RU2830281C1 - Substances providing protein degradation and use thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, which can be used to treat a disorder, a disease or a condition mediated by a BRD4 target protein. In formula I, X¹ is a divalent fragment selected from -C(O)-; R¹ is hydrogen; each R² is independently hydrogen or -R⁶; ring A is , where ring B is a fused ring selected from 6-member aryl containing 0–2 nitrogen atoms; each R⁴ is independently hydrogen or -R⁶; each R⁶ is C_1-6 alkyl; L is a divalent saturated linear C_1-20 hydrocarbon chain, where 0–6 methylene links of L are independently replaced with -O- or -NR-; TBM is a target binding moiety, wherein the target binding moiety is a BRD4 binding moiety, wherein the BRD4 binding moiety is ; m is 0, 1, 2, 3 or 4; and each R is independently hydrogen. Invention also relates to a pharmaceutical composition containing said compound, and to a method of destroying a target protein in a biological sample using the same, wherein the target protein is BRD4.

EFFECT: substances providing degradation of proteins and their application are disclosed.

6 cl, 4 tbl, 11 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0001] The present invention relates to compounds and methods that can be used to modulate targeted ubiquitination, particularly with respect to a variety of polypeptides and other proteins that are degraded and/or otherwise inhibited by the compounds of the present invention. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using said compositions in the treatment of various disorders.

LEVEL OF TECHNOLOGY

[0002] 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 many cellular processes and, when defective or imbalanced, contributes to the pathogenesis of various diseases. Covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases include over 500 different proteins and are divided into several classes defined by the structural element of their E3 functional activity.

[0003] Cereblon (CRBN) interacts with damaged DNA-binding protein 1 and forms an E3 ubiquitin ligase complex with cullin 4, in which it functions as a substrate receptor, and proteins recognized by CRBN can be ubiquitinated and degraded by the proteasome.

[0004] Proteasome-mediated degradation of unnecessary or damaged proteins plays a very important role in maintaining regular cellular functions such as survival, proliferation and growth. A novel role for CRBN has been identified in that the binding of immunomodulatory drugs (EVIiDs) such as thalidomide to CRBN has now been associated with teratogenicity as well as cytotoxicity of EVIiDs including lenalidomide, which are widely used to treat patients with multiple myeloma. CRBN likely plays a key role in binding, ubiquitinating and degrading factors involved in maintaining myeloma cell function. These new findings regarding the role of CRBN in the action of EVIiDs have stimulated intensive investigation of the downstream factors of CRBN involved in maintaining regular cell function (Chang and Stewart Int J Biochem Mol Biol. 2011; 2(3): 287-294).

[0005] UPP plays a key role in the degradation of short-lived and regulatory proteins essential for a variety of fundamental cellular processes including cell cycle regulation, modulation of cell surface receptors and ion channels, and antigen presentation. This pathway has been implicated in several forms of cancer, the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), immune surveillance/viral pathogenesis, and muscle wasting disease. Many diseases are associated with abnormal UPP and negatively impact the cell cycle and division, cellular response to stress and extracellular modulators, neuronal network morphogenesis, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair, and organelle biogenesis.

[0006] It has recently been established that disturbances in this process are involved in the pathogenesis of certain diseases, both hereditary and acquired. These diseases are divided into two main groups: (a) those that result from loss of function followed by stabilization of certain proteins, and (b) those that result from gain of function, i.e., abnormal or accelerated degradation of the target protein.

[0007] UPP is used to induce selective protein degradation, including the use of fusion proteins for artificial ubiquitination of target proteins and synthetic small molecule probes to induce proteasome-dependent degradation. Bifunctional compounds containing a target protein binding ligand and an E3 ubiquitin ligase ligand induce proteasome-mediated degradation of selected proteins by recruiting them to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules provide the ability to transiently control protein expression. Such compounds are capable of inducing inactivation of the protein of interest when added to cells or administered to an animal or human and can be used as biochemical reagents and provide a new system for treating diseases by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1):40-46).

[0008] There is a pressing need in the art for effective treatment of disease, particularly hyperplasia and cancers such as multiple myeloma. However, non-specific effects and the inability to simultaneously target and modulate specific protein classes, such as transcription factors, remain an obstacle to the development of effective anti-cancer agents. Thus, small molecule therapeutic agents that utilize or enhance the substrate specificity of cereblon and are at the same time "tunable" to target and modulate with specificity across a wide range of protein classes would be highly suitable for use as therapeutic agents. Accordingly, there remains a need to find bifunctional compounds that mediate protein degradation and that can be used as therapeutic agents.

BRIEF DESCRIPTION OF THE INVENTION

[0009] The present application relates to novel bifunctional compounds that function by recruiting target proteins to an E3 ubiquitin ligase for degradation, methods for making the same, and uses thereof. In particular, the present disclosure provides bifunctional compounds that can be used as modulators of targeted ubiquitination of various polypeptides and other proteins that are subsequently degraded and/or otherwise inhibited by the bifunctional compounds described herein. An advantage of the compounds provided herein is the possibility of a wide range of pharmacological activities corresponding to the degradation/inhibition of target polypeptides from virtually any class or family of proteins. Additionally, the present disclosure provides methods of using an effective amount of the compounds described herein to treat or reduce a disease state, such as cancer, for example, multiple myeloma.

[0010] The present application also relates to targeted degradation of proteins through the use of bifunctional molecules, including bifunctional molecules that couple a cereblon-binding moiety to a ligand that binds to a target protein.

[0011] The present application also relates to a bifunctional compound having the following structure:

Where

TBM is a target binding moiety capable of binding to target protein(s);

L is a divalent moiety that links TBM to UBM; and UBM is a ubiquitin-binding moiety capable of binding to a ubiquitin ligase such as an E3 ubiquitin ligase (e.g., cereblon).

[0012] In the present invention, it has been found that the compounds of the present invention or pharmaceutically acceptable compositions thereof are effective for modulating targeted ubiquitination. Such compounds have the general formula I:

or are a pharmaceutically acceptable salt of said compound, wherein each variable is as defined and described herein.

[0013] Other compounds of the present invention and pharmaceutically acceptable compositions thereof have also been found to be effective in modulating targeted ubiquitination. Such compounds have the general formula I'':

or are a pharmaceutically acceptable salt of said compound, wherein each variable is as defined and described herein.

[0014] Other compounds of the present invention and pharmaceutically acceptable compositions thereof have also been found to be effective in modulating targeted ubiquitination. Such compounds have the general formula II-A:

or are a pharmaceutically acceptable salt of said compound, wherein each variable is as defined and described herein.

[0015] It has also been found that other compounds of the present invention and pharmaceutically acceptable compositions thereof are effective for modulating targeted ubiquitination. Such compounds have the general formula II''-A:

or are a pharmaceutically acceptable salt of said compound, wherein each variable is as defined and described herein.

[0016] It has also been found that other compounds of the present invention and pharmaceutically acceptable compositions thereof are effective for modulating targeted ubiquitination. Such compounds have the general formula II-B:

or are a pharmaceutically acceptable salt of said compound, wherein each variable is as defined and described herein.

[0017] It has also been found that other compounds of the present invention and pharmaceutically acceptable compositions thereof are effective for modulating targeted ubiquitination. Such compounds have the general formula II''-B:

or are a pharmaceutically acceptable salt of said compound, wherein each variable is as defined and described herein.

[0018] The compounds of the present invention and pharmaceutically acceptable compositions thereof are suitable for use in the treatment of various diseases, disorders, or conditions. Such diseases, disorders, or conditions include those described herein.

[0019] The compounds provided in the present invention are suitable for use in the study of CRBN and target proteins in biological and pathological phenomena; the study of CRBN and target proteins present in tissues of the body; and the comparative evaluation of new CRBN ligands or target proteins or other regulators of CRBN or target proteins in vitro or in vivo.

DETAILED DESCRIPTION OF SOME IMPLEMENTATION OPTIONS

1. General description of some embodiments of the present invention:

[0020] The compounds of the present invention and compositions thereof are suitable for use in modulating targeted ubiquitination.

[0021] As defined herein, the terms "binder," "modulator," and "ligand" are used interchangeably and describe a compound that binds to, modulates, or is a ligand for CRBN or a target protein.

[0022] In some embodiments of the present invention, a compound of formula I is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from the covalent bond, -CH ₂ ,

-C(O) -C(S)- or

R ¹ represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R,-

NR ₂ or an optionally substituted C _1-4 aliphatic group;

each R ₂ independently represents hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or

-N(R)S(O) _2R ;

ring A is a bi- or tricyclic ring selected from

ring B is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5-7-membered partially saturated carbocyclyl, 5-7-membered partially saturated heterocyclyl with 1-2 heteroatoms,

independently selected from nitrogen, oxygen or sulfur, or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R ³ is selected from hydrogen, halogen, -OR, -N(R) ₂ or -SR;

each R ⁴ independently represents hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂

or

-N(R)S(O) _2R ;

R ⁵ represents hydrogen, C _1-4 aliphatic group or -CN;

each R ⁶ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)- -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, Where:

each -Cu- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4- to 7-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

TBM is a target-binding fragment;

m is 0, 1, 2, 3 or 4;

each of n is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0023] In some embodiments of the present invention, a compound of formula I' is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, -CH ₂ , -C(O)-, -C(S)- or

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ or an optionally substituted C _1-4 aliphatic group;

each R ² independently represents hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂

or

-N(R)S(O) _2R ;

ring A is a bi- or tricyclic ring selected from where ring B is not imidazo or benzo, where ring B is not benzo, where ring B is not benzo,

where ring B is not benzo,

ring B is a fused ring selected from a 6-membered aryl containing 0-2 nitrogen atoms, a 5-7-membered partially saturated carbocyclyl, a 5-7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R ³ is selected from hydrogen, halogen, -OR, -N(R) ₂ or -SR;

each R ⁴ independently represents hydrogen, R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂

or

-N(R)S(O) _2R ;

R ⁵ represents hydrogen, C _1-4 aliphatic group or -CN;

each R ⁶ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, Where:

each -Cu- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4- to 7-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

TBM is a target-binding fragment;

m is 0, 1, 2, 3 or 4;

each of n is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups at the same nitrogen atom are combined with the atoms separating them to form a 4-7-membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to said nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0024] In some embodiments of the present invention, a compound of formula I'' is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, -C(R) ₂ - -C(O) -C(S)-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S(O)-, -S(O) ₂ - or

X ² represents a carbon atom or a silicon atom;

X ³ is a divalent moiety selected from -C(R) ₂ -, -N(R)-, -CF ₂ - , -CHF-, -S- or -O-;

X ⁴ is a divalent moiety selected from a covalent bond or -C(R) ₂ -;

- represents a single bond or a double bond;

R ¹ is hydrogen, deuterium, halogen, -CN, OR, SR, S(O)R, S(O) ₂ R, NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , optionally substituted C _1-4 aliphatic group, or:

R ¹ and X ¹ or X ⁴ are combined with the atoms separating them to form a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R ₂ independently represents hydrogen, deuterium, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -N(R)S(O) ₂ NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR or -P(O)(NR ₂ ) ₂ ;

ring A is a bi- or tricyclic ring selected from

ring B is a fused ring selected from a 6-membered aryl containing 0-3 nitrogen atoms, a 5-7-membered partially saturated carbocyclyl, a 5-7-membered partially saturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur;

R ³ is selected from hydrogen, deuterium, halogen, -CN, NO ₂ , -OR, -NR ₂ , SR, S(O) ₂ R, S(O) ₂ NR ₂ , S(O)R, C(O) R, C(O)OR, -C(O)NR ₂ , -C(O)NR(OR), -OC(O)R, -OC(O)NR ₂ , -OP(O)(OR) ₂ , -OP(O)(NR ₂ ) ₂ , -OP(O)(OR)NR ₂ , -N(R)C(O)R, -N(R)C( О)OR, -N(R)C(О)NR ₂ , -N(R)S(О) ₂ R, -N(R)S(О) ₂ NR ₂ , -N(R)P(О) (OR) ₂ , -N(R)P(O)(OR)NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si( OH) ₂ R, -Si(OH)(R) ₂ or -Si(R) ₃ ;

each R ⁴ independently represents hydrogen, deuterium, -R ⁶ , halogen, -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R,

-C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -P(O)(OR) ₂ , -P(O)(NR ₂ )OR or -P(O)(NR ₂ ) ₂ ;

R ⁵ is hydrogen, deuterium, optionally substituted C _1-4 aliphatic group or -CN;

each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur; L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy- -O-, -N(R)-, -Si(R) ₂ -, -Si(OH)(R)-, -Si(OH) ₂ -, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S-, -OC(O), -C(O)0-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, Where:

each -Cu- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 3- to 8-membered saturated or partially unsaturated carbocyclylenyl, a 6- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, a 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 10-membered saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, a 6- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, 5-12-membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, or 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur;

TBM is a target-binding fragment;

m is 0, 1, 2, 3 or 4;

each of n is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen, deuterium, or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0025] If the place of attachment shown on ring B, it is assumed, and it will be obvious to a person of ordinary skill in the art, that the point of attachment can be located on ring A and can also be located at any available carbon or nitrogen atom on ring A, including the ring to which ring B is fused. If is attached to the nitrogen atom bonded to R ⁴ or R ⁵ , then R ⁴ or R ⁵ is absent, and takes the place of group R ⁴ or R ⁵ . If is attached to the carbon atom bonded to R ³ , then R ³ is absent, and takes the place of the group R ³ . As an example and for the purpose of clarity, if attached to ring B, ring A is If attached to ring A, ring A is If attached to the nitrogen atom bonded to R ⁴ , ring A is If attached to the nitrogen atom bonded to R ⁵ , ring A is and if attached to the carbon atom bonded to R ³ , ring A is

[0026] If the attachment site of -(R ₂ ) _n is depicted on ring B, it is contemplated and will be apparent to one of ordinary skill in the art that the attachment site of -(R ₂ ) _n may be on ring A, and it may also be on any available boron, carbon, nitrogen, or silicon atom on ring A, including the ring to which ring B is fused. If -R ² is attached to a nitrogen atom bonded to R ⁴ or R 5, then R ⁴ or R ⁵ is absent, and -R ² takes the place of the R ⁴ or R ⁵ group. If -R ² is attached to a carbon atom bonded to R ³ , then R ³ is absent, and -R ² takes the place of the R ³ group.

[0027] In some embodiments of the present invention, a compound of formula II-A is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond,

CH ₂ - -C(O)-, -C(S)- or

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, SR, -S(O)R, -S(O) ₂ R, -NR ₂ or an optionally substituted C _1-4 aliphatic group;

ring A is a mono- or bicyclic ring selected from

each R ₂ independently represents hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂

or

-N(R)S(O) _2R ;

ring B is selected from 6-membered aryl containing 0-2 nitrogen atoms, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ³ independently represents hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂

or

-N(R)S(O) _2R ;

each R ⁴ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ⁵ represents hydrogen, C _1-4 aliphatic group or CN;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)0-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, N(R)C(O)O-, Where:

each Cy is independently an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4- to 7-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from from nitrogen, oxygen and sulfur, a 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

TBM is a target-binding fragment;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is either 0 or 1, and when p is 0, the bond connecting ring A and ring B is connected to

each q is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0028] In some embodiments of the present invention, a compound of formula II'-A is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, -CH ₂ , -C(O)-, -C(S)- or

R ¹ is hydrogen, deuterium, halogen, -CN, OR, SR, -S(O)R, -S(O) ₂ R, -NR ₂ or an optionally substituted C _1-4 aliphatic group;

ring A is a mono- or bicyclic ring selected from

each R ² independently represents hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R ₂ , -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂

or

-N(R)S(O) _2R ;

ring B is selected from 6-membered aryl containing 0-2 nitrogen atoms, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ³ independently represents hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂

or

-N(R)S(O) _2R ;

each R ⁴ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ⁵ represents hydrogen, C _1-4 aliphatic group or -CN;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, Where:

each -Cy- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4- to 7-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms, independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

TBM is a target-binding fragment;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is either 0 or 1, and if p is 0, the bond connecting ring A and ring B is connected to

each q is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0029] In some embodiments of the present invention, a compound of formula II''-A is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, -C(R) ₂ - -C(O) -C(S)-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S(O)-, -S(O) ₂ - or

X ² represents a carbon atom or a silicon atom;

X ³ is a divalent moiety selected from -C(R) ₂ -, -N(R)-, -CF ₂ -, -CHF-, -S- or O;

X ⁴ is a divalent moiety selected from a covalent bond or -C(R) ₂ -;

- represents a single bond or a double bond;

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, S(O) ₂ R, NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , optionally substituted C _1-4 aliphatic group, or:

R ¹ and X ¹ or X ⁴ are combined with the atoms separating them to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; ring A is a mono- or bicyclic ring selected from

each R ₂ independently represents hydrogen, deuterium, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR,

-N(R)C(O)R, -N(R)C(O) _NR2 , -N(R) _S (O) _2R , -N(R)S(O) _2NR2 , -P(O)(OR) ₂ , -P(O)( _NR2 )OR or -P(O)( _NR2 ) ₂ ; ring B is selected from 6-membered aryl containing 0-3 nitrogen atoms or 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur;

each R ³ is selected from hydrogen, deuterium, halogen, -CN, -NO ₂ , -OR, -NR ₂ , -SR, -S(O) ₂ R,

