system containing two or more rings, where the two rings share a common ring carbon. Each ring of a spirocyclic ring system as defined herein independently contains 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.

[0379] The term "cyano" refers to the -C≡N group.

[0380] The "aldehyde" group refers to the –C(O)H group.

[0381] "Alkoxy" refers to –O-alkyl as defined herein.

[0382] "Alkoxycarbonyl" refers to -C(O)-alkoxy as defined in this article.

[0383] “alkylaminoalkyl” refers to -alkyl-NR-alkyl as defined herein.

[0384] "alkylsulfonyl" refers to -SO2 alkyl as defined herein.

[0385] "Amino" refers to -NH2, which is optionally substituted.

[0386] “Aminoalkyl” means –alkyl-amino as defined herein.

[0387] "Amino carbonyl" refers to -C(O)-amino as defined in this article.

[0388] "Arylalkyl" refers to -alkylaryl, where alkyl and aryl are defined herein.

[0389] "Aryloxy group" refers to both –O-aryl and –O-heteroaryl as defined herein.

[0390] "Aryloxycarbonyl" refers to -C(O)-aryloxy as defined in this article.

[0391] "Arylsulfonyl" refers to -SO2 aryl as defined in this article.

[0392] "Carbonyl" refers to the -C(O)- group as defined in this article.

[0393] The "carboxylic acid" group refers to the –C(O)OH group.

[0394] “Cycloalkoxy” refers to the –O-carbon cyclo group as defined in this article.

[0395] The "halogen" or "halogenated" group refers to fluorine, chlorine, bromine, or iodine.

[0396] "Halogenated alkyl" refers to an alkyl group that has been replaced by one or more halogen atoms.

[0397] "Hydroxy group" refers to the -OH group.

[0398] "Nitro" refers to the -NO2 group.

[0399] "O-substituent" refers to the =O substituent.

[0400] "Trihalomethyl" refers to a methyl group that has been replaced by three halogen atoms.

[0401] When referring to a moiety, the term "length" means the minimum number of carbon atoms and / or heteroatoms from one end of the moiety to the other. When referring to a linker, it means the minimum number of atoms from the end attached to the TRK ligand to the end attached to the degradation tag. This applies to both cases where the linker is linear or branched and cases where the linker contains a ring system.

[0402] The term "substituted" means that the specified group or portion carries one or more substituents independently selected from the following: 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).

[0403] The term "absent" means that there are no atoms or parts present, and that there are bonds between adjacent atoms in the structure.

[0404] The term "optionally substituted" means that the specified group may be unsubstituted or substituted with one or more substituents as defined herein. It should be understood that in the compounds of this disclosure, when a group is referred to as "unsubstituted" or "substituted" with fewer valences than those required to fill all atoms in the compound, the remaining valence on such a group is filled with hydrogen. For example, if a C6 aryl group, also referred to herein as "phenyl," is substituted with an additional substituent, then those skilled in the art will understand that such a group has four open positions remaining on the carbon atoms of the C6 aryl ring (six initial positions minus one position where the remainder of the compound is joined and one position of the additional substituent, leaving four open positions). In such cases, each of the remaining four carbon atoms is bonded to a hydrogen atom to fill their valence. Similarly, if a C6 aryl group in the compounds of this invention is referred to as "disubstituted," then those skilled in the art will understand that this means that three remaining carbon atoms of the C6 aryl group are unsubstituted. Each of the three unsubstituted carbon atoms is bonded to a hydrogen atom to fill its valence. Unless otherwise specified, the optionally substituted groups may be unsubstituted or substituted with one or more substituents selected from: halogens, CN, NO2, OR. m SR m NR n R o COR m CO2R m CONR n R o SOR m SO2R m SO2NR n R o NR n COR o NR m C(O)NR n R o NR n SOR o NR n SO2R o C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino, C1-C8 alkyl, C3-C7 carbocyclic, 3-7 membered heterocyclic, C2-C8 alkenyl, C2-C8 alkynyl, aryl and heteroaryl, wherein R m R n and R o Independently selected from no, hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 carbocyclic, 3-7 membered heterocyclic, aryl and heteroaryl, or R n and R oTogether with the atoms they are attached to, they form 3-8 member carbon rings or heterocyclic rings.

[0405] As used in this article, the same symbols in different equations refer to different definitions. For example, the definition of R1 in Equation 1 is as defined with respect to Equation 1, while the definition of R1 in Equation 6 is as defined with respect to Equation 6.

[0406] As used herein, each unit in the connector portion (e.g.) They may be the same as or different from each other. In some implementations, each unit in the connector portion is the same as the other.

[0407] 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.

[0408] The terms "combination therapy," "combination," or "in combination with" refer to the administration of two or more therapeutic agents to treat the disease or condition described in this disclosure (e.g., cancer). Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses the co-administration in multiple or separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. Furthermore, such administration also encompasses the sequential use of each type of therapeutic agent at approximately the same time or at different times. In either case, the treatment regimen will provide the beneficial effect of the combination of drugs in treating the disease or condition described herein.

[0409] Combination therapies can provide a “synergistic effect” and are demonstrated to be “synergistic,” meaning that the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by the use of the compounds alone. Synergistic effects can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously in combined unit-dose formulations; (2) delivered alternately or in parallel in individual formulations; or (3) used via some other regimen. When delivered in alternating therapies, synergistic effects can be achieved by sequential administration or delivery of the compounds, for example by different injections in separate syringes. Generally, in alternating therapies, the effective doses of each active ingredient are administered sequentially (i.e., consecutively), while in combination therapies, the effective doses of two or more active ingredients are administered together.

[0410] As used herein, the term "drug combination" refers to a fixed or non-fixed combination in the form of a single dose unit or a multipart kit for combined administration, wherein two or more therapeutic agents may be administered simultaneously, independently, or separately at time intervals, particularly where these time intervals allow the combination partners to exhibit cooperative effects, such as synergistic effects.

[0411] As used herein, "therapeutic agent" means a therapy that, when administered to a patient in combination with a compound of the present disclosure, has therapeutic activity or enhances therapeutic activity, or when administered to a patient in combination with a compound of the present disclosure, reduces one or more side effects of the compound of the present disclosure, such as molecules, including but not limited to chemical compounds, peptides, antibodies, antibody fragments, antibody conjugates, or nucleic acids; gene or cell therapy; or radiotherapy.

[0412] "Cancer" refers to any cancer caused by the uncontrolled proliferation of abnormal cells, such as tumors, growths, epithelial carcinomas, sarcomas, leukemia, lymphomas, etc. Cancer cells can spread locally or to other parts of the body through the bloodstream and lymphatic system. For example, cancers include, but are not limited to, mesothelioma, leukemia, and lymphomas such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphomas associated with human T-cell lymphotropic virus (HTLV) such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphoma and multiple myeloma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Other examples include myelodyplasia syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas, and common adult solid tumors such as head and neck cancers (e.g., oral, laryngeal, and nasopharyngeal cancers), esophageal cancer, urinary tract cancers (e.g., prostate, bladder, kidney, uterine, ovarian, and testicular cancers), lung cancers (e.g., small cell lung cancer and non-small cell lung cancer), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors associated with Goring syndrome (e.g., medulloblastoma, meningioma, etc.), liver cancer, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid tumors, and gastrointestinal stromal tumors (GIST). Additional exemplary forms of cancer that can be treated with the compounds and compositions described herein include, but are not limited to, skeletal muscle or smooth muscle cancer, gastric cancer, small bowel cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0413] The second agent can be an anticancer agent. The terms "anticancer" or "anticancer agent" refer to agents used to treat cancer (i.e., compounds, antibodies, etc., used to treat cancer). Anticancer effects can be produced through one or more mechanisms, including but not limited to regulating cell growth or proliferation, inhibiting angiogenesis (the formation of new blood vessels), inhibiting metastasis (the spread of tumors from their origin), inhibiting invasion (the spread of tumor cells into adjacent normal structures), inhibiting checkpoint molecules, or promoting apoptosis.

[0414] The anticancer agent may be an antiproliferative agent or an immunomodulator. In one embodiment, the second agent is an immunomodulator.

[0415] As used herein, the terms "antiproliferative" or "antiproliferative agent" refer to agents that inhibit cell growth or cell proliferation. Antiproliferative agents can be cytotoxic agents (e.g., alkylating agents, antimetabolites, etc.), targeting agents (e.g., EGF inhibitors, tyrosine protein kinase inhibitors, angiogenesis inhibitors, etc.), or hormonal agents (e.g., estrogen-selective estrogen receptor modulators, etc.). Examples of antiproliferative agents include alkylating agents, antimetabolites, antibiotics, antidotes, EGFR inhibitors, HER2 inhibitors, histone deacetylase inhibitors, hormones, mitotic inhibitors, mTOR inhibitors, multi-kinase inhibitors, serine / threonine inhibitors, tyrosine kinase inhibitors, VEGF / VEGFR inhibitors; taxanes or taxane derivatives, aromatase inhibitors, anthracyclines, microtubule-targeting drugs, topoisomerase poisons, and inhibitors of molecular targets or enzymes.

[0416] The term "immunomodulatory agent" refers to a drug that alters the immune response or function of the immune system (e.g., by stimulating antibody formation or inhibiting leukocyte activity). Immunomodulatory agents can be immunomodulators, cytokines, vaccines, or antibodies.

[0417] The term "immunomodulator" refers to an inhibitor of immune checkpoint molecules.

[0418] Additional cancers for which the compounds and compositions described herein may be used for prevention, treatment, and research include, for example, colon cancer, familial adenomatous polyposis cancer, and hereditary nonpolyposis colorectal cancer or melanoma. Furthermore, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary thyroid carcinoma and papillary thyroid carcinoma), kidney cancer, renal parenchymal carcinoma, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors), gallbladder cancer, bronchial cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0419] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. The term "pharmaceutically acceptable salt" for any of the compounds described herein is intended to encompass 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.

[0420] "Pharmaceutically acceptable acid addition salts" refer to 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, phosphorous acid, etc. This 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, etc., 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, salicylic acid, etc. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, transbutenediacetes, maleic acid salts, 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 considered (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.

[0421] "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 inorganic 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: 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-diphenylmethylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, diaminobibenzyl, N-methylreduced glucosamine, glucosamine, methylreduced glucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al. (above).

[0422] Example

[0423] This disclosure is also described and illustrated by the following embodiments. However, the use of these and other embodiments anywhere in the specification is merely illustrative and in no way intended to limit the scope and meaning of this disclosure or any of the illustrative terms. Similarly, this disclosure is not limited to any particular preferred embodiment or aspect described herein. In fact, many modifications and variations will be apparent to those skilled in the art upon reading this specification, and such variations may be made without departing from the spirit or scope of the invention. Therefore, the invention will be limited only by the terms of the appended claims and the full scope of their equivalents.

[0424] Example 1.2-(2,6-dioxopiperidin-3-yl)-5-((6-oxo-6-(piperidin-1-yl)hexyl)amino)isoindoline-1,3-dione (GS-001)

[0425]

[0426] EDCI (40 mg, 258 μmol), HOAT (35 mg, 258 μmol), and NMM (39 mg, 387 μmol) were added to a mixture of piperidine (22 mg, 258 μmol) and 6-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)amino)hexanoic acid (50 mg, 129 μmol) in DMSO (1 mL). After stirring the reaction overnight at room temperature, the mixture was purified by C18 chromatography (0–70% MeCN aqueous solution) to provide the title compound as a yellow solid (50.5 mg, yield: 86%). MS (ESI) m / z = 455.6 [M+H] + .

[0427] Example 2.5-((6-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-002)

[0428]

[0429] GS-002 (60 mg, yield: 64%) was synthesized according to the standard procedure for preparing GS-005. MS (ESI) m / z = 727.4 [M+H] + .

[0430] Example 3.5-((6-(4-(1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-003)

[0431]

[0432] GS-003 (44.7 mg, yield: 67%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 521.6 [M+H] + .

