Bifunctional decomposition inducers and methods of using them

Abstract

Described herein are bifunctional degrader compounds, their various targets, their preparation, pharmaceutical compositions containing them, and their use in the treatment of conditions, diseases, and disorders mediated by various target proteins. [Formula 1] TIFF2022547716000696.tif17118

Description

[Technical Field]

[0001] Priority claims This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 901,161, filed September 16, 2019, and U.S. Provisional Patent Application No. 62 / 905,849, filed September 25, 2019, the disclosures of each of which are incorporated herein by reference in their entireties.

[0002] Described herein are bifunctional degrader compounds, their various targets, their preparation, pharmaceutical compositions containing them, and their use in the treatment of conditions, diseases, and disorders mediated by various target proteins.

[0003] Sequence Listing Reference This application is filed with a sequence listing in computer readable form in accordance with 37 CFR § 1.821(c). The text file submitted by EFS, "PAT058639-US-PSP_14293-889_sequence_listing.txt," was created on September 9, 2019, has a file size of 7 kilobytes, and is incorporated herein by reference in its entirety. [Background technology]

[0004] The ubiquitin-proteasome pathway (UPP) is a critical pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to multiple cellular processes, and when deficient or imbalanced, it leads to the pathogenesis of various diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases comprise over 500 different proteins and are divided into classes defined by the structural elements of their E3 functional activity.

[0005] Cereblon (CRBN) interacts with damaged DNA-binding protein 1 and forms an E3 ubiquitin ligase complex with Cullin 4, which functions as a substrate receptor where proteins recognized by CRBN can be ubiquitinated and degraded by the proteasome.

[0006] Proteasome-mediated degradation of unnecessary or damaged proteins plays a crucial role in maintaining normal cellular functions, such as cell survival, proliferation, and growth. More recently, CRBN has been identified as a target of immunomodulatory drugs (IMiDs) such as thalidomide and lenalinomide, and is also associated with the teratogenicity and cytotoxicity of IMiDs, which are widely used to treat multiple myeloma patients. Kroenke et al., Science 343:301-305 (2014); Petzold et al., Nature 532:127-130 (2016); Bjorklund et al., Blood Cancer J. 5, e354 (2015); Lu et al., Science 343:305-309 (2014); Gandhi et al., Br. J. Haematol. 164:811-821 (2014).

[0007] The principle of directed degradation of protein targets as a promising therapeutic approach has been described by Crews, J. Med. Chem. 61(2):403-404 (2018) and references cited therein. There is a need for selectively targeted protein degraders, and this application addresses the generation of bifunctional degrader molecules directed against various protein targets for in vivo target validation and as therapeutic agents. Summary of the Invention [Means for solving the problem]

[0008] In one aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, A targeting ligand is a group capable of binding to a target protein; The linker is a group that covalently links the targeting ligand to the targeting ligase binder; and A targeted ligase binder is a group that can bind to a ligase (e.g., cereblon E3 ubiquitin ligase). or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0009] In one embodiment, the targeted ligase binder has the formula (TLB-I): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); Ring A is a 6-membered aryl or a 5- or 6-membered heteroaryl, each of which is selected from 0 to 4 R d4 is replaced by the presence of; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 cycloalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each R d4 are independently H, oxo, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl and C 1~6heteroalkyl; Each R d5 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 is selected from the group consisting of cycloalkyl; or two R's d5 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d5 is C 3~4 Forming a spirocycloalkyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0010] In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d3 is -CH2OP(O)(OR p )2.

[0011] In certain embodiments, Ring A is selected from the group consisting of phenyl, pyridyl, pyridonyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, and pyrrolyl. In certain embodiments, Ring A is a 5-membered heteroaryl. In certain embodiments, A is a 5-membered nitrogen-containing heteroaryl. In certain embodiments, A is a 6-membered heteroaryl. In certain embodiments, Ring A is a 6-membered nitrogen-containing heteroaryl. In certain embodiments, Ring A is pyridyl or pyridonyl. In certain embodiments, R d4 is hydroxyl or C 1~6 It is alkoxyl.

[0012] In one embodiment, the targeted ligase binder has the formula (TLB-II): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); Q is N or CR d4 and; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each R d4 are independently H, oxo, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0013] In some embodiments, n is 1. In some embodiments, R d3is H. In one embodiment, R d3 is -CH2OP(O)(OR p )2.

[0014] In one embodiment, R d4 is hydroxyl or C 1~6 It is alkoxyl.

[0015] In one embodiment, the targeted ligase binder has the formula (TLB-III): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d4 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0016] In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d1 is H. In one embodiment, R d2 is H. In one embodiment, R d1 and R d2 are both H.

[0017] In one embodiment, the targeted ligase binder has the formula (TLB-IV): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); R d4 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0018] In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, Rd3 is -CH2OP(O)(OR p )2. In one embodiment, R d4 is H or C 1~3 In one embodiment, R d4 is H. In one embodiment, R d5 is H or C 1~3 In one embodiment, R d5 is H.

[0019] In one embodiment, the targeted ligase binder has the formula (TLB-V): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0020] In one embodiment, the targeted ligase binder has the formula (TLB-VI): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); Ring A is a 6-membered aryl or 6-membered heteroaryl, each independently containing 0 to 4 R d6 is replaced by the presence of; Each R d6 are independently H, hydroxyl, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p)2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R p is H or C 1~6 is alkyl; Each R d8 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 selected from the group consisting of heteroalkyl; or two R's d8 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d8 is C 3~4 Forming a spirocycloalkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0021] In certain embodiments, Ring A is selected from the group consisting of phenyl, pyridyl, pyridonyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, and pyrrolyl. In certain embodiments, Ring A is a nitrogen-containing 6-membered heteroaryl. In certain embodiments, Ring A is pyridyl.

[0022] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d7 is -CH2OP(O)(OR p )2. In one embodiment, R d7 is H. In one embodiment, R d8 is H. In one embodiment, R d7 and R d8 and R are both H. In some embodiments, R d6 is H. In one embodiment, R d6 H, halogen, C 1~6 Alkyl, and C 1~6In one embodiment, R d6 H, halogen, C 1~6 Alkyl, and C 1~6 alkoxyl; and R d7 and R d8 are H, respectively.

[0023] In one embodiment, the targeted ligase binder has the formula (TLB-VII): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); U is -CR d6 or N; Each R d6 are independently H, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0024] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, each R d6 are independently H, halogen, C 1~3 Alkyl, and C 1~3 In one embodiment, each R d6 is H. In one embodiment, R d6 is H. In some embodiments, R d6 One of them is not H.

[0025] In one embodiment, the targeted ligase binder has the formula (TLB-VIII): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); U is -CR d6 or N; R d6 is H, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0026] In some embodiments, the targeted ligase binder has the formula (TLB-IX): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); U is independently -CR d6 or N; R d6 is H, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0027] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, U is N. In some embodiments, U is -CR d6 In one embodiment, each R d6 is independently selected from the group consisting of H, methyl, halogen, methoxy, and methoxymethyl. d6 is H. In one embodiment, R d6 is methyl. In one embodiment, R d6 is halogen. In one embodiment, R d6 is methoxy.

[0028] In certain embodiments, the linker has the formula (LI): [ka] (In the formula, L 1 is a bond, O, NR', C(O), C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L in formula (I). 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, O, NR', C(O), C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, C(O), S(O)2, O, NR', *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from L 3 X in (LI) 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 may be simultaneously bonded; and R' is hydrogen or C 1~6 alkyl) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0029] In one embodiment, L 3 is a bond, -O-, -C(O)-, -S(O)2-, C 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 In one embodiment, X is selected from the group consisting of: heteroalkylene; 1 and X 2 In some embodiments, one of X 1 and X 2 One of is a bond and the other is carbocyclyl or heterocyclyl.

[0030] In one embodiment, X 1 and X 2One of X is a bond and the other is heterocyclyl. 1 and X 2 are each independently selected from piperidinyl and piperazinyl. 1 and X 2 and are both piperidinyl. 1 -L 2 -X 2 -teeth, [ka] In certain embodiments, the linker has the following formula: [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0031] In some embodiments, -X 1 -L 2 -X 2 - is 0 to 4 R a The structure is replaced by the presence of [ka] and forming a spiroheterocyclyl having each R a independently, C 1~6 Alkyl, C 1~6 Alkoxyl and C 1~6 hydroxyalkyl.

[0032] In some embodiments, -X 1 -L 2 -X 2 - is 0 to 4 R b The structure is replaced by the presence of [ka] wherein Y is selected from CH, oxygen, and nitrogen; and each R b independently, C 1~6 Alkyl, C 1~6 Alkoxyl and C 1~6 hydroxyalkyl.

[0033] In one embodiment, X 1 and X 2 Each is a bond. 3 are independently -C(O)-, C 2~6 Alkynylene, or C 1~6 heteroalkylene; and L 1 is -C(O)-, C 1~8 Alkylene, C 1~8 heteroalkylene, and *C 1~6 In one embodiment, L 3 -C(O)-, -OC 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 heteroalkylene; and L 1 is C 1~8 Alkylene or C 1~8 In one embodiment, L is heteroalkylene. 3 is -C(O)- or C 1~6 heteroalkylene; and L 1 is C 1~8 Alkylene or C 1~8 In one embodiment, L is heteroalkylene. 3 is a bond or -O-; and L 1 is -C(O)- or C 1~8 In one embodiment, L is heteroalkylene. 3 -O-, -C(O)-, -S(O)2-, and C 1~6 heteroalkylene; and L 1 is C 1~8 Alkylene or C 1~8 In one embodiment, L is heteroalkylene. 2 is -C(O)-, -NR'-, or C1~6 In one embodiment, L 2 is -C(O)-, -O-, or C 1~6 In one embodiment, L 2 is C 1~6 In one embodiment, L 2 is -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 In some embodiments, Y is selected from the group consisting of alkylene, CH, CH(C 1~3 alkyl), C(C 1~3 alkyl), oxygen, NH, or N(C 1~3 alkyl).

[0034] In one embodiment, the targeted ligase binder-linker has the formula (TLB-LI): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR'-, -C(O), C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O), -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (TLB-LI). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; Ring A is a 6-membered aryl or a 5- or 6-membered heteroaryl, each of which is selected from 0 to 4 R d4 is replaced by the presence of; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 cycloalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p)2 is selected from the group consisting of; Each R d4 are independently H, oxo, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl and C 1~6 heteroalkyl; Each R d5 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 is selected from the group consisting of cycloalkyl; or two R's d5 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d5 is C 3~4 Forming a spirocycloalkyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0035] In certain embodiments, Ring A is selected from the group consisting of phenyl, pyridyl, pyridonyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, and pyrrolyl. In certain embodiments, Ring A is a 5-membered heteroaryl. In certain embodiments, Ring A is a 5-membered nitrogen-containing heteroaryl. In certain embodiments, Ring A is a 6-membered heteroaryl. In certain embodiments, Ring A is a 6-membered nitrogen-containing heteroaryl. In certain embodiments, Ring A is pyridyl. In certain embodiments, n is 1. In certain embodiments, R d3 is H. In one embodiment, R d3 is -CH2OP(O)(OR p )2.

[0036] In one embodiment, the targeted ligase binder-linker has the formula (TLB-L-II): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR'-, -C(O), C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O), -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * represents L in formula (TLB-L-II). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; Q is N or CR d4 and; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each R d4 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0037] In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d3 is -CH2OP(O)(OR p )2.

[0038] In another embodiment, the targeted ligase binder-linker has the formula (TLB-L-III): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * represents L in formula (TLB-L-III). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d4 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; Rp is H or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0039] In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d3 is -CH2OP(O)(OR p )2.

[0040] In another embodiment, the targeted ligase binder-linker has the formula (TLB-L-IV): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6alkylene, and * is selected from the group consisting of L 2 X 2 or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (TLB-L-IV). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; R d4 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0041] In some embodiments, n is 1. In some embodiments, n is 2.

[0042] In another embodiment, the targeted ligase binder-linker has the formula (TLB-LV): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (TLB-LV). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0043] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, L 3 , -O-, -C(O)-, -S(O)2-, C 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 In one embodiment, X is selected from the group consisting of: heteroalkylene; 1 and X 2 In some embodiments, one of X 1 and X 2 One of X is a bond and the other is carbocyclyl or heterocyclyl. 1 and X 2 One of is a bond and the other is heterocyclyl.

[0044] In another embodiment, the targeted ligase binder-linker, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is [ka] having a formula selected from

[0045] In another embodiment, the compound has formula (BF-I): [ka] (In the formula, L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 heteroalkylene; *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (BF-I). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; Ring A is a 6-membered aryl or a 5- or 6-membered heteroaryl, each of which is selected from 0 to 4 R d4 is replaced by the presence of; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 cycloalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each R d4 are independently H, oxo, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl and C 1~6 heteroalkyl; Each R d5 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 is selected from the group consisting of cycloalkyl; or two R's d5 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d5 is C 3~4 Forming a spirocycloalkyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2, and the targeting ligand is a group capable of binding to a target protein. or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0046] In certain embodiments, Ring A is selected from the group consisting of phenyl, pyridyl, pyridonyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, and pyrrolyl. In certain embodiments, Ring A is a 5-membered heteroaryl. In certain embodiments, Ring A is a 5-membered nitrogen-containing heteroaryl. In certain embodiments, Ring A is a 6-membered heteroaryl. In certain embodiments, Ring A is a 6-membered nitrogen-containing heteroaryl. In certain embodiments, Ring A is pyridyl.

[0047] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d3 is H.

[0048] In another embodiment, the compound has formula (BF-II): [ka] (In the formula, L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 * is selected from the group consisting of L in formula (BF-II). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; Q is N or CR d4 and; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(ORp )2 is selected from the group consisting of; Each R d4 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2, and the targeting ligand is a group capable of binding to a target protein. or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0049] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d3 is H.

[0050] In another embodiment, the compound has formula (BF-III): [ka] (In the formula, L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (BF-III). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)Rp , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d4 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2, and the targeting ligand is a group capable of binding to a target protein. or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0051] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d3 is H. In some embodiments, -X 1 -L 2 -X 2 teeth, [ka] In one embodiment, L 1 is -O- or C 1~6 In one embodiment, R d1 and R d2 and R are both methyl. d1 and R d2and R are both H. In some embodiments, R d4 is H or C 1~3 In one embodiment, R d5 is H or C 1~3 It is alkyl.

[0052] In another embodiment, the targeted ligase binder-linker has the formula (TLB-L-VI): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR', -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR', -C(O)-, C 1~6 Alkylene, C 1~6 heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * represents L in formula (TLB-L-VI). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; Ring A is a 6-membered aryl or 6-membered heteroaryl, each independently containing 0 to 4 R d6 is replaced by the presence of; Each R d6 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R p is H or C 1~6 is alkyl; Each R d8 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 selected from the group consisting of heteroalkyl; or two R's d8 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d8 is C 3~4 Forming a spirocycloalkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0053] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d3 is H.

[0054] In another embodiment, the targeted ligase binder-linker has the formula (TLB-L-VII): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR', -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR', -C(O)-, C 1~6 Alkylene, C 1~6 heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * represents L in formula (TLB-L-VII). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; U is -CR d6 or N; Each R d6 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d7 is H, -CH2OC(O)R p, -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d8 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0055] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d3 is H. In one embodiment, L 3 is a bond, -O-, -C(O)-, -S(O)2-, C 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 In one embodiment, X is selected from the group consisting of: heteroalkylene; 1 and X 2 In some embodiments, one of X 1 and X 2 One of X is a bond and the other is carbocyclyl or heterocyclyl. 1 and X 2 One of is a bond and the other is heterocyclyl.

[0056] In some embodiments, the targeted ligase binder-linker has the formula (TLB-L-VIII or TLB-L-IX): [ka] where the point of attachment to the targeting ligand is L 1 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0057] In some embodiments, n is 1. In some embodiments, n is 2.

[0058] In another embodiment, the targeted ligase binder-linker, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is [ka] [ka] [ka] [ka] [ka] [ka] having a formula selected from

[0059] In another embodiment, the compound has formula (BF-IV): [ka] (In the formula, L 1 is a bond, -O-, -NR', -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR', -C(O)-, C 1~6 Alkylene, C 1~6 heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 * is selected from the group consisting of L in formula (BF-IV). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; Ring A is a 6-membered aryl or 6-membered heteroaryl, each independently containing 0 to 4 R d6 is replaced by the presence of; Each R d6 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R p is H or C 1~6 is alkyl; Each R d8 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 selected from the group consisting of heteroalkyl; or two R's d8 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d8 is C 3~4 Forming a spirocycloalkyl; m is 1 or 2; and n is 1 or 2, and the targeting ligand is a group capable of binding to a target protein. or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0060] In another embodiment, the compound has the formula (BF-VA or BF-VB): [ka] (In the formula, L 1 is a bond, -O-, -NR', -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR', -C(O)-, C 1~6 Alkylene, C 1~6 heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * represents L in formula (BF-VA or BF-VB). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; U is -CR d6 or N; Each R d6 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d8 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2, and the targeting ligand is a group capable of binding to a target protein. or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0061] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d7 is -CH2OP(O)(OR p )2. In one embodiment, R d7 is H. In certain embodiments, U is -CR d6 In one embodiment, R d8 is H. In one embodiment, R d7 and R d8 are each independently H. In one embodiment, R d6 is H. In one embodiment, R d6 H, halogen, C 1~6 Alkyl, and C 1~6 In one embodiment, R d6H, halogen, C 1~6 Alkyl, and C 1~6 alkoxyl; and R d7 and R d8 are H, respectively.

[0062] In another embodiment, L 1 -X 1 -L 2 -X 2 -L 3 teeth, [ka] is selected from the group consisting of:

[0063] In one embodiment, L 3 is a bond, -O-, -C(O)-, -S(O)2-, C 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 heteroalkylene.

[0064] In another embodiment, the targeting is carried out using a compound of formula (BRD9-I): [ka] (In the formula, R 1 and R 2 are independently hydrogen and C 1~6 alkyl; or R 1 and R 2 together with the atom to which they are attached form an aryl or heteroaryl; R 3 are each independently 1~6 Alkyl, C 1~6 selected from the group consisting of alkoxyl, and halogen; R 5 is hydrogen and C 1~3 selected from the group consisting of alkyl; n is 0, 1, or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0065] In another embodiment, the targeting ligand has the formula (BTK-I): [ka] (In the formula, R 1a is H or halo; R 2a is a halo; R 3a is C 1~6 is alkyl; R 4a is a halo; and R 5a is H or halo) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0066] Another embodiment is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0067] Another embodiment is a pharmaceutical combination comprising a compound described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more additional therapeutic agents.

[0068] Another embodiment is a method for inducing degradation of a target protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0069] Another embodiment is a method of inhibiting, reducing, or eliminating the activity of a target protein, comprising administering to a subject a compound described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0070] In some embodiments, inhibiting, reducing, or eliminating the activity of the target protein comprises recruiting a ligase (e.g., cereblon E3 ubiquitin ligase) with a bifunctional compound, e.g., a targeted ligase binder of a bifunctional compound described herein, e.g., a targeted ligase binder described herein, to form a ternary complex of the target protein, the bifunctional compound, and the ligase, thereby inhibiting, reducing, or eliminating the activity of the target protein.

[0071] In certain embodiments, the target protein is selected from Table 1.

[0072] [Table 1]

[0073] [Table 2]

[0074] [Table 3]

[0075] [Table 4]

[0076] [Table 5]

[0077] [Table 6]

[0078] [Table 7]

[0079] [Table 8]

[0080] [Table 9]

[0081] [Table 10]

[0082] In some embodiments, the target protein is a fusion target protein. In some embodiments, the fusion target protein is selected from Table 2.

[0083] [Table 11]

[0084] [Table 12]

[0085] [Table 13]

[0086] Another embodiment is a method of treating a target protein-mediated disorder, disease, or condition in a patient, comprising administering to the patient a compound described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the disorder is selected from a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease or disorder. In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer.

[0087] Another embodiment is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

[0088] Another embodiment is a compound of formula (ILB-I): [ka] (In the formula, R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each R d4 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, and C 1~6 heteroalkyl; Each R d5 are independently H, C1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 is selected from the group consisting of cycloalkyl; or two R's d5 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d5 is C 3~4 Forming a spirocycloalkyl; R L1 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , C 3~6 Heteroalkyl, C 2~6 Haloalkyl, -(CH2) 1~3 C(O)OH, -(CH2) 1~3 C(O)H, -(CH2) 1~3 O(CH2) 1~3 C(O)H, -(CH2) 0~3 C 3~7 Carbocyclyl, -(CH2) 0~3 and selected from the group consisting of heterocyclyl, C6 aryl, and heteroaryl, wherein carbocyclyl, heterocyclyl, aryl, and heteroaryl are selected from the group consisting of 0 to 2 -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted by the presence of haloalkyl; R c is H, C 1~4 Alkyl or C 1~6 is heteroalkyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0089] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d3 is H.

[0090] In certain embodiments, the compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is [ka] Another embodiment is selected from the formula (ILB-II): [ka] (In the formula, Q is N or CR d4 and; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2(O)(CH2)2Si(CH3)3, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each R d4 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl;C 1~6Alkoxyalkyl, and C 1~6 heteroalkyl; Each R d5 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 is selected from the group consisting of cycloalkyl; or two R's d5 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d5 is C 3~4 Forming a spirocycloalkyl; R L1 is C 2~6 Alkenyl, C 2~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , C 3~6 Heteroalkyl, C 2~6 Haloalkyl, -(CH2) 0~3 C(O)OH, -(CH2) 0~3 C(O)H, -(CH2) 0~3 C 3~7 Carbocyclyl, -(CH2) 0~3 and selected from the group consisting of heterocyclyl, C6 aryl, and heteroaryl, wherein carbocyclyl, heterocyclyl, aryl, and heteroaryl are selected from the group consisting of 0 to 2 -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted by the presence of haloalkyl; R c is H, C 1~4 Alkyl or C 1~6 is heteroalkyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0091] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d3 is H.

[0092] Another embodiment is [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0093] Another embodiment is a compound of formula (ILB-III): [ka] (In the formula, Ring A is [ka] selected from the group consisting of: [ka] denotes the point of attachment to the underlying molecule of (ILB-III); Each R d6 are independently H, oxo, polyethylene glycol (PEG), halogen, C 1~3 Alkyl, C 1~3 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl and -OC 1~7 heteroalkyl; Each R d6a are independently H, hydroxyl, oxo, polyethylene glycol (PEG), halogen, C 1~3 Alkyl, C 1~3 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl and -OC 1~7 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2; Each R d8 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 selected from the group consisting of heteroalkyl; or two R's d8 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d8 is C 3~4 Forming a spirocycloalkyl; R L2 is hydroxyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , -(CH2) 2~6 NR c R d , -O-(CH2) 2~6 NHR c , C 4~8 Heteroalkyl, C 2~6 Haloalkyl, -SO2-NH-(CH2) 2~6 NHR c , -(CH2) 0~3 C(O)OH, -(CH2) 0~3 C(O)OR c , -OC 2~6 Alkenyl, -O-(CH2)0~3 C(O)H, -(CH2) 0~3 C(O)H, -O-(CH2) 1~3 C(O)OH, -(CH2) 0~3 Heterocyclyl, -C(O)-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 C(O)-heterocyclyl, -C 2~6 alkynyl-heterocyclyl, and heteroaryl, wherein alkynyl, heterocyclyl, heteroalkyl, carbocyclyl, and heteroaryl are selected from the group consisting of 0-2 halogen, hydroxyl, -(CH2) 0~3 C(O)H, -(CH2) 2~6 NHR c , -(CH2) 2~6 N(R c )2, heterocyclyl, -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted by the presence of haloalkyl, heterocyclyl may be optionally substituted with halogen; R L2a is H, hydroxyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , -(CH2) 2~6 NR c R d , -O-(CH2) 2~6 NHR c , C 1~8 Heteroalkyl, C 1~6 Haloalkyl, -SO2-NH-(CH2) 2~6 NHR c , -(CH2) 0~3 C(O)OH, -(CH2) 0~3 C(O)OR c , -OC 2~6Alkenyl, -O-(CH2) 0~3 C(O)H, -(CH2) 0~3 C(O)H, -O-(CH2) 1~3 C(O)OH, -(CH2) 0~3 Heterocyclyl, -C(O)-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 C(O)-heterocyclyl, -C 2~6 alkynyl-heterocyclyl, and heteroaryl, wherein alkynyl, heterocyclyl, heteroalkyl, carbocyclyl, and heteroaryl are selected from the group consisting of 0-2 halogen, hydroxyl, -(CH2) 0~3 C(O)H, -(CH2) 2~6 NHR c , -(CH2) 2~6 N(R c )2, heterocyclyl, -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted by the presence of haloalkyl, heterocyclyl may be optionally substituted with halogen; R L2b H, polyethylene glycol (PEG), C 1~3 Alkyl, C 3~6 Cycloalkyl, C 3~6 Alkenyl, C 3~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , -(CH2) 2~6 NR c R d , C 2~8 Heteroalkyl, C 2~6 Haloalkyl, -(CH2) 1~3 C(O)OH, -(CH2) 1~3 C(O)H, -(CH2) 0~3 Heterocyclyl, -C(O)-(CH2)0~3 Heterocyclyl, -C 3~6 alkynyl-heterocyclyl, and heteroaryl, wherein alkynyl, heterocyclyl, heteroalkyl, carbocyclyl, and heteroaryl are selected from the group consisting of 0-2 halogen, hydroxyl, -(CH2) 0~3 C(O)H, -(CH2) 2~6 NHR c , heterocyclyl, -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted by the presence of haloalkyl; R c is H, C 1~4 Alkyl, C 1~6 Heteroalkyl and -C(O)OC 1~6 is alkyl; R d is H or C 1~4 alkyl; or R c and R d together with the nitrogen atom to which they are attached to form a heterocyclyl substituted by 0-2 occurrences of -O-heterocyclyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0094] In certain embodiments, ring A is [ka] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d7 is -CH2OP(O)(ORp )2. In one embodiment, R d7 is H.