S(O) ₂ NR ₂ , S(O)R, C(O)R, C(O)OR, -C(O)NR ₂ , -C(O)NR(OR), -OC(O)R , -OC(O)NR ₂ , -OP(O)(OR) ₂ , -OP(O)(NR ₂ ) ₂ , -OP(O)(OR)NR ₂ , -N(R)C(O) R, -N(R)C(O)OR, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -N(R)S(O) ₂ NR ₂ , -N (R)P(O)(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P (O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ or -Si(R) ₃ ;

each R ⁴ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ⁵ is hydrogen, deuterium, optionally substituted C1-4 aliphatic group or -CN;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, O, N(R), Si(R) ₂ , Si(OH)(R)-, -Si(OH) ₂ -, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S-, -OC(O), -C(O)0- -C(O)-, -S(O)-, -S(O) ₂ - -N(R)S(O) ₂ - -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, Where:

each -Cu- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 3- to 8-membered saturated or partially unsaturated carbocyclylenyl, a 6- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, a 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 10-membered saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, a 6- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, 5-12-membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, or 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur;

TBM is a target-binding fragment;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is either 0 or 1, and if p is 0, the bond connecting ring A and ring B is connected to

each q is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0030] In some embodiments of the present invention, a compound of formula II-B is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, -CH ₂ -, -C(O) -C(S)- or

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ or an optionally substituted C _1-4 aliphatic group;

ring A is a mono- or bicyclic ring selected and

each R ₂ independently represents hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂

or

-N(R)S(O) _2R ;

ring B is selected from 6-membered aryl containing 0-2 nitrogen atoms, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ³ independently represents hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or

-N(R)S(O) _2R ;

each R ⁴ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ⁵ represents hydrogen, C _1-4 aliphatic group or -CN;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, N(R)C(O)O-, Where:

each -Cy- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4- to 7-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms, independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

TBM is a target-binding fragment;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0 or 1;

each q is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0031] In some embodiments of the present invention, a compound of formula II'-B is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from the covalent bond, -CH ₂ - -C(O) -C(S)- or

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ or an optionally substituted C _1-4 aliphatic group;

ring A is a mono- or bicyclic ring selected from

each R ₂ independently represents hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂

or

-N(R)S(O) _2R ;

ring B is selected from 6-membered aryl containing 0-2 nitrogen atoms, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ³ independently represents hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or

-N(R)S(O) _2R ;

each R ⁴ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ⁵ represents hydrogen, C _1-4 aliphatic group or -CN;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)0-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, N(R)C(O)O-, Where:

each -Cu- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4- to 7-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

TBM is a target-binding fragment;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0 or 1;

each q is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0032] In some embodiments of the present invention, a compound of formula II''-B is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, C(R) ₂ - -C(O) -C(S)-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S(O)-, -S(O) ₂ - or

X ² represents a carbon atom or a silicon atom;

X ³ is a divalent moiety selected from -C(R) ₂ -, -N(R)-, -CF ₂ -, -CHF-, -S- or -O-;

X ⁴ is a divalent moiety selected from a covalent bond or -C(R) ₂ -;

represents a single bond or a double bond;

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , an optionally substituted C aliphatic group, or:

R ¹ and X ¹ or X ⁴ are combined with the atoms separating them to form a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

ring A is a mono- or bicyclic ring selected from

each R ² independently represents hydrogen, deuterium, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -N(R)S(O) ₂ NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR or -P(O)(NR ₂ ) ₂ ;

ring B is selected from 6-membered aryl containing 0-3 nitrogen atoms or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ³ is selected from hydrogen, deuterium, halogen, -CN, -NO ₂ , -OR, -NR ₂ , -SR, -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O) R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NR(OR), -OC(O)R, -OC(O)NR ₂ , -OP(O)(OR) ₂ , -OP(O)(NR ₂ ) ₂ , -OP(O)(OR)NR ₂ , -N(R)C(O)R, -N(R)C (O)OR, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -N(R)S(O) ₂ NR ₂ , -N(R)P(O) )(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si( OH) ₂ R, -Si(OH)(R) ₂ or -Si(R) ₃ ;

each R ⁴ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ⁵ is hydrogen, deuterium, optionally substituted C _1-4 aliphatic group or -CN;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -Si(R) ₂ -, -Si(OH)(R)-, -Si(OH) ₂ -, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, Where:

each -Cu- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 3- to 8-membered saturated or partially unsaturated carbocyclylenyl, a 6- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, a 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 10-membered saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, a 6- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, 5-12-membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, or 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur;

TBM is a target-binding fragment;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0 or 1;

each q is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen, deuterium, or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0033] If the place of attachment shown on ring A, it is assumed, and it will be obvious to a person skilled in the art, that the point of attachment can be located at any available carbon or nitrogen atom on ring A. If is attached to a nitrogen atom bonded to an R ³ or R ⁵ atom, then R ³ or R ⁵ is absent, and takes the place of group R ³ or R ⁵ .

[0034] In some embodiments, the present invention provides a compound of formula III-A, III-B, or III-C:

or a pharmaceutically acceptable salt of said compounds, wherein L and TBM are as defined above and described herein, and wherein each of the variables R ¹ , R ² , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁷ , W ¹ , W ² , X and n are as defined in WO 2017/197051, the entire contents of which are incorporated herein by reference, and wherein attached to R ¹ , the ring formed by joining R ¹ and R ² , or R ¹⁷ at the point of attachment of R ¹² are as defined in WO 2017/197051, wherein occupies the place of the substituent R ¹² .

2. Compounds and definitions:

[0035] The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. In the context of the present specification, the following definitions shall apply unless otherwise indicated. For the purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, ^75th Ed. In addition, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999 and March's Advanced Organic Chemistry, ^5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0036] The term "aliphatic" or "aliphatic group" as used herein means a straight (i.e., unbranched) or branched substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is fully saturated or that contains one or more units of unsaturation but is not aromatic (also referred to herein as a "carbocycle,""cycloaliphatic," or "cycloalkyl") that has one point of attachment to the remainder of the molecule. Unless otherwise noted, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic _C3 - _C6 hydrocarbon that is fully saturated or that contains one or more units of unsaturation, but is not aromatic, in which there is one point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0037] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, containing at least one bridgehead. According to the International Union of Pure and Applied Chemistry (IUPAC), a "bridgehead" is a linear chain of atoms, or an atom or valence bond, connecting two "bridgeheads," where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (except hydrogen). In some embodiments, a bridged bicyclic group contains 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups listed below, wherein each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise indicated, a bridged bicyclic group is optionally substituted with one or more substituents as indicated for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Illustrative bridged bicyclic groups include:

[0038] The term "lower alkyl" refers to a C _1-4 straight or branched alkyl group. Illustrative lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0039] The term "lower haloalkyl" refers to a C _1-4 linear or branched alkyl group that is substituted by one or more halogen atoms.

[0040] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; a quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR ⁺ (as in N-substituted pyrrolidinyl)).

[0041] The term "unsaturated" as used herein means that the moiety contains one or more units of unsaturation.

[0042] As used herein, the term "divalent C _1-8 (or C _1-6 ) saturated or unsaturated linear or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains that are linear or branched as defined herein.

[0043] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -( _CH2 ) _n- , where n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0044] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0045] As used herein, the term "cyclopropylenyl" refers to a divalent cyclopropyl group having the following structure:

[0046] The term "halogen" means F, Cl, Br or I.

[0047] The term "aryl" used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl" refers to monocyclic or bicyclic ring systems containing a total of five to fourteen ring members, wherein at least one ring in said system is aromatic, and wherein each ring in said system contains from 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments of the present invention, "aryl" refers to an aromatic ring system that includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may contain one or more substituents. Also included within the scope of the term "aryl" as used herein is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl or tetrahydronaphthyl and the like.

[0048] The terms "heteroaryl" and "heteroar-", whether used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy", refer to groups containing from 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; containing 6, 10, or 14 π-electrons distributed in a cyclic structure; and containing, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-" as used herein also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group may be mono or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by heteroaryl, wherein the alkyl and heteroaryl moieties are independently optionally substituted.

[0049] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and contains, in addition to carbon atoms, one or more heteroatoms, preferably from one to four heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring containing 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, said nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺ NR (as in N-substituted pyrrolidinyl).

[0050] The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that provides a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. The heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions are independently optionally substituted.

[0051] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings containing multiple centers of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0052] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogen atoms of the moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may contain a suitable substituent at each substitutable position of the group, and when more than one position in any particular structure may be substituted with more than one substituent selected from a particular group, the substituent may be the same or different at each position. Combinations of substituents contemplated in the present invention are preferably combinations that provide stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are substantially unaltered by conditions for providing for their preparation, detection, and, in some embodiments, isolation, purification, and use for one or more of the purposes disclosed herein.

[0053] Suitable monovalent substituents on a substitutable carbon atom of the "optionally substituted" group are independently halogen; -(CH ₂ ) _0-4 R ^o ; -(CH ₂ ) _0-4 OR ^o ; -O(CH ₂ ) _0-4 R ^o , -O-(CH ₂ ) _0-4 C(O)OR ^o ; -(CH ₂ ) _0-4 CH(OR ^o ) ₂ ; -(CH ₂ ) _0-4 SR ^o ; -(CH ₂ ) _0-4 Ph, which may be substituted by R ^o ; -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 Ph, which may be substituted by R ^o ; -CH=CHPh, which may be substituted by R ^o ; -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 -pyridyl, which can be substituted by R ^o ; -NO ₂ ; -CN; -N ₃ ; -(CH ₂ ) _0-4 N(R ^o ) ₂ ; -(CH ₂ ) _0-4 N(R ^o )C(O)R ^o ; -N(R ^o )C(S)R ^o ; -(CH ₂ ) _0-4 N(R ^o )C(O)NR ^o ₂ ; -N(R ^o )C(S)NR ^o ₂ ; -(CH ₂ ) _0-4 N(R ^o )C(O)OR ^o ; -N(R ^o )N(R ^o )C(O)R ^o ; -N(R ^o )N(R ^o )C(O)NR ^o ₂ ; -N(R ^o )N(R ^o )C(O)OR ^o ; -(CH ₂ ) _0-4 C(O)R ^o ; -C(S)R ^o ; -(CH ₂ ) _0-4 C(O)OR ^o ; -(CH ₂ ) _0-4 C(O)SR ^o ; -(CH ₂ ) _0-4 C(O)OSiR ^o ₃ ; -(CH ₂ ) _0-4 OC(O)R ^o ; -OC(O)(CH ₂ ) _0-4 SR ^o ; -SC(S)SR ^o ; -(CH ₂ ) _0-4 SC(O)R ^o ; -(CH ₂ ) _0-4 C(O)NR ^o ₂ ; -C(S)NR ^o ₂ ; -C(S)SR ^o ; -(CH ₂ ) _0-4 OC(O)NR ^o ₂ ; -C(O)N(OR ^o )R ^o ; -C(O)C(O)R ^o ; -C(O)CH ₂ C(O)R ^o ; -C(NOR ^o )R ^o ; -(CH ₂ ) _0-4 SSR ^o ; -(CH ₂ ) _0-4 S(O) ₂ R ^o ; -(CH ₂ ) _0-4 S(O) ₂ OR ^o ; -(CH ₂ ) _0-4 OS(O) ₂ R ^o ; -S(O) ₂ NR ^o ₂ ; -(CH ₂ ) _0-4 S(O)R ^o ; -N(R ^o )S(O) ₂ NR ^o ₂ ; -N(R ^o )S(O) ₂ R ^o ; -N(OR ^o )R ^o ; -C(NH)NR ^o ₂ ; -P(O) ₂ R ^o ; -P(O)R ^o ₂ ; -OP(O)R ^o ₂ ; -OP(O)(OR ^o ) ₂ ; -SiR ^o ₃ ; -(C _1-4 linear or branched alkylene)ON(R ^o ) ₂ or -(C _1-4 linear or branched alkylene)C(O)ON(R ^o ) ₂ , wherein each R ^o may be substituted as defined below and is independently hydrogen, a C _1-6 aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, -CH ₂ -(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent R ^o groups taken together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated or aryl mono- or bicyclic ring containing 0-4 a heteroatom independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0054] Suitable monovalent substituents on R ^o (or a ring formed by joining two independent R ^o groups with atoms separating them) are independently halogen, -(CH ₂ ) _0-2 R ^• , -(haloR ^• ), -(CH ₂ ) _0-2 OH, -(CH ₂ ) _0-2 OR ^• , -(CH ₂ ) _0-2 CH(OR ^• ) ₂ ; -O(halogenR ^• ), -CN, -N ₃ , -(CH ₂ ) _0-2 C(O)R ^• , -(CH ₂ ) _0-2 C(O)OH, -(CH ₂ ) _0-2 C(O)OR ^• , -(CH ₂ ) _0-2 SR ^• , -(CH ₂ ) _0-2 SH, -(CH ₂ ) _0-2 NH ₂ , -(CH ₂ ) _0-2 NHR ^• , -(CH ₂ ) _0-2 NR ^• ₂ , -NO ₂ , -SiR ^• ₃ , -OSiR ^• ₃ , -C(O)SR ^• , -(C _1-4 linear or branched alkylene)C(O)OR ^• or -SSR ^• , wherein each R ^• is unsubstituted or, when preceded by "halogen", is substituted only by one or more halogens and is independently selected from C _1-4 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom in R ^o include =O and =S.

[0055] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following substituents: =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O) _2R ^* , =NR ^* , =NOR ^* , -O(C(R ^* ₂ )) _2-3O- , or -S(C(R ^* ₂ )) _2-3S- wherein each independent R ^* group is selected from hydrogen, a _C1-6 aliphatic group that may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bonded to adjacent substitutable carbon atoms of an "optionally substituted" group include -O(CR ^* ₂ ) _2-3O- , wherein each independent R ^* group is selected from hydrogen, a _C1-6 aliphatic group that may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0056] Suitable substituents on an aliphatic group R ^* include halogen, -R ^• , -(haloR ^• ), -OH, -OR ^• , -O(haloR ^• ), -CN, -C(O)OH, -C(O)OR ^• , _-NH2 , -NHR ^• , -NR ^• ₂ , or _-NO2 , wherein each R ^• is unsubstituted or, when preceded by "halo", substituted only by one or more halogens and is independently a _C1-4 aliphatic group, _-CH2Ph , -O( _CH2 ) _0-1Ph , or a 5-6 membered saturated, partially unsaturated, or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0057] Suitable substituents on the substitutable nitrogen atom of the “optionally substituted” group include or where everyone independently represents hydrogen, a C _1-6 aliphatic group which may be substituted as defined below, an unsubstituted -OPh or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent groups combined with their intervening atom(s), form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0058] Suitable substituents on an aliphatic group independently represent halogen, -R ^• , -(halogenR ^• ), -OH, -OR ^• , -O(halogenR ^• ), -CN, -C(O)OH, -C(O)OR ^• , -NH ₂ , -NHR ^• , -NR ^• ₂ or -NO ₂ , wherein each R ^• is unsubstituted or, when preceded by "halogen", substituted only by one or more halogens and independently represents C _1-4 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph or a 5-6-membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0059] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are considered by careful medical judgment to be suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, and the like, and that meet a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of the amino group prepared using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or using organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts and the like.

[0060] Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium, and N ⁺ ( _C1-4alkyl ) ₄ salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts, in suitable cases, include salts containing non-toxic ammonium, quaternary ammonium cations, and amine cations derived using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0061] It is also intended that, unless otherwise indicated, the structures depicted herein include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structures, such as the R and S configurations for each center of asymmetry, the Z and E isomers based on the position of the substituents relative to the double bond, and the conformational Z and E isomers. Thus, single stereochemical isomers as well as mixtures of enantiomers, diastereomers, and geometric (or conformational) isomers of the compounds of the present invention are within the scope of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having structures according to the present invention, including replacement of hydrogen with deuterium or tritium, or replacement of carbon with ^13C- or ^14C -enriched carbon, are within the scope of the present invention. Such compounds are suitable for use, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention. In some embodiments, the provided compound can be replaced with one or more deuterium atoms.

[0062] As used herein, the term "binder" or "inhibitor" is defined as a compound that binds to CRBN and binds to or inhibits a target protein with measurable affinity. In some embodiments, the inhibitor has an _IC50 and/or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0063] A compound of the present invention may be linked to a detectable moiety. It is understood that such compounds are suitable for use as imaging agents. It will be apparent to one skilled in the art that a detectable moiety may be attached to a compound of the invention via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that is capable of covalently attaching to the detectable moiety. Such moieties are well known to one skilled in the art and include groups containing, for example, a carboxylate moiety, an amine moiety, a thiol moiety, or a hydroxyl moiety, and many others. It is understood that such moieties may be attached to a compound of the invention directly or via a linking group, such as a divalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached via click chemistry. In some embodiments, such moieties can be attached by 1,3-cycloaddition of an azide to an alkyne, optionally in the presence of a copper catalyst. Methods of using click chemistry are known in the art and include those described in Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

[0064] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that is detectable, such as primary labels and secondary labels. Primary labels, such as radioisotopes (e.g., tritium, ^32P , ^33P , ^35S , or ^14C ), mass-tags, and fluorescent labels, are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0065] The term "secondary label" as used herein refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate to produce a detectable signal. In the case of biotin, the secondary intermediate may include streptavidin-enzyme conjugates. In the case of antigen labels, secondary intermediates may include antibody-enzyme conjugates. Certain fluorescent groups act as secondary labels because they transfer energy to another group through a process called nonradiative fluorescence resonance energy transfer (FRET), and the second group produces a detectable signal.

[0066] The terms "fluorescent label," "fluorescent dye," and "fluorophore" as used herein refer to moieties that absorb light energy at a particular excitation wavelength and emit light energy at another wavelength. Examples of fluorescent labels include, but are not limited to, Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine 6G, Carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine Dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-Dimethoxyfluorescein, DM-NERF, Eosin, Erythrosine, Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800), JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-tetra-bromosulfonefluorescein, tetramethylrhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0067] The term "mass spectrometric tag" as used herein refers to any moiety that is unambiguously detectable by mass using mass spectrometric (MS) detection methods. Examples of mass spectrometric tags include electrophore release tags such as N-[3-[4'-[(n-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and derivatives thereof. The synthesis and utility of such mass spectrometric labels are described in U.S. Patents 4,650,750, 4,709,016, 5,3608,191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass spectrometric labels include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying lengths and base compositions, oligopeptides, oligosaccharides, and other synthetic polymers of varying lengths and monomer compositions. A variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds), with a suitable mass range (100-2000 Daltons) can also be used as mass spectrometric labels.