[0433] Example 4.2-(3-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2,2-difluoroacetamide (GS-004)

[0434]

[0435] Step 1: Synthesis of ethyl 2-(3-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-2,2-difluoroacetate

[0436]

[0437] Cu(OAc)₂ (101 mg, 558 μmol) and TEA (85 mg, 837.4 μmol) were added to a mixture of 8-bromo-2-[1-(4-piperidinyl)pyrazol-4-yl]quinoxaline (100 mg, 279 μmol) and [3-(2-ethoxy-1,1-difluoro-2-oxo-ethyl)phenyl]boronic acid (136 mg, 558 μmol) in DMF (3 mL). After stirring the reaction overnight at 50 °C, the mixture was filtered and purified by C18 chromatography (0–70% MeCN aqueous solution) to provide the title compound as a white solid (35 mg, yield: 23%). MS (ESI) m / z = 556.4 [M+H] + .

[0438] Step 2: Synthesis of 2-(3-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-2,2-difluoroacetic acid

[0439]

[0440] NaOH (12 mg, 314 μmol) was added to a solution of ethyl 2-(3-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-2,2-difluoroacetate (35 mg, 63 μmol) in methanol (0.5 mL) and water (0.1 mL). After stirring the reaction at room temperature for 1 h, the mixture was purified by C18 chromatography (0–70% MeCN aqueous solution) to provide the title compound as a yellow solid (22 mg, yield: 66%). MS (ESI) m / z = 528.4 [M+H] + .

[0441] Step 3: Synthesis of 2-(3-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-N-((2-(2,6-dioxoperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2,2-difluoroacetamide

[0442]

[0443] To a mixture of 2-(3-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-2,2-difluoroacetic acid (20 mg, 38 μmol) and 3-[5-(aminomethyl)-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (12 mg, 45 μmol) in DMSO (0.5 mL), DMAP (462 μg, 3.79 μmol), HATU (29 mg, 76 μmol), and DIPEA (15 mg, 113 μmol) were added. After stirring the reaction overnight at room temperature, the reaction solution was purified by C18 chromatography (0-70% MeOH aqueous solution) to provide the title compound as a grayish-white solid (4.9 mg, yield: 16%). MS (ESI) m / z = 785.4 [M+H] + .

[0444] Example 5.2-(2,6-dioxopiperidin-3-yl)-5-((6-oxo-6-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)hexyl)amino)isoindoline-1,3-dione (GS-005)

[0445]

[0446] Step 1: Synthesis of tert-butyl 4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0447]

[0448] A mixture of 2-bromoquinoxaline (100 mg, 478.37 μmol), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazol-1-yl]piperidin-1-carboxylic acid tert-butyl ester (270.72 mg, 717.56 μmol), Pd(dppf)Cl2 (35.00 mg, 47.84 μmol), K2CO3 (132.23 mg, 956.74 μmol) in water (0.1 mL) and dioxane (0.4 mL) was stirred for 2 h at 80 °C. The mixture was then concentrated. The resulting residue was purified by silica gel chromatography to provide the title compound (140 mg, yield: 77%). MS (ESI) m / z = 380.5 [M+H] + .

[0449] Step 2: Synthesis of 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline

[0450]

[0451] A solution of tert-butyl 4-(4-quinoxalo-2-ylpyrazol-1-yl)piperidine-1-carboxylate (140 mg, 368.95 μmol) in HCl solution (4 M, in dioxane, 0.4 mL) and DCM (0.3 mL) was stirred for 2 h. The mixture was then concentrated to provide a crude product (95 mg, yield: 82%), which was used directly in the next step without further purification. MS (ESI) m / z = 280.3 [M+H] + .

[0452] Step 3: Synthesis of 2-(2,6-dioxopiridine-3-yl)-5-((6-oxo-6-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidine-1-yl)hexyl)amino)isoindoline-1,3-dione

[0453]

[0454] A solution of 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (30 mg, 95.00 μmol, HCl salt), 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)hexanoic acid (33.45 mg, 86.36 μmol), PyBOP (67.41 mg, 129.54 μmol), and Et3N (34.96 mg, 345.44 μmol) in DMSO (0.4 mL) was stirred overnight at room temperature. The mixture was then purified by reversed-phase chromatography to provide the title compound (15 mg, yield: 27%). MS (ESI) m / z = 649.7 [M+H] + .

[0455] Example 6.2-(2,6-dioxopiperidin-3-yl)-5-((6-oxo-6-(4-(4-(quinolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)hexyl)amino)isoindoline-1,3-dione (GS-006)

[0456]

[0457] GS-006 (23 mg, yield: 35%) was synthesized according to the standard procedure for preparing GS-005. MS (ESI) m / z = 648.8 [M+H] + .

[0458] Example 7.5-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-((2-(2,6-dioxoperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2,2-difluoro-5-oxopentamide (GS-007)

[0459]

[0460] Step 1: Synthesis of 3,3-difluorodihydro-2H-pyran-2,6(3H)-dione

[0461]

[0462] A solution of 2,2-difluoroglutaric acid (100 mg, 595 μmol) in acetyl chloride (2 mL) was stirred overnight at 60 °C. The reaction mixture was concentrated, and the resulting residue was used directly in the next step without further purification.

[0463] Step 2: Synthesis of 5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)amino)-4,4-difluoro-5-oxovaleric acid

[0464]

[0465] Add 90 mg of crude 3,3-difluorodihydro-2H-pyran-2,6(3H)-dione (100 mg, 1.2 mmol) to a solution of 3-[5-(aminomethyl)-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (100 mg, 1.2 mmol) in DMSO (1 mL). Stir the resulting mixture at 60 °C for 1 h. Then, purify it by C18 chromatography (0-70% MeCN aqueous solution) to provide the title compound as a yellow solid (20 mg, yield: 8%). MS (ESI) m / z = 424.3 [M+H] + .

[0466] Step 3: Synthesis of 5-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-((2-(2,6-dioxoperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2,2-difluoro-5-oxopentamide

[0467]

[0468] To a mixture of 5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)amino)-4,4-difluoro-5-oxopentanoic acid (10 mg, 24 μmol) and 8-bromo-2-[1-(4-piperidinyl)pyrazol-4-yl]quinoxaline (13 mg, 35 μmol) in DMSO (0.5 mL), HATU (18 mg, 47 μmol), DMAP (288 μg, 2 μmol), and DIPEA (12 mg, 94 μmol) were added. The reaction mixture was stirred overnight at room temperature and then purified by C18 chromatography (0–70% MeOH aqueous solution) to provide the title compound as an off-white solid (2.3 mg, yield: 13%). MS (ESI) m / z = 765.5 [M+H] + .

[0469] Example 8.2-(2,6-dioxopiperidin-3-yl)-5-((6-oxo-6-(4-(4-(1,2,3,4-tetrahydroquinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)hexyl)amino)isoindoline-1,3-dione (GS-008)

[0470]

[0471] GS-008 (3.8 mg, yield: 7%) was synthesized according to the standard procedure for preparing GS-005. MS (ESI) m / z = 653.6 [M+H] + .

[0472] Example 9. 2-(2,6-dioxopiperidin-3-yl)-5-((6-oxo-6-(4-(4-(pyrazin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)hexyl)amino)isoindoline-1,3-dione (GS-009)

[0473]

[0474] GS-009 (3.7 mg, yield: 6%) was synthesized according to the standard procedure for preparing GS-005. MS (ESI) m / z = 599.6 [M+H] + .

[0475] Example 10.2-(2,6-dioxopiperidin-3-yl)-5-((6-oxo-6-(4-phenylpiperidin-1-yl)hexyl)amino)isoindoline-1,3-dione (GS-010)

[0476]

[0477] GS-010 (82 mg, yield: 61.6%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 531.5 [M+H] + .

[0478] Example 11.2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-morpholinopiperidin-1-yl)-6-oxohexyl)amino)isoindoline-1,3-dione (GS-011)

[0479]

[0480] GS-011 (112 mg, yield: 83%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 540.6 [M+H] + .

[0481] Example 12.5-((6-([1,4'-bipiperidin]-1'-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-012)

[0482]

[0483] GS-012 (95 mg, yield: 71%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 538.7 [M+H] + .

[0484] Example 13.2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-6-oxohexyl)amino)isoindoline-1,3-dione (GS-013)

[0485]

[0486] GS-013 (111 mg, yield: 80.6%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 553.6 [M+H] + .

[0487] Example 14.2-(2,6-dioxopiperidin-3-yl)-5-((6-oxo-6-(4-(pyrimidin-2-yl)piperidin-1-yl)hexyl)amino)isoindoline-1,3-dione (GS-014)

[0488]

[0489] GS-014 (30.7 mg, yield: 31.3%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 533.6 [M+H] + .

[0490] Example 15.2-(2,6-dioxopiperidin-3-yl)-5-((6-oxo-6-(4-(3-(quinoxolin-2-yl)pyrrolidine-1-yl)piperidin-1-yl)hexyl)amino)isoindoline-1,3-dione (GS-015)

[0491]

[0492] GS-015 (17 mg, yield: 45.8%) was synthesized according to the standard procedure for preparing GS-005. MS (ESI) m / z = 652.8 [M+H] + .

[0493] Example 16. 2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-(2-methylbenzoyl)piperazin-1-yl)-6-oxohexyl)amino)isoindoline-1,3-dione (GS-016)

[0494]

[0495] GS-016 (50.2 mg, yield: 58.4%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 574.6 [M+H] + .

[0496] Example 17.2-(2,6-dioxopiperidin-3-yl)-5-((6-oxo-6-(4-(pyridin-2-yl)piperidin-1-yl)hexyl)amino)isoindoline-1,3-dione (GS-017)

[0497]

[0498] GS-017 (40.7 mg, yield: 48.1%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 532.7 [M+H] + .

[0499] Example 18.3-(5-(2-(3-(4-(4-(8-bromoquinoxaloline-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (GS-018)

[0500]

[0501] GS-018 (9.6 mg, yield: 64%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 716.2 [M+H] + .

[0502] Example 19.2-(2,6-dioxopiperidin-3-yl)-5-((6-oxo-6-(4-(pyridin-2-yl)piperazin-1-yl)hexyl)amino)isoindoline-1,3-dione (GS-019)

[0503]

[0504] GA-019 (5.8 mg, yield: 84%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 533.3 [M+H] + .

[0505] Example 20. 6-(4-(4-(8-bromoquinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-6-oxohexanoamide (GS-020)

[0506]

[0507] Step 1: Synthesis of 6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)amino)-6-oxohexanoic acid

[0508]

[0509] A mixture of 3-(5-amino-1-oxoisoindololin-2-yl)piperidin-2,6-dione (20 mg, 0.07 mmol), adipic acid (33 mg, 0.23 mmol), EDCI (22 mg, 0.12 mmol), HOAT (16 mg, 0.12 mmol), and NMM (21 mg, 0.21 mmol) in DMSO (2 mL) was stirred for 16 h at room temperature. The resulting mixture was purified by reversed-phase chromatography to provide the desired product (12 mg, 45% yield) as a white solid. MS (ESI) m / z = 388.3 [M+H] + .

[0510] Step 2: Synthesis of 6-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)-6-oxohexanoamide

[0511]

[0512] GS-020 (8.7 mg, yield: 41%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 727.4 [M+H] + .

[0513] Example 21.5-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-((2-(2,6-dioxoperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-5-oxopentanamide (GS-021)

[0514]

[0515] GS-021 (6.1 mg, yield: 43%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 727.4 [M+H] + .

[0516] Example 22. N-(3-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropyl)-2-((2-(2,6-dioxoperidin-3-yl)-1-oxoisoindoline-5-yl)oxy)acetamide (GS-022)

[0517]

[0518] GS-022 (3 mg, yield: 20%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 729.3 [M+H] + .

[0519] Example 23.3-(4-((2-((3-((4-(4-(8-bromoquinoxaloline-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (GS-028)

[0520]

[0521] Step 1: Synthesis of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindololin-2-yl)piperidine-2,6-dione

[0522]

[0523] DIPEA (5.98 g, 46.26 mmol) was added to a solution of 3-(4-amino-1-oxo-isoindolin-2-yl)piperidin-2,6-dione (2.0 g, 7.71 mmol) and 2,4-dichloropyrimidine (2.30 g, 15.42 mmol) in DMF (50 mL) at room temperature. The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was concentrated and purified by silica gel chromatography (DCM / MeOH = 20 / 1) to provide the title compound (1.5 g, 52% yield). MS (ESI) m / z = 372.3 [M+H] + .