[0095] Another embodiment is [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0096] Another embodiment is a compound of formula (ILB-IV): [ka] (Wherein, ring A is [ka] selected from the group consisting of: [ka] denotes the point of attachment to the underlying molecule of (ILB-IV); R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 cycloalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2; R d4 is H, hydroxyl, oxo, polyethylene glycol (PEG), halogen, C 1~3 Alkyl, C 3~6 Cycloalkyl, C 1~3 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl and -OC 1~7 heteroalkyl; Each R d4a are independently H, polyethylene glycol (PEG), C 1~3 Alkyl, C 3~6 Cycloalkyl, C 2~6 Haloalkyl, and C 2~6 heteroalkyl; Each R d5 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 selected from the group consisting of heteroalkyl; or two R's d8 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d8 is C 3~4 Forming a spirocycloalkyl; R L2 is hydroxyl, halogen, C 2~6 Alkyl, C 1~3 Alkoxyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , -(CH2) 0~6 NR c R d , -O-(CH2) 2~6 NHR c , C 3~8 Heteroalkyl, C 1~6 Haloalkyl, -SO2-NH-(CH2) 2~6 NHR c , -(CH2) 0~3 C(O)OH, -O-(CH2) 1~3 C(O)H, -(CH2) 1~3 C(O)H, -O-(CH2) 1~3 C(O)OH, -(CH2) 0~3 C 3~7 Carbocyclyl, -(CH2) 0~3 Heterocyclyl, -C(O)-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 Heterocyclyl, -C 2~6 Alkynyl-heterocyclyl, -C 2~6 alkynyl-heterocyclyl-heteroaryl, C6 aryl, and heteroaryl, wherein alkynyl, alkoxyl, heterocyclyl, heteroalkyl, carbocyclyl, aryl, and heteroaryl are selected from the group consisting of 0-2 halogens, hydroxyl, -(CH2) 0~3 C(O)H, -C(O)O-benzyl, -(CH2) 2~6 NHR c , heterocyclyl, -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted by the presence of haloalkyl; R c is H, C 1~4 Alkyl, C 1~6 Heteroalkyl and -C(O)OC1~6 is alkyl; R d is H or C 1~4 alkyl; or R c and R d together with the nitrogen atom to which they are attached to form a heterocyclyl substituted by 0-2 occurrences of -O-heterocyclyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0097] In certain embodiments, ring A is [ka] is selected from the group consisting of:

[0098] Another embodiment is [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0099] Another embodiment is a compound of formula (II): [ka] (In the formula, R 1a is H or halo; R 2a is a halo; R 3a is C 1~6 is alkyl; R 4a is a halo; R 5ais H or halo; L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (BF-III). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d4 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; and R p is H or C 1~6 alkyl) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0100] In one embodiment, R 2a is fluoro. In certain embodiments, R 3a is C 1~3 In one embodiment, R 3a is methyl.

[0101] In one embodiment, R 4a is fluoro. In certain embodiments, L 1 is C 1~9In some embodiments, -X is alkylene. 1 -L 2 -X 2 -teeth, [ka] In one embodiment, L 2 is -C(O)-, -O-, or C 1~6 In one embodiment, L 3 is a bond, -O-, -C(O)-, -S(O)2-, C 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 In one embodiment, R is selected from the group consisting of heteroalkylene. d4 is H. In one embodiment, R d1 is H. In one embodiment, R d2 is H. In one embodiment, R d1 and R d2 and are both H. In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d5 is H or C 1~3 It is alkyl.

[0102] In one embodiment, R d5 is H.

[0103] Another embodiment is a compound of formula (IIA): [ka] (In the formula, R 1a is H or halo; R 2a is a halo; R 3a is C 1~6 is alkyl; R 4a is a halo; R 5a is H or halo; L1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (BF-III). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; U is -CR d6 or N; Each R d6 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; U is -CR d6 or N; Each R d6 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d8 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0104] In one embodiment, R 2a is fluoro. In certain embodiments, R 3a is C 1~3 In one embodiment, R 3a is methyl. In one embodiment, R 4a is fluoro. In certain embodiments, L1 is C 1~9 In some embodiments, -X is alkylene. 1 -L 2 -X 2 -teeth, [ka] In one embodiment, L 2 is -C(O)-, -O-, or C 1~6 In one embodiment, L 3 is a bond, -O-, -C(O)-, -S(O)2-, C 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 In one embodiment, R is selected from the group consisting of heteroalkylene. d4 is H. In one embodiment, R d1 is H. In one embodiment, R d2 is H. In one embodiment, R d1 and R d2 and are both H. In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d5 is H or C 1~3 In one embodiment, R d5 is H.

[0105] Another embodiment is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0106] Another embodiment is a pharmaceutical composition comprising any of the compounds described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0107] Another embodiment is a pharmaceutical combination comprising any of the compounds described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a therapeutic agent.

[0108] Another embodiment is a method of treating a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof. In one embodiment, the disorder is a proliferative disorder. In one embodiment, the proliferative disorder is cancer.

[0109] Another embodiment is the use of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the preparation of a medicament for treating a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease or disorder in a subject in need thereof. One aspect is a set of compounds of any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. [Brief explanation of the drawings]

[0110] [Figure 1] 1 shows a schematic diagram of a bifunctional compound, such as those disclosed herein, conjugated to a protein of interest (POI) and tagged with ubiquitin (Ub), recruiting the POI to an E3 ubiquitin ligase binding complex to label the POI for translocation to the proteasome and subsequent degradation following degradation by the ligase. [Figure 2] Figure 1 shows a scheme for the in silico design of bifunctional degraders. "B" is a hypothetical bifunctional degrader with targeting motifs for a target protein (a) and an E3 ligase substrate receptor (c). The curved arrow on "B" indicates the degree of conformational rotation. "A" indicates the target protein. "C" indicates the E3 ligase substrate receptor. [Figure 3A] Figure 3: Figure 3A shows a Hill plot of TNNI3K expression as a function of compound 22 concentration. HEK293 and TMD8 cells were treated with 1 μM dasatinib, 1 μM compound 06, 1 μM compound 07, or DMSO, and protein abundance was analyzed using TMT quantification mass spectrometry. Significant changes were assessed by limma, with log2 fold changes shown on the x-axis and p-values ​​shown on the y-axis. Proteins with kinase annotation in UniProt are shown as boxes, and kinases with log2 fold changes ≤ -0.6 and p-values ​​≤ 0.01 are labeled with the corresponding gene name. [Figure 3B]Figure 3: Figure 3B shows a bar graph of TNNI3K expression as a function of compound 22 concentration. HEK293 and TMD8 cells were treated with 1 μM dasatinib, 1 μM compound 06, 1 μM compound 07, or DMSO, and protein abundance was analyzed using TMT quantification mass spectrometry. Significant changes were assessed by limma, with log2 fold changes shown on the x-axis and p-values ​​shown on the y-axis. Proteins with kinase annotation in UniProt are shown as boxes, and kinases with log2 fold changes ≤ -0.6 and p-values ​​≤ 0.01 are labeled with the corresponding gene name. [Figure 3C] Figure 3: Figure 3C shows a Hill plot of TNNI3K expression as a function of compound 21 concentration. HEK293 and TMD8 cells were treated with 1 μM dasatinib, 1 μM compound 06, 1 μM compound 07, or DMSO, and protein abundance was analyzed using TMT quantification mass spectrometry. Significant changes were assessed by limma, with log2 fold changes shown on the x-axis and p-values ​​shown on the y-axis. Proteins with kinase annotation in UniProt are shown as boxes, and kinases with log2 fold changes ≤ -0.6 and p-values ​​≤ 0.01 are labeled with the corresponding gene name. [Figure 3D] Figure 3: Figure 3D shows a bar graph of TNNI3K expression as a function of compound 21 concentration. HEK293 and TMD8 cells were treated with 1 μM dasatinib, 1 μM compound 06, 1 μM compound 07, or DMSO, and protein abundance was analyzed using TMT quantification mass spectrometry. Significant changes were assessed by limma, with log2 fold changes shown on the x-axis and p-values ​​shown on the y-axis. Proteins with kinase annotation in UniProt are shown as boxes, and kinases with log2 fold changes ≤ -0.6 and p-values ​​≤ 0.01 are labeled with the corresponding gene name. [Figure 3E]Figure 3: Figure 3E shows a volcano plot demonstrating the identification of potential CRBN substrates dependent on degraders. HEK293 and TMD8 cells were treated with 1 μM dasatinib, 1 μM Compound 06, 1 μM Compound 07, or DMSO, and protein abundance was analyzed using TMT quantification mass spectrometry. Significant changes were assessed by limma, with log2 fold changes shown on the x-axis and p-values ​​shown on the y-axis. Proteins with kinase annotation in UniProt are shown as boxes, and kinases with log2 fold changes ≤ -0.6 and p-values ​​≤ 0.01 are labeled with the corresponding gene name. [Figure 4A] Figure 4: Figure 4A shows a Western blot of TNNI3K expression in response to compound 22 concentration. β-actin is used as a control. [Figure 4B] Figure 4: Figure 4B shows a Western blot of TNNI3K expression in response to compound 21 concentration. β-actin is used as a control. DETAILED DESCRIPTION OF THE INVENTION

[0111] Described herein are compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, methods for their preparation, and uses thereof, that function to recruit targeted proteins to E3 ubiquitin ligases for degradation.

[0112] In one aspect, the disclosure provides a compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, that recruits a targeted protein, such as a bromodomain-containing protein or a protein kinase, to an E3 ubiquitin ligase for degradation. In certain embodiments, the compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, has the formula (I): [ka] (In the formula, A targeting ligand is a group capable of binding to a target protein; The linker is a group that covalently links the targeting ligand to the targeting ligase binder; and A targeted ligase binder is a group that can bind to a ligase (e.g., cereblon E3 ubiquitin ligase). or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0113] Target protein In one aspect, the disclosure provides a compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, that recruits a targeted protein, such as a bromodomain-containing protein or a protein kinase, to an E3 ubiquitin ligase for degradation. In one embodiment, the target protein is selected from Table 1 or Table 2.

[0114] Targeting Ligands A targeting ligand is a small molecule moiety that can bind to a target protein or protein of interest (POI). In some embodiments, the target protein or POI is a target protein selected from Table 1. In some embodiments, the target protein or POI is a fusion protein. In some embodiments, the target protein or POI is a target protein selected from Table 2.

[0115] In one embodiment, the targeting ligand has the formula (BRD9-I): [ka] (In the formula, R 1 and R 2 are independently hydrogen and C 1~6 alkyl; or R 1 and R 2 together with the atom to which they are attached form an aryl or heteroaryl; R 3are each independently 1~6 Alkyl, C 1~6 selected from the group consisting of alkoxyl, and halogen; R 5 is hydrogen and C 1~3 selected from the group consisting of alkyl; n is 0, 1, or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0116] In some embodiments, the targeting ligand has the formula (BTK-I): [ka] (In the formula, R 1a is H or halo; R 2a is a halo; R 3a is C 1~6 is alkyl; R 4a is a halo; and R 5a is H or halo) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0117] Additional exemplary targeting ligands include, but are not limited to, the targeting ligands in Table 3.

[0118] [Table 14]

[0119] The targeting ligand may be a linker-targeting ligase binder, e.g., [ka] [ka] [ka] via a modifiable carbon, oxygen, nitrogen, or sulfur atom on the targeting ligand.

[0120] In certain embodiments, the targeting ligand is a targeting ligand described in Huang et al., "A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader," Cell Chem. Biol. 25(1):88-99 (2018); An and Fu, "Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs," EBioMedicine 36:553-562 (2018); Pei et al., "Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery," RSC Adv. 9:16967-16976 (2019); and Zou et al., Cell Biochem. Funct. 37:21-30 (2019), each of which is incorporated herein by reference in its entirety.

[0121] In certain embodiments, the targeting ligand is [ka] is selected from the group consisting of:

[0122] Targeted Ligase Binders The targeting ligase binder links a targeting ligase binder bound to a ubiquitin ligase (e.g., an E3 ubiquitin ligase binding complex), a linker (L), and a targeting ligand (TL) bound to the POI, thereby bringing the protein of interest (POI) into proximity with the ubiquitin ligase for tagging with ubiquitin (Ub), thereby labeling the POI for degradation by the ligase. See, e.g., Figure 1.

[0123] In one embodiment, the targeted ligase binder has the formula (TLB-I): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); Ring A is a 6-membered aryl or a 5- or 6-membered heteroaryl, each of which is selected from 0 to 4 R d4 is replaced by the presence of; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 cycloalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each R d4 are independently H, oxo, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl and C 1~6 heteroalkyl; Each Rd5 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 is selected from the group consisting of cycloalkyl; or two R's d5 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d5 is C 3~4 Forming a spirocycloalkyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0124] In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d3 is -CH2OP(O)(OR p )2. In certain embodiments, ring A is selected from the group consisting of phenyl, pyridyl, pyridonyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, and pyrrolyl. In certain embodiments, ring A is a 5-membered heteroaryl. In certain embodiments, A is a 5-membered nitrogen-containing heteroaryl. In certain embodiments, A is a 6-membered heteroaryl. In certain embodiments, ring A is a 6-membered nitrogen-containing heteroaryl. In certain embodiments, ring A is pyridyl or pyridonyl. In certain embodiments, R d4 is hydroxyl or C 1~6 It is alkoxyl.

[0125] In one embodiment, the targeted ligase binder has the formula (TLB-II): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); Q is N or CR d4 and; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each R d4 are independently H, oxo, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0126] In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d3 is -CH2OP(O)(OR p )2.

[0127] In one embodiment, R d4 is hydroxyl or C 1~6 It is alkoxyl.

[0128] In another embodiment, the targeted ligase binder has the formula (TLB-III): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d4 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0129] In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d1 is H. In one embodiment, R d2 is H. In one embodiment, R d1 and R d2 are both H.

[0130] In one embodiment, the targeted ligase binder has the formula (TLB-IV): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); R d4 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0131] In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d4 is H or C 1~3In one embodiment, R d4 is H. In one embodiment, R d5 is H or C 1~3 In one embodiment, R d5 is H.

[0132] In another embodiment, the targeted ligase binder has the formula (TLB-V): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0133] In one embodiment, the targeted ligase binder has the formula (TLB-VI): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); Ring A is a 6-membered aryl or 6-membered heteroaryl, each independently containing 0 to 4 R d6 is replaced by the presence of; Each R d6 are independently H, hydroxyl, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R p is H or C1~6 is alkyl; Each R d8 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 selected from the group consisting of heteroalkyl; or two R's d8 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d8 is C 3~4 Forming a spirocycloalkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0134] In certain embodiments, Ring A is selected from the group consisting of phenyl, pyridyl, pyridonyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, and pyrrolyl. In certain embodiments, Ring A is a nitrogen-containing 6-membered heteroaryl. In certain embodiments, Ring A is pyridyl.

[0135] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d7 is -CH2OP(O)(OR p )2. In one embodiment, R d7 is H. In one embodiment, R d8 is H. In one embodiment, R d7 and R d8 and R are both H. In some embodiments, R d6 is H. In one embodiment, R d6 H, halogen, C 1~6 Alkyl, and C 1~6 In one embodiment, R d6 H, halogen, C 1~6 Alkyl, and C 1~6alkoxyl; and R d7 and R d8 are H, respectively.

[0136] In one embodiment, the targeted ligase binder has the formula (TLB-VII): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); U is -CR d6 or N; Each R d6 are independently H, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0137] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, each R d6 are independently H, halogen, C 1~3 Alkyl, and C 1~3 In one embodiment, each R d6 is H. In one embodiment, R d6 is H. In some embodiments, R d6 One of them is not H.

[0138] In one embodiment, the targeted ligase binder has the formula (TLB-VIII): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); U is -CR d6 or N; R d6 is H, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0139] In some embodiments, the targeted ligase binder has the formula (TLB-IX): [ka] (In the formula, [ka] means the point of attachment to the linker in formula (I); U is independently -CR d6 or N; R d6 is H, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0140] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, U is N. In some embodiments, U is -CR d6 In one embodiment, each R d6 is independently selected from the group consisting of H, methyl, halogen, methoxy, and methoxymethyl. d6 is H. In one embodiment, R d6 is methyl. In one embodiment, R d6 is halogen. In one embodiment, R d6 is methoxy.

[0141] Linker In certain embodiments, the linker has the formula (LI): [ka] (In the formula, L 1 is a bond, O, NR', C(O), C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L in formula (I). 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, O, NR', C(O), C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, C(O), S(O)2, O, NR', *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from L 3 X in (LI) 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 may be simultaneously bonded; and R' is hydrogen or C 1~6 alkyl) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0142] In one embodiment, L 3 is a bond, -O-, -C(O)-, -S(O)2-, C 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 In one embodiment, X is selected from the group consisting of: heteroalkylene; 1 and X 2 In some embodiments, one of X 1 and X 2 One of X is a bond and the other is carbocyclyl or heterocyclyl. 1 and X 2 One of X is a bond and the other is heterocyclyl. 1 and X 2 are each independently selected from piperidinyl and piperazinyl. 1 and X2 and are both piperidinyl. 1 -L 2 -X 2 -teeth, [ka] In certain embodiments, the linker has the following formula: [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0143] In some embodiments, -X 1 -L 2 -X 2 - is 0 to 4 R a The structure is replaced by the presence of [ka] and forming a spiroheterocyclyl having each R a independently, C 1~6 Alkyl, C 1~6 Alkoxyl and C 1~6 hydroxyalkyl.

[0144] In some embodiments, -X 1 -L 2 -X 2 - is 0 to 4 R b The structure is replaced by the presence of [ka] wherein Y is selected from CH, oxygen, and nitrogen; and each R b independently, C 1~6 Alkyl, C 1~6 Alkoxyl and C 1~6In one embodiment, X is selected from the group consisting of hydroxyalkyl. 1 and X 2 are bonds.

[0145] In one embodiment, L 3 are independently -C(O)-, C 2~6 Alkynylene, or C 1~6 heteroalkylene; and L 1 is -C(O)-, C 1~8 Alkylene, C 1~8 heteroalkylene, and *C 1~6 In one embodiment, L 3 -C(O)-, -OC 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 heteroalkylene; and L 1 is C 1~8 Alkylene or C 1~8 In one embodiment, L is heteroalkylene. 3 is -C(O)- or C 1~6 heteroalkylene; and L 1 is C 1~8 Alkylene or C 1~8 In one embodiment, L is heteroalkylene. 3 is a bond or -O-; and L 1 is -C(O)- or C 1~8 In one embodiment, L is heteroalkylene. 3 -O-, -C(O)-, -S(O)2-, and C 1~6 heteroalkylene; and L 1 is C 1~8 Alkylene or C 1~8 In one embodiment, L is heteroalkylene. 2 is -C(O)-, -NR'-, or C 1~6 It is alkylene.

[0146] In one embodiment, L 2 is -C(O)-, -O-, or C 1~6In one embodiment, L 2 is C 1~6 In one embodiment, L 2 is -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene.

[0147] In certain embodiments, Y is CH, CH(C 1~3 alkyl), C(C 1~3 alkyl), oxygen, NH, or N(C 1~3 alkyl).

[0148] Targeting Ligand-Linker In one embodiment, the targeted ligase binder-linker has the formula (TLB-LI): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR'-, -C(O), C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O), -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (TLB-LI). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; Ring A is a 6-membered aryl or a 5- or 6-membered heteroaryl, each of which is selected from 0 to 4 R d4 is replaced by the presence of; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 cycloalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each Rd4 are independently H, oxo, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl and C 1~6 heteroalkyl; Each R d5 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 is selected from the group consisting of cycloalkyl; or two R's d5 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d5 is C 3~4 Forming a spirocycloalkyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0149] In certain embodiments, Ring A is selected from the group consisting of phenyl, pyridyl, pyridonyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, and pyrrolyl. In certain embodiments, Ring A is a 5-membered heteroaryl. In certain embodiments, Ring A is a 5-membered nitrogen-containing heteroaryl. In certain embodiments, Ring A is a 6-membered heteroaryl. In certain embodiments, Ring A is a 6-membered nitrogen-containing heteroaryl. In certain embodiments, Ring A is pyridyl. In certain embodiments, n is 1.

[0150] In one embodiment, R d3 is H. In one embodiment, R d3 is -CH2OP(O)(OR p )2.

[0151] In one embodiment, the targeted ligase binder-linker has the formula (TLB-L-II): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR'-, -C(O), C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O), -S(O)2-, -O-, *C(O)-C 1~9Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * represents L in formula (TLB-L-II). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; Q is N or CR d4 and; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each R d4 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0152] In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d3 is -CH2OP(O)(OR p )2.

[0153] In one embodiment, the targeted ligase binder-linker has the formula (TLB-L-III): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * represents L in formula (TLB-L-III). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d4 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0154] In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d3 is -CH2OP(O)(OR p )2.

[0155] In one embodiment, the targeted ligase binder-linker has the formula (TLB-L-IV): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C1~6 heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (TLB-L-IV). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; R d4 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0156] In some embodiments, n is 1. In some embodiments, n is 2.

[0157] In one embodiment, the targeted ligase binder-linker has the formula (TLB-LV): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (TLB-LV). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0158] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, L 3 , -O-, -C(O)-, -S(O)2-, C 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 In one embodiment, X is selected from the group consisting of: heteroalkylene; 1 and X 2 In some embodiments, one of X 1 and X 2 One of X is a bond and the other is carbocyclyl or heterocyclyl. 1 and X 2 One of is a bond and the other is heterocyclyl.

[0159] In certain embodiments, the targeted ligase binder-linker, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is [ka] having a formula selected from

[0160] In one embodiment, the targeted ligase binder-linker has the formula (TLB-L-VI): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR', -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR', -C(O)-, C 1~6 Alkylene, C 1~6 heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * represents L in formula (TLB-L-VI). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; Ring A is a 6-membered aryl or 6-membered heteroaryl, each independently containing 0 to 4 R d6 is replaced by the presence of; Each R d6 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R p is H or C 1~6 is alkyl; Each R d8 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 selected from the group consisting of heteroalkyl; or two R's d8 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atomd8 is C 3~4 Forming a spirocycloalkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0161] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d3 is H.

[0162] In one embodiment, the targeted ligase binder-linker has the formula (TLB-L-VII): [ka] (In the formula, [ka] means the point of attachment to the targeting ligand in formula (I); L 1 is a bond, -O-, -NR', -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR', -C(O)-, C 1~6 Alkylene, C1~6 heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * represents L in formula (TLB-L-VII). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; U is -CR d6 or N; Each R d6 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d8is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0163] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d3 is H. In one embodiment, L 3 is a bond, -O-, -C(O)-, -S(O)2-, C 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 In one embodiment, X is selected from the group consisting of: heteroalkylene; 1 and X 2 In some embodiments, one of X 1 and X 2 One of X is a bond and the other is carbocyclyl or heterocyclyl. 1 and X 2 One of is a bond and the other is heterocyclyl.

[0164] In some embodiments, the targeted ligase binder-linker has the formula (TLB-L-VIII or TLB-L-IX): [ka] where the point of attachment to the targeting ligand is L 1 (via or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0165] In some embodiments, n is 1. In some embodiments, n is 2.

[0166] In certain embodiments, the targeted ligase binder-linker, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is [ka] [ka] [ka] [ka] [ka] [ka] having a formula selected from

[0167] compound formula In another aspect, the present disclosure provides a compound of formula (BF-I): [ka] (In the formula, L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 heteroalkylene; *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (BF-I). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; Ring A is a 6-membered aryl or a 5- or 6-membered heteroaryl, each of which is selected from 0 to 4 R d4 is replaced by the presence of; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6cycloalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each R d4 are independently H, oxo, hydroxyl, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl and C 1~6 heteroalkyl; Each R d5 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 is selected from the group consisting of cycloalkyl; or two R's d5 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d5 is C 3~4 Forming a spirocycloalkyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2, and the targeting ligand is a group capable of binding to a target protein. or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0168] In certain embodiments, Ring A is selected from the group consisting of phenyl, pyridyl, pyridonyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, and pyrrolyl. In certain embodiments, Ring A is a 5-membered heteroaryl. In certain embodiments, Ring A is a 5-membered nitrogen-containing heteroaryl. In certain embodiments, Ring A is a 6-membered heteroaryl. In certain embodiments, Ring A is a 6-membered nitrogen-containing heteroaryl. In certain embodiments, Ring A is pyridyl. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, R d3 is -CH2OP(O)(OR p )2. In some embodiments, n R d3 is H.

[0169] In another aspect, the present disclosure provides a compound of formula (BF-II): [ka] (In the formula, L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 * is selected from the group consisting of L in formula (BF-II). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; Q is N or CR d4 and; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each R d4 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2, and the targeting ligand is a group capable of binding to a target protein. or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0170] In one embodiment, n is 1. In another embodiment, n is 2. In one embodiment, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d3 is H.

[0171] In another aspect, the present disclosure provides a compound of formula (BF-III): [ka] (In the formula, L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (BF-III). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d4 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, and C1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2, and the targeting ligand is a group capable of binding to a target protein. or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0172] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d3 is H. In some embodiments, -X 1 -L 2 -X 2 teeth, [ka] is. In one embodiment, L 1 is -O- or C 1~6 In one embodiment, R d1 and R d2 and R are both methyl. d1 and R d2 are both H. In another embodiment, R d4 is H or C 1~3 In one embodiment, R d5 is H or C 1~3 It is alkyl.