[0068] The terms "measurable affinity" and "measurably modulate" as used herein mean a measurable change in CRBN activity between a sample containing a compound of the present invention or composition thereof and CRBN and an equivalent sample containing CRBN in the absence of said compound or composition thereof.

3. Description of illustrative embodiments:

[0069] As described above, in some embodiments of the present invention, a compound of formula I is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, -CH ₂ -, -C(O)-, -C(S)- or

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ or an optionally substituted C _1-4 aliphatic group;

each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

ring A is a bi- or tricyclic ring selected from

Where

ring B is a fused ring selected from a 6-membered aryl containing 0-2 nitrogen atoms, a 5-7-membered partially saturated carbocyclyl, a 5-7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R ³ is selected from hydrogen, halogen, -OR, -N(R) ₂ or -SR;

each R ⁴ is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

R ⁵ represents hydrogen, C _1-4 aliphatic group or -CN;

each R ⁶ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, Where:

each -Cu- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4- to 7-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

TBM is a target-binding fragment;

m is 0, 1, 2, 3 or 4;

each of n is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0070] As described above, in some embodiments of the present invention, a compound of formula I' is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, -CH ₂ -, -C(O)-, -C(S)- or

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ or an optionally substituted C _1-4 aliphatic group;

each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

ring A is a bi- or tricyclic ring selected from where ring B is not imidazo or benzo, where ring B is not benzo, where ring B is not benzo, where ring B is not benzo, Where

ring B is a fused ring selected from a 6-membered aryl containing 0-2 nitrogen atoms, a 5-7-membered partially saturated carbocyclyl, a 5-7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R ³ is selected from hydrogen, halogen, -OR, -N(R) ₂ or -SR;

each R ⁴ is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

R ⁵ represents hydrogen, C _1-4 aliphatic group or -CN;

each R ⁶ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, Where:

each -Cu- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4- to 7-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

TBM is a target-binding fragment;

m is 0, 1, 2, 3 or 4;

each of n is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0071] In some embodiments of the present invention, a compound of formula I'' is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, -C(R) ₂ -, -C(O)-, -C(S)-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S(O)-, -S(O) ₂ - or

X ² represents a carbon atom or a silicon atom;

X ³ is a divalent moiety selected from -C(R) ₂ -, -N(R)-, -CF ₂ -, -CHF-, -S- or -O-;

X ⁴ is a divalent moiety selected from a covalent bond or -C(R) ₂ -;

represents a single bond or a double bond;

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , optionally substituted C _1-4 aliphatic group, or:

R ¹ and X ¹ or X ⁴ are combined with the atoms separating them to form a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R ² independently represents hydrogen, deuterium, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -N(R)S(O) ₂ NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR or -P(O)NR ₂ ;

ring A is a bi- or tricyclic ring selected from

Where

ring B is a fused ring selected from a 6-membered aryl containing 0-3 nitrogen atoms, a 5-7-membered partially saturated carbocyclyl, a 5-7-membered partially saturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur;

R ³ is selected from hydrogen, deuterium, halogen, -CN, -NO ₂ , -OR, -NR ₂ , -SR, -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NR(OR), -OC(O)R, -OC(O)NR ₂ , -OP(O)(OR) ₂ , -OP(O)(NR ₂ ) ₂ , -OP(O)(OR)NR ₂ , -N(R)C(O)R, -N(R)C (O)OR, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -N(R)S(O) ₂ NR ₂ , -N(R)P(O) )(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si( OH) ₂ R, -Si(OH)(R) ₂ or -Si(R) ₃ ;

each R ⁴ independently represents hydrogen, deuterium, -R ⁶ , halogen, -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C( O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -P(O)(OR) ₂ , -P(O)(NR ₂ )OR or -P(O)(NR ₂ ) ₂ ;

R ⁵ is hydrogen, deuterium, optionally substituted C _1-4 aliphatic group or -CN;

each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -Si(R) ₂ -, -Si(OH)(R)-, -Si(OH) ₂ -, -C(H)(CF ₃ )-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, Where:

each -Cu- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8-10-membered bicyclic arylenyl, a 4-8 membered saturated or partially unsaturated carbocyclylenyl, a 6-11-membered saturated or partially unsaturated spirocarbocyclylenyl, a 5-12-membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-10-membered saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, a 6-11-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, 5-12-membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, or 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur;

TBM is a target-binding fragment;

m is 0, 1, 2, 3 or 4;

each of n is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0072] As described above, in some embodiments of the present invention, a compound of formula II-A is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, -CH ₂ -, -C(O)-, -C(S)- or

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ or an optionally substituted C _1-4 aliphatic group;

ring A is a mono- or bicyclic ring selected from

each R ² is independently hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

ring B is selected from 6-membered aryl containing 0-2 nitrogen atoms, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ³ is independently hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

each R ⁴ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ⁵ represents hydrogen, C _1-4 aliphatic group or -CN;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, Where:

each -Cu- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4- to 7-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

TBM is a target-binding fragment;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is either 0 or 1, and if p is 0, the bond connecting ring A and ring B is connected to

each q is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0073] As described above, in some embodiments of the present invention, a compound of formula II'-A is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, -CH ₂ -, -C(O)-, -C(S)- or

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ or an optionally substituted C _1-4 aliphatic group;

ring A is a mono- or bicyclic ring selected from

each R ² is independently hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

ring B is selected from 6-membered aryl containing 0-2 nitrogen atoms, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ³ is independently hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

each R ⁴ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ⁵ represents hydrogen, C _1-4 aliphatic group or -CN;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, Where:

each -Cy- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4- to 7-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms, independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

TBM is a target-binding fragment;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is either 0 or 1, and if p is 0, the bond connecting ring A and ring B is connected to

each q is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0074] In some embodiments of the present invention, a compound of formula II''-A is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, -C(R) ₂ -, -C(O)-, -C(S)-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S(O)-, -S(O) ₂ - or

X ² represents a carbon atom or a silicon atom;

X ³ is a divalent moiety selected from -C(R) ₂ -, -N(R)-, -CF ₂ -, -CHF-, -S- or -O-;

X ⁴ is a divalent moiety selected from a covalent bond or -C(R) ₂ -;

represents a single bond or a double bond;

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , optionally substituted C _1-4 aliphatic group, or:

R ¹ and X ¹ or X ⁴ are combined with the atoms separating them to form a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

ring A is a mono- or bicyclic ring selected from

each R ² independently represents hydrogen, deuterium, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -N(R)S(O) ₂ NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR or -P(O)(NR ₂ ) ₂ ;

ring B is selected from 6-membered aryl containing 0-3 nitrogen atoms or 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur;

each R ³ is selected from hydrogen, deuterium, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -NR ₂ , -SR, -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NR(OR), -OC(O)R, -OC(O)NR ₂ , -OP(O)(OR) ₂ , -OP(O)(NR ₂ ) ₂ , -OP(O)(OR)NR ₂ , -N(R)C(O)R , -N(R)C(O)OR, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -N(R)S(O) ₂ NR ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si (OH) ₂ R, -Si(OH)(R) ₂ or -Si(R) ₃ ;

each R ⁴ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ⁵ is hydrogen, deuterium, optionally substituted C _1-4 aliphatic group or -CN;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -Si(R) ₂ -, -Si(OH)(R)-, -Si(OH) ₂ -, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-,

each -Cu- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 3- to 8-membered saturated or partially unsaturated carbocyclylenyl, a 6- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, a 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 10-membered saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, a 6- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, 5-12-membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, or 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur;

TBM is a target-binding fragment;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is either 0 or 1, and if p is 0, the bond connecting ring A and ring B is connected to

each q is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0075] As described above, in some embodiments of the present invention, a compound of formula II-B is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from the covalent bond, -CH ₂ -,

-C(O)-, -C(S)- or

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ or an optionally substituted C _1-4 aliphatic group;

ring A is a mono- or bicyclic ring selected from

each R ² independently represents hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂

or

-N(R)S(O) _2R ;

ring B is selected from 6-membered aryl containing 0-2 nitrogen atoms, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ³ independently represents hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂

or

-N(R)S(O) _2R ;

each R ⁴ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ⁵ represents hydrogen, C _1-4 aliphatic group or -CN;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-,

each -Cu- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4- to 7-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

TBM is a target-binding fragment;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0 or 1;

each q is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0076] As described above, in some embodiments of the present invention, a compound of formula II'-B is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, -CH ₂ -, -C(O)-, -C(S)- or

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ or an optionally substituted C _1-4 aliphatic group;

ring A is a mono- or bicyclic ring selected from

each R ² independently represents hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂

or

-N(R)S(O) _2R ;

ring B is selected from 6-membered aryl containing 0-2 nitrogen atoms, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R ³ independently represents hydrogen, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂

or

-N(R)S(O) _2R ;

each R ⁴ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ⁵ represents hydrogen, C _1-4 aliphatic group or -CN;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by Cy-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-,

-OC(O)N(R)-, -N(R)C(O)O-,

each -Cy- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4- to 7-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 heteroatoms, independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

TBM is a target-binding fragment;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0 or 1;

each q is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0077] In some embodiments of the present invention, a compound of formula II"-B is provided:

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is a divalent moiety selected from a covalent bond, -C(R) ₂ , -C(O)-, -C(S)-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S(O)-, -S(O) ₂ - or

X ² represents a carbon atom or a silicon atom;

X ³ is a divalent moiety selected from -C(R) ₂ -, -N(R)-, -CF ₂ -, -CHF-, -S- or -O-;

X ⁴ is a divalent moiety selected from a covalent bond or -C(R) ₂ -;

represents a single bond or a double bond;

R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , optionally substituted C _1-4 aliphatic group, or:

R ¹ and X ¹ or X ⁴ are combined with the atoms separating them to form a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

ring A is a mono- or bicyclic ring selected from

each R ² independently represents hydrogen, deuterium, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -N(R)S(O)2NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR or -P(O)(NR ₂ ) ₂ ;

ring B is selected from 6-membered aryl containing 0-3 nitrogen atoms or 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur;

each R ³ is selected from hydrogen, deuterium, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -NR ₂ , -SR, -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NR(OR), -OC(O)R, -OC(O)NR ₂ , -OP(O)(OR) ₂ , -OP(O)(NR ₂ ) ₂ , -OP(O)(OR)NR ₂ , -N(R)C(O)R , -N(R)C(O)OR, -N(R)C(O)NR ₂ , N(R)S(O) ₂ R, -N(R)S(O) ₂ NR ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si (OH) ₂ R, -Si(OH)(R) ₂ or -Si(R) ₃ ;

each R ⁴ independently represents an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ⁵ is hydrogen, deuterium, optionally substituted C _1-4 aliphatic group or -CN;

L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -N(R)-, -Si(R) ₂ -, -Si(OH)(R)-, -Si(OH) ₂ -, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-,

-C(O)N(R)-, -OC(C-)N(R)-, -N(R)C(O)O-,

each -Cu- independently represents an optionally substituted divalent ring selected from phenylenyl, an 8- to 10-membered bicyclic arylenyl, a 3- to 8-membered saturated or partially unsaturated carbocyclylenyl, a 6- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, a 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 10-membered saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, a 6- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, 5-12-membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, or 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur;

TBM is a target-binding fragment;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0 or 1;

each q is independently equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R is independently hydrogen, deuterium, or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring containing 0-3 heteroatoms, in addition to the specified nitrogen, independently selected from nitrogen, oxygen and sulfur.

[0078] As defined above and described herein, X ¹ is a divalent moiety selected from a covalent bond, -CH ₂ -, -C(R) ₂ -, C(O)-, -C(S)-, -CH(R)-, -CH(CF ₃ )-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S(O)-, -S(O) ₂ - or

[0079] In some embodiments, X ¹ is a covalent bond. In some embodiments, X ¹ is -CH ₂ -. In some embodiments, X ¹ is -C(R) ₂ -. In some embodiments, X ¹ is -C(O)-. In some embodiments, X ¹ is -C(S)-. In some embodiments, X ¹ is -CH(R)-. In some embodiments, X ¹ is -CH(CF ₃ )-. In some embodiments, X ¹ is P(O)(OR)-. In some embodiments, X ¹ is -P(O)(R)-. In some embodiments, X ¹ is -P(O)(NR ₂ )-. In some embodiments, X ¹ is -S(O)-. In some embodiments, X ¹ is -S(O) ₂ -. In some embodiments, X ¹ is

[0080] In some embodiments, X ¹ is selected from the options presented in Table 1 below.

[0081] As defined above and described herein, X ² is a carbon atom or a silicon atom.

[0082] In some embodiments, X ² is a carbon atom. In some embodiments, X ² is a silicon atom.

[0083] In some embodiments, X ² is selected from the options presented in Table 1 below.

[0084] As defined above and described herein, X ³ is a divalent moiety selected from -CH ₂ -, -C(R) ₂ -, N(R), -CF ₂ -, -CHF-, -S-, -CH(R)-, or -O-.

[0085] In some embodiments, X ³ is -CH ₂ -. In some embodiments, X ¹ is -C(R) ₂ -. In some embodiments, X ³ is -N(R)-. In some embodiments, X ³ is -CF ₂ -. In some embodiments, X ³ is -CHF-. In some embodiments, X ³ is -S-. In some embodiments, X ³ is -CH(R)-. In some embodiments, X ³ is -O-.

[0086] In some embodiments, X ³ is selected from the options presented in Table 1 below.

[0087] As defined above and described herein, X ⁴ is a divalent moiety selected from a covalent bond, -CH ₂ -, or -C(R) ₂ -.

[0088] In some embodiments, X ⁴ is a covalent bond. In some embodiments, X ⁴ is -CH ₂ -. In some embodiments, X ⁴ is -C(R) ₂ -.

[0089] In some embodiments, X ⁴ is selected from the options presented in Table 1 below.

[0090] As defined above and described herein, R ¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , an optionally substituted C _1-4 aliphatic group, or R ¹ and X ¹ or X ⁴ are combined with the atoms separating them to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0091] In some embodiments, R ¹ is hydrogen. In some embodiments, R ¹ is deuterium. In some embodiments, R ^{1 is a halogen. In some embodiments, R 1 is} -CN. In some embodiments, R ¹ is -OR. In some embodiments, R ¹ is -SR. In some embodiments, R ¹ is -S(O)R. In some embodiments, R ¹ is -S(O) ₂ R. In some embodiments, R ¹ is -NR ₂ . In some embodiments, R ¹ is -P(O)(OR) ₂ . In some embodiments, R ¹ is -P(O)(NR ₂ )OR. In some embodiments, R ¹ is -P(O)(NR ₂ ) ₂ -. In some embodiments, R ¹ is -Si(OH) ₂ R. In some embodiments, R ¹ is -Si(OH)(R) ₂ . In some embodiments, R ¹ is -Si(R) ₃ . In some embodiments, R ¹ is an optionally substituted C _1-4 aliphatic group. In some embodiments, R ¹ and X ¹ or X ⁴ are combined with the atoms separating them to form a 5-7-membered saturated, partially unsaturated, carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0092] In some embodiments, R ¹ is selected from the options presented in Table 1 below.

[0093] As defined above and described herein, each R ² is independently hydrogen, deuterium, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -N(R)S(O) ₂ NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR or -P(O)(NR ₂ ) ₂ .

[0094] In some embodiments, R ² is hydrogen. In some embodiments, R ² is deuterium. In some embodiments, R ² is -R ⁶ . In some embodiments, R ² is a halogen. In some embodiments, R ^{2 is -CN. In some embodiments, R 2 is} -NO ₂ . In some embodiments, R ² is -OR. In some embodiments, R ² is -Si(OH) ₂ R. In some embodiments, R ² is -Si(OH)(R) ₂ . In some embodiments, R ₂ is -SR. In some embodiments, R ₂ is -NR ₂ . In some embodiments, R ₂ is -Si(R) ₃ . In some embodiments, R ₂ is -S(O) ₂ R. In some embodiments, R ₂ is -S(O) ₂ NR ₂ . In some embodiments, R ₂ is -S(O)R. In some embodiments, R ₂ is -C(O)R. In some embodiments, R ₂ is -C(O)OR. In some embodiments, R ₂ is -C(O)NR ₂ . In some embodiments, R ₂ is -C(O)N(R)OR. In some embodiments, R ₂ is -OC(O)R. In some embodiments, R ₂ is -OC(O)NR ₂ . In some embodiments, R ₂ is -N(R)C(O)OR. In some embodiments, R ₂ is -N(R)C(O)R. In some embodiments, R ₂ is -N(R)C(O)NR ₂ . In some embodiments, R ₂ is -N(R)S(O) ₂ R. In some embodiments, R ₂ is -P(O)(OR) ₂ . In some embodiments, R ₂ is -P(O)(NR ₂ )OR. In some embodiments, R ₂ is -P(O)(NR ₂ ) ₂ -.

[0095] In some embodiments, R ₂ is selected from the options presented in Table 1 below.

[0096] As defined above and described herein, Ring A is a bi- or tricyclic ring selected from

[0097] In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is

[0098] In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is

[0099] In some embodiments, ring A is selected from the options presented in Table 1 below.