[0524] Step 2: Synthesis of tert-butyl (3-((4-(4-(8-bromoquinoxaloline-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)phenyl)carbamate

[0525]

[0526] To a solution of 8-bromo-2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (130 mg, 275.27 μmol) in DMSO (5 mL), NaI (41.26 mg, 275.27 μmol) and DIPEA (106.73 mg, 825.82 μmol) were added. The mixture was stirred at room temperature for 16 h, then quenched with brine (20 mL), extracted with EtOAc (20 mL × 2), and concentrated. The resulting residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to provide the title compound (150 mg, 96.7% yield). MS (ESI) m / z = 565.4 [M+H] + .

[0527] Step 3: Synthesis of 3-((4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)aniline

[0528]

[0529] TFA (2 mL) was added to a solution of tert-butyl (3-((4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)phenyl)carbamate (100 mg, 177.47 μmol) in DCM (10 mL) at room temperature. After stirring the mixture for 2 h at room temperature, it was concentrated to provide the title compound (120 mg, 97.8% yield). MS (ESI) m / z = 465.2 [M+H] + .

[0530] Step 4: Synthesis of 3-(4-((2-((3-((4-(4-(8-bromoquinoxaloline-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0531]

[0532] At room temperature, TFA (0.5 mL) was added to a solution of 3-((4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)aniline (80.00 mg, 172.65 μmol) and 3-(4-(((2-chloropyrimidin-4-yl)amino)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (77.02 mg, 207.18 μmol) in tBuOH (5 mL) and DMSO (1 mL). After stirring the mixture at 100 °C for 3 h, it was purified by preparative HPLC to provide the crude product, which was further purified by preparative TLC (DCM / MeOH = 10 / 1) to provide the title compound (102 mg, 74% yield). MS (ESI) m / z = 800.5 [M+H] + .

[0533] Example 24. 3-(4-((2-((4-((4-(4-(8-bromoquinoxaloline-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (GS-030)

[0534]

[0535] GS-030 (70 mg, yield: 51%) was synthesized using a similar procedure to that used for GS-028. MS (ESI) m / z = 800.5 [M+H] + .

[0536] Example 25. 3-(1-oxo-4-((2-((3-((4-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-029)

[0537]

[0538] GS-029 (50 mg, yield: 42.1%) was synthesized using a similar procedure to that used for GS-028. MS (ESI) m / z = 720.8 [M+H] +.

[0539] Example 26. 3-(1-oxo-4-((2-((4-((4-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-031)

[0540]

[0541] GS-031 (50 mg, yield: 42.1%) was synthesized using a similar procedure to that used for GS-028. MS (ESI) m / z = 720.7 [M+H] + .

[0542] Example 27. 3-(1-oxo-4-((2-((3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-025)

[0543]

[0544] GS-025 (18 mg, yield: 79.7%) was synthesized using a similar procedure to that used for GS-028. MS (ESI) m / z = 706.7 [M+H] + .

[0545] Example 28.3-(4-((2-((4-(4-(4-(8-bromoquinoxaloline-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (GS-026)

[0546]

[0547] GS-026 (25 mg, yield: 59.7%) was synthesized using a similar procedure to that used for GS-028. MS (ESI) m / z = 784.5 [M+H] + .

[0548] Example 29.3-(1-oxo-4-((2-((4-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-027)

[0549]

[0550] GS-027 (37 mg, yield: 56%) was synthesized using a similar procedure to that used for GS-028. MS (ESI) m / z = 706.7 [M+H] + .

[0551] Example 30.3-(5-((2-((2-(4-(4-(4-(8-bromoquinoxaloline-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (GS-072)

[0552]

[0553] Step 1: Synthesis of tert-butyl (2-oxo-2,3-dihydro-1H-inden-5-yl)carbamate

[0554]

[0555] Under a nitrogen atmosphere, Pd / C (10%, 100 mg) and (Boc)₂O (609.1 mg, 2.82 mmol) were added to a solution of 5-nitro-1,3-dihydro-2H-indenhydrin-2-one (500.0 mg, 2.82 mmol) in THF (15 mL). The mixture was purged with hydrogen and stirred at room temperature for 2 h using a hydrogen balloon under a hydrogen atmosphere. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 3:1) to provide the title compound as a white solid (344.2 mg, yield: 49.3%). MS (ESI) m / z = 248.1 [M+H] + .

[0556] Step 2: Synthesis of tert-butyl (2-hydroxy-2,3-dihydro-1H-inden-5-yl)carbamate

[0557]

[0558] At 0 °C, NaBH4 (79.2 mg, 2.08 mmol) was added to a solution of (2-oxo-2,3-dihydro-1H-inden-5-yl)carbamate tert-butyl (344.2 mg, 1.39 mmol) in MeOH (10 mL). The mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with water and extracted with DCM (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting residue was used directly in the next step without further purification. MS (ESI) m / z = 250.1 [M+H] + .

[0559] Step 3: Synthesis of 5-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-inden-2-yl ester of 4-methylbenzenesulfonic acid

[0560]

[0561] DMAP (13.4 mg, 0.11 mmol) and TEA (590.8 mg, 5.85 mmol) were added to a solution of (2-hydroxy-2,3-dihydro-1H-inden-5-yl)carbamate tert-butyl ester (294.5 mg, 1.17 mmol) and TsCl (444.6 mg, 2.34 mmol) in DCM (10 mL). After stirring the reaction at room temperature for 3 h, it was diluted with DCM (20 mL) and washed with H₂O and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 3:1) to provide the title compound as a white solid (307.7 mg, yield: 70.2%). MS (ESI) m / z = 404.5 [M+H] + .

[0562] Step 4: Synthesis of tert-butyl carbamate (2-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,3-dihydro-1H-inden-5-yl)carbamate

[0563]

[0564] To a solution of 5-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-inden-2-yl ester of 4-methylbenzenesulfonic acid (30.0 mg, 0.07 mmol) in DMSO (1 mL), 8-bromo-2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (24.9 mg, 0.07 mmol) and K₂CO₃ (29.1 mg, 0.21 mmol) were added. After stirring at 60 °C for 2 h, the reaction was purified by C18 column chromatography to provide the title compound as a pale yellow solid (12.8 mg, yield: 31.2%). MS (ESI) m / z = 589.3 [M+H] + .

[0565] Step 5: Synthesis of 3-(5-((2-((2-(4-(4-(8-bromoquinoxaloline-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0566]

[0567] To a solution of (2-(4-(4-(8-bromoquinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,3-dihydro-1H-indene-5-yl)carbamate (12.8 mg, 0.02 mmol) in IPA (1 mL), 3-(5-(((2-chloropyrimidin-4-yl)amino)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (7.4 mg, 0.02 mmol) and TFA (26.2 mg, 0.23 mmol) were added. The reaction mixture was irradiated in a microwave-irradiated reactor at 80 °C for 3 h. The resulting mixture was purified by reversed-phase rapid chromatography to provide the title compound as a yellow solid (4.4 mg, yield: 26.8%). MS (ESI) m / z = 824.5 [M+H] + .

[0568] Example 31.3-(1-oxo-5-((2-((2-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-073)

[0569]

[0570] GS-073 (3.7 mg, yield: 24.8%) was synthesized using a similar procedure to that used for GS-072. MS (ESI) m / z = 746.7 [M+H] + .

[0571] Example 32.3-(1-oxo-4-((2-(3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)pyrrolidine-1-yl)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-074)

[0572]

[0573] DIPEA (66.76 mg, 516.58 μmol) was added to a solution of 2-[1-(1-pyrrolidin-3-yl-4-piperidinyl)pyrazol-4-yl]quinoxaline (30 mg, 86.10 μmol) and 3-[4-[(2-chloropyrimidin-4-yl)amino]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (32.01 mg, 86.10 μmol) in DMSO (5 mL) at room temperature. After stirring the mixture at 120 °C for 16 h, it was cooled to room temperature and purified by preparative HPLC to provide 100 mg of crude product, which was further purified by preparative TLC (DCM / MeOH = 8 / 1) to provide the title compound as a white solid (45 mg, 76.4% yield). MS (ESI) m / z = 684.7 [M+H] + .

[0574] Example 33.3-(1-oxo-4-((2-((3-(4-phenylpiperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-075)

[0575]

[0576] Step 1: Synthesis of 1-(3-nitrophenyl)-4-phenylpiperidine

[0577]

[0578] To a solution of 4-phenylpiperidine (100 mg, 0.62 mmol) in dioxane (10 mL), 1-bromo-3-nitrobenzene (188 mg, 0.93 mol), Pd2(dba)3 (114 mg, 0.124 mmol), Xantphos (108 mg, 0.19 mmol), and t-BuONa (179 mg, 1.86 mmol) were added. The mixture was irradiated for 2 h in a microwave-irradiated reactor at 100 °C under N2. The mixture was purified by silica gel rapid chromatography to provide the title compound as a yellow solid (130 mg, 74.2% yield).

[0579] Step 2: Synthesis of 3-(4-phenylpiperidin-1-yl)aniline

[0580]

[0581] Pd / C (13 mg) was added to a solution of 1-(3-nitrophenyl)-4-phenyl-piperidine (130 mg, 0.46 mmol) in THF (5 mL). The reaction was stirred for 2 h at 25 °C under H2. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated to provide the title compound as a white solid (106 mg, 91.2% yield), which was used directly in the next step without further purification.

[0582] Step 3: Synthesis of 3-(1-oxo-4-((2-((3-(4-phenylpiperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione

[0583]

[0584] A mixture of 3-(4-phenyl-1-piperidinyl)aniline (20 mg, 0.079 mmol), 3-[4-[(2-chloropyrimidin-4-yl)amino]-1-oxo-isoindololin-2-yl]piperidin-2,6-dione (44 mg, 0.119 mmol), and TFA (27 mg, 0.237 mmol) in t-BuOH (1.0 mL) and DMSO (0.2 mL) was stirred for 3 h at 90 °C. The reaction was concentrated. The resulting residue was purified by reversed-phase column chromatography to provide the title compound as a white solid (19 mg, 40.8% yield). MS (ESI) m / z = 588.5 [M+H] + .

[0585] Example 34.3-(1-oxo-4-((2-((3-(4-(pyridin-2-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-076)

[0586]

[0587] GS-076 (29 mg, yield: 62.5%) was synthesized using a similar procedure to that used for GS-075. MS (ESI) m / z = 590.5 [M+H] + .

[0588] Example 35.3-(1-oxo-4-((2-((3-(4-(pyridin-2-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-077)

[0589]

[0590] GS-077 (4 mg, yield: 8.6%) was synthesized using a similar procedure to that used for GS-075. MS (ESI) m / z = 589.4 [M+H] + .

[0591] Example 36.3-(1-oxo-4-((2-((3-(4-(pyrimidin-2-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-078)

[0592]

[0593] GS-078 (11 mg, yield: 23.8%) was synthesized using a similar procedure to that used for GS-075. MS (ESI) m / z = 591.5 [M+H] + .

[0594] Example 37.3-(1-oxo-4-((2-((3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-079)

[0595]

[0596] GS-079 (2.9 mg, yield: 19.6%) was synthesized using a similar procedure to that used for GS-075. MS (ESI) m / z = 734.7 [M+H] + .

[0597] Example 38.3-(1-oxo-4-((2-((3-(4-(pyridin-2-yl)piperazin-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-080)

[0598]

[0599] GS-080 (3.8 mg, yield: 28.9%) was synthesized using a similar procedure to that used for GS-075. MS (ESI) m / z = 618.5 [M+H] + .

[0600] Example 39.3-(1-oxo-4-((2-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-081)

[0601]

[0602] GS-081 (10 mg, yield: 54.3%) was synthesized using a similar procedure to that used for GS-074. MS (ESI) m / z = 615.5 [M+H] + .

[0603] Example 40. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-(3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclobutyl)acetamide (GS-082)

[0604]

[0605] GS-082 (22 mg, yield: 48.4%) was synthesized using a similar procedure to that used for GS-004. MS (ESI) m / z = 647.3 [M+H] + .

[0606] Example 41. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-(2-(4-(4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)acetamide (GS-083)

[0607]

[0608] Step 1: Synthesis of tert-butyldimethyl(2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)cyclopropyl)ethoxy)silane

[0609]

[0610] At 0 °C, Et₂Zn (32.02 mmol, 32 mL) was added to a solution of tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)but-3-en-1-yl)oxy)silane (2.0 g, 6.40 mmol) in DCM (30 mL). After stirring the mixture at 0 °C for 0.5 h, CH₂I₂ (8.58 g, 32.02 mmol) and TFA (3.65 g, 32.02 mmol) were added at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, followed by stirring at room temperature for 2 h. The reaction was quenched with aqueous NH₄Cl solution, extracted with DCM, and concentrated. The resulting residue was purified by silica gel chromatography (petroleum ether / EtOAc = 10 / 1) to provide the title compound (2.0 g, 95.7% yield) as a colorless oil.