[0173] In another aspect, the present disclosure provides a compound of formula (BF-IV): [ka] (In the formula, L 1 is a bond, -O-, -NR', -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR', -C(O)-, C 1~6 Alkylene, C 1~6 heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 * is selected from the group consisting of L in formula (BF-IV). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; Ring A is a 6-membered aryl or 6-membered heteroaryl, each independently containing 0 to 4 R d6 is replaced by the presence of; Each R d6 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R p is H or C 1~6 is alkyl; Each R d8 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 selected from the group consisting of heteroalkyl; or two R's d8 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d8 is C 3~4 Forming a spirocycloalkyl; m is 1 or 2; and n is 1 or 2, and the targeting ligand is a group capable of binding to a target protein. or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0174] In certain embodiments, the compound has the formula (BF-VA) or (BF-VB): [ka] (In the formula, L 1 is a bond, -O-, -NR', -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR', -C(O)-, C 1~6 Alkylene, C 1~6 heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * represents L in formula (BF-VA or BF-VB). 3 X 2 means the point of attachment to; L 1, X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; U is -CR d6 or N; Each R d6 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d8 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2, and the targeting ligand is a group capable of binding to a target protein. or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0175] In one embodiment, n is 1. In another aspect, n is 2. In another aspect, R d7 is -CH2OP(O)(OR p )2. In another embodiment, R d7 is H. In another embodiment, U is -CR d6 In another embodiment, R d8 is H. In another embodiment, R d7 and Rd8 are each independently H. In another embodiment, R d6 is H. In another embodiment, R d6 H, halogen, C 1~6 Alkyl, and C 1~6 In another embodiment, R is selected from the group consisting of alkoxyl. d6 H, halogen, C 1~6 Alkyl, and C 1~6 alkoxyl; and R d7 , and R d8 are H, respectively.

[0176] In one embodiment, L 1 -X 1 -L 2 -X 2 -L 3 teeth, [ka] In one embodiment, L 3 is a bond, -O-, -C(O)-, -S(O)2-, C 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 heteroalkylene.

[0177] Intermediates Another embodiment is a compound of formula (ILB-I): [ka] (In the formula, R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p)2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each R d4 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, and C 1~6 heteroalkyl; Each R d5 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 is selected from the group consisting of cycloalkyl; or two R's d5 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d5 is C 3~4 Forming a spirocycloalkyl; R L1 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , C 3~6 Heteroalkyl, C 2~6 Haloalkyl, -(CH2) 1~3 C(O)OH, -(CH2) 1~3 C(O)H, -(CH2) 1~3 O(CH2) 1~3 C(O)H, -(CH2) 0~3 C 3~7 Carbocyclyl, -(CH2) 0~3 and selected from the group consisting of heterocyclyl, C6 aryl, and heteroaryl, wherein carbocyclyl, heterocyclyl, aryl, and heteroaryl are selected from the group consisting of 0 to 2 -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted by the presence of haloalkyl; R c is H, C 1~4 Alkyl or C 1~6 is heteroalkyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0178] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d3 is H. In one embodiment, R d4 is H.

[0179] In one embodiment, R L1 is C 2~6 Alkenyl, C 2~6 Hydroxyalkyl, -(CH2) 1~3 C(O)OH, -(CH2) 1~3 C(O)H, -(CH2) 1~3 O(CH2) 1~3 C(O)H, -(CH2) 0~3 heterocyclyl, wherein the heterocyclyl is substituted by 0 to 2 occurrences of -O-heterocyclyl.

[0180] Another embodiment is [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0181] Another embodiment is a compound of formula (ILB-II): [ka] (In the formula, Q is N or CR d4 and; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2(O)(CH2)2Si(CH3)3, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; Each R d4 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl;C 1~6 Alkoxyalkyl, and C 1~6 heteroalkyl; Each R d5 are independently H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 is selected from the group consisting of cycloalkyl; or two R's d5 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d5 is C 3~4 Forming a spirocycloalkyl; R L1 is C 2~6 Alkenyl, C 2~6 Alkynyl, C 2~6Hydroxyalkyl, -(CH2) 2~6 NHR c , C 3~6 Heteroalkyl, C 2~6 Haloalkyl, -(CH2) 0~3 C(O)OH, -(CH2) 0~3 C(O)H, -(CH2) 0~3 C 3~7 Carbocyclyl, -(CH2) 0~3 and selected from the group consisting of heterocyclyl, C6 aryl, and heteroaryl, wherein carbocyclyl, heterocyclyl, aryl, and heteroaryl are selected from the group consisting of 0 to 2 -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted by the presence of haloalkyl; R c is H, C 1~4 Alkyl or C 1~6 is heteroalkyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0182] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d3 is -CH2OP(O)(OR p )2. In one embodiment, R d3 is H.

[0183] In certain embodiments, Q is N; and R L1 is -(CH2) 0~3 C(O)OH.

[0184] In certain embodiments, Q is CR d4 and R L1 is C 2~6 Hydroxyalkyl, -(CH2) 0~3 C(O)OH and -(CH2) 0~3 It is C(O)H.

[0185] Another embodiment is [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0186] Another embodiment is a compound of formula (ILB-III): [ka] (In the formula, Ring A is [ka] and; [ka] denotes the point of attachment to the underlying molecule of (ILB-III); U 1 , U 2 , U 3 , U 4 , and U 5 are each independently N or CR d6 or CR L2 and U 1 , U 2 , U 3 , U 4 , and U 5 up to three of may be N, and U 1 , U 2 , U 3 , U 4 , and U 5 One of them is CRL2 and the remainder is CR d6 and; Z 1 O, S, NR d6a ; or NR L2a selected from the group consisting of: V 1 , V 2 , V 3 , and V 4 are each independently N or C, and V 1 , V 2 , V 3 , and V 4 up to two of may be N, and Z 1 , V 1 , V 2 , V 3 , and V 4 One of them is R L2 is replaced by V 1 , V 2 , V 3 , and V 4 One of these is the point of attachment to the underlying molecule of (ILB-III), and the remaining is R d6 is replaced by; Each R d6 are independently H, hydroxyl, oxo, polyethylene glycol (PEG), halogen, C 1~3 Alkyl, C 1~3 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl and -OC 1~7 heteroalkyl; Each R d6a are independently H, polyethylene glycol (PEG), C 1~3 Alkyl, C 3~6 Cycloalkyl, C 2~6 Haloalkyl, and C 2~6 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2; Each R d8 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 selected from the group consisting of heteroalkyl; or two R's d8 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d8 is C 3~4 Forming a spirocycloalkyl; R L2 is H, hydroxyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , -(CH2) 2~6 NR c R d , -O-(CH2) 2~6 NHR c , C 1~8 Heteroalkyl, C 1~6 Haloalkyl, -SO2-NH-(CH2) 2~6 NHR c , -(CH2) 0~3 C(O)OH, -(CH2) 0~3 C(O)OR c , -OC 2~6 Alkenyl, -O-(CH2) 0~3 C(O)H, -(CH2) 1~3 C(O)H, -O-(CH2) 1~3 C(O)OH, -(CH2) 0~3 Heterocyclyl, -C(O)-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 C(O)-heterocyclyl, -C 2~6 alkynyl-heterocyclyl, and heteroaryl, wherein alkynyl, heterocyclyl, heteroalkyl, carbocyclyl, and heteroaryl are selected from the group consisting of 0-2 halogen, hydroxyl, -(CH2) 0~3 C(O)H, -(CH2)2~6 NHR c , -(CH2) 2~6 N(R c )2, heterocyclyl, -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted by the presence of haloalkyl; R L2a is H, C 3~6 Alkenyl, C 3~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , -(CH2) 2~6 NR c R d , C 2~8 Heteroalkyl, C 2~6 Haloalkyl, -(CH2) 1~3 C(O)OH, -(CH2) 1~3 C(O)H, -(CH2) 0~3 Heterocyclyl, -C(O)-(CH2) 0~3 Heterocyclyl, -C 3~6 alkynyl-heterocyclyl, and heteroaryl, wherein alkynyl, heterocyclyl, heteroalkyl, carbocyclyl, and heteroaryl are selected from the group consisting of 0-2 halogen, hydroxyl, -(CH2) 0~3 C(O)H, -(CH2) 2~6 NHR c , heterocyclyl, -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted by the presence of haloalkyl; R c is H, C 1~4 Alkyl, C 1~6Heteroalkyl and -C(O)OC 1~6 is alkyl; R d is H or C 1~4 alkyl; or R c and R d together with the nitrogen atom to which they are attached to form a heterocyclyl substituted by 0-2 occurrences of -O-heterocyclyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0187] Another embodiment is a compound of formula (ILB-III): [ka] (In the formula, Ring A is [ka] selected from the group consisting of: [ka] denotes the point of attachment to the underlying molecule of (ILB-III); Each R d6 are independently H, oxo, polyethylene glycol (PEG), halogen, C 1~3 Alkyl, C 1~3 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl and -OC 1~7 heteroalkyl; Each R d6a are independently H, hydroxyl, oxo, polyethylene glycol (PEG), halogen, C 1~3 Alkyl, C1~3 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl and -OC 1~7 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2; Each R d8 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 selected from the group consisting of heteroalkyl; or two R's d8 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d8 is C 3~4 Forming a spirocycloalkyl; R L2 is hydroxyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , -(CH2) 2~6 NR c R d , -O-(CH2) 2~6 NHR c , C 4~8 Heteroalkyl, C 2~6 Haloalkyl, -SO2-NH-(CH2) 2~6 NHR c , -(CH2) 0~3 C(O)OH, -(CH2) 0~3 C(O)OR c , -OC 2~6 Alkenyl, -O-(CH2) 0~3 C(O)H, -(CH2) 0~3 C(O)H, -O-(CH2) 1~3 C(O)OH, -(CH2) 0~3Heterocyclyl, -C(O)-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 C(O)-heterocyclyl, -C 2~6 alkynyl-heterocyclyl, and heteroaryl, wherein alkynyl, heterocyclyl, heteroalkyl, carbocyclyl, and heteroaryl are selected from the group consisting of 0-2 halogen, hydroxyl, -(CH2) 0~3 C(O)H, -(CH2) 2~6 NHR c , -(CH2) 2~6 N(R c )2, heterocyclyl, heteroaryl, -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted with any occurrence of haloalkyl, heterocyclyl and heteroaryl with 0-2 occurrences of halogen; R L2a is H, hydroxyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , -(CH2) 2~6 NR c R d , -O-(CH2) 2~6 NHR c , C 1~8 Heteroalkyl, C 1~6 Haloalkyl, -SO2-NH-(CH2) 2~6 NHR c , -(CH2) 0~3 C(O)OH, -(CH2) 0~3 C(O)OR c , -OC 2~6 Alkenyl, -O-(CH2) 0~3 C(O)H, -(CH2) 0~3 C(O)H, -O-(CH2)1~3 C(O)OH, -(CH2) 0~3 Heterocyclyl, -C(O)-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 C(O)-heterocyclyl, -C 2~6 alkynyl-heterocyclyl, and heteroaryl, wherein alkynyl, heterocyclyl, heteroalkyl, carbocyclyl, and heteroaryl are selected from the group consisting of 0-2 halogen, hydroxyl, -(CH2) 0~3 C(O)H, -(CH2) 2~6 NHR c , -(CH2) 2~6 N(R c )2, heterocyclyl, -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted with 0-2 occurrences of haloalkyl and heterocyclyl with 0-2 occurrences of halogen; R L2b H, polyethylene glycol (PEG), C 1~3 Alkyl, C 3~6 Cycloalkyl, C 3~6 Alkenyl, C 3~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , -(CH2) 2~6 NR c R d , C 2~8 Heteroalkyl, C 2~6 Haloalkyl, -(CH2) 1~3 C(O)OH, -(CH2) 1~3 C(O)H, -(CH2) 0~3 Heterocyclyl, -C(O)-(CH2) 0~3 Heterocyclyl, -C 3~6alkynyl-heterocyclyl, and heteroaryl, wherein alkynyl, heterocyclyl, heteroalkyl, carbocyclyl, and heteroaryl are selected from the group consisting of 0-2 halogen, hydroxyl, -(CH2) 0~3 C(O)H, -(CH2) 2~6 NHR c , heterocyclyl, -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted by the presence of haloalkyl; R c is H, C 1~4 Alkyl, C 1~6 Heteroalkyl and -C(O)OC 1~6 is alkyl; R d is H or C 1~4 alkyl; or R c and R d together with the nitrogen atom to which they are attached to form a heterocyclyl substituted by 0-2 occurrences of -O-heterocyclyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0188] In certain embodiments, ring A is [ka] is selected from the group consisting of:

[0189] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R d7is -CH2OP(O)(OR p )2. In one embodiment, R d7 is H.

[0190] In some embodiments, each R d6 are independently H, polyethylene glycol (PEG), halogen, C 1~3 Alkyl, and C 1~3 alkoxyl.

[0191] In some embodiments, each R d6a are independently halogen.

[0192] In one embodiment, R L2 is hydroxyl, C 2~6 Alkynyl, -O-(CH2) 2~6 NHR c , C 4~8 Heteroalkyl, -SO2-NH-(CH2) 2~6 NHR c , -OC 2~6 Alkenyl, -(CH2) 0~3 C(O)H, -O-(CH2) 1~3 C(O)OH, -(CH2) 0~3 Heterocyclyl, -C(O)-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 C(O)-heterocyclyl, -C 2~6 alkynyl-heterocyclyl, and heteroaryl, wherein alkynyl, heterocyclyl, heteroalkyl, and heteroaryl are selected from the group consisting of 0-2 halogen, hydroxyl, —(CH2) 2~6 NHR c , heterocyclyl, heteroaryl, -C(O)-heterocyclyl, where heterocyclyl and heteroaryl are substituted by 0-2 halogen occurrences.

[0193] In certain embodiments, heterocyclyl is [ka] is selected from the group consisting of [ka] is the point of attachment to the underlying molecule of (ILB-III).

[0194] In one embodiment, R L2a is H.

[0195] In one embodiment, R c is H or C 1~6 It is alkyl.

[0196] In one embodiment, R d is H or C 1~4 It is alkyl.

[0197] Another embodiment is [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0198] Another embodiment is a compound of formula (ILB-IV): [ka] (In the formula, Ring A is [ka] and; [ka] denotes the point of attachment to the underlying molecule of (ILB-IV); U 1 , U 2 , U 3 , U 4 , and U 5 are each independently N or CR d4 or CR L2 and U 1 , U 2 , U 3 , U 4 , and U 5 up to three of may be N, and U 1 , U 2 , U 3 , U 4 , and U 5 One of them is CR L2 and the remainder is CR d4 and; Z 1 O, S, NR d4a ; or NR L2a selected from the group consisting of: V 1 , V 2 , V 3 , and V 4 are each independently N or C, and V 1 , V 2 , V 3 , and V 4 up to two of may be N, and Z 1 , V 1 , V2 , V 3 , and V 4 One of them is R L2 The remainder is replaced by R d4 is replaced by; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6 cycloalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2; Each R d4 are independently H, hydroxyl, oxo, polyethylene glycol (PEG), halogen, C 1~3 Alkyl, C 1~3 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl and -OC 1~7 heteroalkyl; Each R d4a are independently H, polyethylene glycol (PEG), C 1~3 Alkyl, C 3~6 Cycloalkyl, C 2~6 Haloalkyl, and C 2~6 heteroalkyl; Each R d5 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 selected from the group consisting of heteroalkyl; or two R's d8 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d8 is C 3~4 Forming a spirocycloalkyl; RL2 is hydroxyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , -(CH2) 2~6 NR c R d , -O-(CH2) 2~6 NHR c , C 4~8 Heteroalkyl, C 2~6 Haloalkyl, -SO2-NH-(CH2) 2~6 NHR c , -(CH2) 0~3 C(O)OH, -(CH2) 0~3 C(O)OR c , -OC 2~6 Alkenyl, -O-(CH2) 0~3 C(O)H, -(CH2) 0~3 C(O)H, -O-(CH2) 1~3 C(O)OH, -(CH2) 0~3 Heterocyclyl, -C(O)-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 C(O)-heterocyclyl, -C 2~6 alkynyl-heterocyclyl, and heteroaryl, wherein alkynyl, heterocyclyl, heteroalkyl, carbocyclyl, and heteroaryl are selected from the group consisting of 0-2 halogen, hydroxyl, -(CH2) 0~3 C(O)H, -(CH2) 2~6 NHR c , -(CH2) 2~6 N(R c )2, heterocyclyl, heteroaryl, -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6substituted with any occurrence of haloalkyl, heterocyclyl and heteroaryl with 0-2 occurrences of halogen; R L2a is H, hydroxyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , -(CH2) 2~6 NR c R d , -O-(CH2) 2~6 NHR c , C 1~8 Heteroalkyl, C 1~6 Haloalkyl, -SO2-NH-(CH2) 2~6 NHR c , -(CH2) 0~3 C(O)OH, -(CH2) 0~3 C(O)OR c , -OC 2~6 Alkenyl, -O-(CH2) 0~3 C(O)H, -(CH2) 0~3 C(O)H, -O-(CH2) 1~3 C(O)OH, -(CH2) 0~3 Heterocyclyl, -C(O)-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 C(O)-heterocyclyl, -C 2~6 alkynyl-heterocyclyl, and heteroaryl, wherein alkynyl, heterocyclyl, heteroalkyl, carbocyclyl, and heteroaryl are selected from the group consisting of 0-2 halogen, hydroxyl, -(CH2) 0~3 C(O)H, -(CH2) 2~6 NHR c , -(CH2) 2~6 N(R c )2, heterocyclyl, -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6Heteroalkyl, and C 1~6 substituted with 0-2 occurrences of haloalkyl and heterocyclyl with 0-2 occurrences of halogen; R c is H, C 1~4 Alkyl, C 1~6 Heteroalkyl and -C(O)OC 1~6 is alkyl; R d is H or C 1~4 alkyl; or R c and R d together with the nitrogen atom to which they are attached to form a heterocyclyl substituted by 0-2 occurrences of -O-heterocyclyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0199] Another embodiment is a compound of formula (ILB-IV): [ka] (In the formula, Ring A is [ka] selected from the group consisting of: [ka] denotes the point of attachment to the underlying molecule of (ILB-IV); R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl, and C 3~6cycloalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2; R d4 is H, hydroxyl, oxo, polyethylene glycol (PEG), halogen, C 1~3 Alkyl, C 3~6 Cycloalkyl, C 1~3 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Heteroalkyl and -OC 1~7 heteroalkyl; Each R d4a are independently H, polyethylene glycol (PEG), C 1~3 Alkyl, C 3~6 Cycloalkyl, C 2~6 Haloalkyl, and C 2~6 heteroalkyl; Each R d5 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 selected from the group consisting of heteroalkyl; or two R's d8 together with the carbon atom to which they are attached form a cycloalkyl; or two R attached to the same carbon atom d8 is C 3~4 Forming a spirocycloalkyl; R L2 is hydroxyl, halogen, C 2~6 Alkyl, C 1~3 Alkoxyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 2~6 Hydroxyalkyl, -(CH2) 2~6 NHR c , -(CH2) 0~6 NR c R d, -O-(CH2) 2~6 NHR c , C 3~8 Heteroalkyl, C 1~6 Haloalkyl, -SO2-NH-(CH2) 2~6 NHR c , -(CH2) 0~3 C(O)OH, -O-(CH2) 1~3 C(O)H, -(CH2) 1~3 C(O)H, -O-(CH2) 1~3 C(O)OH, -(CH2) 0~3 C 3~7 carbocyclyl, -(CH2) 0~3 Heterocyclyl, -C(O)-(CH2) 0~3 Heterocyclyl, -O-(CH2) 0~3 Heterocyclyl, -C 2~6 Alkynyl-heterocyclyl, -C 2~6 alkynyl-heterocyclyl-heteroaryl, C6 aryl, and heteroaryl, wherein alkynyl, alkoxyl, heterocyclyl, heteroalkyl, carbocyclyl, aryl, and heteroaryl are selected from the group consisting of 0-2 halogen, hydroxyl, -(CH2) 0~3 C(O)H, -C(O)O-benzyl, -(CH2) 2~6 NHR c , heterocyclyl, -O-heterocyclyl, -O-carbocyclyl, -C(O)-heterocyclyl, -C(O)-carbocyclyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and C 1~6 substituted by the presence of haloalkyl; R p is H or C 1~6 is alkyl; m is 1 or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0200] In certain embodiments, ring A is [ka] selected from the group consisting of: R c is H, C 1~4 Alkyl, C 1~6 Heteroalkyl and -C(O)OC 1~6 alkyl; and R d is H or C 1~4 alkyl; or R c and R d together with the nitrogen atom to which they are attached form a heterocyclyl substituted by 0-2 occurrences of -O-heterocyclyl.

[0201] In one embodiment, R d4 is H or a halogen.

[0202] In some embodiments, each R d4a are independently H.

[0203] In one embodiment, R L2 is a halogen, -(CH2) 0~6 NR c R d , C 1~6 Haloalkyl, -(CH2) 0~3 C(O)OH, -(CH2) 0~3 Heterocyclyl, and -C(O)O-benzyl.

[0204] In one embodiment, R c is H, C 1~4 Alkyl, or -C(O)OC 1~6 It is alkyl.

[0205] In one embodiment, R d is H or C 1~4 It is alkyl.

[0206] Another embodiment is [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0207] compound Another embodiment is a compound of formula (II): [ka] (In the formula, R 1a is H or halo; R 2a is a halo; R 3a is C 1~6 is alkyl; R 4a is a halo; R 5a is H or halo; L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L2 -X 2 forms a spiroheterocyclyl; L 3 is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (BF-III). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; R d1 and R d2 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d3 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d4 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Alkoxyalkyl, and C 1~6 heteroalkyl; R d5 is H, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, and C1~6 heteroalkyl; and R p is H or C 1~6 alkyl) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0208] In one embodiment, R 2a is fluoro. In certain embodiments, R 3a is C 1~3 In one embodiment, R 3a is methyl.

[0209] In one embodiment, R 4a is fluoro. In certain embodiments, L 1 is C 1~9 In some embodiments, -X is alkylene. 1 -L 2 -X 2 -teeth, [ka] In one embodiment, L 2 is -C(O)-, -O-, or C 1~6 In one embodiment, L 3 is a bond, -O-, -C(O)-, -S(O)2-, -C 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 In one embodiment, R is selected from the group consisting of heteroalkylene. d4 is H. In one embodiment, R d1 is H. In one embodiment, R d2 is H. In one embodiment, R d1 and R d2 and are both H. In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d5 is H or C 1~3In one embodiment, R d5 is H.

[0210] Another embodiment is a compound of formula (IIA): [ka] (In the formula, R 1a is H or halo; R 2a is a halo; R 3a is C 1~6 is alkyl; R 4a is a halo; R 5a is H or halo; L 1 is a bond, -O-, -NR'-, -C(O)-, C 1~9 Alkylene, C 1~9 Heteroalkylene, *C(O)-C 1~6 Alkylene, *C(O)-C 1~6 Heteroalkylene, *C 1~6 Alkylene-C(O), and *C 1~6 heteroalkylene-C(O), and * is selected from the group consisting of L 1 means a point of attachment to a targeting ligand; X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L 2 is a bond, -O-, -NR'-, -C(O)-, C 1~6 Alkylene, C 1~6 Heteroalkylene, and *C(O)NR'-C 1~6 alkylene, and * is selected from the group consisting of L 2 X 2 signifying the point of attachment to; or X 1 -L 2 -X 2 forms a spiroheterocyclyl; L 3is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 1~6 Heteroalkylene, -C(O)-, -S(O)2-, -O-, *C(O)-C 1~9 Alkylene, *C(O)-C 1~6 Alkylene-O, and *C(O)-C 1~9 heteroalkylene, and * is selected from the group consisting of L in formula (BF-III). 3 X 2 means the point of attachment to; L 1 , X 1 , X 2 , L 2 , and L 3 No more than two of may be bonds at the same time; R' is hydrogen or C 1~6 is alkyl; U is -CR d6 or N; Each R d6 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; U is -CR d6 or N; Each R d6 are independently H, oxo, C 1~6 Alkyl, halogen, C 1~6 Alkoxyl, C 1~6 Haloalkyl, and C 1~6 heteroalkyl; R d7 is H, -CH2OC(O)R p , -CH2OP(O)OHOR p , -CH2OP(O)(R p )2, and -CH2OP(O)(OR p )2 is selected from the group consisting of; R d8 is H, C 1~6 Alkyl, halogen, C 1~6Haloalkyl, and C 1~6 heteroalkyl; R p is H or C 1~6 is alkyl; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0211] In one embodiment, R 2a is fluoro. In certain embodiments, R 3a is C 1~3 In one embodiment, R 3a is methyl.

[0212] In another embodiment, R 4a is fluoro. In certain embodiments, L 1 is C 1~9 In some embodiments, -X is alkylene. 1 -L 2 -X 2 -teeth, [ka] In one embodiment, L 2 is -C(O)-, -O-, or C 1~6 In one embodiment, L 3 is a bond, -O-, -C(O)-, -S(O)2-, C 1~6 Alkylene, C 2~6 Alkynylene, and C 1~6 In one embodiment, R is selected from the group consisting of heteroalkylene. d4 is H. In one embodiment, R d1 is H. In one embodiment, R d2 is H. In one embodiment, R d1 and R d2 and are both H. In some embodiments, n is 1. In some embodiments, R d3 is H. In one embodiment, R d5is H or C 1~3 It is alkyl. In one embodiment, R d5 is H.