[00100] As defined above and described herein, Ring B is a fused ring selected from a 6-membered aryl containing 0-3 nitrogen atoms, a 5-7-membered partially saturated carbocyclyl, a 5-7-membered partially saturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[00101] In some embodiments, Ring B is a 6-membered aryl having 0-3 nitrogen atoms. In some embodiments, Ring B is a 5-7-membered partially saturated carbocyclyl. In some embodiments, Ring B is a 5-7-membered partially saturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, Ring B is a 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[00102] In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is

[00103] In some embodiments, each ring B is In some embodiments, each ring B is In some embodiments, each ring B is In some embodiments, each ring B is In some embodiments, ring B is

[00104] In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is

[00105] In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is

[00106] In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is

[00107] In some embodiments, ring B is selected from

[00108] In some embodiments, ring B is selected from the options presented in Table 1 below.

[00109] As defined above and described herein, represents a single or double bond.

[00110] In some embodiments, is a single bond. In some embodiments, represents a double bond.

[00111] In some embodiments, selected from the options presented in Table 1 below.

[00112] As defined above and described herein, R ³ is hydrogen, deuterium, halogen, -CN, -NO ₂ , -OR, -NR ₂ , -SR, -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R,

-C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NR(OR), -OC(O)R, -OC(O)NR ₂ , -OP( O)(OR) ₂ , -OP(O)(NR ₂ ) ₂ , -OP(O)(OR)NR ₂ , -N(R)C(O)R, -N(R)C(O)OR , -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R,

-N(R)S(O) ₂ NR ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ or -Si(R) ₃ .

[00113] In some embodiments, R ³ is hydrogen. In some embodiments, R ³ is deuterium. In some embodiments, R ^{3 is a halogen. In some embodiments, R 3 is} -CN. In some embodiments, R ³ is -NO ₂ . In some embodiments, R ³ is -OR. In some embodiments, R ³ is -NR ₂ . In some embodiments, R ³ is -SR. In some embodiments, R ³ is -S(O) ₂ R. In some embodiments, R ³ is -S(O) ₂ NR ₂ . In some embodiments, R ³ is -S(O)R. In some embodiments, R ³ is -C(O)R. In some embodiments, R ³ is -C(O)OR. In some embodiments, R ³ is -C(O)NR ₂ . In some embodiments, R ³ is -C(O)NR(OR). In some embodiments, R ³ is -OC(O)R. In some embodiments, R ³ is -OC(O)NR ₂ . In some embodiments, R ³ is -OP(O)(OR) ₂ . In some embodiments, R ³ is -OP(O)(NR ₂ ) ₂ . In some embodiments, R ³ is -OP(O)(OR)NR ₂ . In some embodiments, R ³ is -N(R)C(O)R. In some embodiments, R ³ is -N(R)C(O)OR. In some embodiments, R ³ is -N(R)C(O)NR ₂ . In some embodiments, R ³ is -N(R)S(O) ₂ R. In some embodiments, R ³ is -N(R)S(O) ₂ NR ₂ . In some embodiments, R ³ is -N(R)P(O)(OR) ₂ . In some embodiments, R ³ is -N(R)P(O)(OR)NR ₂ . In some embodiments, R ³ is -P(O)(OR) ₂ . In some embodiments, R ³ is -P(O)(NR ₂ )OR. In some embodiments, R ³ is -P(O)(NR ₂ ) ₂ . In some embodiments, R ³ is -Si(OH) ₂ R. In some embodiments, R ³ is -Si(OH)(R) ₂ . In some embodiments, R ³ is -Si(R) ₃ .

[00114] In some embodiments, R ³ is methyl. In some embodiments, R ³ is -OCH ₃ . In some embodiments, R ³ is chloro.

[00115] In some embodiments, R ³ is selected from the options presented in Table 1 below.

[00116] As defined above and described herein, each R ⁴ is independently hydrogen, deuterium, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N (R)C(O)NR ₂ , -N(R)S(O) ₂ R, -P(O)(OR) ₂ , -P(O)(NR ₂ )OR or -P(O)(NR ₂ ) ₂ .

[00117] In some embodiments, R ⁴ is hydrogen. In some embodiments, R ⁴ is -R ⁶ . In some embodiments, R ⁴ is a halogen. In some embodiments, R ⁴ is -CN. In some embodiments, R ⁴ is -NO ₂ . In some embodiments, R ⁴ is -OR. In some embodiments, R ⁴ is -SR. In some embodiments, R ⁴ is -NR ₂ . In some embodiments, R ⁴ is -S(O) ₂ R. In some embodiments, R ⁴ is -S(O) ₂ NR ₂ . In some embodiments, R ⁴ is -S(O)R. In some embodiments, R ⁴ is -C(O)R. In some embodiments, R ⁴ is -C(O)OR. In some embodiments, R ⁴ is -C(O)NR ₂ . In some embodiments, R ⁴ is -C(O)N(R)OR. In some embodiments, R ⁴ is -OC(O)R. In some embodiments, R ⁴ is -OC(O)NR ₂ . In some embodiments, R ⁴ is -N(R)C(O)OR. In some embodiments, R ⁴ is -N(R)C(O)R. In some embodiments, R ⁴ is -N(R)C(O)NR ₂ . In some embodiments, R ⁴ is -N(R)S(O) ₂ R. In some embodiments, R ⁴ is -P(O)(OR) ₂ . In some embodiments, R ⁴ is -P(O)(NR ₂ )OR. In some embodiments, R ⁴ is -P(O)(NR ₂ ) ₂ .

[00118] In some embodiments, R ⁴ is methyl. In some embodiments, R ⁴ is ethyl. In some embodiments, R ⁴ is cyclopropyl.

[00119] In some embodiments, R ⁴ is selected from the options presented in Table 1 below.

[00120] As defined above and described herein, R ⁵ is hydrogen, deuterium, optionally a substitute C _1-4 aliphatic group, or -CN.

[00121] In some embodiments, R ⁵ is hydrogen. In some embodiments, R ⁵ is deuterium. In some embodiments, R ⁵ is an optionally substituted C _1-4 aliphatic group. In some embodiments, R ⁵ is -CN.

[00122] In some embodiments, R ⁵ is selected from the options presented in Table 1 below.

[00123] As defined above and described herein, each R ⁶ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroaryl ring containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[00124] In some embodiments, R ⁶ is an optionally substituted C _1-6 aliphatic group. In some embodiments, R ⁶ is an optionally substituted phenyl. In some embodiments, R ⁶ is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R ⁶ is an optionally substituted 5-6 membered heteroaryl ring containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[00125] In some embodiments, R ⁶ is selected from the options presented in Table 1 below.

[00126] As defined above and described herein, L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced with -Cy-, -O-, -N(R)-, -Si(R) ₂ -, -Si(OH)(R)-, -Si(OH) ₂ -, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(C-)N(R)-, -N(R)C(O)O-,

[00127] In some embodiments, L is a covalent bond. In some embodiments, L is a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced with -Cy-, -O-, -N(R)-, -Si(R) ₂ -, -Si(OH)(R)-, -Si(OH) ₂ -, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-,

[00128] In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is some implementation options, L represents

[00129] In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is

[00130] In some embodiments, L is selected from the options presented in Table 1 below.

[00131] As defined above and described herein, each -Cu- is independently an optionally substituted divalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-8 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spirocarbocyclylenyl, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-10 membered saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 6-11 membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, a 5- to 12-membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, a 5- to 6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur, or an 8- to 10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus or sulfur.

[00132] In some embodiments, -Cy- is an optionally substituted divalent ring selected from phenylenyl. In some embodiments, -Cy- is an optionally substituted 8-10 membered bicyclic arylenyl. In some embodiments, -Cy- is an optionally substituted 3-8 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, -Cy- is an optionally substituted 6-11 membered saturated or partially unsaturated spirocarbocyclylenyl. In some embodiments, -Cy- is an optionally substituted 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl. In some embodiments, -Cy- is an optionally substituted 4-10-membered saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur. In some embodiments, -Cy- is an optionally substituted 6-11-membered saturated or partially unsaturated spiroheterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur. In some embodiments, -Cy- is an optionally substituted 5-12-membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur. In some embodiments, -Cy- is an optionally substituted 5-6-membered heteroarylenyl containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, or an 8-10-membered bicyclic heteroarylenyl containing 1-5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur.

[00133] In some embodiments, -Cy- is

[00134] In some embodiments, -Su- is selected from the options presented in Table 1 below.

[00135] As defined above and described herein, the TBM is a target binding moiety.

[00136] In some embodiments, the TBM is a target binding moiety.

[00137] In some embodiments, the TBM binds to a protein selected from the proteins listed in paragraph [00181].

[00138] In some embodiments, the TBM is selected from one of the drugs listed in Table 2, wherein said drug is attached to any modified carbon, oxygen, sulfur or nitrogen atom.

[00139] In some embodiments, the TBM is selected from one of the drugs listed in Table 2, wherein said drug is attached to any modified carbon, oxygen, sulfur or nitrogen atom.

[00140] In some embodiments, the TBM is selected from one of the drugs listed in Table 2, wherein said drug is attached to any modified carbon, oxygen, sulfur or nitrogen atom.

[00141] In some embodiments, the TBM is selected from one of the drugs listed in Table 2, wherein said drug is attached to any modified carbon, oxygen, sulfur or nitrogen atom.

[00142] In some embodiments, the TVM is In some embodiments, the TVM is In some embodiments, the TVM is In some embodiments, the TVM is In some embodiments, the TVM is In some embodiments, the TVM is In some embodiments, the TVM is In some embodiments, the TVM is

[00143] In some embodiments, the TVM is selected from the options presented in Table 1 below.

[00144] As defined above and described herein, m is 0, 1, 2, 3, or 4.

[00145] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[00146] In some embodiments, m is selected from the options presented in Table 1 below.

[00147] As defined above and described herein, each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[00148] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[00149] In some embodiments, n is selected from the options presented in Table 1 below.

[00150] As defined above and described herein, each R is independently hydrogen, deuterium, or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or two R groups at the same nitrogen atom are combined with the atoms separating them to form a 4-7-membered saturated, partially unsaturated, or heteroaryl ring containing 0-3 heteroatoms in addition to a nitrogen atom independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[00151] In some embodiments, R is hydrogen. In some embodiments, R is deuterium. In some embodiments, R is optionally substituted C _1-6 aliphatic. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is an optionally substituted 4-7-membered saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R is an optionally substituted 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, two R groups on the same nitrogen atom are combined with the atoms separating them to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring containing 0-3 heteroatoms in addition to the nitrogen atom independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[00152] In some embodiments, R is selected from the options presented in Table 1 below.

[00153] In some embodiments, the present invention provides a compound of formula II-A or II-B, wherein X ¹ , R ¹ , R ⁵ , R, -Cy- and TBM are as listed for formula I above and herein, and ring A, ring B, R ² , R ³ , R ⁴ , L, m, n, p and q are as listed for formula II-A and II-B below and herein.

[00154] As defined above and described herein, Ring A is a mono- or bicyclic ring selected from

or

[00155] In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is

[00156] In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is

[00157] In some embodiments, ring A is a mono- or bicyclic ring selected from

[00158] In some embodiments, ring A is a mono- or bicyclic ring selected from

[00159] In some embodiments, ring A is selected from

[00160] In some embodiments, ring A is selected from

[00161] In some embodiments, ring A is selected from the options presented in Table 1 below.

[00162] As defined above and described herein, each R ² is independently hydrogen, deuterium, -R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -N(R)S(O) ₂ NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR or -P(O)(NR ₂ ) ₂ .

[00163] In some embodiments, R ² is hydrogen. In some embodiments, R ² is deuterium. In some embodiments, R ² is -R ⁴ . In some embodiments, R ² is a halogen. In some embodiments, R ^{2 is CN. In some embodiments, R 2 is} NO ₂ . In some embodiments, R ² is -OR. In some embodiments, R ² is -Si(OH) ₂ R. In some embodiments, R ² is Si(OH)(R) ₂ . In some embodiments, R ² is SR. In some embodiments, R ² is -NR ₂ . In some embodiments, R ² is -Si(R) ₃ . In some embodiments, R ² is -S(O) ₂ R. In some embodiments, R ² is -S(O) ₂ NR ₂ . In some embodiments, R ² is -S(O)R. In some embodiments, R ² is -C(O)R. In some embodiments, R ² is -C(O)OR. In some embodiments, R ² is -C(O)NR ₂ . In some embodiments, R ² is -C(O)N(R)OR. In some embodiments, R ² is -OC(O)R. In some embodiments, R ² is -OC(O)NR ₂ . In some embodiments, R ² is -N(R)C(O)OR. In some embodiments, R ² is -N(R)C(O)R. In some embodiments, R ² is -N(R)C(O)NR ₂ . In some embodiments, R ² is -N(R)S(O) ₂ R. In some embodiments, R ² is -P(O)(OR) ₂ . In some embodiments, R ² is -P(O)(NR ₂ )OR. In some embodiments, R ² is -P(O)(NR ₂ ) ₂ .

[00164] In some embodiments, R ² is methyl.

[00165] In some embodiments, R ² is selected from the options presented in Table 1 below.

[00166] As defined above and described herein, ring B is selected from a 6-membered aryl containing 0-3 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[00167] In some embodiments, ring B is a 6-membered aryl containing 0-3 nitrogen atoms. In some embodiments, ring B is a 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[00168] In some embodiments, ring B is selected from the options presented in Table 1 below.

[00169] As defined above and described herein, each R ³ is independently hydrogen, deuterium, halogen, -CN, -NO ₂ , -OR, -NR ₂ , -SR, -S(O) ₂ R, - S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NR(OR), -OC(O)R, -OC(O)NR ₂ , -OP(O)(OR) ₂ , -OP(O)(NR ₂ ) ₂ , -OP(O )(OR)NR ₂ , -N(R)C(O)R, N(R)C(O)OR, -N(R)C(O)NR ₂ , N(R)S(O) ₂ R , N(R)S(O) ₂ NR ₂ , N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, - P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R , -Si(OH)(R) ₂ or -Si(R) ₃ .

[00170] In some embodiments, R ³ is hydrogen. In some embodiments, R ³ is deuterium. In some embodiments, R ³ is a halogen. In some embodiments, R ³ is -CN. In some embodiments, R ³ is NO ₂ . In some embodiments, R ³ is OR. In some embodiments, R ³ is NR ₂ . In some embodiments, R ³ is -SR. In some embodiments, R ³ is -S(O) ₂ R. In some embodiments, R ³ is -S(O) ₂ NR ₂ . In some embodiments, R ³ is -S(O)R. In some embodiments, R ³ is -C(O)R. In some embodiments, R ³ is -C(O)OR. In some embodiments, R ³ is C(O)NR ₂ . In some embodiments, R ³ is C(O)NR(OR). In some embodiments, R ³ is OC(O)R. In some embodiments, R ³ is -OC(O)NR ₂ . In some embodiments, R ³ is -OP(O)(OR) ₂ . In some embodiments, R ³ is -OP(O)(NR ₂ ) ₂ . In some embodiments, R ³ is OP(O)(OR)NR ₂ . In some embodiments, R ³ is -N(R)C(O)R. In some embodiments, R ³ is -N(R)C(O)OR. In some embodiments, R ³ is -N(R)C(O)NR ₂ . In some embodiments, R ³ is -N(R)S(O) ₂ R. In some embodiments, R ³ is N(R)S(O) ₂ NR ₂ . In some embodiments, R ³ is -N(R)P(O)(OR) ₂ . In some embodiments, R ³ is N(R)P(O)(OR)NR ₂ . In some embodiments, R ³ is -P(O)(OR) ₂ . In some embodiments, R ³ is -P(O)(NR ₂ )OR. In some embodiments, R ³ is P(O)(NR ₂ ) ₂ . In some embodiments, R ³ is Si(OH) ₂ R. In some embodiments, R ³ is Si(OH)(R) ₂ . In some embodiments, R ³ is -Si(R) ₃ .

[00171] In some embodiments, R ³ is selected from the options presented in Table 1 below.

[00172] As defined above and described herein, each R ⁴ is independently an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur, and a 5-6 membered heteroaryl ring containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur.

[00173] In some embodiments, R ⁴ is an optionally substituted C _1-6 aliphatic. In some embodiments, R ⁴ is an optionally substituted phenyl. In some embodiments, R ⁴ is an optionally substituted 4-7-membered saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R ⁴ is an optionally substituted 5-6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[00174] In some embodiments, R ⁴ is methyl.

[00175] In some embodiments, R ⁴ is selected from the options presented in Table 1 below.

[00176] As defined above and described herein, L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced with -Cy-, -O-, -N(R)-, -Si(R) ₂ -, -Si(OH)(R)-, -Si(OH) ₂ -, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR ₂ )-, -S-, -OC(O)-, -C(O)0- -C(O)-, -S(O)-, -S(O) ₂ - -N(R)S(O) ₂ -, -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)0-,

[00177] In some embodiments, L is a covalent bond. In some embodiments, L is a divalent, saturated or unsaturated, linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced with -Cy-, O, N(R), Si(R) ₂ , Si(OH)(R)-, -Si(OH) ₂ - -P(O)(OR)-, -P(O)(R)- -P(O)(NR ₂ )-, -S- -OC(O)-, -C(O)0- -C(O)-, -S(O)-, -S(O) ₂ - -N(R)S(O) ₂ - -S(O) ₂ N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)0-,

[00178] In some embodiments, L is selected from the options presented in Table 1 below.

[00179] As defined above and described herein, m is 0, 1, or 2.

[00180] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[00181] In some embodiments, m is selected from the options presented in Table 1 below.

[00182] As defined above and described herein, n is 0, 1, 2, 3, or 4.

[00183] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[00184] In some embodiments, n is selected from the options presented in Table 1 below.

[00185] As defined above and described herein, p is 0 or 1, wherein if p is 0, the bond connecting ring A and ring B is connected to

[00186] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 0 and the bond connecting ring A and ring B is connected to

[00187] In some embodiments, p is selected from the options presented in Table 1 below.