[0611] Step 2: Synthesis of 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cycloprop-1-ol

[0612]

[0613] At 0 °C, a solution of tert-butyldimethyl(2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)cyclopropyl)ethoxy)silane (2.0 g, 6.13 mmol) in THF (50 mL) was added with NaHCO3 (6.13 mmol, 30 mL) and H2O2 (6.13 mmol, 20 mL). After stirring the reaction mixture at 0 °C for 1 h, it was extracted with DCM and concentrated. The resulting residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3 / 1) to provide the title compound as a colorless oil (1.2 g, 90.5% yield).

[0614] Step 3: Synthesis of 2-(1-(1-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropyl)piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline

[0615]

[0616] Zn(Et)₂ (1.00 mmol, 4 mL) was added to a solution of 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (280 mg, 1.00 mmol) and 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cycloprop-1-ol (401.39 mg, 1.85 mmol) in DMF (20 mL) at room temperature. After stirring the mixture at 110 °C for 48 h, it was quenched with aqueous NH₄Cl solution, extracted with DCM, and concentrated. The resulting residue was purified by silica gel chromatography (DCM / MeOH = 15 / 1) to provide the title compound (150 mg, 31.3% yield). MS (ESI) m / z = 478.6 [M+H] + .

[0617] Step 4: Synthesis of 2-(2-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)ethanol-1-ol

[0618]

[0619] TBAF (82.10 mg, 313.99 μmol, 2 mL) was added to a solution of 2-(1-(1-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropyl)piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (150 mg, 313.99 μmol) in THF (5 mL) at room temperature. The mixture was stirred for 0.5 h at room temperature and then concentrated. The resulting residue was purified by preparative HPLC to provide the title compound as a yellow solid (100 mg, 66.7% yield). MS (ESI) m / z = 364.4 [M+H] + .

[0620] Step 5: Synthesis of 2-(2-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)acetic acid

[0621]

[0622] Jones reagent (0.4 mL) was added to a solution of 2-(2-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)ethanol-1-ol (100 mg, 275.14 μmol) in acetone (3 mL) and DMF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was purified by preparative HPLC to provide the title compound (35 mg, 33.7% yield). MS (ESI) m / z = 378.3 [M+H] + .

[0623] Step 6: Synthesis of N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-(2-(4-(4-(quinoxaloline-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)acetamide

[0624]

[0625] GS-083 (30 mg, yield: 38.8%) was synthesized using a similar procedure to that used for GS-001. MS (ESI) m / z = 633.7 [M+H] + .

[0626] Example 42. 3-(1-oxo-4-((2-((3-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)phenyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-084)

[0627]

[0628] GS-084 (9.5 mg, yield: 22.1%) was synthesized using a similar procedure to that used for GS-075. MS (ESI) m / z = 623.4 [M+H] + .

[0629] Example 43. 3-(1-oxo-4-((2-((3-oxo-3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-085)

[0630]

[0631] GS-085 (1.0 mg, yield: 10.3%) was synthesized using a similar procedure to that used for GS-001. MS (ESI) m / z = 686.7 [M+H] + .

[0632] Example 44. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-(3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclohexyl)acetamide (GS-086)

[0633]

[0634] Step 1: Synthesis of methyl 2-(3-oxocyclohexyl)acetate

[0635]

[0636] Add Dess-Martin periodinane (1.5 g, 3.48 mmol) to a stirred solution of methyl 2-(3-hydroxycyclohexyl)acetate (300 mg, 0.17 mmol) in DCM (6.0 mL). Stir the reaction at room temperature for 16 h, then filter. Concentrate the filtrate. Purify the resulting residue by column chromatography (EtOAc: petroleum ether = 1:3) to provide the title compound (265 mg, 76.6% yield) as a pale yellow oil, which is used directly in the next step.

[0637] Step 2: Synthesis of methyl 2-(3-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclohexyl)acetate

[0638]

[0639] An active molecular sieve (50 mg) and NaBH(OAc)3 (114 mg, 0.54 mmol) were added to a stirred solution of methyl 2-(3-oxocyclohexyl)acetate (61 mg, 0.36 mmol) and 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (50 mg, 0.18 mmol) in DCM (2.0 mL). The reaction was stirred for 16 h at room temperature under N2. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by preparative TLC (DCM:MeOH = 10:1) to provide the title compound as a solid (12 mg, 15.4% yield). MS (ESI) m / z = 434.4 [M+H] + .

[0640] Step 3: Synthesis of 2-(3-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclohexyl)acetic acid

[0641]

[0642] LiOH·H₂O (7.0 mg, 0.166 mmol) was added to a solution of methyl 2-(3-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclohexyl)acetate (12 mg, 0.028 mmol) in THF (1.0 mL) and H₂O (1.0 mL). The reaction was stirred at room temperature for 2 h. The pH of the reaction solution was adjusted to 2–3 with HCl (1 M). The mixture was extracted with EtOAc and washed with water and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated to provide the crude product (11 mg, 94.8% yield), which was used directly in the next step. MS (ESI) m / z = 420.5 [M+H] + .

[0643] Step 4: Synthesis of N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-(3-(4-(4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclohexyl)acetamide

[0644]

[0645] To a solution of 2-(3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclohexyl)acetic acid (11 mg, 0.026 mmol) in DMF (2.0 mL), DIEA (17 mg, 0.131 mmol), HATU (15 mg, 0.0394 mmol), and 3-(5-(aminomethyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione hydrochloride (10 mg, 0.031 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated. The resulting residue was purified by preparative TLC (DCM:MeOH = 5:1) to provide the title compound as a white solid (16 mg, 90% yield). MS (ESI) m / z = 675.7 [M+H] + .

[0646] Example 45. N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl)methyl)-2-((3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)amino)acetamide (GS-087)

[0647]

[0648] Step 1: Synthesis of 5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-carboxylon

[0649]

[0650] A solution of 3-(1-bromo-4-oxo-4H-thieno[3,4-c]pyrrolo-5(6H)-yl)piperidin-2,6-dione (500 mg, 1.52 mmol), Pd2(dba)3 (139 mg, 0.152 mmol), Zn(CN)2 (534 mg, 4.56 mmol), and DPPF (84 mg, 0.152 mmol) in DMF (6 mL) was irradiated for 1 h at 150 °C under an argon atmosphere in a microwave-irradiated reactor. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1) to provide the title compound as a grayish-yellow solid (300 mg, 71.7% yield). MS (ESI) m / z = 274.0 [MH] - .

[0651] Step 2: Synthesis of tert-butyl carbamate ((5-(2,6-dioxopiridine-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl)methyl)carbamate

[0652]

[0653] A solution of methyl 5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-carboxynitrile (300 mg, 1.09 mmol), Raney Ni (100 mg), and Boc2O (594 mg, 2.73 mmol) in THF (20 mL) was stirred for 48 h at room temperature under a hydrogen atmosphere (15 psi). The mixture was filtered, and the filtrate was concentrated under vacuum to provide the residue, which was purified by silica gel column chromatography (petroleum ether:EtOAc = 1:1) to provide the title compound as a grayish-yellow solid (60 mg, 14.5% yield). 1 H NMR (400MHz, DMSO-d6): δ10.99(s,1H),7.86(s,1H),7.55(t,J=6.4Hz,1H),5.02(dd,J=13.2Hz,4.8Hz,1H), 4.29–4.14(m,4H),2.89–2.84(m,1H),2.73–2.57(m,1H),2.32–2.26(m,1H),2.07–1.95(m,1H),1.46(s,9H). MS(ESI)m / z=324.1[M+H] + .

[0654] Step 3: Synthesis of 3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrole-5(6H)-yl)piperidine-2,6-dione

[0655]

[0656] TFA (1.5 mL) was added to a solution of ((5-(2,6-dioxopiridine-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl)methyl)carbamate tert-butyl ester (380 mg, 1.0 mmol) in DCM (3.0 mL). After stirring the reaction mixture for 2 h at room temperature, it was concentrated to provide the crude title compound, which was used directly in the next step without further purification.

[0657] Step 4: Synthesis of (3-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)glycine tert-butyl ester

[0658]

[0659] A mixture of 3-[4-(4-quinoxaloline-2-ylpyrazole-1-yl)-1-piperidinyl]aniline (100 mg, 0.27 mmol), tert-butyl 2-bromoacetate (63 mg, 0.32 mmol), and NaHCO3 (45 mg, 0.54 mmol) in DMF (2 mL) was stirred for 12 h at 70 °C. The mixture was purified by reversed-phase column chromatography to provide the title compound (50 mg, 38.2% yield) as a yellow solid. MS (ESI) m / z = 485.6 [M+H] + .

[0660] Step 5: Synthesis of (3-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)glycine

[0661]

[0662] A mixture of 2-[3-[4-(4-quinoxalo-2-ylpyrazole-1-yl)-1-piperidinyl]anilino]tert-butyl acetate (50 mg, 0.10 mmol) and TFA (2 mL) in DCM (2 mL) was stirred for 1 h at 25 °C. The reaction was concentrated to provide the title compound as a yellow solid (30 mg, 67.9% yield). MS (ESI) m / z = 429.4 [M+H] + .

[0663] Step 6: Synthesis of N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl)methyl)-2-((3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)amino)acetamide

[0664]

[0665] To a solution of 2-[3-[4-(4-quinoxalo-2-ylpyrazol-1-yl)-1-piperidinyl]anilino]acetic acid (12 mg, 0.027 mol) in DMSO (0.5 mL), HOAt (7.3 mg, 0.054 mol), EDCI (10.3 mg, 0.054 mmol), and NMM (9.1 mg, 0.09 mol) were added. The mixture was stirred at room temperature for 2 min, followed by the addition of 3-[3-(aminomethyl)-6-oxo-4H-thieno[3,4-c]pyrrolo-5-yl]piperidin-2,6-dione (5 mg, 0.018 mmol). After stirring the reaction at 25 °C for 12 h, the mixture was purified by reversed-phase column chromatography to provide the title compound (4.7 mg, 38.1% yield). MS (ESI) m / z = 690.6 [M+H] + .

[0666] Example 46.3-(1-oxo-4-((2-((3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-088)

[0667]

[0668] Step 1: Synthesis of 3-(4-((2-((3-hydroxypropyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

[0669]

[0670] DIEA (174 mg, 1.35 mmol) was added to a stirred solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (100 mg, 0.269 mmol) and 3-aminoprop-1-ol (40.3 mg, 0.538 mmol) in DMSO (5 mL). After stirring the mixture overnight at 90 °C, it was diluted with H₂O (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The resulting residue was purified by rapid chromatography to provide the title compound as a yellow solid (760 mg, 42.4% yield).

[0671] Step 2: Synthesis of 3-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)pyrimidin-2-yl)amino)propionaldehyde

[0672]

[0673] Add 165 mg (0.39 mmol) of Des Martin periodane to a stirred solution of 3-(4-((2-((3-hydroxypropyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindololin-2-yl)piperidin-2,6-dione (80 mg, 0.195 mmol) in DMSO (5 mL) and DCM (5 mL). Stir the reaction mixture at room temperature for 1.5 h, then concentrate it and purify it by preparative HPLC to provide the title compound as a white solid (65 mg, 82.3% yield). MS (ESI) m / z = 409.4 [M+H] + .

[0674] Step 3: Synthesis of 3-(1-oxo-4-((2-((3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione

[0675]

[0676] To a stirred solution of 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (7.28 mg, 0.026 mmol) and 3-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)pyrimidin-2-yl)amino)propionaldehyde (10.0 mg, 0.026 mmol) in DCM (5 mL), MgSO4 (50 mg, 0.416 mmol) and NaBH(OAc)3 (16.5 mg, 0.078 mmol) were added. The reaction mixture was stirred at 40 °C for 3 h, followed by quenching with H2O. The mixture was extracted with DCM (20 mL × 2), washed with brine, dried over Na2SO4, and concentrated.

[0677] The resulting residue was purified by preparative HPLC, followed by preparative TLC to provide the title compound as a yellow solid (4.3 mg, 25.3% yield). MS (ESI) m / z = 672.5 [M+H] + .