[0213] Another embodiment is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0214] In certain embodiments, when the compound is a compound of formula (IIA), the compound is rac-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, (R)—N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, (S)—N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-ethoxybenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((1-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl)piperidin-4-yl)ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)oxy)piperidin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)piperidin-4-yl)oxy)piperidin-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(3-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)propyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((1-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((1-(3-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)propyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl)ethyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)ethyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, rac-N-(3-(6-(4-((1-(2-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)oxy)-3-hydroxypropyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-methylpropyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((1-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl)ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazine-1-carbonyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, rac-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, (S)—N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, (R)—N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-1-(hydroxymethyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzamido)butyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro-N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)amino)pentyl)-N,4-dimethylbenzamide, 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluoro-N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)amino)pentyl)-4-methylbenzamide, 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)amino)pentyl)-N,4-dimethylbenzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-carbonyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)oxy)piperidin-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((8-(2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzamido)ethyl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(4-((2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl)ethyl)amino)butoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzamido)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((1-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)ethyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzamido)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl)butyl)amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((((1s,4s)-4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)oxy)cyclohexyl)oxy)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(5-((4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)amino)pentyl)-N-methylbenzamide, N-(3-(6-(4-((1-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)ethyl)piperidin-4-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzamido)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((3-((2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl)ethyl)amino)propoxy)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((1r,4r)-4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)oxy)cyclohexyl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzamido)propyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((8-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)piperidin-4-yl)oxy)piperidin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((1-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl)ethyl)piperidin-4-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((2-(2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzamido)ethyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((2-(2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzamido)ethyl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-(((1s,4s)-4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)oxy)cyclohexyl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((((1r,4r)-4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)oxy)cyclohexyl)oxy)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, N-(3-(6-(4-((9-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzamido)propyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, and N-(3-(6-(4-((1-(2-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)oxy)ethyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide, or a pharmaceutically acceptable salt thereof.

[0215] definition One embodiment is a compound of any of the formulae described herein, e.g., a compound of formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, that modulates, e.g., decreases, the amount of a targeted protein or protein of interest, e.g., one or more proteins from Table 1 or Table 2.

[0216] Another embodiment is a compound of any of the formulae described herein, e.g., a compound of formula (I), (II), (III), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, that degrades targeted proteins via the ubiquitin-proteasome pathway (UPP).

[0217] The formation of a viable ternary complex between a target protein, a bifunctional degrader, and an E3 ligase substrate receptor is enabled by the use of targeted bifunctional degraders, which rely on three components: a "targeting ligand," a "targeting ligase binder" (also called a "warhead"), and a binding segment, also called a "linker." The likelihood that a bifunctional degrader can form an energetically favorable viable complex can be assessed using in silico computational methods. Energetic disadvantages can arise from enthalpic contributions (steric or electronic clashes between the protein target and the degrader), entropic contributions (reduced degrees of freedom associated with the formation of the ternary complex), or a combination of the two. Using in silico methods, unfavorable linkers can be rapidly identified and deprioritized. Various methods have been described for designing bifunctional degraders. See Drummond and Williams, J. Chem. Inf. Model. 59:1634-1644 (2019). The in silico ternary complex modeling protocol consists of four steps (see Figure 2): (1) Generate a conformational ensemble of the bifunctional degrader. Various conformational search methods available in standard modeling programs can be used for this task. (2) Tightly superimpose the coordinates of one of the warheads (either the "targeting ligand" or the "targeting ligase binder") with the coordinates of the same warhead bound to the binary complex structure, either as observed in the crystal structure or by docking in the respective proteins. (3) Select to preserve the sterically competent conformation of the bifunctional degrader with the first protein. (4) Tightly superimpose the bound warhead in the other binary complex structure with the coordinates of the corresponding warhead in the degrader. Conformations of the targeted bifunctional degrader that cause significant clashes between any of the three components of the ternary complex are selected. The preserved and generated conformations can be further clustered and refined using standard molecular dynamics techniques, allowing for the alleviation of minor steric clashes and electrostatic mismatches.It also gives an indication of the stability of the ternary complex; linkers that do not contact proteins can be said to be entropically unfavorable.

[0218] For example, the methods described herein have been applied to compounds 01 and 02. Although both compounds bind to CRBN (Table 4), compound 2 allows for the formation of a ternary complex according to the methods described herein, resulting in BTK degradation (>95%). However, compound 01 is predicted not to form a ternary complex, and no BTK degradation was observed experimentally (Table 4).

[0219] Modified linkers can also be designed using de novo or generative methods to improve physicochemical properties or some other scoring metric. See Ertl and Lewis, J. Comput Aided Mol. Des. 26(11):1207-1215 (2012). Evaluation of both ternary complex formation and favorable properties can be combined to identify optimal linker space.

[0220] The term "therapeutically effective amount" of a compound described herein refers to an amount of a compound described herein that will elicit a biological or medical response in a subject (e.g., reducing or inhibiting the activity of an enzyme or protein, or ameliorating a symptom, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease, etc.). In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound described herein that, when administered to a subject, is effective to (1) at least partially alleviate, prevent, and / or ameliorate a condition, disorder, or disease that is (i) mediated by, or (ii) associated with, or (iii) characterized by the activity (normal or abnormal) of a target protein; or (2) reduce or inhibit the activity of a target protein; or (3) reduce or inhibit the expression of a target protein. These effects can be achieved by reducing the amount of the target protein, for example, by degradation of the target protein. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound described herein that, when administered to a cell, or tissue, or non-cellular biomaterial, or culture medium, is effective to at least partially reduce or inhibit the activity of a target protein; or to at least partially reduce or inhibit the expression of a target protein, e.g., by degrading the target protein.

[0221] As used herein, the term cancer refers to a neoplastic disease and includes, for example, a solid tumor, such as a sarcoma or carcinoma, or a cancer of the blood, such as a leukemia or myeloma, or a cancer of the lymphatic system, such as a lymphoma, or a mixture thereof.

[0222] As used herein, the terms "degrade," "degrading," or "degradation" refer to the partial or complete breakdown of a target protein by the cellular proteasome system to such an extent that the biological activity (especially the abnormal activity) of the target protein is reduced or eliminated. Degradation can be achieved through the mediation of E3 ligases, particularly E3-ligase complexes that include the protein cereblon. As used herein, the terms "modulating target protein activity" or "modulating target activity" refer to the alteration, particularly the reduction, inhibition, or elimination, of the activity of a target protein. This can be achieved in vivo or in vitro by degrading the target protein. The amount of target protein degraded can be measured by comparing the initial amount or level of target protein present as measured before treatment with a compound described herein to the amount of target protein remaining after treatment with a compound described herein. In some embodiments, at least about 30% of the target protein is degraded compared to the initial level. In some embodiments, at least about 40% of the target protein is degraded compared to the initial level. In some embodiments, at least about 50% of the target protein is degraded compared to the initial level. In some embodiments, at least about 60% of the target protein is degraded compared to initial levels. In some embodiments, at least about 70% of the target protein is degraded compared to initial levels. In some embodiments, at least about 80% of the target protein is degraded compared to initial levels. In some embodiments, at least about 90% of the target protein is degraded compared to initial levels. In some embodiments, at least about 95% of the target protein is degraded compared to initial levels. In some embodiments, more than about 95% of the target protein is degraded compared to initial levels. In some embodiments, at least about 99% of the target protein is degraded compared to initial levels.

[0223] In some embodiments, the target protein is degraded at about 30% to about 99% of its initial level. In some embodiments, the target protein is degraded at about 40% to about 99% of its initial level. In some embodiments, the target protein is degraded at about 50% to about 99% of its initial level. In some embodiments, the target protein is degraded at about 60% to about 99% of its initial level. In some embodiments, the target protein is degraded at about 70% to about 99% of its initial level. In some embodiments, the target protein is degraded at about 80% to about 99% of its initial level. In some embodiments, the target protein is degraded at about 90% to about 99% of its initial level. In some embodiments, the target protein is degraded at about 95% to about 99% of its initial level. In some embodiments, the target protein is degraded at about 90% to about 95% of its initial level.

[0224] As used herein, the term "selectivity for a target protein" means, for example, that a compound described herein degrades the target protein preferentially or to a greater extent than another protein.

[0225] As used herein, the term "subject" refers to an animal. Typically, an animal is a mammal. A subject also refers to, for example, a primate (e.g., a human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In some embodiments, the subject is a primate. In a preferred embodiment, the subject is a human.

[0226] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0227] As used herein, the terms "treat," "treating," or "treatment," in reference to any disease or disorder, refer, in certain embodiments, to ameliorating the disease or disorder (i.e., slowing or preventing or reducing the development of the disease or at least one of its clinical symptoms). In certain embodiments, "treat," "treating," or "treatment" refers to alleviating or improving at least one physical parameter, including those that may not be discernible by the patient.

[0228] As used herein, the term "preventing" refers to reducing the frequency of a condition or disease or delaying the onset of its symptoms.

[0229] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0230] As used herein, the terms "a," "an," "the," and similar terms as used within the context of this disclosure (especially in the context of the claims) are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0231] The term "alkyl" refers to a group of linear or branched saturated hydrocarbon groups having 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl).

[0232] "Alkylene" refers to a divalent radical of an alkyl group, e.g., -CH2-, -CH2CH2-, and -CH2CH2CH2-.

[0233] "Heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur in one or more terminal positions of the parent chain (i.e., interposed between adjacent carbon atoms thereof) and / or located at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("heteroC"). 1~10 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~7 In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~6In some embodiments, heteroalkyl groups are saturated groups having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~5 In some embodiments, heteroalkyl groups are saturated groups having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~3 In some embodiments, heteroalkyl groups are saturated groups having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~2 In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is alkyl.

[0234] "Heteroalkylene" refers to a divalent radical of a heteroalkyl group.

[0235] "Alkoxy" or "alkoxyl" refers to an -O-alkyl group. In some embodiments, alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. In some embodiments, alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms. In some embodiments, alkoxy groups have 1 to 4 carbon atoms.

[0236] As used herein, the term "aryl" refers to a stable aromatic monocyclic or bicyclic ring group having a specified number of ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. The related term "aryl ring" similarly refers to a stable aromatic monocyclic or bicyclic ring group having a specified number of ring carbon atoms.

[0237] As used herein, the term "heteroaryl" refers to a stable, aromatic, monocyclic or bicyclic ring group having the specified number of ring atoms and containing one or more heteroatoms individually selected from nitrogen, oxygen, and sulfur. The heteroaryl group can be attached via a carbon atom or a heteroatom. Examples of heteroaryl groups include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, oxadiazolyl, benzothiazolyl, quinoxalinyl, and the like. The related term "heteroaryl ring" similarly refers to a stable, aromatic, monocyclic or bicyclic ring having the specified number of ring atoms and containing one or more heteroatoms individually selected from nitrogen, oxygen, and sulfur.

[0238] As used herein, the term "carbocyclyl" refers to a stable saturated or unsaturated non-aromatic monocyclic or bicyclic (fused, bridged, or spiro) ring group having the specified number of ring carbon atoms. Examples of carbocyclyl groups include, but are not limited to, the cycloalkyl groups identified above, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. In certain embodiments, the specified number is C3-C6. 12 The related term "carbocyclic ring" similarly refers to a stable saturated or unsaturated non-aromatic monocyclic or bicyclic (fused, bridged, or spiro) ring having a specified number of ring carbon atoms. In certain embodiments, a carbocyclyl may be substituted or unsubstituted. In certain embodiments, a carbocyclyl may be substituted or unsubstituted by 0 to 4 Ra and each R a independently, C 1~6 Alkyl, C 1~6 is selected from the group consisting of alkoxyl, and halogen.

[0239] As used herein, the term "heterocyclyl" refers to a stable saturated or unsaturated non-aromatic monocyclic or bicyclic (fused, bridged, or spiro) ring group having the specified number of ring atoms and containing one or more heteroatoms individually selected from nitrogen, oxygen, and sulfur. The heterocyclyl group can be attached via a carbon atom or a heteroatom. In some embodiments, the specified number is C3 to C6. 12

[0037] The carbon atom of the heterocyclyl group is 0, 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, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, a and each R a independently, C 1~6 Alkyl, C 1~6 is selected from the group consisting of alkoxyl, and halogen.

[0240] As used herein, "spirocycloalkyl" or "spirocyclyl" refers to a carbobicyclic ring system in which both rings are connected through a single atom. The rings may be different in size and nature or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both rings in a spirocycle may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. For example, (C3-C 12 ) A spirocycloalkyl is a spiro ring containing 3 to 12 carbon atoms.

[0241] As used herein, "spiroheterocycloalkyl" or "spiroheterocyclyl" refers to a spiro ring in which at least one of the rings is a heterocycle (one or more of the carbon atoms can be replaced with a heteroatom (e.g., one or more of the carbon atoms can be replaced with a heteroatom in at least one of the rings)). One or both of the rings in a spiroheterocycle can be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.

[0242] As used herein, "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0243] As used herein, "haloalkyl" refers to an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl.

[0244] As used herein, "substituted," whether preceded by the term "optionally," means that one or more hydrogens at a designated site are replaced with a suitable substituent.

[0245] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than one time in any structure, shall be independent of its definition elsewhere in the same structure.

[0246] Various embodiments of the present disclosure are described herein. It will be recognized that the features specified in each embodiment may be combined with other specified features, including those set forth in the embodiments below, to provide further embodiments of the present disclosure.

[0247] It is understood that in the following embodiments, combinations of substituents or variables of the depicted formulae are permissible only if such combinations result in stable compounds.

[0248] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are defined in the Handbook of Chemistry and Physics, 75 th The elements are identified according to the Periodic Table of the Elements in CAS format, which is on the inside cover of the ed., and specific functional groups are generally defined as set forth therein. Further, general principles of organic chemistry and specific functional moieties and reactivities are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th ed, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd ed., Cambridge University Press, Cambridge, 1987.

[0249] Certain compounds described herein may exist in particular geometric or stereoisomeric forms. For example, if a particular enantiomer of a compound described herein is desired, it may be prepared by asymmetric synthesis or derivatization with an asymmetric auxiliary, the resulting diastereomeric mixture separated, and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts may be formed with an appropriate optically active acid or base, followed by separation of the diastereomers thus formed by fractional recrystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomers.

[0250] Unless otherwise specified, structures depicted herein are intended to include all geometric (or conformational) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E stereoisomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the disclosed compounds are within the scope of the disclosure. Unless otherwise specified, all tautomeric forms of the compounds described herein are within the scope of the disclosure. Furthermore, unless otherwise specified, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or the replacement of carbon by methyl or methyl. 13 C-rich carbon or 14 Compounds having the disclosed structures containing C-rich carbon replacements are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present disclosure.

[0251] The "enantiomeric excess" or "% enantiomeric excess" of a composition can be calculated using the formula shown below. In the example shown below, the composition contains 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer. ee = (90 - 10) / 100 x 100 = 80%.

[0252] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. The compounds or compositions described herein may contain one form of the compound, e.g., the S-enantiomer, in an enantiomeric excess of at least 50%, 75%, 90%, 95%, or 99%. In other words, such compounds or compositions contain an enantiomeric excess of the S-enantiomer over the R-enantiomer.

[0253] When a particular enantiomer is preferred, in some embodiments it may be provided substantially free of the corresponding enantiomer and may also be referred to as "optically enriched." As used herein, "optically enriched" means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99% by weight of the preferred enantiomer. The preferred enantiomer may be isolated from a racemic mixture by any method known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972).

[0254] Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. Any examples provided herein, or the use of exemplary language (e.g., "etc."), are intended merely to further clarify the disclosure and do not limit the scope of the disclosure unless otherwise stated.

[0255] Any resulting mixture of isomers can be separated on the basis of the physical chemical differences of the components into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional recrystallization.

[0256] Any resulting racemic forms of final products or intermediates can be resolved into their optical antipodes by known methods, for example, by separation of their diastereomeric salts obtained with optically active acids or bases, liberating the optically active acidic or basic compounds. In particular, compounds described herein may be resolved into their optical antipodes by fractional recrystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid, using basic moieties in this manner. Racemic products can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC), using a chiral adsorbent.

[0257] pharmaceutically acceptable salts Pharmaceutically acceptable salts of the compounds described herein are also contemplated for the uses described herein. As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds described herein. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds disclosed herein and that are not typically biologically or otherwise undesirable. In many cases, the compounds disclosed herein are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0258] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0259] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0260] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0261] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0262] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0263] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0264] Another embodiment is acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlorotheophylline, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate. and compounds 1-35 of formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35 in the form of a salt, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate, or xinafoate salt.

[0265] Pharmaceutical Composition Another embodiment is a pharmaceutical composition comprising one or more compounds described herein or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting any subject composition or its components. Each carrier must be "acceptable" in the sense of being compatible with the subject composition and its components, and not deleterious to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; and (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, and corn oil. and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0266] The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions of the present disclosure are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present disclosure may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as a solvent or suspending medium.

[0267] For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants such as carboxymethylcellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween®, Span, and other emulsifiers, or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for formulation.

[0268] The pharmaceutically acceptable compositions described herein can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also usually added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.If necessary, certain sweeteners, flavorings or coloring agents can also be added.

[0269] Alternatively, the pharmaceutically acceptable composition of the present disclosure can be administered in the form of suppositories for rectal administration.These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, so that it melts in the rectum and releases the drug.Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0270] The pharmaceutically acceptable compositions of the present disclosure can also be administered topically, especially when the target of treatment includes areas or organs that are easily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations can be easily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be carried out in a rectal suppository formulation (see above) or a suitable enema formulation. Topical transdermal patches can also be used.

[0271] For topical application, pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0272] Pharmaceutically acceptable compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline utilizing benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. The amount of a compound of the present disclosure that may be combined with a carrier material to produce a composition in a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01 and 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0273] isotope labeled compounds The compounds described herein or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers are also intended to be unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structure shown by the formulas provided herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 I. The present disclosure provides various isotopically labeled compounds as defined herein, such as 3 H and 14 Radioactive isotopes such as C, or 2 H and 13 These isotope-labeled compounds include those in which non-radioactive isotopes such as C are present. 14 C), reaction rate tests (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiation treatment of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying examples and preparations, substituting the appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0274] Additionally, heavier isotopes, especially deuterium (i.e. 2 Substitution with H or D) may result in certain therapeutic benefits resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, or improved therapeutic index. It is understood that deuterium in this context is considered to be a substituent of the compounds described herein or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope. When a substituent in a compound described herein is designated as deuterium, such compound has, for each designated deuterium atom, an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0275] Dosage Toxicity and therapeutic efficacy of the compounds described herein, including pharmaceutically acceptable salts and deuterated variants, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. 50 ED is the dose that is lethal to 50% of the population. 50 is the dose that is therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects (LD 50 / ED 50) is the therapeutic index. Compounds that exhibit large therapeutic indices are preferred. Compounds that exhibit toxic side effects may also be used, but care should be taken to design a delivery system that targets such compounds to the site of affected tissue to minimize the possibility of damaging uninfected cells, thereby reducing side effects.

[0276] The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. Such compounds can be administered at doses that produce little or no toxicity and ED 50 The circulating concentration of the compound may be within a range including the IC50 or IC60 as determined in cell culture. The dosage may vary within this range depending on the dosage form and route of administration utilized. For any compound, the therapeutically effective dose can be estimated initially from cell culture assays. The dose can be determined based on the IC50 or IC60 as determined in cell culture. 50 Animal models can be developed to achieve a circulating plasma concentration range that includes (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms). Such information can be used to more accurately determine useful doses in humans. Plasma levels can be measured, for example, by high performance liquid chromatography.

[0277] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the attending physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend on the particular compound in the composition.

[0278] How to use Another embodiment is a method of modulating a target protein, e.g., a target protein listed in Table 1 or Table 2, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0279] Another embodiment is a method of inhibiting a target protein, e.g., a target protein listed in Table 1 or Table 2, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0280] Another embodiment is a method of inducing degradation of a target protein, e.g., a target protein listed in Table 1 or Table 2, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0281] In another aspect, the disclosure provides a method of inhibiting, reducing, or eliminating the activity of a target protein, e.g., a target protein listed in Table 1 or Table 2, comprising administering to a subject a compound of formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0282] In some embodiments, inhibiting, reducing, or eliminating the activity of a target protein, e.g., a target protein listed in Table 1 or Table 2, comprises recruiting a ligase (e.g., cereblon E3 ubiquitin ligase) with a compound, e.g., a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or a targeted ligase binder of Compounds 1-35, e.g., a targeted ligase binder described herein, to form a ternary complex of the target protein, the compound, and the ligase, thereby inhibiting, reducing, or eliminating the activity of the target protein.

[0283] Another embodiment is a method of treating or preventing a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease or disorder mediated by a target protein, e.g., a target protein listed in Table 1 or Table 2, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0284] Another embodiment is a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0285] In certain embodiments, the cancer is a neoplastic disease, including, for example, a solid tumor, such as, for example, a sarcoma or carcinoma, or a cancer of the blood, such as, for example, a leukemia or myeloma, or a cancer of the lymphatic system, such as, for example, a lymphoma, or a mixture thereof.

[0286] In another aspect, the disclosure provides a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in inhibiting or modulating a target protein in a subject in need thereof.

[0287] In another aspect, the disclosure provides a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in inhibiting a target protein in a subject in need thereof.

[0288] Another embodiment is a pharmaceutical composition comprising a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier for use in inhibiting a target protein, e.g., a target protein listed in Table 1 or Table 2, in a subject in need thereof.

[0289] Another embodiment is a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease or disorder mediated by a target protein, e.g., a target protein listed in Table 1 or Table 2, in a subject in need thereof.

[0290] Another embodiment is a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing cancer in a subject in need thereof.

[0291] In certain embodiments, the cancer is a neoplastic disease, including, for example, a solid tumor, such as, for example, a sarcoma or carcinoma, or a cancer of the blood, such as, for example, a leukemia or myeloma, or a cancer of the lymphatic system, such as, for example, a lymphoma, or a mixture thereof.

[0292] Another embodiment is the use of a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for inhibiting or modulating a target protein, for example, a target protein listed in Table 1 or Table 2, in a subject in need thereof.

[0293] Another embodiment is the use of a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for inhibiting a target protein, such as a target protein listed in Table 1 or Table 2, in a subject in need thereof.

[0294] Another embodiment is the use of a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating or preventing cancer mediated by a target protein, e.g., a target protein listed in Table 1 or Table 2, in a subject in need thereof.

[0295] In certain embodiments, the cancer is a neoplastic disease, including, for example, a solid tumor, such as, for example, a sarcoma or carcinoma, or a cancer of the blood, such as, for example, a leukemia or myeloma, or a cancer of the lymphatic system, such as, for example, a lymphoma, or a mixture thereof.

[0296] Another embodiment is a method for treating or preventing a cancer mediated by a target protein, e.g., a target protein listed in Table 1 or Table 2, in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0297] In certain embodiments, the cancer is a neoplastic disease, including, for example, a solid tumor, such as, for example, a sarcoma or carcinoma, or a cancer of the blood, such as, for example, a leukemia or myeloma, or a cancer of the lymphatic system, such as, for example, a lymphoma, or a mixture thereof.

[0298] Another embodiment is the use of a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating or preventing a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease or disorder in a subject in need thereof.

[0299] Combination therapy Another embodiment is a pharmaceutical combination comprising a compound of Formula (I), (II), (IIA), (BF-I), (BF-II), (BF-III), (BF-IV), (BF-VA), (BF-VB), or compounds 1-35, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more additional therapeutic agents for simultaneous, separate, or sequential use in therapy.

[0300] In certain embodiments, the additional therapeutic agent is selected from the group consisting of antiproliferative agents, anticancer agents, immunomodulatory agents, anti-inflammatory agents, neurological therapeutic agents, antiviral agents, antifungal agents, antiparasitic agents, antibiotics, and general anti-infective agents.

[0301] In certain embodiments, the additional therapeutic agent is selected from the group consisting of a second target protein inhibitor.

[0302] Production method The compounds described herein can be prepared in several ways well known to those skilled in the art of organic synthesis. As an example, the compounds of the present disclosure can be synthesized using the following methods, along with synthetic methods known in the art of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, the following methods.

[0303] The disclosed compounds can be synthesized according to the general methods described below in synthetic schemes 1, 1a, 1b, 2-4, 4a, 5, 5a, 6, 6a, 7-16, 16a, 17-18, 18a, 18b, 19, 19a, and 20-21. Starting materials are either commercially available or made by known procedures reported in the literature or as illustrated.