[00188] As defined above and described herein, each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[00189] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6. In some embodiments, q is 7. In some embodiments, q is 8. In some embodiments, q is 9. In some embodiments, q is 10.

[00190] In some embodiments, q is selected from the options presented in Table 1 below.

[00191] In preferred aspects of the present invention, the TBM moiety is a moiety that binds to target proteins. The TBM moiety may have multiple types of targets, and said targets are selected from proteins that are expressed in a cell such that at least a portion of the sequences are in the cell and can bind to the TBM moiety. The term "protein" includes oligopeptides and polypeptide sequences of sufficient length that they can bind to the TBM moiety of the present invention. Any protein in a eukaryotic system as described herein is a target for ubiquitination mediated by the compounds of the present invention.

[00192] The TBM groups of the present invention include, for example, any moiety that specifically binds to a protein (binds to a target protein), and include the following non-limiting examples of small molecule target protein binding moieties: Hsp90 inhibitors, kinase inhibitors, HDM2 and MDM2 inhibitors, compounds targeting human BET family bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, compounds targeting nuclear hormone receptors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), as well as many others. The compositions described below illustrate some of the elements of these nine types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of said compositions, as well as other small molecules that can target a protein of interest. Said binding moieties are connected to a ubiquitin ligase binding moiety, preferably via a linker to bring the target protein (to which the target protein binding moiety is linked) into close proximity to the ubiquitin ligase for ubiquitination and degradation.

[00193] Any protein that can bind to a target binding moiety or group of TBM and that can be acted upon by a ubiquitin ligase or that can be degraded by a ubiquitin ligase is a target protein according to the present invention. In general, target proteins may include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins associated with integral cell function, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulatory activity, signal transducer activity, structural molecule activity, binding activity (with proteins, lipids, carbohydrates), receptor activity, proteins involved in cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimuli, proteins influencing behavior, cell adhesion proteins, proteins involved in cell death, proteins involved in transport including transporter protein activity, nuclear transport, ion transporter activity, channel/transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcriptional regulator activity, extracellular organization and biogenesis activity, translational regulator activity. Proteins of interest may include, among many others, proteins from eukaryotes and prokaryotes including humans as targets for drug therapy, other animals including domestic animals, microbes for identifying targets for antibiotics and other antimicrobials, and plants and even viruses.

[00194] A TBM (or target binding moiety) is a small molecule that can bind or does bind to a target protein of interest.

[00195] Some embodiments of the present application relate to TBM fragments that include, but are not limited to, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET family bromodomain-containing proteins, compounds targeting the cytosolic signaling protein FKBP12, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR).

[00196] In some embodiments, the TBM is a BRD ligand selected from

where R denotes the attachment to

[00197] In some embodiments, TBM is a CREBBP ligand selected from

where R denotes the attachment to

or X is N or C; and n is 0-8.

[00198] In some embodiments, the TBM is a SMARCA4/PB1/SMARCA2 ligand selected from

where R denotes the attachment to

or X is N or C; and n is 0-8.

[00199] In some embodiments, the TBM is a TRIM24/BRPF1 ligand selected from

where R denotes the attachment to ,

or and n is 0-8.

[00200] In some embodiments, the TBM is a glucocorticoid receptor ligand selected from

where R denotes the attachment to or

[00201] In some embodiments, the TVM is an estrogen/androgen receptor ligand selected from

where R denotes the attachment to or

[00202] In some embodiments, the TBM is a DOT1L ligand selected from

, where R denotes the addition to

or X is N or C; and n is 0-8.

[00203] In some embodiments, the TBM is a BRAF ligand selected from

where R denotes the attachment to

or

[00204] In some embodiments, the TBM is a Ras ligand selected from

where R denotes the attachment to or

[00205] In some embodiments, the TBM is a RasG12C ligand selected from

where R denotes the attachment to

or

[00206] In some embodiments, the TBM is a Her3 ligand selected from

where R denotes the attachment to

or and R' represents -CH ₂ CH ₃ or -CH=CH ₃ .

[00207] In some embodiments, the TBM is a Bcl-2/Bcl-XL ligand selected from

where R denotes the attachment to

[00208] In some embodiments, the TVM is an HDAC ligand selected from

, where R denotes the addition to

[00209] In some embodiments, the TBM is a PPAR-γ ligand selected from

, where R denotes the addition to

[00210] In some embodiments, the TVM is selected from

attached to a modified carbon, oxygen, nitrogen, or sulfur atom.

[00211] In some embodiments, the TBM is a ligand of Abl, KRAS, SHP2, cRAF, MerTK, or PRMT5, which are selected from the following non-limiting examples:

Abl

KRAS

SHP2

cRAF

MerTK

and PRMT5

attached to a modified carbon, oxygen, nitrogen, or sulfur atom.

[00212] In some embodiments, the TBM moiety is selected from the PTM moieties listed in WO 2016/197032, the entire contents of which are incorporated herein by reference. In some embodiments, the TBM moiety is selected from those inhibitors described in WO 2016/197032 in paragraphs [00116]-[00173], and the reference to a "Linker" moiety in WO 2016/197032 corresponds to the -L- group defined and described herein.

[00213] In some embodiments, the TBM is a KRAS ligand selected from

attached to a modified carbon, oxygen, nitrogen, or sulfur atom.

[00214] Illustrative compounds according to the present invention are shown in Table 1 below.

[00215] In some embodiments, the method comprises using a compound as provided in Table 1 above, or a pharmaceutically acceptable salt thereof.

[00216] In some embodiments, the present invention provides a compound of Formula I, wherein said compound is not any of the compounds shown in Table A-1 below.

[00217]

[00218] In some embodiments, the present invention provides a compound of Formula II-A, wherein said compound is not any of the compounds shown in Table A-2 below.

[00219]

[00220] In some embodiments, the TBM is one of the compounds shown in Table 2 below, where

attached to a modified carbon, oxygen, nitrogen, or sulfur atom.

[00221]

5. Applications, preparation of compositions and introduction

Pharmaceutically acceptable compositions

[00222] According to another embodiment of the present invention, there is provided a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is such that it is effective to achieve measurable binding of CRBN or a mutant thereof and a target protein or mutant thereof in a biological sample or in a patient. In some embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[00223] The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.

[00224] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not interfere with the pharmacological activity of the compound formulated therewith.

Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the composition of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, partial glycerides of a mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin (wool fat).

[00225] “Pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present invention that, when administered to a recipient, is capable of providing either directly or indirectly the compound of the present invention or an inhibitory-active metabolite or residue thereof.

[00226] As used herein, the term "active metabolite or residue thereof" means that the metabolite or residue thereof also binds to CRBN or a mutant thereof or a target protein or a mutant thereof.

[00227] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or by implantable reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention can be in the form of an aqueous or oily suspension. These suspensions can be prepared according to methods 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 nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly employed as a solvent or suspending medium.

[00228] Any light (blend) fixed oil, including synthetic mono- or diglycerides, can be used for this purpose. Fatty acids such as oleic acid and its glyceride derivatives can be used to prepare injectable forms, examples being natural pharmaceutically acceptable oils such as olive oil or castor oil, particularly in their polyoxyethylated forms. These oil solutions or suspensions can also contain a solvent or dispersing agent based on a long-chain alcohol, such as carboxymethylcellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used to prepare pharmaceutically acceptable solid, liquid or other dosage forms can also be used to prepare the formulations.

[00229] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers typically include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, suitable diluents include lactose and dry corn starch. When aqueous suspensions for oral use are required, the active ingredient is combined with emulsifying and suspending agents. If desired, sweetening, flavoring or coloring agents may be added.

[00230] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the agent with a non-irritating excipient that is solid at room temperature and liquid at rectal temperature, so that it will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

[00231] The pharmaceutically acceptable compositions of the present invention can also be administered topically, especially when the target for treatment includes areas or organs readily accessible for topical application, including diseases of the eye, skin, and lower gastrointestinal tract. Suitable formulations for topical application can be readily prepared for each of these areas or organs.

[00232] Topical application to the lower gastrointestinal tract may be accomplished using a rectal suppository formulation (see above) or a suitable enema formulation. Topical transdermal patches may also be used.

[00233] For topical administration, the pharmaceutically acceptable compositions provided herein can be formulated as 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 invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided herein can be formulated as a suitable lotion or cream containing the active ingredients 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 alcohol esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[00234] For ophthalmic use, the pharmaceutically acceptable compositions of the present invention may be formulated as micronized suspensions in isotonic, pH-adjusted, sterilized saline or as solutions in isotonic, pH-adjusted, sterilized saline, with or without the addition of a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated as an ointment such as petrolatum.

[00235] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or by inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.

[00236] Most preferably, the pharmaceutically acceptable compositions of the present invention are prepared as formulations for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[00237] The amount of a compound of the present invention that can be combined with carrier materials to produce a composition in a single dosage form will vary depending on the host being treated and the particular route of administration. Preferably, the present compositions should be prepared such that a dose of 0.01-100 mg/kg body weight/day of the compound can be administered to a patient receiving a dose of the composition.

[00238] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound being used, age, body weight, general health, sex, diet, time of administration, rate of elimination, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a compound of the present invention in a composition will also depend on the particular compound in the composition.

Uses of the compounds and pharmaceutically acceptable compositions

[00239] Disclosed herein are compositions and methods that relate to the surprising and unexpected discovery that an E3 ubiquitin ligase protein, such as cereblon, ubiquitinates a target protein once the target protein is brought into proximity to it via a bifunctional or chimeric construct that binds to the E3 ubiquitin ligase protein and the target protein. Accordingly, the present invention provides such compounds and compositions comprising an E3 ubiquitin ligase binding moiety ("UBM") linked to a target protein binding moiety ("TBM") that provides for ubiquitination of a selected target protein, which results in degradation of the target protein by the proteasome.

[00240] The compounds and compositions described herein are generally suitable for use in modulating targeted ubiquitination, particularly with respect to various polypeptides and other proteins that are subject to degradation and/or other inhibition. In some embodiments, the protein inhibited by the compounds and methods of the present invention includes the proteins set forth in paragraph [00181].

[00241] The compounds and compositions described herein exhibit a broad spectrum of pharmacological activity consistent with the degradation/inhibition of target polypeptides.

[00242] Accordingly, compounds that bind to CRBN provide advantages, particularly those compounds that have selectivity for E3 ligases. Such compounds should provide a pharmacological response that beneficially provides treatment for one or more conditions described herein without the side effects associated with binding to E3 ligases.

[00243] Although CRBN binders are known in the art, there is an unmet need to provide new binders that have more effective or preferred pharmaceutically relevant properties. For example, compounds with increased activity, selectivity for other E3 ligases, and ADMET (absorption, distribution, metabolism, excretion, and/or toxicity) properties are needed. Accordingly, some embodiments of the present invention provide binders for CRBN that exhibit selectivity for other E3 ligases.

[00244] The activity of a compound used in the present invention as a binder for CRBN or a mutant thereof can be determined in vitro, in vivo, or in a cell line. In vitro assays include assays that determine the subsequent functional circumstances or activity of activated CRBN or a mutant thereof. Alternative in vitro assays quantify the ability of a compound to bind to CRBN. Binding can be determined by radioactively labeling the compound prior to binding, isolating the compound/CRBN complex, and determining the amount of bound radiolabel. Alternatively, compound binding can be determined by conducting a competitive binding experiment in which novel compounds are incubated with CRBN bound to known radioactive ligands. Examples of in vitro and in vivo assays suitable for use in the CRBN binder assay include those described and disclosed in Boichenko et al. J. Med. Chem. (2016) 59, 770-774 and Iconomou and Saunders Biochemical Journal (2016) 473, 4083-4101, the entire contents of each of which are incorporated herein by reference. Detailed conditions for the analysis of compounds used in the present invention as a binder for CRBN or a mutant thereof are provided in the Examples section below.

[00245] The term "ubiquitin ligase" refers to a family of proteins that accelerate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with the E2 ubiquitin-conjugating enzyme, mediates the attachment of ubiquitin to a lysine on a target protein and then targets specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligase alone or in combination with the E2 ubiquitin-conjugating enzyme is responsible for the transfer of ubiquitin to target proteins. In general, ubiquitin ligase is involved in polyubiquitination, in which a second ubiquitin is attached to the first, a third to the second, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are a few ubiquitination situations that are limited to monoubiquitination, in which the ubiquitin ligase adds only one ubiquitin to the substrate molecule. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead their location or function in the cell must be altered, for example by binding to other proteins that contain domains capable of binding to ubiquitin. Another complicating factor is that different lysines on ubiquitin can be targeted by E3 to form chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine that is used to generate the polyubiquitin that is recognized by the proteasome.

[00246] As used herein, the terms "treating," "treating," and "treating" refer to reversing, alleviating, delaying the onset of, or suppressing the progression of a disease or disorder or one or more symptoms thereof, as described herein. In some embodiments, the treatment may be administered after one or more symptoms have developed. In other embodiments, the treatment may be administered in the absence of symptoms. For example, the treatment may be administered to an individual suspected of having the above before symptoms have developed (e.g., in light of a history of symptoms and/or in light of genetic or other prognostic factors). The treatment may also be continued after symptoms have resolved, for example, to prevent or delay their onset.

[00247] The present disclosure provides therapeutic compositions described herein for degrading proteins of interest to treat or reduce a disease, such as cancer. In some other embodiments, the disease is multiple myeloma. Accordingly, in another aspect, the present disclosure provides a method for ubiquitinating/degrading a target protein in a cell. In some embodiments, the method comprises administering a bifunctional compound as described herein, comprising, for example, a UBM and a TBM linked by a linker moiety as described herein, wherein said UBM is linked to the TBM, and wherein said UBM recognizes a ubiquitin pathway unit (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase such as, for example, cereblon), and the TBM recognizes a target protein, whereby degradation of the target protein will occur when the target protein becomes located in proximity to the ubiquitin ligase, which provides degradative/inhibitory effects on the target protein and regulation of protein levels. The regulation of protein levels achieved by the present invention provides for treatment of a disease state or condition that is modulated by the target protein by reducing the levels of said protein in a cell, for example, in a patient's cell. In some embodiments, the method comprises administering an effective amount of a compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, other biologically active agent, or a combination thereof.

[00248] In additional embodiments, the present disclosure provides methods for treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, comprising administering to a subject in need thereof a composition comprising an effective amount, such as a therapeutically effective amount, of a compound described herein or a salt form thereof and a pharmaceutically acceptable excipient, carrier, adjuvant, other biologically active agent, or a combination thereof, wherein said composition is effective for treating or ameliorating the disease or disorder, or symptom thereof, in the subject.

[00249] In another aspect, the present disclosure provides methods for identifying the effects of degradation of proteins of interest in a biological system using the compounds of the present invention.

[00250] In another embodiment, the present invention relates to a method of treating a human patient in need of modulation of a disease state or condition via a protein, wherein degradation of said protein will provide a therapeutic effect for said patient, wherein said method comprises administering to a patient in need an effective amount of a compound of the present invention, optionally in combination with another biologically active agent. The disease state or condition may be a disease caused by a microbial agent or other exogenous agent such as a virus, bacterium, fungus, protozoa or other microorganisms, or it may be a disease state that is caused by overexpression of a protein that leads to the disease state and/or condition.

[00251] Disease states or conditions that can be treated using the compounds of the present invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various types of cancer, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease associated with mutations in the PKD1 gene or in the PKD2 gene located on chromosome 4, Prader-Willi syndrome, sickle cell anemia, Tay-Sachs, Turner syndrome.

[00252] Other disease states or conditions that can be treated with the compounds of the present invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorder, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes mellitus, type 2 diabetes mellitus, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette's syndrome, vasculitis.