[0678] Example 47. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-(4-(4-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclohexyl)acetamide (GS-089)

[0679]

[0680] GS-089 (18 mg, yield: 93.3%) was synthesized using a similar procedure to that used for GS-086. MS (ESI) m / z = 675.6 [M+H] + .

[0681] Example 48. 3-(1-oxo-4-((6-((3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)amino)pyridin-2-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-090)

[0682]

[0683] Step 1: Synthesis of 6-chloro-N-(3-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)pyridine-2-amine

[0684]

[0685] BINAP (1.9 mg, 0.003 mmol), Pd2(dba)3 (0.68 mg, 0.003 mmol), and K2CO3 (74 mg, 0.536 mmol) were added to a solution of 3-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)aniline (67.5 mg, 0.182 mmol) and 2,6-dichloropyridine (20 mg, 0.135 mmol) in 1,4-dioxane (2.0 mL). The reaction was stirred and irradiated in a microwave-irradiated reactor at 130 °C for 30 min, followed by concentration and purification by preparative TLC (EtOAc:petroleum ether = 1:1) to provide the title compound as a yellow solid (54.5 mg, 84% yield). MS (ESI) m / z = 482.4 [M+H] + .

[0686] Step 2: Synthesis of 3-(1-oxo-4-((6-((3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)amino)pyridin-2-yl)amino)isoindoline-2-yl)piperidin-2,6-dione

[0687]

[0688] Pd2(dba)3 (0.68 mg, 0.003 mmol), Xantphos (5.3 mg, 0.009 mmol), and Cs2CO3 (30 mg, 0.035 mmol) were added to a solution of 6-chloro-N-(3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)pyridine-2-amine (22 mg, 0.046 mmol) and 3-(4-amino-1-oxoisoindoline-2-yl)piperidin-2,6-dione (17.8 mg, 0.069 mmol) in 1,4-dioxane (1.0 mL). The reaction was irradiated in a microwave-irradiated reactor at 125 °C for 30 min, followed by concentration and purification by preparative TLC (DCM:MeOH = 10:1) to provide the title compound as a yellow solid (11.6 mg, 36% yield). MS(ESI)m / z = 705.5[M+H] + .

[0689] Example 49. 3-(1-oxo-4-((2-((2-oxo-2-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-091)

[0690]

[0691] GS-091 (2.1 mg, yield: 16%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 672.6 [M+H] + .

[0692] Example 50. 3-(1-oxo-4-((2-((3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopentyl)amino)pyrimidin-4-yl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-092)

[0693]

[0694] GS-092 (10 mg, yield: 12%) was synthesized using a similar procedure to that used for GS-074. MS (ESI) m / z = 698.6 [M+H] + .

[0695] Example 51.1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl)methyl)-3-(3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)urea (GS-093)

[0696]

[0697] Step 1: Synthesis of 4-nitrobenzene carbamate (3-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)carbamate

[0698]

[0699] At room temperature, 11 mg (0.054 mmol) of chloroformate was added to a stirred solution of 3-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)aniline (25 mg, 0.068 mmol) and pyridine (16 mg, 0.204 mmol) in anhydrous THF (2.5 mL). The mixture was stirred for 2 h. The mixture was then used directly in the next step without further processing. MS (ESI) m / z = 536.4 [M+H] + .

[0700] Step 2: Synthesis of 1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl)methyl)-3-(3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)urea

[0701]

[0702] To a stirred solution of 4-nitrobenzene carbamate (29 mg, 0.054 mmol) in anhydrous DMF (0.5 mL) and THF (2.5 mL), 3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrolo-5(6H)-yl)piperidin-2,6-dione (15 mg, 0.054 mmol) and Cs₂CO₃ (26 mg, 0.081 mol) were added to the mixture. The resulting mixture was stirred at 60 °C for 2 h. The mixture was purified by reversed-phase column chromatography, followed by preparative TLC (DCM:MeOH = 10:1) to provide the title compound as a white solid (6.6 mg, 18% yield). MS (ESI) m / z = 676.5 [M+H]+ .

[0703] Example 52.3-(4-((2-((3-([1,4'-piperidinindoline-1'-yl)phenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (GS-094)

[0704]

[0705] GS-094 (1.1 mg, yield: 2%) was synthesized using a similar procedure to that used for GS-075. MS (ESI) m / z = 595.5 [M+H] + .

[0706] Example 53.3-(1-oxo-6-(6-oxo-6-(4-phenylpiperidin-1-yl)hexyl)isoindoline-2-yl)piperidin-2,6-dione (GS-095)

[0707]

[0708] GS-095 (2.13 mg, yield: 30.4%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 502.5 [M+H] + .

[0709] Example 54.3 - (1-oxo-6-(7-oxo-7-(4-(pyridin-2-yl)piperazin-1-yl)heptyl)isoindoline-2-yl)piperidin-2,6-dione (GS-096)

[0710]

[0711] GS-096 (9.6 mg, yield: 69.1%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 518.6 [M+H] + .

[0712] Example 55.3 -(1-oxo-6-(7-oxo-7-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)heptyl)isoindoline-2-yl)piperidin-2,6-dione (GS-097)

[0713]

[0714] GS-097 (10 mg, yield: 58.8%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 634.7 [M+H] + .

[0715] Example 56.3 -(1-oxo-6-(7-oxo-7-(4-(4-(quinolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)heptyl)isoindoline-2-yl)piperidin-2,6-dione (GS-098)

[0716]

[0717] GS-098 (5.8 mg, yield: 25.2%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 633.6 [M+H] + .

[0718] Example 57.3-(1-oxo-6-(7-oxo-7-(4-phenylpiperidin-1-yl)heptyl)isoindoline-2-yl)piperidin-2,6-dione (GS-099)

[0719]

[0720] GS-099 (5.6 mg, yield: 37.3%) was synthesized according to the standard procedure for preparing GS-001. MS (ESI) m / z = 516.6 [M+H] + .

[0721] Example 58.2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclohexyl)ethyl)amino)isoindoline-1,3-dione (GS-100)

[0722]

[0723] Step 1: Synthesis of 2-(4-hydroxycyclohexyl)-N-(4-methoxybenzyl)acetamide

[0724]

[0725] At room temperature, HOAt (1.37 g, 10.11 mmol), EDCI (1.94 g, 10.11 mmol), and TEA (2.05 g, 20.23 mmol) were added to a solution of 2-(4-hydroxycyclohexyl)acetic acid (800 mg, 5.06 mmol) and (4-methoxyphenyl)methylamine (693.73 mg, 5.06 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction was concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 20 / 1) to provide the title compound (850 mg, 60.6% yield). MS (ESI) m / z = 278.3 [M+H] + .

[0726] Step 2: Synthesis of 4-(2-((4-methoxybenzyl)amino)ethyl)cyclohexyl-1-ol

[0727]

[0728] LAH (415.18 mg, 10.93 mmol) was added to a solution of 2-(4-hydroxycyclohexyl)-N-[(4-methoxyphenyl)methyl]acetamide (850 mg, 3.06 mmol) in THF (20 mL) at room temperature. The mixture was heated to 68 °C and stirred for 16 h. The reaction was quenched with an aqueous solution of NaOH (1 N, 0.8 mL), filtered, and concentrated to provide the crude title compound (650 mg, 80.7% yield), which was used directly in the next step. MS (ESI) m / z = 264.3 [M+H] + .

[0729] Step 3: Synthesis of tert-butyl (2-(4-hydroxycyclohexyl)ethyl)(4-methoxybenzyl)carbamate

[0730]

[0731] At room temperature, Boc₂O (810.73 mg, 3.70 mmol) and TEA (998.94 mg, 9.87 mmol) were added to a solution of 4-[2-[(4-methoxyphenyl)methylamino]ethyl]cyclohexanol (650 mg, 2.47 mmol) in THF (20 mL). After stirring the mixture at room temperature for 16 h, it was concentrated and purified by silica gel chromatography (DCM / MeOH = 20 / 1) to provide the title compound (820 mg, 91.4% yield). MS (ESI) m / z = 308.1 [M-56+H] + .

[0732] Step 4: Synthesis of 4-methylbenzenesulfonic acid 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)ethyl)cyclohexyl ester

[0733]

[0734] At room temperature, 4-methylbenzenesulfonyl chloride (559.11 mg, 2.93 mmol), DMAP (275.60 mg, 2.26 mmol), and TEA (2.28 g, 22.56 mmol) were added to a solution of (2-(4-hydroxycyclohexyl)ethyl)(4-methoxybenzyl)carbamate tert-butyl ester (820 mg, 2.26 mmol) in DCM (10 mL). After stirring the reaction at room temperature for 3 h, it was concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 10 / 1) to provide the title compound (500 mg, 42.8% yield). MS (ESI) m / z = 462.3 [M-56+H] + .

[0735] Step 5: Synthesis of tert-butyl (4-methoxybenzyl)(2-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)cyclohexyl)ethyl)carbamate

[0736]

[0737] At room temperature, NaH (55.63 mg, 1.39 mmol, 60% purity) was added to a solution of 2-(1H-pyrazol-4-yl)quinoxaline (136.45 mg, 695.42 μmol) in DMF (20 mL). After stirring the mixture at room temperature for 0.5 h, NaI (104.24 mg, 695.42 μmol) and 4-methylbenzenesulfonic acid [4-[2-[tert-butoxycarbonyl-[(4-methoxyphenyl)methyl]amino]ethyl]cyclohexyl] ester (360 mg, 695.42 μmol) were added. After heating the reaction mixture to 80 °C and stirring for 16 h, it was quenched with aqueous NH4Cl solution, extracted with DCM, and concentrated. The resulting residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3 / 1 to 1 / 1) to provide the title compound (130 mg, 34.5% yield). MS(ESI)m / z = 542.5[M+H] + .

[0738] Step 6: Synthesis of N-(4-methoxybenzyl)-2-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)cyclohexyl)ethyl-1-amine

[0739]

[0740] At room temperature, HCl / dioxane (1 M, 4 mL) was added to a solution of N-[(4-methoxyphenyl)methyl]-N-[2-[4-(4-quinoxaloline-2-ylpyrazol-1-yl)cyclohexyl]ethyl]carbamate tert-butyl ester (130 mg, 239.99 μmol) in DCM (10 mL). After stirring the mixture at room temperature for 2 h, it was concentrated to provide the title compound (115 mg, 99% yield), which was used directly in the next step. MS (ESI) m / z = 442.5 [M+H] + .

[0741] Step 7: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((4-methoxybenzyl)(2-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)cyclohexyl)ethyl)amino)isoindoline-1,3-dione

[0742]

[0743] DIPEA (186.55 mg, 1.44 mmol) was added to a solution of N-[(4-methoxyphenyl)methyl]-2-[4-(4-quinoxaloline-2-ylpyrazol-1-yl)cyclohexyl]ethylamine (115 mg, 240.57 μmol) and 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione (66.45 mg, 240.57 μmol) in DMSO (10 mL) at room temperature. After heating the mixture to 120 °C and stirring for 16 h, it was purified by preparative HPLC to provide the crude product, which was further purified by preparative TLC (DCM / MeOH = 10 / 1) to provide the title compound (12 mg, 7.2% yield). MS (ESI) m / z = 698.6 [M+H] + .

[0744] Step 8: Synthesis of 2-(2,6-dioxadiazin-3-yl)-5-((2-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)cyclohexyl)ethyl)amino)isoindoline-1,3-dione

[0745]

[0746] TFA (2 mL) was added to a solution of 2-(2,6-dioxo-3-piperidinyl)-5-[(4-methoxyphenyl)methyl-[2-[4-(4-quinoxalin-2-ylpyrazol-1-yl)cyclohexyl]ethyl]amino]isoindoline-1,3-dione (12 mg, 17.20 μmol) in DCM (2 mL) at room temperature. After stirring the mixture for 0.5 h at room temperature, it was concentrated and purified by preparative TLC (DCM / MeOH = 10 / 1) to provide the title compound as a yellow solid (4.2 mg, 42.3% yield). MS (ESI) m / z = 578.5 [M+H] + .

[0747] Example 59.3 -(1-oxo-6-(6-oxo-6-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)hexyl)isoindoline-2-yl)piperidin-2,6-dione (GS-101)

[0748]

[0749] GS-101 (13.3 mg, yield: 77.2%) was synthesized using a similar procedure to that used for GS-001. MS (ESI) m / z = 620.7 [M+H] + .