[0304] Compounds of formula (I) (X 1 is a nitrogen-containing heterocyclyl, such as piperidinyl or piperazinyl, and X 2 , L 1 , L 2 , L 3 X (wherein X is as defined above) can be synthesized from a compound of formula (III) and a compound of formula (IV) according to Scheme 1 using a reductive amination reaction. 1 is a bond, Scheme 1 also provides compounds of formula (IV) (L 2 is a primary or secondary amine) with a compound of formula (III) to produce (I). 1a L 1 If the formula of is acceptable, L 1 (e.g., in one embodiment, L 1 If is -CH2CH2-, L 1a is -CH2-). 1 As for C 1~6 Alkylene and C 1~6Examples of suitable conditions include ZnCl and NaBHCN in a solvent mixture such as THF / DMSO and MeOH. Alternative conditions include treatment with NaBH(OAc) in NaOAc, AcOH, and DCM. Scheme 1 [ka]

[0305] Similarly, in further embodiments, bifunctional compounds (X) of formula (BF-I), (BF-II), (BF-III), (BF-VA), (BF-VB), and (BF-IV) are 1 is a nitrogen-containing heterocyclyl, such as piperidinyl or piperazinyl, and R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , X 2 , L 1 , L 2 , L 3 , m and n are as defined above) can be prepared from compounds of formula (III) and compounds of formula (IVa), (IVb), (IVc), (IVd), (IVe), and (IVf), respectively, according to Scheme 1a. Scheme 1a [ka]

[0306] In a further embodiment, the compound of formula (II) (X 1 is a nitrogen-containing heterocyclyl, such as piperidinyl or piperazinyl, and R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , X 2 , L 1 , L2 , L 3 , m and n are as defined above) can be reacted according to Scheme 1b to give a compound of formula (IIIa) (R 1a , R 2a , R 3a , R 4a , R 5a and L 1a is as defined previously) and a compound of formula (IVc), the same conditions as those described herein above apply. Scheme 1b [ka]

[0307] Intermediates (X) of formula (IVa), (IVb), (IVc), (IVd), (IVe) and (IVf) 1 where X is a nitrogen-containing heterocyclyl, e.g., piperidinyl or piperazinyl, can also be applied to the synthesis of compounds of formulas (BF-I), (BF-II), (BF-III), (BF-VA), (BF-VB), and (BF-IV), respectively, containing an amide bond by reaction with a carboxylic acid of formula (V) using an amide coupling reaction according to Scheme 2. Similarly, X 1 is a bond, Scheme 2 also provides compounds of formula (IVa-f) (L 2 is a primary or secondary amine) with a compound of formula (III) to produce (BF-I), (BF-II), (BF-III), (BF-VA), (BF-VB), and (BF-IV), respectively. 1b is a linker L containing a carbonyl group 1 and thus can provide compound (V) containing a carboxylic acid functionality. The conditions include using an amide coupling reagent such as HATU in a solvent such as DMF in the presence of a base such as DIPEA. Scheme 2 [ka]

[0308] In further embodiments, bifunctional compounds (X) of formula (BF-I), (BF-II), (BF-III), (BF-VA), (BF-VB), and (BF-IV) are 1 wherein X is a nitrogen-containing heterocyclyl, for example, piperidinyl or piperazinyl, can be prepared from compounds of formula (VI) (LG represents a leaving group such as halide or mesylate) and compounds of formula (IVa), (IVb), (IVc), (IVd), (IVe), and (IVf), respectively, using an alkylation reaction according to Scheme 3. Similarly, X 1 is a bond, Scheme 3 also provides compounds of formula (IVa-f) (L 2 is a primary or secondary amine) with a compound of formula (VI) to produce (BF-I), (BF-II), (BF-III), (BF-VA), (BF-VB), and (BF-IV), respectively. Scheme 3 [ka]

[0309] Typical conditions would be to treat an alkyl chloride of formula (VI) with an appropriate amine (IVa-f) in a solvent such as DMA with an iodide reagent such as potassium iodide and a base such as DIPEA at a temperature such as 80°C.

[0310] Compounds (X) of formula (BF-I), (BF-II), (BF-III), (BF-VA), (BF-VB), and (BF-IV) 2 wherein X is a nitrogen-containing heterocyclyl, e.g., piperidinyl or piperazinyl, can be prepared by reacting a compound of formula (VII) with a compound of formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), and (VIIIf), respectively, in an amide coupling reaction according to Scheme 4. Similarly, X 2 is a bond, Scheme 4 also provides compounds of formula (VIIIa-f) (L 2is a primary or secondary amine) with a compound of formula (VII) to produce (BF-I), (BF-II), (BF-III), (BF-VA), (BF-VB), and (BF-IV), respectively. Scheme 4 [ka]

[0311] In this embodiment, L in the compounds (VIIIa to VIIIf) 3a is a linker L containing a carbonyl group 3 and thus can provide compounds (VIIIa-f) containing a carboxylic acid functionality (e.g., in some embodiments, L 3a When is -CH2-C(O)-, L 3a -OH is defined as -CH2-CO2H). Suitable conditions include those for the amide coupling reaction as already described herein above.

[0312] Further, more specific embodiments of the carboxylic acid intermediate include compounds of formula (VIIIg) and (VIIIh), which can be reacted with a compound of formula (VII) according to Scheme 4a (in a manner similar to that described herein above for compounds (VIIIa-f)) to provide a compound of formula (BF-VA) or (BF-VB). Scheme 4a [ka]

[0313] Compounds (X) of formula (BF-I), (BF-II), (BF-III), (BF-VA), (BF-VB), and (BF-IV) 2wherein X is a nitrogen-containing heterocyclyl, such as piperidinyl or piperazinyl, can also be prepared by reacting compounds of formula (VII) with compounds of formula (IXa), (IXb), (IXc), (IXd), (IXe), and (IXf), respectively, in a reductive amination reaction according to Scheme 5. Similarly, X 2 is a bond, Scheme 5 also provides compounds of formula (IXa-f) (L 2 is a primary or secondary amine) with a compound of formula (VII) to produce (BF-I), (BF-II), (BF-III), (BF-VA), (BF-VB), and (BF-IV), respectively.

[0314] Regarding compounds (IXa to IXf), L 3b L 3 If the formula of is acceptable, L 3 (e.g., in one embodiment, L 3 If is -CH2CH2-, L 3b is -CH2-). 3 As for C 1~6 Alkylene and C 1~6 Examples of suitable conditions include ZnCl and NaBHCN in a solvent mixture such as THF / DMSO and MeOH. Alternative conditions include treatment with NaBH(OAc) in NaOAc, AcOH, and DCM. Scheme 5 [ka]

[0315] It will be apparent to those skilled in the art that masked aldehyde equivalents, such as the corresponding adduct (e.g., compound of formula (X)) formed from an aldehyde such as (IXg) and sodium disulfite in aqueous ethanol, are similarly suitable reactants for effecting this overall reductive amination transformation, and the embodiment depicted in Scheme 5a is representative. In this case, the reaction of (X) with (VII) can be carried out in the presence of sodium acetate and picoline borane complex in a solvent such as methanol. Scheme 5a [ka]

[0316] Compounds of formula (IV), more particularly X 1 and X 2 are both nitrogen-containing heterocyclyl, e.g., piperidinyl or piperazinyl, or X 1 -L 2 -X 2 Compounds of formula (IVa), (IVb), (IVc), (IVd), (IVe), and (IVf), such as those in which PG is spiroheterocyclyl, can be synthesized from the corresponding aldehydes (IXa), (IXb), (IXc), (IXd), (IXe), and (IXf), respectively, according to Scheme 6. The aldehyde undergoes a reductive amination reaction under conditions already described herein above using a compound of formula (XI) in which PG represents a protecting group such as t-butoxycarbonyl. Subsequent deprotection using conditions such as TFA in DCM or HCl in 1,4-dioxane and methanol provides compounds of formula (IVa-f). Scheme 6 illustrates the conversion of (IXa) to (IVa) as a representative embodiment. Scheme 6 [ka]

[0317] In certain embodiments, a compound of formula (IXc) can undergo reductive amination similar to specific examples of (XI), such as (XIa), according to Scheme 6a, followed by deprotection under conditions already described herein above, to provide a compound of formula (IVc-1). This compound (IVc-1) can then be reacted with a compound of formula (IIIa) in a reductive amination reaction to provide a compound of formula (II), in the same manner as other embodiments of (IVc). Scheme 6a [ka]

[0318] Compounds of formula (IV), specifically X 1 and X 2 are both nitrogen-containing heterocyclyl, e.g., piperidinyl or piperazinyl, or X 1 -L 2 -X 2 Compounds of formula (IVa), (IVb), (IVc), (IVd), (IVe), and (IVf), such as those in which is spiroheterocyclyl, can also be synthesized from the corresponding carboxylic acids (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), and (VIIIf), respectively, according to Scheme 7. In this embodiment, an amide coupling reaction is utilized with compounds of formula (XI) using a reagent such as HATU in a solvent such as DMF in the presence of a base such as DIPEA, followed by a deprotection reaction using conditions such as TFA in DCM or HCl in 1,4-dioxane and methanol to provide compounds of formula (IVa-f). The scheme illustrates the conversion of (VIIIa) to (IVa) as a representative embodiment. Scheme 7 [ka]

[0319] In certain embodiments, compounds of formula (IV), such as compounds of formula (IVd) or (IVe), can be synthesized from carboxylic acids of formula (VIIIg) or (VIIIh) by reaction with a monoprotected diamine (such as compound (XIII)) in an amide coupling reaction, followed by a deprotection reaction, using conditions as already described hereinabove (Scheme 8). In the example shown, X 2 does not exist. Scheme 8 [ka]

[0320] Other compounds of formula (IV), such as L 3 C 2~6 Alkynylene compounds of formula (IVd) and (IVe) can be synthesized according to Scheme 9. Thus, a palladium-catalyzed coupling between an alkyne compound of formula (XIV) where PG is a protecting group such as t-butoxycarbonyl and a compound of formula (XV) where Hal is a halogen atom such as iodine, followed by a deprotection reaction, yields a compound of formula (IVd) or (IVe). The palladium-catalyzed reaction is the Sonogashira reaction, which is carried out using a catalyst such as PdCl2(PPh3)2 and CuI and a base such as triethylamine in a solvent such as DMF. Optionally, the product from the palladium-catalyzed reaction can be reduced under hydrogenation conditions, for example, using H2 gas and a Pd / C catalyst, prior to the deprotection reaction. In this case, L 3 C 1~6 -alkylene final products (IVd / IVe) are produced. Compounds (XIVa) and (XIVb) are specific embodiments of compound (XIV) that can undergo these reaction sequences. Compounds (XIVa) and (XIVb) can then be synthesized by alkylation of compounds of formula (XI) using an alkynylene bromide, such as 4-bromo-1-butyne or propargyl bromide, respectively, in the presence of a base, such as KCO, in a solvent, such as acetonitrile. Scheme 9 [ka]

[0321] Other compounds of formula (IV), such as L 3 Compounds of formula (IVd) and (IVe) containing an ether bond can be synthesized according to Scheme 10 starting from a phenol of formula (XVI). Thus, alkylation of (XVI) using an alkyl bromide such as (XVII) with a base such as KCO in a solvent such as DMF leads to compounds of formula (IVd / IVe) after deprotection; the specific examples shown are 1 and X 2 Both of 2represents a compound of formula (IVd / IVe) in which NR'. This product can then undergo reductive amination with a compound of formula (III) under the conditions already described hereinabove to provide a compound of formula (I). An alternative synthetic route is to react phenol (XVI) with an N-protected amino alcohol in a Mitsunobu reaction in the presence of a phosphine reagent, such as triphenylphosphine, and an azocarboxylic acid ester, such as diethyl azodicarboxylate, to form an ether bond, followed by a deprotection reaction to provide a compound of formula (IVd / IVe). A linker can also be constructed in the sequence of steps to convert a compound of formula (XVI) to a compound of formula (IV), such as (IVg) or (IVh). In certain embodiments, phenol (XVI) can be reacted with an N-protected amino alcohol, such as (XVIIIa), in a Mitsunobu reaction in the presence of a phosphine reagent, such as triphenylphosphine, and an azocarboxylic acid ester, such as diethyl azodicarboxylate, to form an ether bond, followed by a deprotection reaction to provide a compound of formula (IVg). This compound can be extended by further reductive amination with an N-protected aminoaldehyde, such as t-butyl 4-(2-oxoethyl)piperazine-1-carboxylate, to afford a chain-extended compound of formula (IVh). Both (IVg) and (IVh) can be reacted with a compound of formula (III) using reductive amination using the conditions already described herein above to afford a compound of formula (I). In certain embodiments, reductive amination with an aldehyde-ester, such as t-butyl-5-oxopentanoate, followed by deprotection of the ester functionality using an acid, such as TFA in DCM, can afford a carboxylic acid of formula (XII). Compound (XII) can be reacted with a targeting ligand (XXIV) containing an available primary or secondary amine functionality via amide coupling under the conditions described herein above to afford a compound of formula (I) (X). 1 is a bond, and L 1 is C(O). Scheme 10 [ka]

[0322] L 3 and X 1 each represents a bond, and X 2 Compounds of formula (IV), such as (IVd) or (IVe), wherein is a 1,2,3-triazole, can be prepared according to Scheme 11 using a Cu-catalyzed cycloaddition reaction between an alkyne of formula (XIX) and an azide of formula (XX) using a Cu(II) salt, such as Cu(II)SO4, and sodium L-ascorbate in a solvent mixture, such as THF and water. Deprotection of the protecting group under the conditions already described herein above leads to compounds of formula (IV). Scheme 11 [ka]

[0323] X 1 and X 2 are both nitrogen-containing heterocyclyl, e.g., piperidinyl or piperazinyl, or X 1 -L 2 -X 2 Compounds of formula (VII) where X is spiroheterocyclyl can be synthesized from compounds of formula (III) and compounds of formula (XXI) following a reductive amination, deprotection sequence under the conditions already described herein above, according to Scheme 12. Alternatively, different compounds of formula (VII) can be prepared from carboxylic acids of formula (V) by reacting with a compound of formula (XXI) in an initial amide coupling reaction, followed by a deprotection reaction under the conditions already described herein above. This scheme also leads to certain cases of compounds of formula (VII) where certain linker elements are bonds, an example being X 1 and X 2 When compound (XXIa) in which both of the formulas are bonds is used. Scheme 12 [ka]

[0324] Compounds of formula (III) can also be converted to primary amines of formula (XXII) using reductive amination, for example, using methanolic ammonia and hydrogen gas in the presence of a catalyst such as Raney nickel. In certain embodiments, compounds of formula (IIIa) react under similar conditions to afford (XXIIa). Subsequent reductive amination with aldehydes of formula (XXIII) using conditions such as ZnCl and NaBHCN in a solvent mixture such as THF / DMSO and MeOH affords exemplary compounds of formula (II) (X 1 and X 2 are each represented by a bond) (Scheme 13). Scheme 13 [ka]

[0325] Nitriles of formula (XXV) can be reduced to amines of formula (XXVI) using conditions such as hydrogen gas and a catalyst such as Raney nickel in the presence of aqueous ammonium hydroxide with a co-solvent such as MeOH, according to Scheme 14. These amines can be reacted with N-protected amino acids (PG represents a protecting group such as t-butoxycarbonyl) in an amide coupling reaction. Subsequent deprotection under acidic conditions provides compounds of formula (IV); in some embodiments, (XXVI) can be reacted with (XXVII) to give compounds of formula (IVi) (X 1 and X 2 Both of these are bonds. Scheme 14 [ka]

[0326] Mitsunobu coupling can be used to synthesize compounds of formula (VII) (where the linker contains a direct ether bond to the targeting ligand) from compounds of formula (XXVIII) (where the hydroxy group is part of a phenol or hydroxypyridine) according to Scheme 15, followed by a deprotection reaction. Scheme 15 [ka]

[0327] It will be understood by those skilled in the art of organic synthesis that the molecules of the present invention can be constructed in a modular manner that allows for different reaction sequences. For example, the Mitsunobu coupling described in Scheme 15 can be applied to a synthetic fragment such as compound (XXX) (where the pyridyl ring is part of the targeting ligand). Thus, (XXX) can undergo reaction with a compound of formula (XXXI) to give another reaction intermediate (XXXII). This intermediate (XXXII) then requires further synthetic steps to construct the targeting ligand itself, in addition to synthetic steps designed to link the molecule to a suitable ligase targeting fragment, according to the procedures fully described herein above. Compounds of formula (XXXIII) (B(OR x )2 defines either a boronic acid or ester (including cyclic boronic esters such as pinacol esters) is another embodiment that can be utilized by the Mitsunobu reaction. In this embodiment, the aryl ring is a fragment of the targeting ligand (which will require further elaboration), and the Mitsunobu reaction adds to it several linker elements according to the definitions defined herein above.

[0328] Aryldihydrouracil derivatives, such as compounds of formulae (VIIId / VIIIe), (VIIIg), (VIIIh), (XV), (XVI), (XIX), and (XXV), can be synthesized from the corresponding amines (XXXIV), (XXXIVa), (XXXIVb), (XXXV), (XXXVI), (XXXVII), and (XXXVIII), respectively, according to Scheme 16. The conversion proceeds via conjugate addition to acrylic acid, typically with a cosolvent such as water and heating above 70°C, followed by reaction with urea and acetic acid, also at elevated temperatures such as 120°C, to form the dihydrouracil. In the case of (VIIIg), dihydrouracil formation may be carried out on the corresponding phenolic acetate ester (XXXIVa), and the ester can be hydrolyzed using acidic conditions such as HCl treatment in a final step. Scheme 16 [ka]

[0329] Compounds of formula (XXXIVa) can be obtained from aminophenols with a protected nitrogen (XXXIX), e.g., a Boc-protected nitrogen, in two steps according to Scheme 17. First, alkylation of the phenol using a base such as CsCO and a 2-haloacetate such as methyl bromoacetate in a solvent such as acetone with an additive such as potassium iodide leads to an intermediate that can undergo N-deprotection using an acid such as TFA in a solvent such as dioxane to yield compounds of formula (XXXIXa). Also according to Scheme 17, dihydrouracil intermediates (IXg) can be synthesized by applying the dihydrouracil-forming chemistry to allyloxyanilines such as (XXXX). Oxidative cleavage of the allyl group, e.g., using an ozonolysis reaction, leads to aldehydes of formula (IXg). Dihydrouracil intermediates (IVj) with sulfonamide linker chains can be synthesized from compounds of formula (XXXXI) in a similar manner to other dihydrouracil building blocks, followed by a deprotection reaction. Scheme 16a [ka]

[0330] Heteroaryldihydrouracil derivatives (VIIIf-1) (A is a 5- or 6-membered heteroaryl ring) bearing a carboxylic acid functionality can be prepared according to Scheme 16a using a reaction sequence similar to that described in Scheme 16. In this case, reaction of the corresponding amino acid (XXXIVc) or derivative (e.g., amino ester) with acrylic acid at 70°C or higher and a cosolvent, such as water, followed by reaction with urea and acetic acid, also at elevated temperatures, such as 100°C, provides the heteroaryldihydrouracil (VIIIf-1). Specific examples are the aminopyrazole derivatives (VIIIf-2) and (VIIIf-3), generated from the aminopyrazole tert-butyl ester derivatives (XXXIVd) and (XXXIVe), respectively. In some cases, such as (VIIIf-2), the reaction conditions result in simultaneous hydrolysis of the tert-butyl ester to the carboxylic acid; for other cases, such as (VIIIf-3), a separate hydrolysis step using an acid, such as TFA, may be required to generate the free carboxylic acid. Scheme 17 [ka]

[0331] Compounds of formula (XXXXVII), an embodiment of compound (IXc), can be derived from compounds of formula (XXXXII) using an oxidative cleavage reaction such as ozonolysis, as shown in Scheme 18. Compounds of formula (XXXXII) can be derived from the corresponding amines of formula (XXXXIII) via conjugate addition of the amine to acrylic acid followed by reaction with urea and acetic acid to form dihydrouracils using conditions previously described herein. Amines of formula (XXXXIII) can be derived from 3-cyanopyridin-2-ones by first reducing the nitrile using conditions such as hydrogenation in the presence of Raney nickel in a methanol / ammonia solution, followed by protection of the nitrogen to provide compounds of formula (XXXXIV) with a typical amine protecting group, such as a tert-butoxycarbonyl group. Alkylation of intermediate (XXXXIV) with an alkylating agent such as allyl bromide and a base such as potassium carbonate in a solvent such as DMF, followed by deprotection using, for example, HCl in a solvent mixture of DCM and dioxane, provides compounds of formula (XXXXIII). Alternatively, compounds of formula (XXXXVII) can be synthesized from compounds of formula (XXXXIV) via alkylation using an alkylating agent containing a protected alcohol, followed by removal of the protecting group PG, to yield molecules having formula (XXXXV). Dihydrouracil formation using methods previously described yields compounds of formula (XXXXVI). Alcohol deprotection, followed by oxidation to the aldehyde using an oxidant such as Dess-Martin periodinane, yields compounds of formula (XXXXVII). Scheme 18 [ka]

[0332] Two alternative methods are described in Scheme 19 and Scheme 20, which illustrate the synthesis of intermediates having formula (ILB III). Hydrogenation of 2,4-dihydroxypyrimidines of formula (XXXXVIII) under pressure (e.g., 30 psi) using a catalyst such as rhodium on carbon in a solvent such as water, followed by acetylation with PMBCl in a solvent mixture such as DMSO / DCM in the presence of a base such as CsCO, provides compounds of formula (XXXXIX) as shown in Scheme 19. Subsequent copper-catalyzed arylation of (XXXXIX) using heteroaryl substrates (L) or (LI) (Hal represents a halogen atom, preferentially bromine or iodine) provides compounds of formula (ILB IIIa) and (ILB IIIb), respectively. Suitable conditions use a ligand such as DMEDA and a base such as KCO in a solvent such as DMF; subsequent deprotection is carried out under acidic conditions such as TFA / TfOH.

[0333] With respect to compounds of formula (L) and (LI), U 1 , U 2 , U 3 , U 4 , U 5 , V 1 , V 2 , V 3 , V 4 and Z 1 is as defined herein before.

[0334] Scheme 18a [ka] Aldehydes of compound class (XXXXVII) / (IXc), such as example (XXXXVIIa), can be oxidized according to Scheme 18a, for example by treatment with potassium permanganate in THF at room temperature, to give the corresponding carboxylic acid (VIIIc-1), or can be reduced, for example using sodium borohydride in THF at room temperature, to give the alcohol derivative (XXXXVIa).

[0335] Scheme 18b [ka] Benzylic and heterobenzylic dihydrouracil compounds bearing a carboxylic acid functionality belonging to class (VIIIa) / (VIIIb) can be synthesized according to Scheme 18b. Reaction of amino acids (XXXIVf) or (XXXIVg) or derivatives (such as amino esters) with acrylic acid in water and a cosolvent such as MeCN, or toluene at 70° C. or above, followed by reaction with urea and acetic acid, also at elevated temperatures such as 100° C., provides dihydrouracils (VIIIa-1) and (VIIIb-1), respectively.

[0336] Representative examples are derivatives (VIIIb-2), (VIIIb-3), and (VIIIb-4) generated from amines (XXXIVh), (XXXIVi), and (XXXIVj), respectively. It will be clear to those skilled in the art that the removal of protecting groups can be performed at different stages of the synthesis, such as in the case of (VIIIb-2), where ester hydrolysis using LiOH can be performed before the cyclization reaction, or in the case of (VIIIb-3), where ester hydrolysis can be performed after the cyclization reaction. In the latter case, the ring-opening of the dihydrouracil required further treatment with acid to rearrange the dihydrouracil ring. Furthermore, the use of a primary alcohol in this reaction sequence, such as in the case of (VIIIb-4), required subsequent treatment with aqueous acid to hydrolyze the acetate ester formed during the dihydrouracil cyclization reaction. Scheme 19 [ka]

[0337] In one embodiment, the same reaction sequence can be carried out according to Scheme 19a to prepare a compound of formula (ILB IIIc) (U 4 or U 2where one of the groups is a nitrogen atom. In certain cases, deprotection of the PMB group also results in the deprotection of other functional groups in the aromatic substituent, an example being the debenzylation of benzyl ethers. Scheme 19a [ka]

[0338] An alternative method for synthesizing ILB III is shown in Scheme 20. Amide coupling of an N-protected amino acid (LII) with dimethoxybenzylamine using a standard coupling reagent such as CDI in an aprotic solvent such as DCM, followed by Boc-deprotection under acidic conditions, for example, with HCl in ethyl acetate, leads to compounds of formula (LIII). Cyclization to compounds of formula (LIV) is achieved by reacting (LIII) with CDI in the presence of a base such as DIEA in an aprotic solvent such as DCE. Copper-catalyzed arylation of (LIV) using a 6-membered heterocycle of formula (L) or a 5-membered heterocycle of formula (LI) in the presence of a ligand and catalyst under conditions already described herein above (Scheme 19) leads to compounds of formula ILB IIId and ILB IIIe, respectively. Scheme 20 [ka]

[0339] Targeting ligands can be synthesized using a variety of methods. In certain embodiments, compounds of formula (IIIa) are synthesized by a palladium-catalyzed coupling reaction, such as the Suzuki reaction, between compounds of formula (LV) and compounds of formula (LVI) using a catalyst (e.g., PdCl(dppf)) and a base (e.g., CsCO) in a solvent mixture (e.g., dioxane / water), according to Scheme 21. Compound (LV) can be made from ester (LVII) by reduction to the alcohol using a reducing agent such as LiALH in a solvent such as THF, followed by oxidation to the aldehyde using MnO in THF. Scheme 21 [ka]

[0340] The synthesis of other specific intermediates containing targeting ligands is described in the experimental section. TNNI3K targeting binding moieties are prepared in accordance with literature procedures. See International Publication No. 2011 / 56740. The reported improved intermediate 2-((6-chloro-2-methylpyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (CAS No. [302964-08-5]) was also utilized in the preparation of bifunctional compounds.

[0341] Compounds of formulas (III), (IIIa), (V), (VI), (XXIV), (XXII), (XXIIa), and (XXVIII) containing suitable functional groups for binding to targeting ligands and linkers and ligase targeting ligands can be prepared by a variety of standard synthetic methods and procedures known to those skilled in the art or that will be apparent to skilled chemists in light of the teachings herein. It is understood that, depending on the nature of the targeting ligand, similar targeting ligands but with different functional groups can be applied to the synthesis of compounds of the present invention. Thus, compounds such as (III), (V), (VI), (XXIV), (XXII), and (XXVIII) can be interconverted using functional group interconversions well known to those skilled in the art of organic synthesis.

[0342] The mixtures of enantiomers, diastereomers and cis / trans isomers resulting from the above processes can be separated into their single components by chiral salt techniques, chromatography using normal phase, reverse phase or chiral columns, depending on the nature of the separation.