[00253] Other additional disease states or conditions that can be treated with the compounds of the present invention include aceruloplasminemia, achondrogenesis type II, achondroplasia, acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, aminolevulinic acid dehydratase (ALA dehydratase) deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA dehydratase deficiency porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuric ochronosis, alpha-1-antitrypsin deficiency, alpha-1-proteinase inhibitor deficiency, emphysema, amyotrophic lateral sclerosis, Alstrom syndrome, Alexander disease, amelogenesis imperfecta, deficiency ALK dehydratase, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse angiokeratoma of the body, retinal angiomatosis (Von Hippel-Lindau disease), Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, congenital multiple arthrochalasia (Ehlers-Danlos syndrome, arthrochalasia type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beer-Stevenson syndrome with cutis gyrata, familial Mediterranean fever, Benjamin syndrome, beta-thalassemia, bilateral acoustic neurofibromatosis (neurofibromatosis type II), factor V Leiden mutation thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti syndrome), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ulrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion disease, Birt-Hogg-Dubé syndrome, "cry-man" disease (osteogenesis imperfecta), broad thumb syndrome (Rubinstein-Taybi syndrome), bronze diabetes/pigmentary cirrhosis (hemochromatosis), bulbar spinal muscular atrophy (Kennedy disease), Buerger-Grutz syndrome (lipoprotein lipase deficiency), chronic granulomatous disease (CGD), campomelic dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cri d'chat syndrome, VASD (congenital absence of vas deferens), cardiofacial syndrome Cuyler syndrome (CDOP), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, chondrodystrophy syndrome (achondroplasia), otospondylomega-epiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome, familial adenomatous polyposis, congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia/congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, conotruncal facial anomaly syndrome, Cooley's anemia (beta-thalassemia), copper storage disease (Wilson disease), copper transfer disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial dysostosis (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Kurschmann-Batten-Steinert syndrome (myotonic dystrophy), Beer-Stevenson syndrome with cutis gyrata skin disorder, primary hyperoxaluria, spondylometaphyseal dysplasia (Strudwick type), muscular dystrophy, Duchenne and Becker types (DBMD), Usher syndrome, degenerative nerve diseases including de Gruchy syndrome and Dejerine-Sottas syndrome, developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, globoid cell leukodystrophy (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity, Down syndrome, dwarfism, erythropoietic protoporphyria, erythroid 5-aminolevulinate synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, porphyria cutanea tarda, familial neuropathy with pressure sensitivity, primary pulmonary hypertension (PPH), fibrocystic disease of the pancreas, fragile X syndrome, galactosemia, genetic disorders of the brain, giant cell hepatitis (neonatal hemochromatosis), Gronblad-Strandberg syndrome (pseudomonas elasticum), Gunther's disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren's disease, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), von Hippel-Lindau disease (Von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria, hyperandrogenism, hypochondroplasia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney disease including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, lacunar dementia, Langer-Saldino achondrogenesis, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, multiple neurofibromatosis, Nancy-Insley syndrome, Nancy-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive Chorea, Chronic Hereditary (Huntington's) (Huntington's disease), Progressive Muscular Atrophy, Spinal Muscular Atrophy, Propionic Acidemia, Protoporphyria, Proximal Myotonic Dystrophy, Pulmonary Arterial Hypertension, PXE (Pseudoxanthoma Elasticum), RB (Retinoblastoma), Recklinghausen's Disease (Neurofibromatosis Type I), Relapsing Polyserositis, Retinal Lesions, Retinoblastoma, Rett Syndrome, Recessive Familial Amyotrophic Lateral Sclerosis (RFALS) Type 3, Ricker Syndrome, Riley-Day Syndrome, Roussy-Levy Syndrome, Severe Achondroplasia with Developmental Delay and Acanthosis Nerves (SADDAN), Li-Fraumeni Syndrome, Sarcoma, Breast Cancer, Leukemia, and Adrenal Cancer Syndrome (SBLA), tuberous sclerosis, senile dementia of the Alzheimer type (SDAT), congenital SED (spondyloepiphyseal dysplasia congenita), SED Struwick (spondylometaepiphyseal dysplasia, Struwick type), SEDc (spondyloepiphyseal dysplasia congenita), SEMD, Struwick type (spondylometaepiphyseal dysplasia, Struwick type), Shprintzen syndrome, skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South African genetic porphyria (variegate porphyria), infantile hereditary progressive spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta thalassemia, thyroid disease, tomacular neuropathy (hereditary neuropathy with a tendency to nerve compression palsies), Treacher Collins syndrome, trisomy X syndrome (triple X syndrome), trisomy 21 (Down syndrome), trisomy X, von Hippel-Lindau syndrome (Von Hippel-Lindau disease), visual impairment and blindness (Alstrom syndrome), Vrolik disease, Waardenburg syndrome, Warburg-Shaw-Fledelius syndrome, Weissenbacher-Zweimüller syndrome, Wolff-Hirschhorn syndrome, Wolff periodic disease, Weissenbacher-Zweimüller syndrome, and xeroderma pigmentosum, among others. [00254] The term "neoplasm" or "cancer" throughout the present disclosure refers to a pathological process that results in the formation and growth of a cancerous or malignant neoplasm, that is, abnormal tissue that grows through cell proliferation, often faster than normal tissue, and continues to grow after the stimuli that initiated the new growth have disappeared.

Malignant neoplasms are characterized by a partial or complete lack of structural organization and functional coordination with normal tissue and in most cases invade surrounding tissues, metastasize to several areas of the body and are capable of recurring after attempted removal and causing death of the patient if not treated appropriately. As used herein, the term "neoplasm" is used to describe all cancerous disease states and comprises or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors. Typical cancers that can be treated using the compounds of the present invention either alone or in combination with at least one additional anticancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas and renal cell carcinomas, cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinoma. Additional cancers that can be treated using the compounds of the present invention include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B-ALL, pre-B lymphomas, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive chronic myeloid leukemia (CML).

[00255] In some embodiments, the present invention provides a method of treating one or more disorders, wherein said disorders are selected from autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplantation-related disorders, wherein said method comprises administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[00256] In some embodiments, the compounds of the present invention induce ubiquitination and degradation of a target protein,

Protein level control

[00257] The present disclosure also provides methods for controlling protein levels in a cell. These methods are based on the use of compounds described herein that are known to interact with a specific target protein such that degradation of the target protein in vivo provides control of the amount of protein in a biological system, preferably with a specific therapeutic effect.

[00258] Furthermore, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, for the preparation of a medicament for the treatment of an autoimmune disorder, an inflammatory disorder, or a proliferative disorder, or a disorder commonly associated with transplantation.

Combination therapy

[00259] Depending on the particular condition or disease being treated, additional therapeutic agents that are typically administered to treat that condition can be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents that are typically administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[00260] In some embodiments, the proposed combination or composition thereof is administered in combination with another therapeutic agent.

[00261] Examples of agents with which combinations may also be prepared according to the present invention include, but are not limited to: drugs for the treatment of Alzheimer's disease, such as Aricept ^® and Excelon ^® ; drugs for the treatment of HIV, such as ritonavir; drugs for the treatment of Parkinson's disease, such as levodopa/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; agents for the treatment of multiple sclerosis (MS), such as beta-interferon (e.g., Avonex ^® and Rebif ^® ), Copaxone ^® and mitoxantrone; drugs for the treatment of asthma, such as albuterol and Singulair ^® ; agents for the treatment of schizophrenia such as ^Zyprexa® , Risperdal, ^Seroquel® , and haloperidol; anti-inflammatory agents such as corticosteroids, tumor necrosis factor (TNF) blockers, interleukin-1 (IL-1) receptor antagonists, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressant agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, monoamine oxidase (MAO) inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian agents; agents for the treatment of cardiovascular diseases such as beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for the treatment of liver diseases such as corticosteroids, cholestyramine, interferons and antiviral agents; agents for the treatment of blood diseases such as corticosteroids, antileukemic agents and growth factors; agents that increase or improve pharmacokinetic parameters such as cytochrome P450 inhibitors (i.e. metabolic breakdown inhibitors) and CYP3A4 inhibitors (e.g. ketoconazole and ritonavir), and agents for the treatment of immunodeficiency states such as gamma globulin.

[00262] In some embodiments, the combination drugs of the present invention or a pharmaceutically acceptable composition thereof are administered in combination with a monoclonal antibody or an siRNA drug.

[00263] These additional agents may be administered separately from the proposed combination therapy, as part of a multiple dosing regimen. Alternatively, these agents may be part of a single dosage form, being mixed with a compound of the present invention in a single composition. When administered as part of a multiple dosing regimen, the two active agents may be administered simultaneously, sequentially, or within a time interval of each other, typically within five hours of each other.

[00264] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a combination according to the present invention can be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single dosage form.

[00265] The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount that is typically included in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will be from about 50% to 100% of the amount that is typically present in a composition containing that agent as the sole therapeutically active agent.

[00266] In one embodiment, the present invention provides a composition comprising a compound of Formula I, Formula I', Formula I", Formula II-A, Formula II'-A, Formula II"-A, Formula II-B, Formula II'-B, or Formula II"-B and one or more additional therapeutic agents. The therapeutic agent can be administered together with the compound of Formula I, Formula I', Formula I", Formula II-A, Formula II'-A, Formula II"-A, Formula II-B, Formula II'-B, or Formula II"-B, or can be administered before or after administration of the compound of Formula I, Formula I', Formula I", Formula II-A, Formula II'-A, Formula II"-A, Formula II-B, Formula II'-B, or Formula II"-B. Suitable therapeutic agents are described in further detail below. In some embodiments, the compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B may be administered 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before administration of the therapeutic agent. In other embodiments, the compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II'-A, Formula II-B, Formula II'-B, or Formula II'-B may be administered 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after administration of the therapeutic agent.

[00267] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecule compounds or recombinant biological agents and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac (Lodine ^® ) and celecoxib, colchicine (Colcrys ^® ), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone and the like, probenecid, allopurinol, febuxostat (Uloric ^® ), sulfasalazine (Azulfidine ^® ), antimalarials such as hydroxychloroquine (Plaquenil ^® ) and chloroquine (Aralen ^® ), methotrexate (Rheumatrex ^® ), gold salts such as aurothioglucose (Solganal ^® ), aurothiomalate (Myochrysine ^® ) and auranofin (Ridaura ^® ), D-penicillamine (Depen ^® or Cuprimine ^® ), azathioprine (Imuran ^® ), cyclophosphamide (Cytoxan ^® ), chlorambucil (Leukeran ^® ), cyclosporine (Sandimmune ^® ), leflunomide (Arava ^® ) and "anti-TNF" agents such as etanercept (Enbrel ^® ), infliximab (Remicade ^® ), golimumab (Simponi ^® ), certolizumab pegol (Cimzia ^® ) and adalimumab (Humira ^® ), "anti-IL-1" agents such as anakinra (Kineret ^® ) and rilonacept (Arcalyst ^® ), canakinumab (Ilaris ^® ), Janus kinase inhibitors (anti-Jak) such as tofacitinib, antibodies such as rituximab (Rituxan ^® ), "anti-T-cell" agents such as abatacept (Orencia ^® ), "anti-IL-6" agents such as tocilizumab (Actemra ^® ), diclofenac, cortisone, hyaluronic acid (Synvisc ^® or Hyalgan ^® ), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine ^® or Liquaemin ^® ) and warfarin (Coumadin ^® ), antidiarrheals such as diphenoxylate (Lomotil ^® ) and loperamide (Imodium ^® ), bile acid binders such as cholestyramine, alosetron (Lotronex ^® ), lubiprostone (Amitiza ^® ), laxatives such as magnesium hydroxide, polyethylene glycol (MiraLax ^® ), Dulcolax ^® , Correctol ^{® ,} and Senokot ^® , anticholinergics or antispasmodics such as dicyclomine (Bentyl ^® ), Singulair ^® , beta2-adrenergic receptor agonists such as albuterol (Ventolin ^® HFA, Proventil ^® HFA), levalbuterol (Hopepex ^® ), metaproterenol (Alupent ^® ), pirbuterol acetate (Maxair ^® ), terbutaline sulfate (Brethaire ^® ), salmeterol xinafoate (Serevent ^® ) and formoterol (Foradil ^® ), anticholinergic agents such as ipratropium bromide (Atrovent ^® ) and tiotropium (Spiriva ^® ), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent ^® , Qvar ^® , and Vanceril ^® ), triamcinolone acetonide (Azmacort ^® ), mometasone (Asthmanex ^® ), budesonide (Pulmocort ^® ), and flunisolide (Aerobid ^® ), Afviar ^® , Symbicort ^® , Dulera ^® , sodium cromoglycate (Hital ^® ), methylxanthines such as theophylline (Theo-Dur ^® , Theolair ^® , Slo-bid ^® , Uniphyl ^® , Theo-24 ^® ) and aminophylline, IgE antibodies such as omalizumab (Xolair ^® ), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir ^® ), abacavir (Ziagen ^® ), abacavir/lamivudine (Epzicom ^® ), abacavir/lamivudine/zidovudine (Trizivir ^® ), didanosine (Videx ^® ), emtricitabine (Emtriva ^® ), lamivudine (Epivir ^® ), lamivudine/zidovudine (Combivir ^® ), stavudine (Zerit ^® ) and zalcitabine (Hivid ^® ), non-nucleoside reverse transcriptase inhibitors transcriptases such as delavirdine (Rescriptor ^® ), efavirenz (Sustiva ^® ), nevirapine (Viramune ^® ) and etravirine (Intelence ^® ), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread ^® ), protease inhibitors such as amprenavir (Agenerase ^® ), atazanavir (Reyataz ^® ), darunavir (Prezista ^® ), fosamprenavir (Lexiva ^® ), indinavir (Crixivan ^® ), lopinavir and ritonavir (Kaletra ^® ), nelfinavir (Viracept ^® ), ritonavir (Norvir ^® ), saquinavir (Fortovase ^® or Invirase ^® ), and tipranavir (Aptivus ^® ), fusion inhibitors such as enfuvirtide (Fuzeon ^® ) and maraviroc (Selzentry ^® ), integrase inhibitors such as raltegravir (Isentress ^® ), doxorubicin (Hydrodaunorubicin ^® ), vincristine (Oncovin ^® ), bortezomib (Velcade ^® ) and dexamethasone (Decadron ^® ) in combination with lenalidomide (Revlimid ^® ), or any combination(s) thereof.

[00268] In another embodiment of the present invention, there is provided a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac ( ^Lodine® ) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone and the like, sulfasalazine ( ^Azulfidine® ), antimalarials such as hydroxychloroquine ( ^Plaquenil® ) and chloroquine ( ^Aralen® ), methotrexate (Rheumatrex ^® ), gold salts such as aurothioglucose (Solganal ^® ), aurothiomalate (Myochrysine ^® ) and auranofin (Ridaura ^® ), D-penicillamine (Depen ^® or Cuprimine ^® ), azathioprine (Imuran ^® ), cyclophosphamide (Cytoxan ^® ), chlorambucil (Leukeran ^® ), cyclosporine (Sandimmune ^® ), leflunomide (Arava ^® ) and "anti-TNF" agents such as etanercept (Enbrel ^® ), infliximab (Remicade ^® ), golimumab (Simponi ^® ), certolizumab pegol (Cimzia ^® ) and adalimumab (Humira ^® ), “anti-IL-1” agents such as anakinra (Kineret ^® ) and rilonacept (Arcalyst ^® ), antibodies such as rituximab (Rituxan ^® ), “anti-T-cell” agents such as abatacept (Orencia ^® ), and “anti-IL-6” agents such as tocilizumab (Actemra ^® ).

[00269] In some embodiments, the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac ( ^Lodine® ) and celecoxib, diclofenac, cortisone, hyaluronic acid ( ^Synvisc® or ^Hyalgan® ), and monoclonal antibodies such as tanezumab.

[00270] In some embodiments, the present invention provides a method of treating systemic lupus erythematosus comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac ( ^Lodine® ) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone and the like, antimalarial agents such as hydroxychloroquine ( ^Plaquenil® ) and chloroquine ( ^Aralen® ), cyclophosphamide ( ^Cytoxan® ), methotrexate (Rheumatrex ^® ), azathioprine (Imuran ^® ), and anticoagulants such as heparin (Calcinparine ^® or Liquaemin ^® ) and warfarin (Coumadin ^® ).

[00271] In some embodiments, the present invention provides a method of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and one or more additional therapeutic agents selected from mesalamine ( ^Asacol® ), sulfasalazine ( ^Azulfidine® ), antidiarrheals such as diphenoxylate ( ^Lomotil® ) and loperamide ( ^Imodium® ), bile acid binders such as cholestyramine, alosetron ( ^Lotronex® ), lubiprostone ( ^Amitiza® ), laxatives such as magnesium hydroxide, polyethylene glycol ( ^MiraLax® ), Dulcolax®, ^® , Correctol ^® and Senokot ^® and anticholinergics or antispasmodics such as dicyclomine (Bentyl ^® ), TNF blocking drugs, steroids and antibiotics such as Flagyl ^® or ciprofloxacin.

[00272] In some embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and one or more additional therapeutic agents selected from ^Singulair® , beta2-adrenergic receptor agonists such as albuterol ( ^Ventolin® HFA, ^{Proventil® HFA} ), levalbuterol (Xorepex®), metaproterenol ( ^Alupent® ), pirbuterol acetate ( ^Maxair® ), terbutaline sulfate ( ^Brethaire® ), salmeterol xinafoate ( ^Serevent® ), and formoterol ( ^Foradil® ), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium ( ^Spiriva® ), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate ( ^Beclovent® , Qvar® ^, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide ( ^Pulmocort® ), flunisolide ( ^Aerobid® ), ^Afviar® , Symbicort® ^, and ^Dulera® , sodium cromoglycate ( ^Intal® ), methylxanthines such as theophylline (Theo- ^Dur® , ^Theolair® , Slo- ^bid® , ^Uniphyl® , Theo- ^24® ) and aminophylline, and antibodies IgE, such as omalizumab (Xolair ^® ).

[00273] In some embodiments, the present invention provides a method of treating COPD comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and one or more additional therapeutic agents selected from beta2-adrenergic receptor agonists such as albuterol ( ^Ventolin® HFA, ^Proventil® HFA), levalbuterol ( ^Xorepex® ), metaproterenol ( ^Alupent® ), pirbuterol acetate ( ^Maxair® ), terbutaline sulfate (Brethaire®), salmeterol xinafoate ( ^{Serevent® )} , and formoterol ( ^Foradil® ), anticholinergic agents such as ipratropium bromide (Atrovent®), and leucorrhoea (Ventolin® HFA, Proventil® HFA). ^® ) and tiotropium (Spiriva ^® ), methylxanthines such as theophylline (Theo-Dur ^® , Theolair ^® , Slo-bid ^® , Uniphyl ^® , Theo-24 ^® ) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent ^® , Qvar ^® , and Vanceril ^® ), triamcinolone acetonide (Azmacort ^® ), mometasone (Asthmanex ^® ), budesonide (Pulmocort ^® ), flunisolide (Aerobid ^® ), Afviar ^® , Symbicort ^{® ,} and Dulera ^® .

[00274] In another embodiment, the present invention provides a method of treating a malignant disease of the hematopoietic system, comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and one or more additional therapeutic agents selected from rituximab ( ^Rituxan® ), cyclophosphamide ( ^Cytoxan® ), doxorubicin ( ^{Hydrodaunorubicin®} ), vincristine ( ^Oncovin® ), prednisone, a hedgehog signaling pathway inhibitor, a BTK inhibitor, a JAK/pan-JAK (selective/non-selective Janus kinase inhibitor), a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[00275] In another embodiment, the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and one or more additional therapeutic agents selected from rituximab ( ^Rituxan® ), cyclophosphamide ( ^Cytoxan® ), doxorubicin ( ^{Hydrodaunorubicin®} ), vincristine ( ^Oncovin® ), prednisone, a hedgehog signaling pathway inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[00276] In another embodiment, the present invention provides a method of treating a hematopoietic malignancy comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and an inhibitor of the hedgehog (Hh) signaling pathway. In some embodiments, the hematopoietic malignancy is DLBCL (Ramirez et al, "Denning causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma," Leuk. Res. (2012), published online July 17, the entire contents of which are incorporated herein by reference).