[0750] Example 60.3-(1-oxo-6-(6-oxo-6-(4-(4-(quinolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)hexyl)isoindoline-2-yl)piperidin-2,6-dione (GS-102)

[0751]

[0752] GS-102 (13 mg, yield: 75.1%) was synthesized using a similar procedure to that used for GS-001. MS (ESI) m / z = 619.8 [M+H] + .

[0753] Example 61.3 - (1-oxo-6-(6-oxo-6-(4-(pyridin-2-yl)piperazin-1-yl)hexyl)isoindoline-2-yl)piperidin-2,6-dione (GS-103)

[0754]

[0755] GS-103 (5.21 mg, yield: 46.4%) was synthesized using a similar procedure to that used for GS-001. MS (ESI) m / z = 504.6 [M+H] + .

[0756] Example 62.3 - (1-oxo-6-(6-oxo-6-(4-(pyridin-2-yl)piperidin-1-yl)hexyl)isoindoline-2-yl)piperidin-2,6-dione (GS-104)

[0757]

[0758] GS-104 (6.64 mg, yield: 59.2%) was synthesized using a similar procedure to that used for GS-001. MS (ESI) m / z = 503.5 [M+H] + .

[0759] Example 63.3-(1-oxo-6-(7-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)heptyl)isoindololin-2-yl)piperidin-2,6-dione (GS-105)

[0760]

[0761] A mixture of 7-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)heptyl 4-methylbenzenesulfonic acid (10.0 mg, 0.02 mmol), 2-(1H-pyrazol-4-yl)quinoxaline (synthesized via a similar procedure to step 1 of CG-563, 5.47 mg, 0.02 mmol), Cs₂CO₃ (12.67 mg, 0.035 mmol), and NaI (2.93 mg, 0.020 mmol) in DMF (0.2 mL) was stirred for 3 h at 85 °C. The mixture was then purified by C18 column chromatography to provide the title compound as a white solid (9.8 mg, 91.2% yield). MS (ESI) m / z = 537.5 [M+H] + .

[0762] Example 64. 3-(1-oxo-6-(6-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)hexyl)isoindololin-2-yl)piperidine-2,6-dione (GS-106)

[0763]

[0764] GS-106 (8.2 mg, yield: 78.4%) was synthesized using a similar procedure to that used for GS-105. MS (ESI) m / z = 523.5 [M+H] + .

[0765] Example 65. 2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione (GS-107)

[0766]

[0767] Step 1: Synthesis of methyl 3-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate

[0768]

[0769] A mixture of methyl 3-(toluenesulfonyloxy)cyclobutane-1-carboxylate (28.98 mg, 0.102 mmol), 2-(1H-pyrazol-4-yl)quinoxaline (10.0 mg, 0.051 mmol), Cs₂CO₃ (49.73 mg, 0.153 mmol), and NaI (11.48 mg, 0.077 mmol) in DMF (1 mL) was stirred for 3 h at 85 °C. The mixture was then purified by C18 column chromatography to provide the title compound as a white solid (8 mg, 51% yield). MS (ESI) m / z = 309.3 [M+H] + .

[0770] Step 2: Synthesis of (3-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)cyclobutyl)methanol

[0771]

[0772] At 0 °C, methyl 3-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (10 mg, 0.025 mmol) in THF (1 mL) was added dropwise to a mixture of LiAlH4 (9.48 mg, 0.25 mmol) in THF (1 mL). After stirring the mixture at 0 °C for 1 h, H2O (0.01 mL), 15% NaOH aqueous solution (0.01 mL), and H2O (0.01 mL) were added to the mixture. The precipitate was filtered off. The filtrate was concentrated. The resulting residue was dissolved in THF (2 mL). MnO2 (10 mg) was added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was filtered, and the filtrate was concentrated to provide the title compound as a white solid (10 mg, yield: 99.9%). MS (ESI) m / z = 281.1 [M+H] + .

[0773] Step 3: Synthesis of 3-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxaldehyde

[0774]

[0775] At 0 °C, 1,1,1-tris(acetyloxy)-1H-pyrazol-1-yl)cyclobutyl)ethanol (10 mg, 0.036 mmol) in anhydrous dichloromethane (1 mL) was added to a solution of 3-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)-3-(1H)-one (30.54 mg, 0.072 mmol). The reaction was stirred for 3 h at room temperature under nitrogen, followed by dilution with DCM, washing with brine, drying over Na2SO4, filtration, and concentration. The resulting residue was purified by preparative TLC to provide the title compound (8 mg, yield: 79.9%). MS (ESI) m / z = 279.1 [M+H] + .

[0776] Step 4: Synthesis of (E)-3-(3-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acrylonitrile

[0777]

[0778] At 0 °C, 3-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxaldehyde (10 mg, 0.036 mmol) was added to a solution of (cyanomethyl)triphenylphosphonium chloride (12.15 mg, 0.036 mmol) and NaOH (12 mg, 0.3 mmol) in water (0.1 mL) and DCM (0.3 mL). The mixture was stirred at room temperature for 4 h. The mixture was diluted with DCM (5 mL) and water (5 mL). The organic phase was washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by rapid chromatography to provide the title compound as a white solid (6 mg, 55.5% yield). MS (ESI) m / z = 302.1 [M+H] + .

[0779] Step 5: Synthesis of 3-(3-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)cyclobutyl)propyl-1-amine

[0780]

[0781] Ammonia (0.1 mL) and Raney Ni (6 mg) were added to a solution of (E)-3-(3-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acrylonitrile (6 mg, 0.02 mmol) in MeOH (0.5 mL). The reaction mixture was purged with hydrogen and shaken for 6 h at room temperature under a hydrogen atmosphere (45 psi) using a standard hydrogenation apparatus. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was dissolved in THF (2 mL), followed by the addition of MnO2 (6 mg). The mixture was stirred for 10 min at room temperature and then filtered. The filtrate was concentrated to provide the title compound as a white solid (6 mg, yield: 99.9%). MS (ESI) m / z = 308.2 [M+H] + .

[0782] Step 6: Synthesis of 2-(2,6-dioxadiazin-3-yl)-5-((3-(3-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione

[0783]

[0784] To a solution of 3-(3-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)propyl-1-amine (6 mg, 0.02 mmol) in DMSO (0.5 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (5.52 mg, 0.02 mmol) and DIEA (0.1 mL) were added. After stirring at 100 °C for 5 h, the mixture was purified by preparative HPLC to provide the title compound as a yellow solid (1.2 mg, yield: 10.7%). (ESI) m / z = 564.4 [M+H] + .

[0785] Example 66. 3-(1-oxo-4-((4-((4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)benzyl)oxy)isoindoline-2-yl)piperidin-2,6-dione (GS-108)

[0786]

[0787] Step 1: Synthesis of (4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)methanol

[0788]

[0789] At 0 °C, imidazole (13.6 g, 199.76 mmol) was added to a solution of 1,4-benzyldiethanol (13.8 g, 99.88 mmol) in DCM (400 mL), followed by the addition of TBSCl (15.05 g, 99.88 mmol). The resulting mixture was stirred for 16 h at room temperature, then concentrated, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 10:1 to 5:1) to provide the desired product (15 g, yield: 59%) as a colorless oil.

[0790] Step 2: Synthesis of ((4-(bromomethyl)benzyl)oxy)(tert-butyl)dimethylsilane

[0791]

[0792] At 0 °C, CBr4 (496 mg, 1.5 mmol) and PPh3 (392 mg, 1.5 mmol) were added to a solution of (252 mg, 1 mmol) tert-butyldimethylsilyl)oxy)methyl)phenyl)methanol in DCM (10 mL). The resulting mixture was stirred at room temperature for 4 h, then concentrated and the resulting residue was purified by preparative TLC to provide the desired product (240 mg, yield: 76%) as a white solid.

[0793] Step 3: Synthesis of 3-(4-((4-(hydroxymethyl)benzyl)oxy)-1-oxoisoindololin-2-yl)piperidine-2,6-dione

[0794]

[0795] K₂CO₃ (674 mg, 4.88 mmol) was added to a solution of ((4-(bromomethyl)benzyl)oxy)(tert-butyl)dimethylsilane (770 mg, 2.44 mmol) and 3-(4-hydroxy-1-oxoisoindoline-2-yl)piperidin-2,6-dione (635 mg, 2.44 mmol) in DMF (10 mL). The resulting mixture was stirred at 40 °C for 16 h, followed by the addition of TBAF (2.55 g, 9.77 mmol). The reaction mixture was purified by preparative HPLC to provide the desired product as a white solid (450 mg, yield: 48%). MS (ESI) m / z = 381.3 [M+H] + .

[0796] Step 4: Synthesis of 4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)benzyl methanesulfonate

[0797]

[0798] MsCl (15 mg, 0.132 mmol) was added to a solution of 3-(4-((4-(hydroxymethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (25 mg, 0.066 mmol) and TEA (13 mg, 0.132 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2 h, and then concentrated to provide a crude product, which was used directly in the next step without further purification.

[0799] Step 5: 3-(1-oxo-4-((4-((4-(4-((quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)benzyl)oxy)isoindoline-2-yl)piperidin-2,6-dione

[0800]

[0801] A mixture of methyl methanesulfonic acid [4-[[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]oxymethyl]phenyl]methyl ester (30 mg, 0.064 mmol), DIEA (25 mg, 0.19 mmol), NaI (19 mg, 0.13 mmol), and 2-[1-(4-piperidinyl)pyrazol-4-yl]quinoxaline (18 mg, 0.064 mmol) in CH3CN (3 mL) was stirred for 12 h at 70 °C. The mixture was purified by reversed-phase column chromatography to provide the title compound (19 mg, 46% yield) as a yellow solid. MS (ESI) m / z = 642.6 [M+H] + .

[0802] Example 67. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-(2-(4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclopropyl)acetamide (GS-109)

[0803]

[0804] Step 1: Synthesis of 2-(1-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropyl)-1H-pyrazol-4-yl)quinoxaline

[0805]

[0806] Add Cu(OAc)₂ (369.00 mg, 2.04 mmol), Cs₂CO₃ (662.56 mg, 2.04 mmol), and bipyridine (318.40 mg, 2.04 mmol) to a solution of 2-(1H-pyrazol-4-yl)quinoxaline (200 mg, 1.02 mmol) and [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]cyclopropyl]boronic acid (497.86 mg, 2.04 mmol) in DMF (15 mL) to a solution of 2-(1H-pyrazol-4-yl)quinoxaline (200 mg, 1.02 mmol), [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]cyclopropyl]boronic acid (497.86 mg, 2.04 mmol), [3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]cyclopropyl]boronic acid (497.86 mg, 2.04 mmol), [4 ... Molecular sieve (100 mg). The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction was purified by preparative HPLC to provide the title compound (150 mg, 37.3% yield). MS (ESI) m / z = 395.5 [M+H] + .

[0807] Step 2: Synthesis of N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-(2-(4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclopropyl)acetamide

[0808]

[0809] GS-109 (15 mg, yield: 19.1%) was synthesized using a similar procedure to that used for GS-083. MS (ESI) m / z = 550.5 [M+H] + .

[0810] Example 68.3-(1-oxo-4-((3-((3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)amino)cyclohexyl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-110)

[0811]

[0812] Step 1: Synthesis of 3-((3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)amino)cyclohexane-1-one

[0813]

[0814] A mixture of 3-[4-(4-quinoxalo-2-ylpyrazol-1-yl)-1-piperidinyl]aniline (350 mg, 0.94 mmol) and cyclohexyl-2-en-1-one (118 mg, 1.23 mmol) in THF (0.5 mL) was stirred for 18 min at room temperature. The resulting mixture was purified by preparative HPLC to provide the title compound as a yellow solid (135 mg, 30.6% yield). MS (ESI) m / z = 467.5 [M+H] + .