[0343] Any resulting racemic forms of the compounds or intermediates of the present disclosure can be resolved into their optical antipodes by known methods, for example, by separating their diastereomeric salts obtained with optically active acids or bases, and liberating the optically active acidic or basic compounds. In particular, compounds of the present disclosure can be resolved into their optical antipodes by, for example, fractional recrystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid, using such basic moieties. Racemic compounds or racemic intermediates of the present disclosure can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC), using a chiral adsorbent.

[0344] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization on the basis of the physical chemical differences of the constituent components.

[0345] In the descriptions and formulas set forth above, it should be understood that the various groups and variables are as previously defined herein unless otherwise indicated. Furthermore, for purposes of synthesis, the compounds of Schemes 1, 1a, 1b, 2-4, 4a, 5, 5a, 6, 6a, 7-16, 16a, 17-18, 18a, 18b, 19, 19a, and 20-21 are merely representative, with selected groups intended to illustrate the general synthetic methodology of the compounds disclosed herein. The preparation of specific intermediates and examples using the above general methods is provided in detail in the Experimental Section. [Example]

[0346] The following examples further illustrate the present disclosure, but should not be construed as limiting the disclosure in scope or spirit of the specific procedures described herein. It should be understood that the examples are provided to illustrate particular embodiments and do not thereby limit the scope of the disclosure. Furthermore, it should also be understood that various other embodiments, modifications, and equivalents thereof, which may suggest themselves to those skilled in the art, may be used without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0347] The compounds described herein can be prepared by methods known in the art of organic synthesis. In all methods, it is understood that protecting groups for sensitive or reactive groups can be utilized where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis. See, for example, TW Green and PG M Buts, Protective Groups in Organic Synthesis, 3 rdedition, John Wiley & Sons (1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.

[0348] Temperatures are given in degrees Celsius. The abbreviations used are conventional in the art and are listed below.

[0349] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art. Additionally, the compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art, as shown in the examples below.

[0350] Abbreviation ACN Acetonitrile AcOH acetic acid app. obvious aq. water-based ATP adenosine 5'-triphosphate BINAP Racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BISPIN Bis(pinacolato)diboron BOC tert-butoxycarbonyl br Broad BSA Bovine serum albumin CDI Carbonyldiimidazole CHX Cyclohexane Concentrated d double line dd double line double line DCE 1,2-dichloroethane DCM dichloromethane DEA Diethylamine DEAD Diethyl azodicarboxylate DIAD Diisopropyl azodicarboxylate DIBAL-H Diisobutylaluminum hydride DIEA Diethylisopropylamine DIPEA Diisopropylethylamine DMA Dimethylacetamide DMBNH2 2,4-Dimethoxy-benzyl chloride DME 1,4-dimethoxyethane DMEDA 1,2-dimethylethylenediamine DMF N,N-dimethylformamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMSO dimethyl sulfoxide Dppf 1,1'-bis(diphenylphosphino)ferrocene EDTA Ethylenediaminetetraacetic acid e.g. eq. equivalent weight ESI electrospray ionization Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol h time GC Gas Chromatography HATU 1-[bis(dimethylamino)methylene]-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HCl Hydrogen chloride HCOOH formic acid H2O Water HOAc acetic acid HOBt 1-hydroxy-7-azabenzotriazole HPLC High Performance Liquid Chromatography HV high vacuum iPrOH isopropanol K Kelvin KOAc Potassium Acetate L liters LC-MS Liquid Chromatography and Mass Spectrometry LiHMDS Lithium bis(trimethylsilyl)amide m multiplet M molar concentration MeOH Methanol mg milligram MgSO4 Magnesium Sulfate MHz Megahertz min mL milliliter mm millimeters μm micrometer mmol millimole mM millimolar concentration MS mass spectrometry Ms methanesulfonyl MsCl methanesulfonyl chloride Ms2O methanesulfonic anhydride MTBE Methyl tert-butyl ether MW molecular weight m / z mass-to-charge ratio NaBH4 Sodium borohydride NaBH3CN Sodium cyanoborohydride NaBH(OAc)3 Sodium triacetoxyborohydride NaH sodium hydride NaHCO3 Sodium bicarbonate NaOAc Sodium Acetate NaOH Sodium hydroxide NH4Cl Ammonium chloride NH4OAc Ammonium Acetate NH4OH Ammonium hydroxide NMM N-methylmorpholine NMP N-methyl-2-pyrrolidine NMR nuclear magnetic resonance OAc acetate PdCl2(dppf) 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride PdCl2(dppf)-CH2Cl2 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex PdCl2(PPh3)2 Bis(triphenylphosphine)palladium dichloride Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium PE Petroleum Ether PG protecting group PMBCl para-methoxy-benzyl chloride PPh3 Triphenylphosphine ppm parts per million PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate rac racemic RM reaction mixture Rt retention time RT room temperature s single line sat. saturation SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride SFC Supercritical Fluid Chromatography t triple line t-BuOH tert-butyl alcohol t-BuOK Potassium tert-butoxide TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate TBDPS tert-butyldiphenylsilyl TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran Tris·HCl Aminotris(hydroxymethyl)methane hydrochloride

[0351] Example 1 Analysis method General conditions NMR NMR spectra were analyzed on a Bruker AVANCE 400 MHz or 500 MHz NMR mass spectrometer under TopSpin program control using ICON-NMR. Spectra were measured at 298 K unless otherwise specified and were referenced to the solvent resonance.

[0352] LC-MS Mass spectra were acquired on LC-MS, SFC-MS, or GC-MS systems using electrospray, chemical, and electron impact ionization methods from various instruments configured as follows: a Waters Acquity UPLC / SQD system using a photodiode array detector and a single quadrupole mass detector or an Agilent 1200 system equipped with a G 6110 series mass detector. [M+H] + refers to the protonated molecular ion of a chemical species.

[0353] Method LCMS1 Column: ACQUITY UPLC® HSS T3 (2.1 x 50 mm x 1.8 μm) Column temperature: 60℃ Eluent: A: Water + 0.05% FA + 3.75mM AA B:ACN+0.04% FA Flow rate: 1.0mL / min Gradient: 5% to 98% B in 1.4 min

[0354] Method LCMS2 Column: ACQUITY UPLC® HSS T3 (2.1 x 50 mm x 1.8 μm) Column temperature: 60℃ Eluent: A: Water + 0.05% FA + 3.75mM AA B:ACN+0.04% FA Flow rate: 1.0mL / min Gradient: 1% to 98% B concave in 1.4 minutes

[0355] Method LCMS3 Column: ACQUITY UPLC® BEH C18 (2.1 x 50 mm, 1.7 μm) Column temperature: 80℃ Eluent: A: Water + 0.05% FA + 3.75mM AA B: iPrOH + 0.05% FA Flow rate: 0.6mL / min Gradient: 5% to 98% B in 1.7 min

[0356] Method LCMS4 Column: XBridge® BEH™ C18 (2.1 x 50 mm, 2.5 μm) Column temperature: 80℃ Eluent: A: Water + 5mM NH4OH B: ACN + 5mM NH4OH Flow rate: 1.0mL / min Gradient: 2% to 98% B in 1.4 min

[0357] Method LCMS5 Column: ACQUITY UPLC® HSS T3 (2.1 x 100 mm x 1.8 μm) Column temperature: 60℃ Eluent: A: Water + 0.05% FA + 3.75mM AA B:ACN+0.04% FA Flow rate: 0.8mL / min Gradient: 5% to 98% B in 9.4 min

[0358] Method LCMS6 Column: ACQUITY UPLC® BEH C18 (2.1 x 100 mm, 1.7 μm) Column temperature: 80℃ Eluent: A: Water + 0.05% FA + 3.75mM AA B: iPrOH + 0.05% FA Flow rate: 0.4mL / min Gradient: 5 to 60% B in 8.4 minutes, 60 to 98% B in 1 minute

[0359] Method LCMS7 Column: ACQUITY UPLC® BEH C18 (2.1 x 50 mm, 1.7 μm) Column temperature: 80℃ Eluent: A: Water + 4.76% iPrOH + 0.05% FA + 3.75mM AA B: iPrOH + 0.04% FA Flow rate: 0.6mL / min Gradient: 1% to 98% B in 1.7 min

[0360] Method LCMS8 Column: Kinetex Evo C18 (2.1 x 50 mm, 1.7 μm) Column temperature: 60℃ Eluent: A: Water + 0.05% FA + 3.75mM AA B:ACN+0.04% FA Flow rate: 1.0mL / min Gradient: 5% to 98% B in 1.4 min

[0361] Method LCMS9 Column: Ascentis® Express C18 2.7 μm 2.1 × 50 mm Column temperature: 80℃ Eluent: A: Water + 4.76% isopropanol + 0.05% FA + 3.75mM AA B: Isopropanol + 0.05% FA Flow rate: 1.0mL / min Gradient: 1% to 50% B in 1.4 min, 50 to 98% B in 0.3 min

[0362] Method LCMS10 Column: Kinetex EVO C18 (30*2.1mm, 5um) Column temperature: 50℃ Eluent: A: 0.0375% TFA in water (v / v) B: 0.01875% TFA in acetonitrile (v / v) Flow rate: 1.5ml / min Gradient: 0% to 60% B in 1.55 min

[0363] Method LCMS11 Column: Kinetex EVO C18 (30*2.1mm, 5um) Column temperature: 50℃ Eluent: A: 0.0375% TFA in water (v / v) B: 0.01875% TFA in acetonitrile (v / v) Flow rate: 1.5ml / min Gradient: 0% to 60% B in 7 minutes

[0364] Method LCMS12 Column: CORTECS (trademark) C18+2.7μm Column temperature: 80.0℃ Eluent: A: Water + 4.76% isopropanol + 0.05% FA + 3.75mM AA B: Isopropanol + 0.05% FA Flow rate: 1.0mL / min Gradient: 1 to 50% B in 1.4 min, 50 to 98% B in 0.3 min

[0365] Method LCMS13 Column: Waters XSelect HSS T3 3.5um 4.6*50mm Column temperature: 50℃ Eluent: A: 0.0375% TFA in water (v / v) B: 0.01875% TFA (v / v) in ACN Flow rate: 1ml / min Gradient: 0% to 30% B in 5 minutes

[0366] Example 2 Analysis method General conditions: NMR NMR spectra were analyzed on a Bruker AVANCE 400 MHz or 500 MHz NMR mass spectrometer under TopSpin program control using ICON-NMR. Spectra were measured at 298 K unless otherwise specified and were referenced to the solvent resonance.

[0367] LC-MS Mass spectra were acquired on LC-MS, SFC-MS, or GC-MS systems using electrospray, chemical, and electron impact ionization methods from various instruments configured as follows: a Waters Acquity UPLC / SQD system using a photodiode array detector and a single quadrupole mass detector or an Agilent 1200 system equipped with a G 6110 series mass detector. [M+H] + refers to the protonated molecular ion of a chemical species.

[0368] Method A Column: XBridge C18 (4.6 x 50 mm 3.5 μm) Column temperature: 50℃ Eluent: A: aq. ammonium bicarbonate (10 mM); B: ACN Flow rate: 1.8mL / min Gradient: 5% to 95% B in 1.5 min

[0369] Method B Column: SunFire C18 (4.6 x 50 mm, 3.5 μm) Column temperature: 50℃ Eluent: A: aq. TFA (0.01%); B: ACN containing TFA (0.01%) Flow rate: 2.0mL / min Gradient: 5% to 95% B in 1.4 min

[0370] Method C Column: SunFire C18 (4.6 x 50 mm, 3.5 μm) Column temperature: 50℃ Eluent: A: aq. TFA (0.01%); B: ACN containing TFA (0.01%) Flow rate: 2.0mL / min Gradient: 5% to 95% B in 1.3 min

[0371] Method D Column: HALO C18 (4.6 x 30 mm, 2.7 μm) Column temperature: 50℃ Eluent: A: aq. TFA (0.01%); B: ACN containing TFA (0.01%) Flow rate: 2.2mL / min Gradient: 5% to 95% B in 1.0 min

[0372] Method E Column: SunFire C18 (4.6 x 50 mm, 3.5 μm) Column temperature: 50℃ Eluent: A: aq. TFA (0.01%); B: ACN containing TFA (0.01%) Flow rate: 2.0mL / min Gradient: 5% to 95% B in 1.2 min

[0373] Method F Column: SunFire C18 (4.6 x 50 mm, 3.5 μm) Column temperature: 50℃ Eluent: A: aq. TFA (0.01%); B: ACN containing TFA (0.01%) Flow rate: 2.0mL / min Gradient: 5% to 95% B in 1.2 min, followed by 95% B for 1.3 min

[0374] Method G Column: XBridge C18 (4.6 x 50 mm 3.5 μm) Column temperature: 40℃ Eluent: A: aq. ammonium bicarbonate (10 mM); B: CAN Flow rate: 1.8mL / min Gradient: 5% to 95% B in 1.4 min, followed by 95% B for 1.6 min

[0375] Method H Column: XBridge C18 (4.6 x 50 mm 3.5 μm) Column temperature: 40℃ Eluent: A: aq. ammonium bicarbonate (10 mM); B: ACN Flow rate: 2.0mL / min Gradient: 5% to 95% B in 1.5 min

[0376] Preparative Chromatography Normal and reverse phase chromatographic purifications were performed on a Biotage Isolera One system.

[0377] Achiral preparative HPLC method Method PB with basic modifier Equipment: Gilson 281 (PHG012) Column: Xtimate C18 (21.2 x 250 mm, 10 μm) Column temperature: RT Eluent: A: aq. ammonium bicarbonate (10 mM); B: ACN Flow rate: 30mL / min Detection: 254nm, 214nm UV

[0378] Method PA with Acid Modifier Equipment: Gilson 281 (PHG012) Column: Xtimate C18 (21.2 x 250 mm, 10 μm) Column temperature: RT Eluent: A: aq. TFA (0.1%); B: ACN Flow rate: 30mL / min Detection: 254nm, 214nm UV

[0379] Method PA2 with Acid Modifier Column: Waters Xbridge (150*25*10 μm) Column temperature: 25℃ Eluent: A: aq. TFA (0.1%); B: ACN Flow rate: 25.0ml / min Gradient: 34% to 54% B in 10 minutes

[0380] Method PA3 with acidic modifier Equipment: Gilson GX-215 and Shimadzu LCMS2020 Column: Waters Atlantis T3 150*30mm*5um Column temperature: RT Eluent: A: aq. TFA (0.1%); B: ACN Flow rate: 25mL / min Detection: 254nm, 220nm UV

[0381] Example 3 Analysis method General conditions NMR NMR spectra were recorded on a Bruker AVANCE 400 MHz, 500 MHz, or 600 MHz NMR mass spectrometer under TopSpin program control using ICON-NMR. Spectra were measured at 298 K unless otherwise specified and were referenced to solvent resonances according to values ​​described in J. Org. Chem. 62:7512-7515 (1997) (e.g., DMSO-d at 2.50 ppm, CDCl at 7.26 ppm, DO at 4.79 ppm, and MeOD-d at 3.31 ppm). Significant peaks are grouped in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; v, extreme) and number of protons.

[0382] LC-MS Mass spectra were acquired on LC-MS, SFC-MS, or GC-MS systems using electrospray, chemical, and electron impact ionization techniques from various instruments configured as follows: a Waters Acquity UPLC / SQD system using a photodiode array detector and a single quadrupole mass detector, or an Agilent 1200 system equipped with a G 6110 series mass spectrometer. [M+H] + refers to the protonated molecular ion of a chemical species.

[0383] Method XA Column: Waters Acquity HSS T3 1.8 μm 2.1 x 50 mm or 2.1 x 100 mm Column temperature: 60℃ Eluent: A: aq. formic acid (0.05%) + aq. ammonium acetate (3.75 mM); B: ACN containing formic acid (0.04%) Flow rate: 1.0mL / min Gradient: 5% to 98% B in 1.4 min

[0384] Method XB Column: Waters Acquity HSS T3 1.8 μm 2.1 x 50 mm or 2.1 x 100 mm Column temperature: 60℃ Eluent: A: aq. formic acid (0.05%) + aq. ammonium acetate (3.75 mM); B: ACN containing formic acid (0.04%) Flow rate: 0.8mL / min Gradient: 5% to 98% B in 9.4 min

[0385] Method XC Column: Waters Acquity HSS T3 1.8 μm 2.1 x 50 mm or 2.1 x 100 mm Column temperature: 50℃ Eluent: A: aq. formic acid (0.05%) + aq. ammonium acetate (3.75 mM); B: ACN containing formic acid (0.04%) Flow rate: 1.2mL / min Gradient: 2% to 98% B in 1.4 min

[0386] Method XD Column: SunFire C18, 4.6 x 50 mm, 3.5 μm Column temperature: 50℃ Eluent: A: aq. TFA (0.01%); B: acetonitrile containing TFA (0.01%) Flow rate: 2.0mL / min Gradient: 5% to 95% B in 1.4 min

[0387] Method XE Column: SunFire C18, 4.6 x 50 mm, 3.5 μm Column temperature: 50℃ Eluent: A: aq. TFA (0.01%); B: acetonitrile containing TFA (0.01%) Flow rate: 2.0mL / min Gradient: 5% to 95% B in 1.2 min, 95% B in 1.3 min

[0388] Method XF Column: Phenomenex, 3.0 x 30 mm, 5 μm Column temperature: 50°C Eluent: A: aq. ammonium bicarbonate (10 mM); B: acetonitrile Flow rate: 1.5mL / min Gradient: 5% to 95% B in 1.5 min, 95% B in 0.7 min

[0389] Method XG Column: XBridge C18, 4.6 x 50 mm, 3.5 μm Column temperature: 40℃ Eluent: A: aq. ammonium bicarbonate (10 mM); B: acetonitrile Flow rate: 2.0mL / min Gradient: 5% to 95% B in 1.5 min

[0390] Method XH Column: XBridge C18, 4.6 x 50 mm, 3.5 μm Column temperature: 50℃ Eluent: A: aq. ammonium bicarbonate (10 mM); B: acetonitrile Flow rate: 1.8mL / min Gradient: 5% to 95% B in 1.5 min, 95% B in 1.5 min

[0391] Method XI Column: SunFire C18, 3 x 30 mm, 2.5 μm Column temperature: 50℃ Eluent: A: aq. TFA (0.01%); B: acetonitrile containing TFA (0.01%) Flow rate: 1.5mL / min Gradient: 5% to 95% B in 1.5 min

[0392] Method XJ Column: XBridge C18, 4.6 x 50 mm, 3.5 μm Column temperature: 40℃ Eluent: A: aq. ammonium bicarbonate (10 mM); B: acetonitrile Flow rate: 1.8mL / min Gradient: 5% to 95% B in 1.4 min, 95% B in 1.6 min

[0393] Chiral analysis HPLC method Method XK Equipment: Agilent 1200 system Column: Chiralpak ID 5um 4.6 x 250mm Column temperature: RT Eluent: Hept:DCM:MeOH(40:35:25)+DEA(0.1%) Flow rate: 1.0mL / min Gradient: uniform concentration Detection: UV at 254 nm

[0394] Preparative Chromatography Normal and reversed phase chromatographic purifications were performed on a CombiFlash Rf200 or Rf+ system. Alternatively, chromatographic purifications or reversed phase were performed on an Interchim Puriflash 4250 system.

[0395] Achiral SFC chromatographic separations were performed using a Waters preparative SFC-100-MS equipped with either a Waters 2998 photodiode array detector or a Waters MS single quadrupole detector using MeOH as a modifier. The back pressure was 120 bar, the flow rate was 100 g CO2 / min, and the column temperature was 40°C. Column types varied and are indicated in the individual experimental sections. Reversed-phase HPLC purifications were performed on a Waters HPLC preparative system equipped with either a Waters 2998 photodiode array detector or a Waters MS single quadrupole detector.

[0396] Achiral preparative HPLC method Method XL Equipment: Gilson GX-281 Column: SunFire C18 Column temperature: RT Mobile phase: ACN containing TFA (0.1%) Flow rate: 40mL / min Detection: UV at 254 nm

[0397] Chiral preparative chromatography Method XM Equipment: Gilson Trilution I HPLC system Column: ChiralPak ID, 5μM, 250×20mm Column temperature: RT Mobile phase: heptane / DCM / MeOH (40:35:25) containing DEA (0.05%) Flow rate: 10mL / min Detection: UV at 254 nm

[0398] Method XN: Equipment: Gilson Column: Reprosil 100 C18 (250 x 30 mm, 5 μm) Column temperature: room temperature Eluent: A: Water (0.1% TFA), B: ACN Flow rate: 25mL / min Gradient: 0–2 min. 100% Eluent A, 2–26 min. 100%–5% Eluent A Detection: UV at 254 nm

[0399] Method XN-A: Equipment: Gilson Column: Reprosil 100 C18 (250 x 30 mm, 5 μm) Column temperature: room temperature Eluent: A: Water (0.1% TFA), B: ACN Flow rate: 25mL / min Gradient: 0–2 min. 100% Eluent A, 2–26 min. 100%–50% Eluent A Detection: UV at 254 nm

[0400] Method XO Column: AcQuity UPLC BEH C18, 2.1 x 30 mm, 1.7 μm Column temperature: 50℃ Eluents: A: 5mM NH4OH in water; B: 5mM NH4OH in ACN Flow rate: 1.0mL / min Gradient: 1% to 30% B in 1.20 min; 30% to 98% B in 0.95 min; 98% to 1% B in 0.04 min

[0401] Method XP Column: AcQuity UPLC BEH C18, 2.1 x 50 mm, 1.7 μm Column temperature: 50℃ Eluents: A: 5mM NH4OH in water; B: 5mM NH4OH in ACN Flow rate: 1.0mL / min Gradient: 1% to 30% B in 3.20 min; 30% to 98% B in 1.95 min; 98% to 1% B in 0.04 min

[0402] Method XP-A Column: AcQuity UPLC BEH C18, 2.1 x 50 mm, 1.7 μm Column temperature: 50℃ Eluent: A: 0.1% formic acid in water B: 0.1% formic acid in acetonitrile Flow rate: 1.0mL / min Gradient: 1% to 30% B in 1.20 min; 30% to 98% B in 0.95 min; 98% to 1% B in 0.04 min

[0403] Method XQ Column: AcQuity UPLC BEH C18 1.7 μm 2.1 x 30 mm Column temperature: 50℃ Eluent: A: 0.1% formic acid in water; B: 0.1% formic acid in acetonitrile Flow rate: 1.0mL / min Gradient: 2% B for 0.10 min, 2% to 98% in 1.40 min, 98% B for 0.30 min, 98% to 2% B in 0.10 min, 2% B for 0.10 min

[0404] Method XR Column: AcQuity UPLC BEH C18 1.7 μm 2.1 x 50 mm Column temperature: 50℃ Eluents: A: 5mM NH4OH in water; B: 5mM NH4OH in ACN Flow rate: 1.0mL / min Gradient: 2% to 98% B in 4.40 min; 98% B in 0.75 min; 98% to 2% B in 0.04 min

[0405] Method XR-A Column: AcQuity UPLC BEH C18 1.7 μm 2.1 x 50 mm Column temperature: 50℃ Eluent: A: 0.1% formic acid in water B: 0.1% formic acid in acetonitrile Flow rate: 1.0mL / min Gradient: 2% to 98% B in 5 min; 98% B in 0.75 min; 98% to 2% B in 0.04 min

[0406] Method XV-B Column: AcQuity UPLC BEH C18 1.7 μm 2.1 x 30 mm Column temperature: 50℃ Eluent: A: 5 mM ammonium hydroxide in water; B: 5 mM ammonium hydroxide in acetonitrile Flow rate: 1.0mL / min Gradient: 2% to 98% B in 1.80 min

[0407] Method XS Detection: Waters 2998 photodiode array detector -Waters MS Single Quadrupole Detection Column temperature: RT Eluent A: water / Eluent B: acetonitrile, both containing 0.1% trifluoroacetic acid

[0408] Method XT Detection: Waters 2998 photodiode array detector -Waters MS Single Quadrupole Detection Column temperature: RT Eluent A: Water / Eluent B: Acetonitrile, both containing 0.1% NH4OH

[0409] Method XU Equipment: Waters preparative SFC-100-MS system Detection: Waters 2998 photodiode array detector -Waters MS Single Quadrupole Detection Modifier: Methanol ABPR:120bar Column temperature: 40℃ Flow rate: 100g / min.

[0410] Method XX Equipment: Gilson GX-281, Gilson 155, Gilson 331 Column: Sunfire C18 (30 x 100 mm, 5 μm) Column temperature: RT Eluent: A: aq. TFA (0.1%); B: ACN Flow rate: 50mL / min Detection: 254nm, 214nm UV

[0411] Materials for solid-phase extraction The following solid phase extraction (SPE) cartridges were used according to the product instructions to generate the corresponding free bases from the different salts:

[0412] PL-HCO3MP SPE cartridges were purchased from Agilent StratosPhere - Ref: PL-HCO3MP-Resin, 1.8mmol / g, 100A, 150-300μm, 500mg, 6mL.

[0413] SCX cartridges were purchased from Agilent - Ref.: HF Mega DE-SCX, 2g, 12mL.

[0414] Example 4 Synthesis of synthetic intermediates and reagents Intermediate AAN-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylbenzyl)-5-(methylamino)pentanamide [ka] Step 1: 3-((5-cyano-2-methylphenyl)amino)propanoic acid [ka] A solution of 3-amino-4-methylbenzonitrile (CAS No. [60710-80-7], 10 g, 75.66 mmol) and acrylic acid (CAS No. [79-10-7], 3 g, 151.33 mmol) in toluene (25 mL) was stirred at 120 °C under N for 16 h. The RM was concentrated to dryness to give the title compound (15 g) as a pale yellow solid. Method G: Rt = 1.34 min; [M+H] + =204.