[00277] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and one or more additional therapeutic agents selected from rituximab ( ^Rituxan® ), cyclophosphamide ( ^Cytoxan® ), doxorubicin ( ^{Hydrodaunorubicin®} ), vincristine ( ^Oncovin® ), prednisone, a hedgehog signaling pathway inhibitor, and combinations thereof.

[00278] In another embodiment, the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and one or more additional therapeutic agents selected from bortezomib ( ^Velcade® ), dexamethasone ( ^Decadron® ), a hedgehog signaling pathway inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide ( ^Revlimid® ).

[00279] In another embodiment, the present invention provides a method of treating or reducing the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and a BTK inhibitor, wherein said disease is selected from inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, severe pseudoparalytic myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis (atrophic form of autoimmune thyroiditis), Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu arteritis, temporal arteritis, autoimmune hemolytic anemia with warm agglutinin syndrome, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, autonomic dystonia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigus, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disease, organ or tissue transplant rejection, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, transfusion, anaphylaxis, allergies (eg, to pollens, latex, drugs, foods, insect venoms, animal dander, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, IgA nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B-cell proliferative disorder such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal B-cell lymphoma marginal zone lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia or lymphomatoid granulomatosis, breast cancer, prostate cancer or mast cell cancer (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint disorders including but not limited to rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis, thromboembolic disorder (e.g., myocardial infarction, angina, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after coronary artery bypass grafting, restenosis after coronary artery bypass grafting, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism, deep vein thrombosis), pelvic inflammatory disease, urethritis, sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute organ transplant rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic conditions, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, severe pseudoparalytic myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia/reperfusion injury), and Graves' disease.

[00280] In another embodiment, the present invention provides a method of treating or reducing the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and a PI3K inhibitor, wherein said disease is selected from cancer, a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormonal disease, conditions associated with organ transplantation, immunodeficiency conditions, destructive bone disease, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathological immune conditions accompanied by T-cell activation, cardiovascular disorder and CNS related disorder.

[00281] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and a PI3K inhibitor, wherein said disease is selected from a benign or malignant tumor, a carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastrointestinal tract, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone, or thyroid gland, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, in particular colon cancer or colorectal adenoma, or head and neck tumor, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasm, neoplasm of epithelial nature, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphomas (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin's disease)), breast carcinoma, follicular carcinoma, undifferentiated carcinoma, seminoma, melanoma or leukemia, diseases including Cowden syndrome, Lhermitte-Dudos syndrome and Bannayan-Zonana syndrome, or diseases accompanied by abnormal activation of the PI3K/PKB signaling pathway, asthma of any type or origin, including both endogenous (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma and asthma caused by bacterial infection, acute lung injury (ALI), adult respiratory distress syndrome (ARDS)/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease or airways disease (COPD or COPD), including associated chronic bronchitis or dyspnea, emphysema, as well as exacerbation of airway hyperreactivity due to other drug therapy, in particular other inhaled drug therapy, bronchitis of any type or origin, including, but not limited to, acute, arachidic, catarrhal, croupous, chronic or suppurative tuberculous bronchitis, pneumoconiosis (an inflammatory, usually occupational, lung disease often associated with airway obstruction, chronic or acute, caused by repeated inhalation of dust) of any type or origin, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis, Loeffler's syndrome, a form of eosinophilic pneumonia, parasitic infestations (particularly metazoans) (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophilia-related disorders of the respiratory tract caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigus, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis and inflammatory disease in which autoimmune reactions are involved or which has an autoimmune component or etiology including autoimmune disorders of the hematopoietic system (e.g. hemolytic anemia, aplastic anemia, pure red cell aplasia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, severe pseudoparalytic myasthenia, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy), restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and cerebral ischemia and neurodegenerative disease caused by traumatic injury, neurotoxic effects of glutamate and hypoxia.

[00282] In some embodiments, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I, Formula I', Formula I'', Formula II-A, Formula II'-A, Formula II''-A, Formula II-B, Formula II'-B, or Formula II''-B and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematopoietic neoplasm, or solid tumor.

[00283] The compounds and compositions according to the method of the present invention can be administered in any amount and by any route of administration effective to treat or lessen the severity of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. The precise amount required will vary from subject to subject depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, the route of administration, and the like. The compounds of the present invention are preferably prepared in unit dosage form for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically discrete unit of agent appropriate for a patient in need of treatment. It is to be understood, however, that total daily dosages of the compounds and compositions of the present invention will be determined by the attending physician as part of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors including the disorder being treated and the severity of that disorder; the activity of the particular compound employed; the particular composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the particular compound employed; the duration of treatment; drugs used in combination or simultaneously with the particular compound employed, and similar factors well known in the medical art. The term "patient" as used herein means an animal, preferably a mammal and most preferably a human.

[00284] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g., via powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In some embodiments, the compounds of the present invention can be administered orally or parenterally at doses of from about 0.01 mg/kg to about 50 mg/kg, and preferably from about 1 mg/kg to about 25 mg/kg of subject body weight per day, one or more times per day, to obtain the desired therapeutic effect.

[00285] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms can contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, compositions for oral administration may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[00286] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution listed in the United States Pharmacopoeia (U.S.P.), and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as a solvent or suspending medium. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used for the preparation of injectable preparations.

[00287] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injection medium prior to use.

[00288] In order to prolong the effect of the compound of the present invention, it is often desirable to slow the absorption of the compound upon subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low solubility in water. The rate of absorption of the compound thus depends on the rate of its dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered form of the compound is achieved by dissolving or suspending the compound in an oil medium. Injectable depot forms are prepared by forming microcapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the amounts of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[00289] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore soften in the rectum or vaginal cavity to release the active compound.

[00290] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or a) fillers or bulking agents, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

[00291] Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain matting agents and may also be formulated to release the active ingredient(s) exclusively or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of enclosing compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[00292] The active compounds may also be in the form of microcapsules with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, release-controlling coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, as is common practice, additional substances other than inert diluents, for example, tableting lubricants and other tableting excipients such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. They may optionally contain matting agents and may also be formulated so that they release the active ingredient(s) exclusively or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of enclosing compositions that may be used include polymeric substances and waxes.

[00293] Dosage forms for topical or transdermal administration of the compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. A formulation for intraocular administration, ear drops and eye drops are also included within the scope of the present invention. In addition, the present invention provides the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled either by providing a rate-regulating membrane or by dispersing the compound in a polymer matrix or gel.

[00294] According to one embodiment, the present invention relates to a method of modulating CRBN activity in a biological sample, comprising the step of contacting said biological sample with a compound of the present invention or a composition comprising said compound.

[00295] According to another embodiment, the present invention relates to a method of binding CRBN or a mutant variant thereof, activity in a biological sample, comprising the step of contacting said biological sample with a compound of the present invention or a composition comprising said compound.

[00296] As used herein, the term "biological sample" includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[00297] The binding activity of CRBN (or a mutant variant thereof) in a biological sample is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, storage of biological samples and biological assays.

[00298] Another embodiment of the present invention relates to a method of modulating CRBN activity in a patient, comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound.

[00299] According to another embodiment, the present invention relates to a method of modulating the activity of CRBN or a mutant variant thereof in a patient, comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound. According to some embodiments, the present invention relates to a method of reversibly or irreversibly modulating the activity of one or more CRBN or mutant variants thereof in a patient, comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound. In other embodiments, the present invention provides a method of treating a disorder mediated by CRBN or a mutant variant thereof in a patient in need thereof, comprising the step of administering to said patient a compound of the present invention or a pharmaceutically acceptable composition thereof, such disorders being described in detail herein.

[00300] Depending on the particular condition or disease being treated, additional therapeutic agents that are typically administered to treat that condition may also be present in the compositions of the present invention. As used herein, additional therapeutic agents that are typically administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[00301] A compound of the present invention may also be used to advantage in combination with other therapeutic compounds. In some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; compounds having microtubule activity; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platinum compounds; compounds that target/reduce protein kinase or lipid kinase activity and other antiangiogenic compounds; compounds that target, reduce, or inhibit protein phosphatase or lipid phosphatase activity; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; oncogenic Ras isoform inhibitors; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of malignant diseases of the hematopoietic system; compounds that target, reduce, or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminoethylamino-17-demethoxygeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (Temodal ^® ); kinesin spindle protein inhibitors such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, and leucovorin. As used herein, the term "aromatase inhibitor" refers to a compound that inhibits estrogen production, such as the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, in particular atamestane, exemestane and formestane, and in particular non-steroidal compounds, in particular aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. The combination according to the present invention, containing a chemotherapeutic agent which is an aromatase inhibitor, is suitable, in particular, for the treatment of hormone receptor-positive tumors, such as breast tumors.

[00302] As used herein, the term "antiestrogen" refers to a compound that antagonizes the effect of estrogens at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant is available for administration under the trade name Faslodex™. The combination of the present invention comprising a chemotherapeutic agent that is an antiestrogen is particularly suitable for use in the treatment of estrogen receptor-positive tumors, such as breast tumors.

[00303] As used herein, the term "antiandrogen" refers to any substance that is capable of inhibiting the biological effects of androgen hormones, and includes, but is not limited to, bicalutamide (Casodex™). As used herein, the term "gonadorelin agonist" includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is available for administration under the trade name Zoladex™.

[00304] As used herein, the term "topoisomerase I inhibitor" includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148. Irinotecan is available for administration, e.g., in the form in which it is marketed, e.g., under the trade name Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[00305] As used herein, the term "topoisomerase II inhibitor" includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulation such as Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26-Bristol. Doxorubicin is marketed under the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron.

[00306] The term "microtubule active agent" refers to compounds that stabilize microtubules, destabilize microtubules, and inhibit microtubule polymerization, including, but not limited to, taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; colchicine; and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastin R.P™. Vincristine sulfate is marketed under the trade name Farmistin™.

[00307] As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or a nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.

[00308] The term "histone deacetylase inhibitors" or "HDAC inhibitors" refers to compounds that inhibit histone deacetylase and that have antiproliferative activity. These include, but are not limited to, suberoylanilide hydroxamic acid (SAHA).

[00309] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

[00310] As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cisplatin, cisplatin, and oxaliplatin. Carboplatin is available for administration, e.g., in the form as it is marketed, e.g., under the trade name Carboplat™. Oxaliplatin is available for administration, e.g., in the form as it is marketed, e.g., under the trade name Eloxatin™.

[00311] As used herein, the term "compounds that target/reduce protein kinase or lipid kinase activity; or protein phosphatase or lipid phosphatase activity; or other antiangiogenic compounds" includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, reduce or inhibit platelet-derived growth factor receptors (PDGFR) activity, such as compounds that target, reduce or inhibit PDGFR activity, in particular compounds that inhibit the TRF receptor, such as an N-phenyl-2-pyrimidineamine derivative such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit fibroblast growth factor receptors (FGFR) activity; c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, reduce or inhibit the activity of IGF-IR, in particular compounds that inhibit the kinase activity of IGF receptor I or antibodies that target the extracellular domain of IGF receptor I or its growth factors; d) compounds that target, reduce or inhibit the activity of members of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds that target, reduce or inhibit the activity of members of the AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of Kit/SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce or inhibit the activity of C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds that target, reduce or inhibit the activity of members of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, such as imatinib; i) compounds that target, reduce or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g., BCR-Abl kinase) and mutant variants, such as compounds that target, reduce or inhibit the activity of members of the c-Abl family and their gene fusion products, such as an N-phenyl-2-pyrimidineamine derivative such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds that target, reduce or inhibit the activity of protein kinase C (PKC) family members and the Raf family of serine/threonine kinases, MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, BTK and TEC families and/or cyclin-dependent kinase (CDK) family members, including staurosporine derivatives such as midostaurin; examples of other compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY379196; isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, reduce, or inhibit the activity of protein tyrosine kinase inhibitors, such as compounds that target, reduce, or inhibit the activity of protein tyrosine kinase inhibitors, including imatinib mesylate (Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; (+)-enantiomer of Tyrphostin B44; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin, adamantyl ester of (4-{[(2,5-dihydroxyphenyl)methyl]amino}benzoic acid; NSC 680410, adaphostin); 1) compounds that target, reduce or inhibit the activity of members of the epidermal growth factor receptor family of tyrosine kinases (EGFR1 ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and mutant variants thereof, such as compounds that target, reduce or inhibit the activity of members of the epidermal growth factor receptor family, in particular compounds, proteins or antibodies that inhibit members of the EGF receptor family of tyrosine kinases, such as the EGF receptor, ErbB2, ErbB3 and ErbB4, or bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180. trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, or E7.6.3 and 7H-pyrrolo[2,3-d]pyrimidine derivatives; m) compounds that target, reduce or inhibit c-Met receptor activity, such as compounds that target, reduce or inhibit c-Met activity, in particular compounds that inhibit the kinase activity of the c-Met receptor or antibodies that target the extracellular domain of c-Met or binding to HGF, n) compounds that target, reduce or inhibit the kinase activity of one or more members of the JAK family (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including, but not limited to, PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib and ruxolitinib; o) compounds that target, reduce or inhibit the kinase activity of PI3 kinase (PI3K), including, but not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765 and idelalisib; and; and q) compounds that target, reduce or inhibit the signaling effects of the hedgehog protein (Hh) or smooth muscle receptor (SMO) pathways, including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

[00312] As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes of the phosphatidylinositol 3-kinase family, including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors suitable for use in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[00313] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against Bruton tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[00314] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[00315] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds that have inhibitory activity against B-cell lymphoma protein 2 (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's rap-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (University of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule drug. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[00316] Other examples of BTK inhibiting compounds and conditions that can be treated with such compounds in combination with the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

[00317] Other examples of SYK inhibiting compounds and conditions that can be treated with such compounds in combination with the compounds of the present invention can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

[00318] Other examples of PI3K inhibitory compounds and conditions that can be treated with such compounds in combination with the compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.

[00319] Other examples of JAK inhibiting compounds and conditions that can be treated with such compounds in combination with compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.

[00320] Other antiangiogenic compounds include compounds whose activity is mediated by another mechanism, such as one not related to protein kinase or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[00321] Examples of proteasome inhibitors suitable for use in combination with the compounds of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[00322] Compounds that target, reduce or inhibit protein phosphatase or lipid phosphatase activity are, for example, phosphatase 1, phosphatase 2A or CDC25 inhibitors, such as okadaic acid or a derivative thereof.

[00323] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α- or δ-tocopherol, or α-γ- or δ-tocotrienol.

[00324] As used herein, the term "cyclooxygenase inhibitor" includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives thereof such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[00325] As used herein, the term "bisphosphonates" includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term "mTOR inhibitors" refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and that have antiproliferative activity, such as sirolimus (Rapamune ^® ), everolimus (Certican™), CCI-779, and ABT578.

[00326] As used herein, the term "heparanase inhibitor" refers to compounds that target, reduce, or inhibit the degradation of heparin sulfate. The term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to a lymphokine or interferons.

[00327] As used herein, the term "inhibitor of oncogenic Ras isoforms" such as H-Ras, K-Ras, or N-Ras refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras; for example, a "farnesyl transferase inhibitor" such as L-744832, DK8G557, or R115777 (Zarnestra™). As used herein, the term "telomerase inhibitor" refers to compounds that target, reduce, or inhibit telomerase activity. Compounds that target, reduce, or inhibit telomerase activity include, but are not limited to, compounds that inhibit the telomerase receptor, such as telomestatin.

[00328] As used herein, the term "methionine aminopeptidase inhibitor" refers to compounds that target, reduce, or inhibit the activity of methionine aminopeptidase. Compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[00329] As used herein, the term "proteasome inhibitor" refers to compounds that target, reduce, or inhibit the activity of the proteasome. Compounds that target, reduce, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade™) and MLN 341.

[00330] As used herein, the term "matrix metalloproteinase inhibitor" (or "MMP inhibitor") includes, but is not limited to, peptidomimetic and non-peptidomimetic collagen inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs, marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996.

[00331] As used herein, the term "compounds used to treat malignant diseases of the hematopoietic system" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce, or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c), and bisulfan; ALK inhibitors, which are compounds that target, reduce, or inhibit the activity of anaplastic lymphoma kinase, and Bcl-2 inhibitors.

[00332] Compounds that target, reduce or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are, in particular, compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.

[00333] As used herein, the term "HSP90 inhibitors" includes, but is not limited to, compounds that target, reduce, or inhibit the ATPase activity of HSP90; that participate in the degradation of HSP90-dependent proteins, target, reduce, or inhibit them via the ubiquitin-proteasome pathway. Compounds that target, reduce, or inhibit the ATPase activity of HSP90 include, but are not limited to, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin-related compounds; radicicol, and HDAC inhibitors.

[00334] As used herein, the term "antiproliferative antibodies" includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab ( ^Rituxan® ), the PR064553 antibody (anti-CD40), and 2C4. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, polyspecific antibodies obtained from at least 2 intact antibodies, and antibody fragments, provided that they exhibit the desired biological activity.