[0815] Step 2: Synthesis of 3-(1-oxo-4-((3-((3-(4-(4-(1,2,3,4-tetrahydroquinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)amino)cyclohexyl)amino)isoindoline-2-yl)piperidin-2,6-dione

[0816]

[0817] A mixture of 3-[3-[4-(4-quinoxalo-2-ylpyrazol-1-yl)-1-piperidinyl]anilino]cyclohexanone (103 mg, 0.22 mmol) and 3-(4-amino-1-oxo-isoindoline-2-yl)piperidin-2,6-dione (86 mg, 0.33 mmol) in DMF (4 mL) was stirred for 2 min at 0 °C, followed by the addition of TMSCl (72 mg, 0.66 mmol). The reaction was stirred at 0 °C for 40 min, at which point NaBH4 (12.5 mg, 0.33 mmol) was added, and the reaction was stirred for another 12 h. The mixture was purified by reversed-phase chromatography to provide the title compound (40 mg, 25.4% yield). MS (ESI) m / z = 714.6 [M+H] + .

[0818] Step 3: Synthesis of 3-(1-oxo-4-((3-((3-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)amino)cyclohexyl)amino)isoindoline-2-yl)piperidin-2,6-dione

[0819]

[0820] A mixture of 3-[1-oxo-4-[[3-[3-[4-[4-(1,2,3,4-tetrahydroquinoxolin-2-yl)pyrazol-1-yl]-1-piperidinyl]aniline]cyclohexyl]amino]isoindoline-2-yl]piperidin-2,6-dione (40 mg, 0.056 mmol) and MnO2 (48.75 mg, 0.56 mmol) in THF (5 mL) was stirred for 10 min at 25 °C. MnO2 was removed by filtration, and the filtrate was purified by reversed-phase chromatography, followed by preparative TLC (MeOH / DCM = 1:13) to provide the title compound as a pale yellow solid (4.7 mg, 11.8% yield). MS (ESI) m / z = 710.7 [M+H] + .

[0821] Example 69.3-(1-oxo-6-(7-oxo-7-(4-(pyridin-2-yl)piperidin-1-yl)heptyl)isoindoline-2-yl)piperidin-2,6-dione (GS-111)

[0822]

[0823] GS-111 (9.6 mg, yield: 30.1%) was synthesized using a similar procedure to that used for GS-001. MS (ESI) m / z = 517.7 [M+H] + .

[0824] Example 70.2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)cyclohexyl)propyl)amino)isoindoline-1,3-dione (GS-112)

[0825]

[0826] GS-112 (5.2 mg, yield: 14.7%) was synthesized using a similar procedure to that used for GS-107. MS (ESI) m / z = 592.5 [M+H] + .

[0827] Example 71.3-(6-(6-(4-(3-chlorophenyl)piperidin-1-yl)-6-oxohexyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (GS-113)

[0828]

[0829] GS-113 (15 mg, yield: 27.3%) was synthesized using a similar procedure to that used to prepare GS-001. MS (ESI) m / z = 536.4 [M+H] + .

[0830] Example 72.3-(6-(6-(4-(4-chlorophenyl)piperidin-1-yl)-6-oxohexyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (GS-114)

[0831]

[0832] GS-114 (16 mg, yield: 29.2%) was synthesized using a similar procedure to that used to prepare GS-001. MS (ESI) m / z = 536.4 [M+H] + .

[0833] Example 73.3-(6-(7-(4-(3-chlorophenyl)piperidin-1-yl)-7-oxohepyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (GS-115)

[0834]

[0835] GS-115 (20.68 mg, yield: 69.9%) was synthesized using a similar procedure to that used for GS-001. MS (ESI) m / z = 550.5 [M+H] + .

[0836] Example 74.3-(6-(7-(4-(4-chlorophenyl)piperidin-1-yl)-7-oxohepyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (GS-116)

[0837]

[0838] GS-116 (24.34 mg, yield: 82.3%) was synthesized using a similar procedure to that used for GS-001. MS (ESI) m / z = 550.5 [M+H] + .

[0839] Example 75.2-(2,6-dioxopiperidin-3-yl)-5-((4-(4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)phenethyl)amino)isoindoline-1,3-dione (GS-117)

[0840]

[0841] GS-117 (1.6 mg, yield: 5.1%) was synthesized using a similar procedure to that used for GS-100. MS (ESI) m / z = 572.3 [M+H] + .

[0842] Example 76.2-(2,6-dioxopiperidin-3-yl)-5-((2-(((2-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)cyclopropyl)methyl)amino)ethyl)amino)isoindoline-1,3-dione (GS-118)

[0843]

[0844] To a mixture of 5-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (11.2 mg, 35.42 μmol), acetic acid (1 drop), and 2-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)cyclopropane-1-carboxaldehyde (7.8 mg, 29.51 μmol) in a DCE (0.5 mL), NaBH3CN (4.6 mg, 73.78 μmol) was added. The reaction mixture was stirred at room temperature for 12 h. Then, 2-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)cyclopropane-1-carboxaldehyde (7.8 mg, 29.51 μmol) and NaBH3CN (4.6 mg, 73.78 μmol) were added to the reaction mixture, and it was stirred again at room temperature for 12 h. The reaction mixture was diluted with brine and extracted with DCM. The organic layer was concentrated, and the resulting residue was purified by preparative TLC (DCM / MeOH = 12:1) and preparative HPLC (C18, 0.1% TFA in acetonitrile) to provide the title compound as a white solid (1.49 mg, 8.9% yield). MS (ESI) m / z = 565.4 [M+H] + .

[0845] Example 77.3-(1-oxo-4-((3-((2-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)pyrimidin-4-yl)amino)cyclohexyl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-119)

[0846]

[0847] Step 1: Synthesis of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)cyclohexyl)carbamate

[0848]

[0849] At 0 °C, TMSCl (648.00 mg, 6.00 mmol) was added to a solution of N-(3-oxocyclohexyl)carbamate tert-butyl ester (960 mg, 4.50 mmol) and 3-(4-amino-1-oxoisoindolin-2-yl)piperidin-2,6-dione (777.78 mg, 3.00 mmol) in 10 mL of DMF. After the addition was complete, the reaction mixture was stirred at 0 °C for 0.5 h, followed by the addition of NaBH4 (171.00 mg, 4.50 mmol). The resulting mixture was stirred at 0 °C for 3 h, then heated to room temperature and stirred for 16 h. The reaction was purified by preparative HPLC to provide the title compound (1.3 g, 94.9% yield) as a white solid. MS (ESI) m / z = 401.3 [M-56+H] + .

[0850] Step 2: Synthesis of 3-(4-((3-aminocyclohexyl)amino)-1-oxoisoindololin-2-yl)piperidine-2,6-dione

[0851]

[0852] To a solution of N-[3-[[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-4-yl]amino]cyclohexyl]tert-butyl carbamate (1.3 g, 2.85 mmol) in DCM (20 mL), HCl / dioxane (1 M, 20 mL) was added. After the addition was complete, the reaction mixture was stirred for 2 h at room temperature. The reaction was concentrated to provide the title compound as a white solid (1.1 g, 98.3% yield). MS (ESI) m / z = 357.2 [M+H] + .

[0853] Step 3: Synthesis of 3-(4-((3-((2-chloropyrimidin-4-yl)amino)cyclohexyl)amino)-1-oxoisoindololin-2-yl)piperidine-2,6-dione

[0854]

[0855] DIPEA (657.91 mg, 5.09 mmol) was added to a solution of 3-[4-[(3-aminocyclohexyl)amino]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (200 mg, 509.06 μmol) and 2,4-dichloropyrimidine (151.68 mg, 1.02 mmol) in DMF (5 mL) at room temperature. After heating the mixture to 80 °C and stirring for 16 h, it was concentrated and purified by silica gel chromatography (DCM / MeOH = 30 / 1 to 20 / 1) to provide the title compound (200 mg, 83.8% yield). MS (ESI) m / z = 469.3 [M+H] + .

[0856] Step 4: Synthesis of 3-(1-oxo-4-((3-((2-(4-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)pyrimidin-4-yl)amino)cyclohexyl)amino)isoindoline-2-yl)piperidin-2,6-dione

[0857]

[0858] DIPEA (77.73 mg, 601.42 μmol) was added to a solution of 2-[1-(4-piperidinyl)pyrazol-4-yl]quinoxaline (28 mg, 100.24 μmol) and 3-[4-[[3-[(2-chloropyrimidin-4-yl)amino]cyclohexyl]amino]-1-oxo-isoindoline-2-yl]piperidin-2,6-dione (47.00 mg, 100.24 μmol) in DMSO (5 mL) at room temperature. After heating the mixture to 100 °C and stirring for 16 h, it was purified by preparative HPLC and preparative TLC (DCM / MeOH = 10 / 1) to provide the title compound (45 mg, 63.1% yield). MS (ESI) m / z = 712.7 [M+H] + .

[0859] Example 78. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-3-(4-(4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-carbonyl)bicyclo[1.1.1]pentane-1-carboxamide (GS-120)

[0860]

[0861] GS-120 (14 mg, yield: 44%) was synthesized using a similar procedure to that used for GS-004. MS (ESI) m / z = 673.6 [M+H] + .

[0862] Example 79. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-(3-(4-(4-(quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)acetamide (GS-121)

[0863]

[0864] GS-121 (4.7 mg, yield: 36.7%) was synthesized using a similar procedure to that used for GS-001. MS (ESI) m / z = 687.6 [M+H] + .

[0865] Example 80. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-(4-(4-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)acetamide (GS-122)

[0866]

[0867] GS-122 (2.2 mg, yield: 45.3%) was synthesized using a similar procedure to that used for GS-001. MS (ESI) m / z = 669.5 [M+H] + .

[0868] Example 81.2-(2,6-dioxopiperidin-3-yl)-5-((5-(1-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)pentyl)amino)isoindoline-1,3-dione (GS-123)

[0869]

[0870] Step 1: Synthesis of tert-butyl (6-oxo-6-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)hexyl)carbamate

[0871]

[0872] A mixture of 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (250 mg, 0.90 mmol), 6-((tert-butoxycarbonyl)amino)hexanoic acid (207.25 mg, 0.90 mmol), HOAt (182.25 mg, 1.35 mmol), EDCI (259.2 mg, 1.35 mmol), and 4-methylmorpholine (272.2 mg, 2.7 mmol) in DMSO (5 mL) was stirred for 12 h at room temperature. The mixture was then purified by rapid silica C18 chromatography to provide the title compound (400 mg, yield: 90.3%) as a yellow solid. MS (ESI) m / z = 493.5 [M+H] + .

[0873] Step 2: Synthesis of tert-butyl carbamate (5-(1-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)pentyl)carbamate

[0874]

[0875] Under a nitrogen atmosphere, tert-butyl (6-oxo-6-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)hexyl)carbamate (30 mg, 0.062 mmol) was dissolved in THF (2 mL), followed by the addition of tetraisopropyl titanate (52.8 mg, 0.186 mmol), and then a 3.4 M solution of ethyl magnesium bromide in THF (0.1 mL, 0.31 mmol). The reaction was monitored by TLC, and after completion, it was quenched with saturated NH4Cl aqueous solution and filtered. The filter cake was washed with ethyl acetate (10 mL x 2), and the combined organic layers were washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by preparative TLC to provide the title compound as a white solid (12 mg, 38.4% yield). MS (ESI) m / z = 505.3 [M + H] + .

[0876] Step 3: Synthesis of 5-(1-(4-(4-(quinoxalo-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)pentane-1-amine

[0877]

[0878] TFA (1 mL) was added to a solution of (5-(1-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)pentyl)tert-butyl carbamate (50 mg, 0.099 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 1 h, and then concentrated to provide the title compound (43 mg, yield: 99.9%) as a brown oil, which was used directly in the next step without further purification. MS (ESI) m / z = 405.3 [M+H] + .

[0879] Step 4: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((5-(1-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)pentyl)amino)isoindoline-1,3-dione

[0880]

[0881] A mixture of 5-(1-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)pentan-1-amine (21 mg, 0.05 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (15 mg, 0.057 mmol), and KF (58.1 mg, 1 mmol) in DMSO (0.5 mL) was heated for 30 min under microwave at 130 °C. The mixture was then filtered, and the filtrate was purified by rapid silica C18 chromatography to provide the title compound as a yellow solid (8.9 mg, yield: 26.9%). MS (ESI) m / z = 661.6 [M+H] + .

[0882] Example 82.2-(2,6-dioxopiperidin-3-yl)-5-((4-(1-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)butyl)amino)isoindoline-1,3-dione (GS-124)

[0883]

[0884] GS-124 (3.9 mg, yield: 23.2%) was synthesized using a similar procedure to that used for GS-123. MS (ESI) m / z = 647.7 [M+H] + .