[0415] Step 2: 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzonitrile [ka] A solution of 3-((5-cyano-2-methylphenyl)amino)propanoic acid (7.8 g, 38.19 mmol) and urea (CAS No. [57-13-6], 11.5 g, 191 mmol) in AcOH (CAS No. [64-19-7], 100 mL) was stirred at 120° C. for 16 h. The RM was poured onto crushed ice (200 g), stirred for 30 min, and filtered to give the title compound as a pale yellow solid (4 g). Method F: Rt=1.31 min; [M+H] + =230.

[0416] Step 3: 1-(5-(aminomethyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A solution of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzonitrile (4 g, 17.45 mmol) and Raney nickel (500 mg) in MeOH / NHOH (1000 mL / 200 mL) was stirred at RT under H for 16 h. The mixture was filtered through Celite® filter aid and concentrated to dryness. The crude compound was purified by reverse-phase HPLC (5% to 95% ACN / H2O, 0.01% TFA) to give the title compound (1.1 g) as the TFA salt. Method F: Rt = 0.379 min; [M+H] + =234.

[0417] Step 4: tert-butyl (5-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylbenzyl)amino)-5-oxopentyl)(methyl)carbamate [ka] HATU (CAS No. [148893-10-1], 324 mg, 0.85 mmol) was added to a stirred solution of 1-(5-(aminomethyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (250 mg, 0.72 mmol) and 5-((tert-butoxycarbonyl)(methyl)amino)pentanoic acid (CAS No. [124073-08-1], 200 mg, 0.86 mmol), followed by the addition of DIEA (CAS No. [7087-68-5], 186 mg, 1.44 mmol). The resulting solution was stirred at RT for 16 h. The RM was purified by reverse-phase HPLC (0% to 50% ACN, 0.1% NH4CO3 in HO) to give the title compound as a white solid. Method G: Rt=1.36 minutes; [M-BOC+H] + =347.

[0418] Step 5: N-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylbenzyl)-5-(methylamino)pentanamide [ka] tert-Butyl (5-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylbenzyl)amino)-5-oxopentyl)(methyl)carbamate (200 mg, 0.45 mmol) was dissolved in DCM (2 mL). TFA (6 mL) was added and the RM was stirred at RT for 16 h. The solution was concentrated to give the title compound as a dark liquid. Method G: Rt=1.26 min; [M+H] + =347.

[0419] Intermediate BB: 1-(4-iodophenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1: 3-((4-iodophenyl)amino)propanoic acid [ka] 4-Iodoaniline (4.0 g, 18.26 mmol) and acrylic acid (1.503 mL, 21.92 mmol) were dissolved in toluene (100 mL), and the reaction mixture was refluxed at 110 °C for 4 days. The reaction mixture was then cooled to room temperature and concentrated. The crude solid was redissolved in a 1:1:1 solution of DMSO / water / ACN and purified via reverse-phase chromatography on a Redisep® C18 column eluting with ACN (10-80%) in an aqueous solution of TFA (1%) to afford the TFA salt of the title compound as a light brown solid (3.70 g, 9.14 mmol). Method XQ: Rt = 0.85 min; [M+H] + =292.1.

[0420] Step 2: 1-(4-iodophenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 3-((4-Iodophenyl)amino)propanoic acid (3.7 g, 12.71 mmol) was dissolved in acetic acid (50 mL) and sodium cyanate (2.479 g, 38.1 mmol) was added. The reaction was heated at 90° C. for 18 h. The reaction mixture was cooled to RT, neutralized with 1 N NaOH, and extracted with EtOAc (3×50 mL). The combined organics were washed with water (1×25 mL) and brine (1×25 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified via reverse-phase chromatography on a Redisep® C18 column eluting with FCC (0-15% MeOH / DCM) followed by ACN (10-75%) in an aqueous solution of NH4OH (0.1%) to afford the title compound (400 mg). Method XR: Rt=1.38 min; [M+H] + =317.0. 1 H NMR(400MHz,DMSO-d6)δ 10.41(s,1H),7.81-7.65(m,2H),7.23-7.10(m,2H),3.78(t,J=6.6Hz,2H),2.70(t,J=6.6Hz,2H).

[0421] Intermediate CC: 3-((7-(3-chloropropoxy)quinazolin-4-yl)amino)-4-(dimethylamino)-N-methylbenzenesulfonamide [ka] This compound was prepared according to the procedure published in WO 2011 / 56740 A1; page 49, Example 16.

[0422] Intermediate DD: tert-butyl 4-(prop-2-yn-1-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate [ka] To a solution of K2CO3 (415 mg, 3.00 mmol) in acetonitrile (10 mL) was added tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (CAS No. [930785-40-3], 550 mg, 2.146 mmol) under argon. After 10 min, a solution of propargyl bromide in toluene (0.335 mL, 3.00 mmol) was added. The mixture was heated at reflux for 18 h, at which point an additional 8 mg of K2CO3 and 10 mg of propargyl bromide were added to the reaction mixture. The reaction mixture was refluxed for an additional 24 h, then cooled to room temperature and filtered to remove solids. The filtrate was concentrated and purified via flash chromatography (0–100% EtOAc / cyclohexane) to give the title compound (594 mg, 2.018 mmol). Method LCMS1: Rt=0.95 min; [M+H] + =295.3.

[0423] Intermediate EE: 1-(3-iodophenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1: 3-((3-iodophenyl)amino)propanoic acid [ka] To a solution of 3-iodoaniline (10 g, 45.66 mmol) in toluene (131 mL) was added acrylic acid (4.28 g, 59.36 mmol). The mixture was stirred at 115° C. for 48 hours. The solvent was removed to give the title compound as an orange oil (15 g, crude). Method H: Rt=1.36 min; [M+H] + =291.9.

[0424] Step 2: 1-(3-iodophenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a solution of 3-((3-iodophenyl)amino)propanoic acid (15 g, 51.5 mmol) in AcOH (125 mL) was added urea (9.284 g, 154.6 mmol). The mixture was stirred at 120° C. for 16 h. The solvent was removed and water (200 mL) was added. The mixture was filtered. The filter cake was washed with water (2×20 mL) and dried in vacuo. The solid was suspended in EtOAc (60 mL) and triturated at RT for 16 h. The mixture was filtered. The filter cake was washed with EtOAc (2×5 mL) and dried to give the title compound as a pale solid (7.9 g). Method E: Rt=1.43 min; [M+H] + =317.0.

[0425] Intermediate FF: 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxy-N-(4-(piperazin-1-yl)butyl)benzamide [ka] Step 1: tert-butyl 4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxybenzamido)butyl)piperazine-1-carboxylate [ka] A solution of 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxybenzoic acid (ILB-81, 155 mg, 0.539 mmol), 4-(4-amino-butyl)-piperazine-1-carboxylic acid tert-butyl ester (CAS No. [745048-07-1], 146 mg, 0.539 mmol), HATU (293 mg, 0.755 mmol), and NMM (0.30 mL, 2.70 mmol) in DMF (5 mL) was stirred at RT for 3 h. The crude product was loaded onto a Redisep® C18 column and eluted with water + 0.1% TFA / ACN 98:2 to 1:9 to give the title compound (179 mg) as a white powder. Method LCMS1: Rt = 0.59 min; [M+H] + =504.

[0426] Step 2: 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxy-N-(4-(piperazin-1-yl)butyl)benzamide [ka] A solution of tert-butyl 4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxybenzamido)butyl)piperazine-1-carboxylate (175 mg, 0.269 mmol) and HCl 4N in dioxane (4 mL, 16 mmol) in methanol (2 mL) was stirred at RT for 1.5 h. The solvent was removed and the residue was redissolved in ACN / H2O and lyophilized to give the title compound as a pale beige powder (131 mg). Method LCMS2: Rt=0.69 min; [M+H] + =404.

[0427] Intermediate GG: 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a 100 mL round-bottom flask were added dihydropyrimidine-2,4(1H,3H)-dione (2.7 g, 23.66 mmol) and anhydrous DMPU (35 mL). A solution of LiHMDS (1 M) in THF (25 mL, 25.00 mmol) was added under argon, and the RM was vigorously stirred at 60 °C for 40 min. The RM was cooled to RT. SEM-Cl (5 mL, 28.20 mmol) was added, and the RM was stirred at 60 °C for 18 h. The RM was diluted with saturated NaHCO solution and brine and extracted with EtOAc (×3). The organic phase was washed with water and brine, dried over MgSO, and concentrated. The residue was purified by chromatography on silica gel eluting with EtOAc (0% to 100%) in CHX followed by MeOH (0% to 20%) to give the title compound (4.7 g) as a pale yellow oil. Method LCMS4: Rt=0.76 min; [MH] - =243.

[0428] Compound HH: 4-(2-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)ethoxy)butanal [ka] Step 1: tert-butyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3-oxopropyl)piperidine-1-carboxylate [ka] A MW vial was charged with lenalidomide (CAS No. [191732-72-6], 50 mg, 0.193 mmol), N-Boc-4-piperidinepropionic acid (CAS No. [154775-43-6], 65 mg, 0.212 mmol), and HATU (83 mg, 0.212 mmol), followed by 1.25 mL of ACN and 0.5 mL of DMF. After adding DIPEA (0.1 mL, 0.579 mmol), the vial was flushed with N2 and capped. The pale yellow mixture was stirred for 21 h. The RM was concentrated and partitioned between EtOAc (5-6 mL) and pH = 4 buffer (commercially available solution, Fluka Product No. 33643, containing citric acid, sodium hydroxide, and sodium chloride, 5 mL). The layers were separated, the aqueous layer was extracted with EtOAc (5 mL), and the combined organic layers were dried over MgSO, filtered, and concentrated under high vacuum overnight to give a pale yellow resin. The crude product was purified on a Redisep® ISCO-column 12 g SiO with a DCM / iPrOH gradient to give the title compound (87 mg) as a white solid. Method LCMS1: Rt=0.89 min; [M−H] + =499.1. 1H NMR(400MHz,DMSO-d6):0.92-1.03(m,2H)1.34-1.46(m,10H)1.54(q,J=7.09Hz,2H)1.64(br d,J=11.86Hz,2H)1.96-2.06(m,1H)2.30-2.40(m,3H)2.55-2.75(m,3H)2.83-2.97(m,1H)3.91(br d,J=12.10Hz,2H)4.25-4.42(m,2H)5.13(dd,J=13.27,5.07Hz,1H)7.42-7.54(m,2H)7.79(dd,J=6.97,1.47Hz,1H)9.76(s,1H)11.00(s,1H).

[0429] Step 2: N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-3-(piperidin-4-yl)propanamide [ka] tert-Butyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3-oxopropyl)piperidine-1-carboxylate (265 mg, 0.532 mmol) and 3.98 mL of 4 M HCl gave a white suspension which was stirred at RT under N2 atmosphere. After 1 h, the RM was concentrated to dryness and dried under HV pump. The solid residue was then co-evaporated with DCM (2x) to give a pale yellow powder which was dried under HV overnight to give the final product in 86% purity as determined by NMR. The compound was used in the next reaction without further purification. Method LCMS1: Rt = 0.43 min; [M−H] + =399.2.

[0430] Step 3: tert-butyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3-oxopropyl)piperidine-1-carboxylate [ka] N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-3-(piperidin-4-yl)propanamide (20 mg, 0.046 mmol) and BODIPY-FL propionic acid (13.43 mg, 0.046 mmol) were dissolved in DMF (volume: 0.5 mL) to give a fluorescent reddish solution (commercially available, see preparation Krajcovicova et al., Chemistry-A European Journal, 24(19):4957-4966 (2018)). DIPEA (0.060 mL, 0.343 mmol) was added, and the reaction was stirred in the dark and monitored by UPLC / MS after 45 min. Trifluoroacetic acid (14.17 μL, 0.184 mmol) was added until the color changed to greenish. The crude product was subjected to RP purification using Method XS (Sunfire C18 (5 μm, 30 × 100 mm), 40 mL / min, 29–49% over 16 min, 21 min total). Pure fractions were lyophilized overnight to give the title compound as a light orange fluffy powder that turns fluorescent yellow in solution in DMSO (27 mg). Method LCMS1: Rt = 0.93 min; [M−H] + =673.4.

[0431] Example 5: Synthesis of intermediate compounds ILB-1: 1-((1-allyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1: 3-(aminomethyl)pyridin-2(1H)-one [ka] To a 1 L round-bottom flask were added 2-oxo-1,2-dihydropyridine-3-carbonitrile (CAS No. [20577-27-9], 12 g, 100 mmol), Raney Ni (3 g), a solution of NH3 (7 M) in MeOH (100 mL), and MeOH (150 mL). The reaction mixture was stirred under H2 (1 atm) at RT for 48 h, filtered, and the filtrate was concentrated to give a yellow oil (13.5 g), which was used for the next step without further purification. Method A: Rt = 0.48 min; [M+H] + =125.

[0432] Step 2: tert-butyl ((2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamate [ka] To a 1 L round-bottom flask was added 3-(aminomethyl)pyridin-2(1H)-one (13.5 g, 100 mmol), DIEA (25.8 g, 200 mmol), MeOH (200 mL), DCM (300 mL), and di-tert-butyl dicarbonate (21.8 g, 100 mmol). The reaction mixture was stirred at RT for 16 h, concentrated, and the residue was purified by chromatography on silica gel eluting with 0% to 8% MeOH in DCM to give the title compound (10.0 g) as an oil. Method B: Rt = 1.61 min; [M+H] + =225.

[0433] Step 3: tert-Butyl ((1-allyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamate [ka] To a 250 mL round-bottom flask was added tert-butyl ((2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamate (10.0 g, 45 mmol), K2CO3 (12.4 g, 90 mmol), DMF (80 mL), and 3-bromoprop-1-ene (CAS No. [106-95-6], 8.1 g, 67 mmol). The RM was stirred at RT for 16 h, filtered, and the filtrate was poured into water (500 mL). The mixture was extracted with EtOAc (4 x 300 mL), and the combined organic phases were dried over Na2SO4 to give the title compound (14.0 g) as an oil. Method B: Rt = 1.78 min; [M+H] + =265.

[0434] Step 4: 1-Allyl-3-(aminomethyl)pyridin-2(1H)-one [ka] To a 1 L round-bottom flask was added tert-butyl ((1-allyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamate (14.0 g), DCM (300 mL), and a solution of HCl (4 M) in 1,4-dioxane (50 mL). The reaction mixture was stirred at RT for 16 h, the solvent was removed, and the residue was purified by reverse-phase chromatography on a Biotage Agela C18 column (120 g, spherical 20-35 μm, 100 Å) eluting with 5%-40% ACN in aq. ammonium bicarbonate (0.1%) to give the title compound (7.2 g) as an oil. Method B: Rt = 1.14 min; [M+H] + =165.

[0435] Step 5: 3-(((1-allyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)amino)propanoic acid [ka] To a 250 mL round-bottom flask was added 1-allyl-3-(aminomethyl)pyridin-2(1H)-one (3.28 g, 20 mmol), acrylic acid (4.32 g, 60 mmol), and toluene (100 mL). The RM was stirred at 100° C. for 18 h and concentrated to give the crude title compound, which was used in the next step without further purification. Method C: Rt=0.34 min; [M+H] + =237.

[0436] Step 6: 1-((1-allyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a 250 mL round-bottom flask was added 3-(((1-allyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)amino)propanoic acid (8 g), urea (3.6 g, 60 mmol), and acetic acid (40 mL). The reaction mixture was stirred at 120° C. for 18 h, concentrated, and the residue was purified by reverse-phase chromatography on a Biotage Agela C18 column (120 g, spherical 20-35 μm, 100 Å) eluting with 5%-50% ACN in aq. ammonium bicarbonate (0.1%) to give the title compound (3.4 g) as a solid. Method B: Rt=1.40 min; [M+H] + =262.

[0437] ILB-2: 2-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)acetaldehyde [ka] To a 250 mL round-bottom flask was added 1-((1-allyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)dihydropyrimidine-2,4(1H,3H)-dione (ILB-1, 3.9 g, 15 mmol), THF (120 mL), and a solution of OsO (4%) in water (8 mL). The reaction mixture was stirred at RT under nitrogen for 45 min. Solid NaIO (9.6 g, 45 mmol) was added, and the reaction mixture was stirred at RT under nitrogen for 16 h. The mixture was filtered, the solvent removed, and the residue purified by reverse-phase chromatography on a Biotage Agela C18 column (120 g, spherical 20-35 μm, 100 Å) eluting with 0% to 30% ACN in aq. ammonium bicarbonate (0.1%) to give the title compound (3.6 g) as a solid. Method D: Rt=0.42 min; [M+H] + =264

[0438] ILB-3: 1-((1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a mixture of ILB-2 (80 mg, 0.30 mmol) in THF (3 mL) was added NaBH (17 mg, 0.46 mmol) at 25 °C, and the reaction mixture was stirred at 25 °C for 0.5 h. Then, the RM was cooled to 0 °C, and water (1 mL) was carefully added. The solvent was removed in vacuo, and the crude mixture was purified by flash chromatography on silica gel eluting with 0-10% MeOH in DCM to give the desired product, 1-((1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)dihydropyrimidine-2,4(1H,3H)-dione (52 mg), as a white solid. Method G: Rt = 0.466 min; [M+H] + =266. 1H NMR(500MHz,DMSO)δ 10.16(s,1H),7.55(m,1H),7.28(d,J=6.8Hz,1H),6.20(t,J=6.8Hz,1H),4.88(t,J=5.4Hz,1H),4.2 7(s,2H),3.96(t,J=5.4Hz,2H),3.62(q,J=5.4Hz,2H),3.42(t,J=6.8Hz,2H),2.57(t,J=6.8Hz,2H).

[0439] ILB-5: 4-(2-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)ethoxy)butanal [ka] Step 1: 12,12-dimethyl-1,11,11-triphenyl-2,5,10-trioxa-11-silatridecane [ka] To a solution of 2-(benzyloxy)ethan-1-ol (CAS No. [622-08-2], commercially available, 9.91 g, 65.15 mmol) in THF (150 mL) was slowly added NaH (6.95 g, 173.73 mmol). The reaction mixture was warmed to 80 °C and stirred at this temperature for 1 h. After cooling to RT, (4-bromobutoxy)(tert-butyl)diphenylsilane (CAS No. [125010-58-4], Angew. Chem. Int. Ed. 54(51):15717-15720(2015), 17 g, 43.43 mmol) was added dropwise. The resulting solution was stirred at 80 °C for 16 h. The reaction mixture was slowly added to water (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product. The crude mixture was purified by flash chromatography on silica gel eluting with a 0-5% gradient of petroleum ether and EtOAc to give the desired product (7 g) as a colorless oil. Method G: Rf = 2.88 min, [M+NH4]+ =480.3.

[0440] Step 2: 2-(4-((tert-butyldiphenylsilyl)oxy)butoxy)ethan-1-ol [ka] To a solution of 12,12-dimethyl-1,11,11-triphenyl-2,5,10-trioxa-11-silatridecane (10.8 g, 23.34 mmol) in EtOH / HO (100 mL / 4 mL) was slowly added Pd / C (150 mg). The mixture was stirred at 40 °C under an atmosphere of H for 16 h. The RM solution was filtered and the solvent was evaporated. The crude mixture was purified by chromatography on silica gel eluting with a 0-50% gradient of petroleum ether and EtOAc to give the title compound (8.1 g) as a pale yellow oil. Method G: Rf = 2.310 min, [M+H] + =373.3.

[0441] Step 3: 2-(4-((tert-butyldiphenylsilyl)oxy)butoxy)ethyl methanesulfonate [ka] To a solution of 2-(4-((tert-butyldiphenylsilyl)oxy)butoxy)ethan-1-ol (8.1 g, 21.74 mmol) and TEA (6.60 g, 65.22 mmol) in DCM (50 mL) was slowly added MsCl (2.49 g, 21.74 mmol) dissolved in DCM (20 mL) via a dropping funnel at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 3 h. Water (20 mL) was slowly added, and the mixture was extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over NaSO, and concentrated in vacuo to give the crude title compound (9.23 g) as a yellow oil, which was used directly in the next step without further purification. Method G: Rf = 2.355 min, [M+NH] + =468.

[0442] Step 4: tert-butyl(4-(2-iodoethoxy)butoxy)diphenylsilane [ka] To a solution of 2-(4-((tert-butyldiphenylsilyl)oxy)butoxy)ethyl methanesulfonate (9.23 g, 20.48 mmol) in MeCN (100 mL) was added KI (34 g, 204.81 mmol) at RT and the mixture was stirred at 80° C. for 16 h. The mixture was poured into water (200 mL), extracted with EtOAc (2×100 mL) and the combined organic layers were concentrated in vacuo to give the crude title compound (9.25 g) as a yellow oil, which was used directly in the next step without further purification. Method G: Rf=2.879 min, no mass observed (non-ionized). Purity: 100% (254 nm).

[0443] Step 5: tert-butyl ((1-(2-(4-((tert-butyldiphenylsilyl)oxy)butoxy)ethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamate [ka] To a solution of tert-butyl ((2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamate (ILB-1, step 2, 4.3 g, 19.17 mmol) and tert-butyl(4-(2-iodoethoxy)butoxy)diphenylsilane (9.25 g, 19.17 mmol) in DMF (20 mL) was added K2CO3 (7.95 g, 33.44 mmol), and the mixture was stirred at RT for 16 h. The mixture was poured into water (200 mL) and extracted with EtOAc (2 × 100 mL); the combined organic layers were washed with brine (5 × 5 mL) to remove DMF. The organic layer was concentrated to give the crude product as a yellow oil, which was purified by flash chromatography on silica gel (petroleum ether, 10–60% ethyl acetate) to give the title compound (6.3 g) as a pale yellow oil. Method G: Rf=2.48 min, [M+H]+ =579.

[0444] Step 6: tert-butyl ((1-(2-(4-hydroxybutoxy)ethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamate [ka] TBAF (3.4 g, 13.06 mmol) was added to a solution of tert-butyl ((1-(2-(4-((tert-butyldiphenylsilyl)oxy)butoxy)ethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamate (6.3 g, 10.88 mmol) in 20 mL THF, and the mixture was stirred at RT for 2 h. After evaporation of the solvent, the crude product was purified by flash chromatography on silica gel (10-100% EtOAc in petroleum ether, followed by 0-10% MeOH in DCM) to give the title compound (3.3 g) as a pale yellow oil. Method G: Rf = 1.56 min, [M+H] + =341.

[0445] Step 7: 3-(aminomethyl)-1-(2-(4-hydroxybutoxy)ethyl)pyridin-2(1H)-one [ka] To a solution of tert-butyl ((1-(2-(4-hydroxybutoxy)ethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamate (1.8 g, 5.29 mmol) in DCM / MeOH (30 mL / 3 mL) was slowly added a solution of HCl in 1,4-dioxane (4 M) (13.2 mL, 52.9 mmol) at 0 °C. The RM was warmed to RT and stirring was continued for 16 h. After removal of volatile components under reduced pressure, the residue was dissolved in HO / MeOH (8 mL / 2 mL) and the pH was adjusted to 7.0 with aqueous NaCO. The mixture was purified by reverse-phase chromatography using Method PB to give the title compound (800 mg) as a white solid. Method H: Rf = 0.94 min, [M+H]+ =241.3.

[0446] Step 8: 3-(((1-(2-(4-hydroxybutoxy)ethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)amino)propanoic acid [ka] A mixture of 3-(aminomethyl)-1-(2-(4-hydroxybutoxy)ethyl)pyridin-2(1H)-one (1.3 g, 5.42 mmol) and acrylic acid (780 mg, 10.8 mmol) in ACN (30 mL) was stirred at 80° C. for 4 h. The solvent was removed in vacuo to give the title compound (1.5 g) as a yellow oil, which was used for the next step without further purification. Method H: Rf=0.89 min, [M+H] + =313.2.

[0447] Step 9: 4-(2-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)ethoxy)butyl acetate [ka] A mixture of 3-(((1-(2-(4-hydroxybutoxy)ethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)amino)propanoic acid (1.5 g, crude, 4.8 mmol) and urea (1.15 g, 19.2 mmol) in HOAc (20 mL) was stirred at 100° C. for 16 h. The solvent was evaporated and the residue was purified by reverse-phase chromatography using Method PB to give the title compound (800 mg) as a white solid. Method XH: Rf=1.44 min, [M+H] + =380.0.

[0448] Step 10: 1-((1-(2-(4-hydroxybutoxy)ethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a solution of 4-(2-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)ethoxy)butyl acetate (800 mg, 2.11 mmol) in 1,4-dioxane (10 mL) was added HCl (aq., 6 M, 20 mL). The reaction mixture was stirred at 90° C. for 30 min. The volatile components were removed under reduced pressure, the evaporation residue was dissolved in water / MeCN (8 mL / 2 mL) and the pH value was adjusted to 7.0 with aqueous NaCO solution. The crude product solution was purified by reversed-phase chromatography using Method PB to give the title compound (600 mg) as an off-white solid. Method H: Rf=1.10 min, [M+H] + =338.3.

[0449] Step 11: 4-(2-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)ethoxy)butanal [ka] A mixture of 1-((1-(2-(4-hydroxybutoxy)ethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.593 mmol) and pyridinium chlorochromate (255 mg, 1.187 mmol) in DCM (10 mL) was stirred at RT for 4 h. The solids were removed by filtration and the filtrate was evaporated. The residue after evaporation was purified by reverse phase chromatography using Method PB to give the title compound (70 mg) as a pale yellow solid. Method G: Rf=1.50 min, [M+H] + =336.1.