[0885] Example 83.3-(1-oxo-4-((3-((4-(4-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-125)

[0886]

[0887] Step 1: Synthesis of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)cyclohexyl)carbamate

[0888]

[0889] At 0 °C, TMSCl (648 mg, 6.0 mmol) was added to a solution of N-(3-oxocyclohexyl)carbamate tert-butyl ester (960 mg, 4.50 mmol) and 3-(4-amino-1-oxo-isoindoline-2-yl)piperidin-2,6-dione (777.78 mg, 3.0 mmol) in DMF (10 mL). After the addition was complete, the reaction mixture was stirred at 0 °C for 0.5 h, at which point NaBH4 (171 mg, 4.5 mmol) was added. The mixture was stirred at 0 °C for another 3 h, then heated to room temperature and stirred for 16 h. The reaction mixture was purified by preparative HPLC to provide the title compound as a white solid (1.3 g, 94.9% yield). MS (ESI) m / z = 401.3 [M-56+H] + .

[0890] Step 2: Synthesis of 3-(4-((3-aminocyclohexyl)amino)-1-oxoisoindololin-2-yl)piperidine-2,6-dione

[0891]

[0892] To a solution of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)cyclohexyl)carbamate (1.3 g, 2.85 mmol) in DCM (20 mL), HCl / dioxane (1 M, 20 mL) was added. After stirring the reaction mixture for 2 h at room temperature, it was concentrated to provide the title compound as a white solid (1.1 g, 2.80 mmol, 98.3% yield). MS (ESI) m / z = 357.2 [M+H] + .

[0893] Step 3: Synthesis of 3-(4-((3-((2-chloropyrimidin-4-yl)amino)cyclohexyl)amino)-1-oxoisoindololin-2-yl)piperidine-2,6-dione

[0894]

[0895] DIPEA (657.91 mg, 5.09 mmol) was added to a solution of 3-(4-((3-aminocyclohexyl)amino)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (200 mg, 509.06 μmol) and 2,4-dichloropyrimidine (151.68 mg, 1.02 mmol) in DMF (5 mL) at room temperature. After heating the mixture to 80 °C and stirring for 16 h, it was concentrated and purified by silica gel chromatography (DCM / MeOH = 30 / 1 to 20 / 1) to provide the title compound (200 mg, 83.8% yield). MS (ESI) m / z = 469.3 [M+H] + .

[0896] Step 4: Synthesis of 3-(1-oxo-4-((3-((4-(4-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)isoindoline-2-yl)piperidin-2,6-dione

[0897]

[0898] DIPEA (77.73 mg, 601.42 μmol) was added to a solution of 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (28 mg, 100.24 μmol) and 3-(4-((3-(((2-chloropyrimidin-4-yl)amino)cyclohexyl)amino)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (47 mg, 100.24 μmol) in DMSO (5 mL) at room temperature. After heating the mixture to 100 °C and stirring for 16 h, it was purified by preparative HPLC and preparative TLC (DCM / MeOH = 10 / 1) to provide the title compound (45 mg, 63.1% yield). MS (ESI) m / z = 712.7 [M+H] + .

[0899] Example 84. 3-(1-oxo-5-((5-(1-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)pentyl)amino)isoindoline-2-yl)piperidin-2,6-dione (GS-126)

[0900]

[0901] Add 5-(1-(4-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)pentan-1-amine (56 mg, 0.14 mmol), Cu(OAc)2 (14.62 mg, 0.08 mmol), TEA (0.1 mL) to a solution of (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)boronic acid (20 mg, 0.07 mmol) in DCM (0.4 mL) and DMF (0.1 mL). Molecular sieve (20 mg). The mixture was stirred for 16 h at room temperature under oxygen. After the reaction was complete, the solid was filtered. The filtrate was concentrated under vacuum and the resulting residue was purified by reversed-phase FC to provide the title compound as a white solid (6.2 mg, yield: 13.7%). MS (ESI) m / z = 647.5 [M+H] + .

[0902] Example 85.3 -(1-oxo-6-(7-(4-(quinoxolin-2-yl)-1H-pyrazol-1-yl)octyl)isoindololin-2-yl)piperidine-2,6-dione (GS-127)

[0903]

[0904] Step 1: Synthesis of 3-(6-(7-hydroxyoct-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

[0905]

[0906] A mixture of 3-(6-bromo-1-oxoisoindoline-2-yl)piperidin-2,6-dione (409 mg, 1.22 mmol), Pd(dppf)Cl2 (89.18 mg, 0.122 mmol), oct-7-yn-2-ol (230 mg, 1.83 mmol), TEA (1.23 g, 12.2 mmol), and CuI (23.24 mg, 0.122 mmol) in DMSO (5 mL) was stirred for 16 h at 80 °C. The reaction mixture was purified by reversed-phase chromatography to provide the title compound (300 mg, 66.8% yield) as a yellow solid. MS (ESI) m / z = 369.3 [M+H] + .

[0907] Step 2: Synthesis of 3-(6-(7-hydroxyoctyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

[0908]

[0909] Pd / C (35 mg) was added to a solution of 3-(6-(7-hydroxyoct-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (350 mg, 0.95 mmol) in MeOH (20 mL). After stirring at room temperature for 16 h, the reaction mixture was purified by reversed-phase chromatography to provide the title compoun...

Claims

1. A compound comprising structural formula 1 or a pharmaceutically acceptable salt thereof: Formula 1 in, R 1 It does not exist; R 2 It is hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, 3-10-membered carbon cycloyl or 3-10-membered heterocyclic, wherein the 3-10-membered heterocyclic is optionally substituted with C1-C4 alkyl. X does not exist; The connector is the connecting part that attaches the degradation label to ring B, wherein the connecting part has a structure of Formula 9: Formula 9, in, A L W L and B L Each time it appears, it is either absent independently or selected from the following divalent moieties: C1-C8 alkylene groups, 3-10 cyclic carbon groups, and 3-10 heterocyclic carbon groups; and m L =1; The degradation label has the following structure: Ring B is the part that contains structural formula B-2: Formula B-2; in, R 12 It is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl, 3-6 membered carbon cycloyl group; * indicates a connection to the connector portion; and ** indicates a connection to X and / or ring A; and Ring A is the part that includes structural formula A-5: Formula A-5 in, X 1 It is CR 10 Or N; X 3 It is N; R 10 It is hydrogen; and R 11 It is a 3- to 10-membered heterocyclic group consisting of hydrogen, halogen, C1-C4 alkyl, or optionally substituted with methyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 12 It is hydrogen, CH3, CF3, CF2, cyclopropyl, cyclobutyl, or cyclopentyl.

3. The compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein the connector comprises structural formula 9: Formula 9 in, A L It is a 3-10 member carbon cyclo group; W L and B L Each time it appears, it is either absent independently or selected from the following divalent moieties: C1-C8 alkylene groups; and m L It is 1.

4. The compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein the linker is –(3-10-membered carbocyclic)-(C1-C8 alkylene)- or –(3-10-membered heterocyclic)-(C1-C8 alkylene)-.

5. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: 5-(((trans-3-(3-cyclopropyl-4-(6-morpholinoquinoxaline-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-066), 3-(1-oxo-6-(7-(4-(quinoxalo-2-yl)-1 H -pyrazol-1-yl)heptyl)isoindololin-2-yl)piperidin-2,6-dione (GS-105) 2-(2,6-dioxopiperidin-3-yl)-5-((3-(trans-3-(3-methyl-4-(quinoxalo-2-yl)-1) H -pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione (GS-171), 2-(2,6-dioxadiazin-3-yl)-5-((3-(3-(4-(7-morpholinoquinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione (GS-173), 2-(2,6-dioxopiperidin-3-yl)-5-((3-(trans-3-(4-(7-(tetrahydro-2-yl)) H -pyran-4-yl)quinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione (GS-181), 2-(2,6-dioxopiperidin-3-yl)-5-((3-(cis-3-(4-(7-(tetrahydro-2-yl)) H -pyran-4-yl)quinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione (GS-182), 2-(2,6-dioxopiperidin-3-yl)-5-((3-(cis-3-(4-(7-(tetrahydro-2-yl)) H -pyran-4-yl)quinoxalin-2-yl)-3-(trifluoromethyl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione (GS-210), 5-((3-(cis-3-(3-cyclopropyl-4-(7-(tetrahydro-2-) H -pyran-4-yl)quinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-213), 2-(2,6-dioxopiperidin-3-yl)-5-((3-(cis-3-(3-methyl-4-(7-morpholinoquinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione (GS-221), 2-(2,6-dioxopiperidin-3-yl)-5-((3-(cis-3-(3-methyl-4-(7-(tetrahydro-2-yl)) H -pyran-4-yl)quinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione (GS-223), 5-((3-(cis-3-(3-cyclopropyl-4-(7-morpholinoquinoxaline-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-227), 5-((3-(trans-3-(3-(difluoromethyl)-4-(quinoxalo-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-243), 5-(((trans-3-(3-cyclopropyl-4-(5-morpholinoquinoxaline-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-266). 5-(((trans-3-(3-cyclopropyl-4-(5-(4-methylpiperazin-1-yl)quinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-267). 5-(((trans-3-(3-cyclopropyl-4-(6-(4-methylpiperazin-1-yl)quinoxalin-2-yl)-1 H (-pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-314) 5-((6-(4-(8-bromoquinoxalo-2-yl)-1 H -pyrazol-1-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-315), 2-(2,6-dioxadiazine-3-yl)-5-((6-(4-(quinoxalin-2-yl)-1 H -pyrazol-1-yl)hexyl)amino)isoindoline-1,3-dione (GS-339), 2-(2,6-dioxopiperidin-3-yl)-5-((3-(trans-3-(3-methyl-4-(7-morpholinoquinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione (GS-399). 2-(2,6-dioxadiazin-3-yl)-5-((3-(trans-3-(3-methyl-4-(5-(1-methylpiperidin-4-yl)quinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione (GS-418), 2-(2,6-dioxopiperidin-3-yl)-5-((3-(trans-3-(4-(5-(piperidin-4-yl)quinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione (GS-431), 2-(2,6-dioxopiperidin-3-yl)-5-((3-(cis-3-(3-methyl-4-(6-(piperazin-1-yl)quinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione (GS-434) 5-(((trans-3-(3-cyclopropyl-4-(7-morpholinoquinoxaline-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-464) 5-((6-(3-cyclopropyl-4-(quinoxalo-2-yl)-1 H -pyrazol-1-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-552), 5-((3-(trans-3-(3-cyclopropyl-4-(quinoxalo-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-568) 5-((6-(3-cyclopropyl-4-(7-morpholinoquinoxaline-2-yl)-1 H -pyrazol-1-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-569), 5-((6-(3-cyclopropyl-4-(7-(4-methylpiperazin-1-yl)quinoxalin-2-yl)-1 H -pyrazol-1-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-570), 5-((6-(3-cyclopropyl-4-(7-(tetrahydro-2-) H -pyran-4-yl)quinoxalin-2-yl)-1 H -pyrazol-1-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-571), 5-((3-(trans-3-(3-cyclopropyl-4-(6-morpholinoquinoxaline-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-573), 5-((3-(trans-3-(3-cyclopropyl-4-(7-((1)) R 4 R )-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-574) 5-((3-(trans-3-(4-(7-(( S )-3,4-Dimethylpiperazin-1-yl)quinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-575) 2-(2,6-dioxopiperidin-3-yl)-5-((3-(trans-3-(4-(7-(( S )-3-methylpiperazin-1-yl)quinoxalin-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)propyl)amino)isoindoline-1,3-dione (GS-576), or 5-(((trans-3-(3-cyclopropyl-4-(quinoxalo-2-yl)-1 H -pyrazol-1-yl)cyclobutyl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GS-579).

6. A pharmaceutical composition comprising the compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

7. Use of the compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, inflammation, viral infection or immune disease.

8. Use of the compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating autoimmune diseases.

9. A combination of a compound comprising any one of claims 1-5 or a pharmaceutically acceptable salt thereof, and an FLT3 inhibitor selected from giretinib, midotulin, sorafenib, sunitinib, and retalitinib for the treatment of cancer.

10. Use in the preparation of a medicament for treating cancer, comprising any one of claims 1-5, a pharmaceutically acceptable salt thereof, and an FLT3 inhibitor selected from giretinib, midottolin, sorafenib, sunitinib, and retalitinib.

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