[0450] ILB-6: 1-((2-oxo-1-(2-(4-(piperidin-4-yloxy)piperidin-1-yl)ethyl)-1,2-dihydropyridin-3-yl)methyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1: tert-butyl 4-(1-(2-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)ethyl)piperidin-4-yloxy)piperidine-1-carboxylate [ka] To a 250 mL round-bottom flask was added 2-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)acetaldehyde (ILB-2, 3.6 g, 13.6 mmol), tert-butyl 4-(piperidin-4-yloxy)piperidine-1-carboxylate (CAS No. [845305-83-1], 3.86 g, 13.6 mmol), a solution of ZnCl (1 M) in THF (20.4 mL, 20.4 mmol), and DMSO (40 mL). The RM was stirred at RT for 2 h, solid NaBHCN (2.57 g, 40.8 mmol) and MeOH (8 mL) were added, and the reaction mixture was stirred at RT for 16 h, concentrated, and purified by reverse-phase chromatography on a Biotage Agela C18 column (120 g, spherical 20-35 μm, 100 Å) eluting with 5%-60% ACN in aq. ammonium bicarbonate (0.1%) to give the title compound (2.8 g) as a solid. Method A: Rt = 1.81 min; [M+H] + =532.

[0451] Step 2: 1-((2-oxo-1-(2-(4-(piperidin-4-yloxy)piperidin-1-yl)ethyl)-1,2-dihydropyridin-3-yl)methyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a 250 mL round-bottom flask was added tert-butyl 4-(1-(2-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)ethyl)piperidin-4-yloxy)piperidine-1-carboxylate (2.8 g, 5.2 mmol), DCM (30 mL), and a solution of HCl (4 M) in 1,4-dioxane (10 mL). The reaction mixture was stirred at RT for 6 h. The mixture was concentrated, and the residue was purified by reverse-phase chromatography on a Biotage Agela C18 column (120 g, spherical 20-35 μm, 100 Å) eluting with 0% to 50% ACN in aq. ammonium bicarbonate (0.1%) to give the title compound (1.8 g) as a solid. Method B: Rt=1.36 min; [M+H] + =432.

[0452] ILB-7: 1-(3-(2-hydroxyethyl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1: 2-(3-(aminomethyl)phenyl)ethan-1-ol [ka] To a solution of ethyl 2-(3-(aminomethyl)phenyl)acetate (600 mg, 4.0 mmol) in THF (30 mL) was added dropwise a solution of LiAlH (1 M in THF, 8 mL, 8 mmol) at 0 °C, and the mixture was stirred at RT for 4 h. The reaction was quenched by dropwise addition of an aqueous solution of NaSO at 0 °C, and the mixture was filtered and subsequently evaporated. The residue was purified by reverse-phase chromatography eluting with ACN in an aqueous solution of NHCOH (0.1%) to give the desired product, 2-(3-(aminomethyl)phenyl)ethan-1-ol (240 mg), as a yellow solid. LCMS Method XJ: Rt = 1.45 min; [M+H] + =152.

[0453] Step 2: 3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)phenethyl acetate [ka] A mixture of 2-(3-(aminomethyl)phenyl)ethan-1-ol (240 mg, 1.6 mmol) and acrylic acid (137 mg, 1.9 mmol) in toluene (10 mL) was heated at 100° C. for 16 h, then cooled to RT. The solvent was removed in vacuo to give a yellow solid. Acetic acid (5 mL) was added, followed by urea (384 mg, 6.4 mmol). The reaction mixture was heated at 120° C. for 72 h, then cooled to RT, and the acetic acid was removed in vacuo. Purification by reverse phase chromatography eluting with ACN in a solution of formic acid (0.1%) in water gave the desired product (170 mg) as a yellow solid. LCMS Method XJ: Rt=1.57 min; [M+H] + =291.

[0454] Step 3: 1-(3-(2-hydroxyethyl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Aqueous hydrochloric acid (6 M, 2 mL) was added to 3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)phenethyl acetate (170 mg, 0.6 mmol) in dioxane (4 mL). The reaction mixture was stirred at 80° C. for 1 h and then cooled to RT. The solvent was removed in vacuo and the residue was purified by reverse phase chromatography (Method PB) eluting with ACN in an aqueous solution of NH4CO3H to give the title compound (50 mg) as a white solid. LCMS Method XE: Rt=1.27 min; [M+H] + =249. 1H NMR(500MHz,DMSO)δ 7.25(t,J=7.9Hz,1H),7.13-7.09(m,3H),4.63(br.s,1H),4.49(s,2H),3.60- 3.57(m,2H),3.27(t,J=6.8Hz,2H),2.71(t,J=7Hz,2H),2.53(t,J=6.8Hz,2H).

[0455] ILB-8: 2-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)isonicotinic acid [ka] Step 1: 3-(((4-(methoxycarbonyl)pyridin-2-yl)methyl)amino)propanoic acid [ka] To a mixture of methyl 2-cyanoisonicotinate (7 g, 43.2 mmol) in MeOH (100 mL) was added Pd / C (500 mg) and concentrated HCl (5 mL). The mixture was then stirred at 30 °C under an atmosphere of H (15 psi) for 2 h. The mixture was filtered to remove the Pd / C, and the filtrate was then concentrated under reduced pressure to give methyl 2-(aminomethyl)isonicotinate (7 g, crude) as a yellow solid. To this material (7 g, 42.1 mmol), which was used without further purification, was added MeCN (35 mL), water (7 mL), and finally acrylic acid (3.96 g, 54.7 mmol). The mixture was stirred at 80 °C for 16 h, and then the mixture was concentrated to dryness under vacuum. The solid was purified by flash chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with 0-100% DCM / MeOH) to give the title compound 3-(((4-(methoxycarbonyl)pyridin-2-yl)methyl)amino)propanoic acid as a yellow oil (5 g, 92% pure). Method LCMS10: Rt=0.26 min; [M+H] + =239.0.

[0456] Step 2: 2-(((2-carboxyethyl)amino)methyl)isonicotinic acid [ka] To a solution of 3-(((4-(methoxycarbonyl)pyridin-2-yl)methyl)amino)propanoic acid (2 g, 8.39 mmol) in MeOH (5 mL) was added THF (5 mL), HO (5 mL), and LiOH (1.01 g, 42 mmol). The mixture was stirred at 25° C. for 12 h. The mixture was then concentrated to give crude 2-(((2-carboxyethyl)amino)methyl)isonicotinic acid (2 g) as a yellow solid. Method LCMS 10: Rt=0.13 min; [M+H] + =225.0.

[0457] Step 3: 2-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)isonicotinic acid [ka] To a solution of 2-(((2-carboxyethyl)amino)methyl)isonicotinic acid (2 g, 8.92 mmol) in HOAc (20 mL) was added urea (1.61 g, 26.8 mmol) at 25° C. The reaction mixture was then heated with stirring at 100° C. for 12 h. After cooling to RT, the reaction mixture was concentrated in vacuo to remove HOAc, yielding an oil (2.5 g, crude). The oil was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent 0-100% DCM / MeOH) to yield a yellow solid (500 mg, 91% purity) after lyophilization. This product was further purified by preparative HPLC (Method PA2) to give the title compound 2-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)isonicotinic acid (156 mg, 0.6 mmol, 97.8% purity) as a white solid. Method LCMS11: Rt=2.66 min; [M+H]+=250.1. 1H NMR(400MHz,DMSO)δ 10.25(s,1H),8.75-8.69(m,1H),7.74-7.70(m,2H),4.71(s,2H),3.46(t,J=6.8Hz,2H),2.59(t,J=6.8Hz,2H).

[0458] ILB-9: 3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-4-methoxybenzoic acid [ka] Step 1: 3-((2-methoxy-5-(methoxycarbonyl)benzyl)amino)propanoic acid [ka] A mixture of methyl 3-(aminomethyl)-4-methoxybenzoate (CAS [771579-95-4], 1.90 g, 9.73 mmol) and acrylic acid (2.004 mL, 29.2 mmol) in toluene (48.7 mL) was stirred at 100 °C overnight. The RM was concentrated to dryness to give the title compound (3.75 g) as a yellow resin. Method LCMS7: Rt = 0.41 min; [M+H] + =268.

[0459] Step 2: Methyl 3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-4-methoxybenzoate [ka] Under argon, a mixture of 3-((2-methoxy-5-(methoxycarbonyl)benzyl)amino)propanoic acid (3.7 g, 13.84 mmol) and urea (1.663 g, 27.7 mmol) in acetic acid (18.5 mL) was stirred at 120° C. overnight. The mixture was cooled to RT and then mixed with approximately 100 mL of ice and 20 mL of concentrated HCl. The opaque beige mixture was left stirring for 30 min and then stored in the refrigerator overnight. The cooled mixture was filtered and the residue was washed with a small amount of water followed by EtO and then dried under high vacuum to give 1.82 g of the desired product as an off-white solid. Method LCMS7: Rt=0.69 min; [M+H] + =293

[0460] Step 3: 3-((1-(2-carboxyethyl)ureido)methyl)-4-methoxybenzoic acid [ka] A solution of lithium hydroxide monohydrate (CAS[1310-66-3], 2.58 g, 61.6 mmol) in water (30.8 mL) was added to a mixture of methyl 3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-4-methoxybenzoate (1.80 g, 6.16 mmol) in THF (30.8 mL). The mixture was stirred at RT for 2.5 h. The THF was then removed under reduced pressure, and the aqueous layer was washed with DCM and acidified to approximately pH 3 with 1N HCl (a white precipitate appeared after standing for several minutes). The mixture was then sonicated and filtered. The residue was washed with water, followed by EtO, and then dried to give 1.69 g of product as an off-white solid. Method LCMS7: Rt=0.54 min; [M+H] + =297

[0461] Step 4: 3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-4-methoxybenzoic acid [ka] A mixture of 3-((1-(2-carboxyethyl)ureido)methyl)-4-methoxybenzoic acid (1.52 g, 5.13 mmol) in concentrated HCl (15.6 mL, 513 mmol) was stirred at 100° C. for 1 h. The mixture was then cooled to RT and diluted with ice water. The precipitate was filtered off, washed with water and EtO, and then dried to give 1.23 g of the desired product as a white solid. Method LCMS7: Rt=0.60 min; [M+H] + =279

[0462] ILB-10: 3-((2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)methyl)benzaldehyde [ka] Step 1: 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a 100 mL round-bottom flask under argon were added dihydropyrimidine-2,4(1H,3H)-dione (2.7 g, 23.66 mmol) and DMPU (35 mL). A solution of LiHMDS (1 M) in THF (25 mL, 25.00 mmol) was added, and the RM was vigorously stirred at 60 °C for 40 min. The RM was cooled to RT, and 2-(trimethylsilyl)ethoxymethyl chloride (5 mL, 28.20 mmol) was added, and the RM was stirred at 60 °C for 18 h. The RM was diluted with a saturated solution of NaHCO and brine, and the mixture was extracted with EtOAc. The combined organic phases were washed with water and brine, dried over MgSO, and the residue was purified by silica gel chromatography eluting with EtOAc in CHX (0% to 100%) followed by MeOH in EtOAc (0% to 20%) to give the title compound (4.7 g) as an oil. Method LCMS4: Rt=0.76 min; [MH] + 243.

[0463] Step 2: 3-((2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)methyl)benzaldehyde [ka] A 10 mL round-bottom flask was charged with 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (150 mg, 0.602 mmol) and DMF (3 mL) under an argon atmosphere. The mixture was cooled to 0 °C, solid NaH (60% dispersion in mineral oil, 16 mg, 25.0 mmol) was added, and the mixture was stirred at RT for 10 min. 3-(Bromomethyl)-benzaldehyde (132 mg, 0.632 mmol) was added, and the RM was stirred at RT for 2 h. A saturated aqueous solution of NH4Cl and water was added, the aqueous phase was extracted with EtOAc, the combined organic phases were washed with brine, dried over MgSO4, and the residue was purified by reverse phase chromatography on a RediSep® Gold HP C18 column (15.5 g) eluting with ACN (1% to 100%) in an aqueous solution of NH4HCO3 (0.1%) to give the title compound (62 mg) as an oil. Method LCMS1: Rt = 1.06 min; [M+H] + =380.

[0464] ILB-12: 1-(2-chloro-4-hydroxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1: 3-((2-chloro-4-methoxyphenyl)amino)propanoic acid, 3,3'-((2-chloro-4-methoxyphenyl)azanediyl)dipropanoic acid [ka] A mixture of 4-methoxy-2-methylaniline (4.82 g, 30.6 mmol) and acrylic acid (8.40 mL, 122 mmol) in toluene (volume: 10 mL) was heated at 100° C. for 1 h. After 1.5 h, the RM was evaporated to dryness to give 7.02 g of a mixture of structures I and II as a black resin. UPLC-MS showed 47% structure I / 19% structure II. Method LCMS1 for structure I: Rt=0.78 min; [M+H] + = 230.1. Method LCMS1 for Structure II: Rt = 0.84 min; [M+H] + =302.1.

[0465] Step 2: 1-(2-chloro-4-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a mixture of 3-((2-chloro-4-methoxyphenyl)amino)propanoic acid, 3,3'-((2-chloro-4-methoxyphenyl)azanediyl)dipropanoic acid (7.02 g, 30.6 mmol) in toluene (35 mL, ratio: 1.0) / acetic acid (35.0 mL, ratio: 1.0) was added urea (9.18 g, 153 mmol). The RM was heated at 120°C overnight. The RM was evaporated to dryness. The greasy residue was poured into 300 mL of ice and stirred until it reached room temperature. The precipitate that formed was filtered off and washed with water. The filter cake was washed with diisopropyl ether and then dried overnight in vacuo at 50°C to give the title compound (5.11 g) as a blue-violet solid. Method LCMS1: Rt = 0.66 min; [2M+H] + =509.2.

[0466] Step 3: 1-(2-chloro-4-hydroxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a mixture of 1-(2-chloro-4-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (2.29 g, 8.27 mmol) in DCM (40 mL) was added BBr3 1M in CHCl (23.16 mL, 23.16 mL) dropwise at RT. The RM was stirred at RT for 1.5 h. The RM was evaporated, adsorbed onto silica gel, and purified by flash chromatography on a 24 g silica flash column eluting with DCM / MeOH to give the title compound (1.69 g). Method LCMS1: Rt=0.47 min; [M−H] + =239.1.

[0467] ILB-13: 1-(4-hydroxy-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1: 3-((4-methoxy-2-methylphenyl)amino)propanoic acid, 3,3'-((4-methoxy-2-methylphenyl)azanediyl)dipropanoic acid [ka] A mixture of 4-methoxy-2-methylaniline (4.82 g, 35.1 mmol) and acrylic acid (9.65 mL, 141 mmol) in toluene (10 mL) was heated at 100° C. for 1.5 h. The RM was evaporated to dryness to give a black resin. The black resin was used directly in 1-(4-methoxy-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione. Method LCMS1: Rt=0.53 min; [M+H] + =210.1 min Structure I. Method LCMS1: Rt=0.49 min; [M+H] + =282.2 Structure II.

[0468] Step 2: 1-(4-methoxy-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a mixture of 3-((4-methoxy-2-methylphenyl)amino)propanoic acid (7.34 g, 35.1 mmol) in toluene (35 mL, ratio: 1.0) / acetic acid (35.0 mL, ratio: 1.0) was added urea (10.54 g, 176 mmol). The RM was heated at 120° C. overnight. The RM was evaporated to dryness. The greasy residue was poured into 300 mL of ice and stirred until it reached room temperature. The precipitate that formed was filtered off and washed thoroughly with water. The mass was dissolved in diisopropyl ether (soluble in acetonitrile), filtered, and then dried overnight in vacuo at 50° C. to give the title compound (4.34 g) as a blue-violet solid. Method LCMS1: Rt=0.61 min; [M+H] + =235.1.

[0469] Step 3: 1-(4-hydroxy-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a mixtu...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, The targeting ligand is a group capable of binding to a target protein and has the formula selected from the group consisting of: 【Chemistry 2】 having The linker is a group that covalently links the targeting ligand to the targeting ligase binder and has the formula (LI): 【Transformation 3】 and The targeted ligase binder is a group capable of binding to cereblon E3 ubiquitin ligase and has the formula (TLB-I): 【Chemistry 4】 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof; During the ceremony, 【Transformation 5】 means the point of attachment to the linker in formula (I); Ring A is a 6-membered aryl or a 5- or 6-membered heteroaryl, each of which is selected from 0 to 4 R ｄ４ is replaced by the presence of L １ is a bond, O, NR', C(O), C １～９ Alkylene, C １～９ Heteroalkylene, *C(O)-C １～６ Alkylene, *C(O)-C １～６ Heteroalkylene, *C １～６ Alkylene-C(O), and *C １～６ heteroalkylene-C(O), and * is selected from the group consisting of L in formula (I). １ means the point of attachment to said targeting ligand; X １ and X ２ are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L ２ is a bond, O, NR', C(O), C １～６ Alkylene, C １～６ heteroalkylene, and *C(O)NR'-C １～６ alkylene, and * is selected from the group consisting of L ２ X ２ means the point of attachment to X １ -L ２ -X ２ forms a spiroheterocyclyl; L ３ is a bond, C １～６ Alkylene, C ２～６ Alkenylene, C ２～６ Alkynylene, C １～６ Heteroalkylene, C(O), S(O) ２ , O, NR', *C(O)-C １～９ Alkylene, and *C(O)-C １～９ heteroalkylene, and * is L in (LI). ３ X ２ means the point of attachment to L １ , X １ , X ２ , L ２ , and L ３ no more than two of may be bonds simultaneously; R ｄ１ and R ｄ２ are each independently H, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Heteroalkyl, and C ３～６ cycloalkyl; R ｄ３ is H; Each R ｄ４ are independently H, oxo, hydroxyl, C １～６ Alkyl, halogen, C １～６ Haloalkyl, C １～６ Alkoxyl and C １～６ heteroalkyl; Each R ｄ５ are independently H, C １～６ Alkyl, halogen, C １～６ Haloalkyl, C １～６ Heteroalkyl, and C ３～６ cycloalkyl; R' is H or C １～６ is alkyl; m is 1 or 2; and n is 1) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

2. Formula (I): 【Transformation 6】 (In the formula, The targeting ligand is a group capable of binding to a target protein and has the formula selected from the group consisting of: 【Transformation 7】 having The linker is a group that covalently links the targeting ligand to the targeting ligase binder and has the formula (LI): 【Transformation 8】 and The targeted ligase binder is a group capable of binding to cereblon E3 ubiquitin ligase and has the formula (TLB-VI): 【Chemistry 9】 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof; During the ceremony, 【Chemistry 10】 means the point of attachment to the linker in formula (I); Ring A is a 6-membered aryl or 6-membered heteroaryl, each independently containing 0 to 4 R ｄ６ is replaced by the presence of L １ is a bond, O, NR', C(O), C １～９ Alkylene, C １～９ Heteroalkylene, *C(O)-C １～６ Alkylene, *C(O)-C １～６ Heteroalkylene, *C １～６ Alkylene-C(O), and *C １～６ heteroalkylene-C(O), and * is selected from the group consisting of L in formula (I). １ means the point of attachment to said targeting ligand; X １ and X ２ are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L ２ is a bond, O, NR', C(O), C １～６ Alkylene, C １～６ heteroalkylene, and *C(O)NR'-C １～６ alkylene, and * is selected from the group consisting of L ２ X ２ means the point of attachment to X １ -L ２ -X ２ forms a spiroheterocyclyl; L ３ is a bond, C １～６ Alkylene, C ２～６ Alkenylene, C ２～６ Alkynylene, C １～６ Heteroalkylene, C(O), S(O) ２ , O, NR', *C(O)-C １～９ Alkylene, and *C(O)-C １～９ heteroalkylene, and * is L in (LI). ３ X ２ means the point of attachment to When the targeting ligand is (TL-1) or (TL-5), L ３ is not C(O); L １ , X １ , X ２ , L ２ , and L ３ no more than two of may be bonds simultaneously; Each R ｄ６ are independently H, hydroxyl, oxo, C １～６ Alkyl, halogen, C １～６ Alkoxyl, C １～６ Haloalkyl, and C １～６ heteroalkyl; R ｄ７ is H; R' is H or C １～６ is alkyl; Each R ｄ８ are independently H, C １～６ Alkyl, halogen, C １～６ Haloalkyl, and C １～６ heteroalkyl; m is 1 or 2; and n is 1 or 2. or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

3. 3. The bifunctional compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein Ring A is selected from the group consisting of phenyl, pyridyl, pyridonyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, and pyrrolyl.

4. The targeted ligase binder has the formula (TLB-VII): 【Chemistry 11】 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein 【Chemistry 12】 means the point of attachment to the linker in formula (I); U is -CR ｄ６ or N; Each R ｄ６ are independently H, hydroxyl, C １～６ Alkyl, halogen, C １～６ Alkoxyl, C １～６ Haloalkyl, and C １～６ heteroalkyl; and n is 1 or 2.

3. The bifunctional compound of claim 2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, having the formula:

5. Formula (II): 【Chemistry 13】 (In the formula, R １ａ is H or halo; R ２ａ is a halo; R ３ａ is C １～６ is alkyl; R ４ａ is a halo; R ５ａ is H or halo; L １ represents a bond, —O—, —NR′—, —C(O)—, C １～９ Alkylene, C １～９ Heteroalkylene, *C(O)-C １～６ Alkylene, *C(O)-C １～６ Heteroalkylene, *C １～６ Alkylene-C(O), and *C １～６ heteroalkylene-C(O), and * is selected from the group consisting of L １ means the point of attachment to said targeting ligand; X １ and X ２ are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L ２ represents a bond, —O—, —NR′—, —C(O)—, C １～６ Alkylene, C １～６ heteroalkylene, and *C(O)NR'-C １～６ alkylene, and * is selected from the group consisting of L ２ X ２ means the point of attachment to X １ -L ２ -X ２ forms a spiroheterocyclyl; L ３ is a bond, C １～６ Alkylene, C ２～６ Alkenylene, C ２～６ Alkynylene, C １～６ Heteroalkylene, —C(O)—, —S(O) ２ -, -O-, *C(O)-C １～９ Alkylene, and *C(O)-C １～９ heteroalkylene, and * is selected from the group consisting of L ３ X ２ means the point of attachment to L １ , X １ , X ２ , L ２ , and L ３ no more than two of may be bonds simultaneously; R' is hydrogen or C １～６ is alkyl; R ｄ１ and R ｄ２ are each independently H, C １～６ Alkyl, C １～６ Haloalkyl, and C １～６ heteroalkyl; R ｄ３ is H, -CH ２ O.C.(O.)R. ｐ , -CH ２ OP(O)OHOR ｐ , -CH ２ OP (O) (R ｐ ) ２ , and -CH ２ OP (O) (OR ｐ ) ２ selected from the group consisting of: R ｄ４ is H, C １～６ Alkyl, halogen, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Alkoxyalkyl, and C １～６ heteroalkyl; R ｄ５ is H, C １～６ Alkyl, halogen, C １～６ Haloalkyl, and C １～６ heteroalkyl; and R ｐ is H or C １～６ alkyl) 10. The bifunctional compound of claim 1, having the structure:

6. Formula (IIA): 【Chemistry 14】 (In the formula, R １ａ is H or halo; R ２ａ is a halo; R ３ａ is C １～６ is alkyl; R ４ａ is a halo; R ５ａ is H or halo; L １ represents a bond, —O—, —NR′—, —C(O)—, C １～９ Alkylene, C １～９ Heteroalkylene, *C(O)-C １～６ Alkylene, *C(O)-C １～６ Heteroalkylene, *C １～６ Alkylene-C(O), and *C １～６ heteroalkylene-C(O), and * is selected from the group consisting of L １ means the point of attachment to said targeting ligand; X １ and X ２ are each independently selected from the group consisting of a bond, carbocyclyl, heterocyclyl, and heteroaryl; L ２ represents a bond, —O—, —NR′—, —C(O)—, C １～６ Alkylene, C １～６ heteroalkylene, and *C(O)NR'-C １～６ alkylene, and * is selected from the group consisting of L ２ X ２ means the point of attachment to X １ -L ２ -X ２ forms a spiroheterocyclyl; L ３ is a bond, C １～６ Alkylene, C ２～６ Alkenylene, C ２～６ Alkynylene, C １～６ Heteroalkylene, —C(O)—, —S(O) ２ -, -O-, *C(O)-C １～ ９ Alkylene, and *C(O)-C １～９ heteroalkylene, and * is selected from the group consisting of L ３ X ２ means the point of attachment to L １ , X １ , X ２ , L ２ , and L ３ no more than two of may be bonds simultaneously; R' is hydrogen or C １～６ is alkyl; U is -CR ｄ６ or N; Each R ｄ６ are independently H, oxo, C １～６ Alkyl, halogen, C １～６ Alkoxyl, C １～６ Haloalkyl, and C １～６ heteroalkyl; U is -CR ｄ６ or N; Each R ｄ６ are independently H, oxo, C １～６ Alkyl, halogen, C １～６ Alkoxyl, C １～６ Haloalkyl, and C １～６ heteroalkyl; R ｄ７ is H, -CH ２ O.C.(O.)R. ｐ , -CH ２ OP(O)OHOR ｐ , -CH ２ OP (O) (R ｐ ) ２ , and -CH ２ OP (O) (OR ｐ ) ２ selected from the group consisting of: R ｄ８ is H, C １～６ Alkyl, halogen, C １～６ Haloalkyl, and C １～６ heteroalkyl; R ｐ is H or C １～６ is alkyl; and n is 1 or 2.

3. The bifunctional compound of claim 2 having the structure: or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

7. below: 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 3. The bifunctional compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, selected from the group consisting of:

8. 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

9. 10. The pharmaceutical composition of claim 8, used to treat or prevent a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease or disorder in a subject in need thereof.

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