[00335] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention may be used in combination with standard therapies for leukemia, particularly in combination with therapies used to treat AML. In particular, the compounds of the present invention may be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs suitable for use in the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin, and PKC412. In some embodiments, the present invention provides a method of treating AML associated with an internal tandem duplication (ITD) and/or the D835Y mutation, comprising administering a compound of the present invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitors are selected from quizartinib (AC220), a staurosporine derivative (e.g., midostaurin or lestaurtinib), sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tosasertib, and sunitinib. In some embodiments, the FLT3 inhibitors are selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.

[00336] Other antileukemic compounds include, for example, Ara-C, a pyrimidine analog that is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analog hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Compounds that target, reduce, or inhibit histone deacetylase (HDAC) activity, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and the compounds disclosed in U.S. Patent 6,555,065, including but not limited to N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof, particularly the lactate salt. As used herein, "somatostatin receptor antagonists" refer to compounds that target, interfere with, or inhibit the somatostatin receptor, such as octreotide and SOM230. "Tumor cell-directed approaches" refer to approaches such as ionizing radiation. The term "ionizing radiation," as used above and below, means ionizing radiation that occurs in the form of either electromagnetic radiation (such as x-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation has been proposed for, without limitation, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1, pp. 248-275 (1993).

[00337] Also included are EDG binders and ribonucleotide reductase inhibitors. The term "EDG binders" as used herein refers to a class of immunosuppressants that modulate lymphocyte recycling, such as FTY720. The term "ribonucleotide reductase inhibitors" refers to pyrimidine or purine nucleoside analogs, including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (particularly in combination with ara-C against ALL), and/or pentostatin. Ribonucleotide reductase inhibitors are, in particular, hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[00338] Also included are, but are not limited to, compounds, proteins, or monoclonal antibodies against vascular endothelial growth factor (VEGF) such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies such as rhuMAb and RHUFab, a VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, anti-VEGFR-2 IgGl antibody, angiozyme (RPI 4610) and bevacizumab (Avastin™).

[00339] "Photodynamic therapy" as used herein refers to therapy that uses certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[00340] “Angiostatic steroids” as used herein refer to compounds that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, and dexamethasone.

[00341] Implants containing corticosteroids include compounds such as fluocinolone and dexamethasone.

[00342] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or other compounds or compounds with a different or unknown mechanism of action.

[00343] The compounds of the present invention are also suitable as adjunctive therapeutic compounds for use in combination with other drugs such as anti-inflammatory, bronchodilator or antihistamine drugs, in particular in the treatment of obstructive or inflammatory airway diseases such as those mentioned earlier herein, for example as substances that enhance the therapeutic activity of such drugs or as a means of reducing the required dosage or reducing the potential side effects of such drugs. A compound of the present invention may be mixed with another drug in a fixed pharmaceutical composition, or it may be administered separately, before, simultaneously or after another drug. Accordingly, the present invention includes a combination of a compound of the present invention as described herein above with an anti-inflammatory, bronchodilator, antihistamine or antitussive drug, wherein said compound of the present invention and said drug are in the same or different pharmaceutical compositions.

[00344] Suitable anti-inflammatory drugs include steroids, particularly glucocorticosteroids such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such as cilomilast (Ariflo ^® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), arophylline (Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists and beta2-adrenergic receptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol and, in particular, formoterol and its pharmaceutically acceptable salts. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi) and glycopyrrolate.

[00345] Suitable antihistamine drugs include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratadine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[00346] Other suitable combinations of the compounds of the present invention with anti-inflammatory drugs are combinations with chemokine receptor antagonists, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular CCR-5 antagonists such as the antagonists SC-351125, SCH-55700 and SCH-D from Schering-Plough and antagonists from Takeda such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzocyclohepten-8-yl]carbonyl]amino]phenyl]methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[00347] The structure of the active compounds indicated under code numbers, nonproprietary names or trade names can be found in the current edition of the standard reference "The Merck Index" or in databases such as Patents International (e.g., IMS World Publications).

[00348] The compound of the present invention can also be used in combination with known therapeutic processes, such as hormone administration or radiation. In some embodiments, the proposed compound is used as a radiosensitizer, in particular for the treatment of tumors that exhibit poor sensitivity to radiotherapy.

[00349] The compound of the present invention can be administered alone or in combination with one or more other therapeutic compounds, whereby possible combination therapy takes the form of fixed combinations, or the administration of the compound of the present invention and one or more other therapeutic compounds alternately or independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. The compound of the present invention can, in addition to or in addition, be administered, in particular for the treatment of tumors, in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgery or a combination thereof. Long-term therapy is also possible, as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are maintenance therapy after tumor regression or even chemopreventive therapy, for example in patients at risk.

[00350] These additional agents may be administered separately from the present composition containing the compound of the present invention, as part of a multiple-dose regimen. Alternatively, these agents may be part of a single dosage form, being mixed with the compound of the present invention in a single composition. When administered as part of a multiple-dose regimen, the two active agents may be administered simultaneously, sequentially, or within a time interval of each other, typically within five hours of each other.

[00351] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents of the present invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[00352] The amount of both the compound of the present invention and the additional therapeutic agent (in those compositions that contain an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated and the particular route of administration. Preferably, the compositions of the present invention should be prepared such that the dose of the compound of the present invention is from 0.01 to 100 mg/kg body weight/day.

[00353] In those compositions that contain an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention may act synergistically. Accordingly, the amount of additional therapeutic agent in such compositions will be less than that required for monotherapy using only that therapeutic agent. In such compositions, a dose of 0.01 to 1000 mcg/kg body weight/day of the additional therapeutic agent may be administered.

[00354] The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount that is typically included in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will be from about 50% to 100% of the amount that is typically present in a composition containing that agent as the sole therapeutically active agent.

[00355] The compounds of the present invention or pharmaceutical compositions thereof can also be included in compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Implantable devices coated with a compound of the present invention are another embodiment of the present invention.

EXAMPLES

[00356] As shown in the examples below, in certain illustrative embodiments, compounds were prepared according to the following general procedures. It will be appreciated that while the general procedures provided demonstrate the synthesis of certain compounds of the present invention, the following general procedures and other procedures known to those of ordinary skill in the art may be applied to all compounds and subclasses and species of each of the compounds described herein.

[00357] Example 1. Synthesis of 3-(2-Oxo-2,3-dihydro-1H-indol-1-yl)piperidine-2,6-dione, Compound 3

Scheme 1

[00358] 3-Bromopiperidine-2,6-dione. To a stirred solution of piperidine-2,6-dione (5 g, 44.20 mmol) in CHCl-3 (10 mL) was added Br-2 (2.25 mL) in one portion at room temperature under nitrogen atmosphere. The reaction mixture was tightly capped in a test tube and stirred for 4 h at 110 °C. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 50% ethyl acetate in petroleum ether, to give 3-bromopiperidine-2,6-dione as a pink solid (3.2 g, 38%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.05 (br s, 1H), 4.89 (dd, J=5.2, 3.9 Hz, 1H), 2.60 (dt, J=9.8, 4.7 Hz, 2H), 2.46 (ddd, J=9.6, 5.1, 3.9 Hz, 1H), 2.15 (dq, J=14.9, 4.9 Hz, 1H); LC/MS (ESI, m/z): [(M+1)] ⁺ =192.1, 194. 1.

[00359] 3-(2-Oxo-2,3-dihydro-1H-indol-1-yl)piperidine-2,6-dione. To a stirred solution of 2,3-dihydro-1H-indol-2-one (228 mg, 1.71 mmol) in DMFA (2 mL) was added NaH (75.3 mg, 1.88 mmol, 60% w/w, dispersed in mineral oil) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 20 min at 0 °C. To the above mixture was added dropwise a solution of 3-bromopiperidine-2,6-dione (164.4 mg, 0.86 mmol) in DMF (0.5 mL) at 0 °C. The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was quenched with AcOH (0.5 mL) and concentrated under reduced pressure. The residue was purified using prep. TLC eluted with 50% ethyl acetate in petroleum ether to give 3-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine-2,6-dione, 3, as a light yellow solid (14.2 mg, 4%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.55-10.43 (m, 1H), 7.33-7.11 (m, 1H), 7.01-6.90 (m, 2H), 6.84 (t, J=9.0 Hz, 1H), 4.09-3.94 (m, 1H), 2.67-2.59 (m, 1H), 2.47-2.36 (m, 1H), 2.02-1.72 (m, 1H), 1.62-1.35 (m, 1H); LC/MS (PER, m/z): [(M+1)] ⁺ = 245.2.

[00360] Example 2. Synthesis of 3-(2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione, 1

Scheme 2

[00361] 3-(2-Oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione. To a stirred solution of 2,3-dihydro-1,3-benzoxazol-2-one (210 mg, 1.55 mmol) in DMF (3 mL) was added NaH (68.3 mg, 1.71 mmol, 60% w/w, dispersed in mineral oil) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 20 min at 0 °C. To the above mixture was added dropwise a solution of 3-bromopiperidine-2,6-dione (149.2 mg, 0.78 mmol) in DMF (0.5 mL) at 0 °C. The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was quenched with AcOH (0.2 mL) and concentrated under reduced pressure. The residue was purified using prep. TLC eluted with 50% ethyl acetate in petroleum ether to give 3-(2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)piperidine-2,6-dione, 1, as a light yellow solid (30.2 mg, 8%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.23 (br s, 1H), 7.42-7.38 (m, 1H), 7.32-7.14 (m, 3H), 5.39 (dd, J=12.8, 5.2 Hz, 1H), 2.98-2.80 (m, 1H), 2.78-2.60 (m, 2H), 2.24-2.11 (m, 1H); LC/MS (ESI, m/z): [(M+1)] ⁺ =247.1.

[00362] Example 3 Synthesis of 3-(3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidin-2,6-dione, 2

S Scheme

[00363] 3-(3-Methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione. To a stirred solution of 1-methyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (217 mg, 1.46 mmol) in DMF (2 mL) was added NaH (64.5 mg, 1.61 mmol, 60% w/w, dispersed in mineral oil) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 20 min at 0 °C. To the above mixture was added dropwise a solution of 3-bromopiperidine-2,6-dione (140.6 mg, 0.73 mmol) in DMF (0.5 mL) at 0 °C. The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was quenched with AcOH (0.5 mL) and concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: XBridge Shield RP18 EVO Column, 5 μm, 19×150 mm; Mobile phase A: water (plus 0.05% FA), Mobile phase B: ACN; Flow rate: 20 mL/min; Gradient: 10% B to 35% B over 7 min; Detector: UV 220 nm; Rt: 6.30 min. The desired fractions were collected and concentrated under reduced pressure. The residue was lyophilized to give 3-(3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione, 2, as a white solid (30.4 mg, 21%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.03 (br s, 1H), 7.13-6.97 (m, 4H), 5.30 (dd, J=12.7, 5.4 Hz, 1H), 3.35 (s, 3H), 2.90-2.78 (m, 1H), 2.73-2.49 (m, 2H), 2.03-1.90 (m, 1H); LC/MS (ESI, m/z): [(M+1)] ⁺ =260.2.

[00364] Example 4 Synthesis of 3-(2-oxo-4-phenylpyrrolidin-1-yl)piperidin-2,6-dione, 29

S Scheme 4

[00365] 3-(2-Oxo-4-phenylpyrrolidin-1-yl)piperidine-2,6-dione. To a stirred solution of 4-phenylpyrrolidin-2-one (211 mg, 1.31 mmol) in DMF (2 mL) was added NaH (57.6 mg, 1.44 mmol, 60% w/w, dispersed in mineral oil) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 20 min at 0 °C. To the above mixture was added dropwise a solution of 3-bromopiperidine-2,6-dione (125.7 mg, 0.65 mmol) in DMF (0.5 mL) at 0 °C. The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was quenched with AcOH (0.5 mL) and concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: XBridge Shield RP18 EVO Column, 5 μm, 19×150 mm; Mobile phase A: water (plus 0.05% FA), Mobile phase B: ACN; Flow rate: 20 mL/min; Gradient: 15% B to 45% B over 7 min; Detector: UV 220 nm; Rt: 5.72 min). The desired fractions were collected and concentrated under reduced pressure. The residue was lyophilized to give 3-(2-oxo-4-phenylpyrrolidin-1-yl)piperidine-2,6-dione, 29, as a white solid (29.4 mg, 9%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.94 (br s, 1H), 7.40-7.31 (m, 4H), 7.27 (dt, J=5.9, 2.8 Hz, 1H), 4.93-4.86 (m, 1H), 3.79-3.56 (m, 2H), 3.33-3.15 (m, 1H), 2.90-2.69 (m, 2H), 2.60-2.50 (m, 1H), 2.48-2.36 (m, 1H), 2.35-2.16 (m, 1H), 1.92-1.80 (m, 1H); LC/MS (ESI, m/z): [(M+1)] ⁺ =273.2.

[00366] Example 5. Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Analysis

[00367] Equal volumes of His-tagged CRBN-DDB1 complex (56 nM) were mixed with Eu cryptate-labeled Anti-6HIS monoclonal antibody (50-fold dilution of commercial stock solution, Vender: Cisbio, Cat. No. 61HI2KLA) in a final buffer containing 20 mM HEPES pH 7.0, 150 mM NaCl, 0.005% Tween-20. The resulting solution was then mixed with Cy5-labeled thalidomide (final concentration 8 nM) and compounds at various concentrations (serial 3-fold dilution with a maximum concentration of 200 μM). The mixture was incubated at room temperature for 1 hour. FRET signals were determined on an EnVision plate reader (Perkin Elmer) with excitation at 340 nm and emission recording at 615 nm as a no-FRET control and 665 nm for FRET signals with a 60 μs delay. FRET efficiency was calculated as the ratio of fluorescence signals at 665 nm/615 nm. Quantitative losses in FRET efficiency as a function of compound concentrations were fitted to a four-parameter logistic function using GraphPad Prism 7.0, and IC50 values were determined for each compound.

[00368] Table 2 presents the results for selected compounds in the time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Compound numbers correspond to the compound numbers in the Examples. Compounds with activity designated "A" provided an _IC50 of <1 μM; compounds with activity designated "B" provided an _IC50 of 1-10 μM; compounds with activity designated "C" provided an _IC50 of 10-100 μM, and compounds with activity designated "D" provided an _IC50 of >100 μM. For comparison, known CRBN binders showed the following IC ₅₀ values in the TR-FRET assay: thalidomide (IC ₅₀ = 2.9 μM), lenalidomide (IC ₅₀ = 1.17 μM), and pomalidomide (IC-50 = 1.28 μM).

[00369]

[00370] Example 6. Analysis by fluorescence polarization (FP) method

[00371] Unlabeled CRBN-DDB1 complex (final concentration 50 nM) was mixed with Cy5-labeled thalidomide (final concentration 20 nM) and various concentrations of compounds (serial 3-fold dilution with the highest concentration of 200 μM). The final solution contained 50 mM HEPES, 200 mM NaCl and 2 mM DTT, pH 7.5. The mixtures were incubated at room temperature for 10 min. FP signals were recorded on an EnVisionate plate reader (Perkin Elmer) with the following settings: excitation light (%): 100; measurement height: 12; G-factor: 1; detector gain 1: 500; detector gain 2: 500; Number of flashes: 100. Dose-dependent decreases in FP signals were fitted with a four-parameter logistic function using GraphPad Prism 7.0 and IC ₅₀ values were determined for each compound.

[00372] Table 3 presents the results for selected compounds in the fluorescence polarization (FP) assay. Compound numbers correspond to the compound numbers in the Examples. Compounds with activity designated "A" provided _IC50s of <1 μM; compounds with activity designated "B" provided _IC50s of 1-10 μM; compounds with activity designated "C" provided _IC50s of 10-100 μM; and compounds with activity designated "D" provided _IC50s of >100 μM. For comparison, known CRBN binders demonstrated the following _IC50s in the FP assay: thalidomide ( _IC50 of 2.4 μM) and pomalidomide ( _IC50 of 1.15 μM).

[00373]

[00374] Example 7. Synthesis of 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propoxy)ethoxy)ethyl)acetamide (I-35)

[00375] 5-Bromo-N-methyl-2-nitroaniline (7.2)

[00376] 4-Bromo-2-fluoro-1-nitrobenzene (23 g, 105 mmol) was dissolved in EtOH (20 mL), MeNH ₂ (250 mL, 33% in EtOH) was added and the mixture was stirred at rt overnight. When LCMS showed that the starting material was consumed, the solvent was evaporated and the resulting crude material was dissolved in EtOAc (300 mL) and washed with water (200 mL x 2) and brine (200 mL), dried over anhydrous Na ₂ SO ₄ . The solid was filtered and the filtrate was concentrated to give the crude product 5-bromo-N-methyl-2-nitroaniline as a yellow solid (23 g, 95% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, J=9.2 Hz, 2H), 7.01 (s, 1H), 6.76 (d, J=9.2 Hz, 1H), 3.02 (s, 3H). LC-MS (ESI ⁺ ): m/z 232.1 (M+H) ⁺ .

[00377] 5-Bromo-N1-methylbenzene-1,2-diamine (7.3)

[00378] 5-Bromo-N-methyl-2-nitroaniline (23.0 g, 0.100 mol) was dissolved in AcOH (230 mL), then EtOAc (230 mL) and H ₂ O (50 mL) were added. The mixture was heated to 50 °C, then Fe powder (20 g, 0.36 mol) was added and the mixture was heated to 80 °C for about 30 min. TLC showed that the starting material was consumed, the mixture was cooled to rt. EtOAc (300 mL) and H ₂ O (300 mL) were added, the organic phase was washed with H ₂ O (500 mL x 2) and brine (300 mL), the organic phase was dried over anhydrous Na ₂ SO ₄ . The solid was filtered and the filtrate was concentrated, the residue was purified by silica gel column chromatography (EA:PE = 1:2) to give the title product 5-bromo-N1-methylbenzene-1,2-diamine (14 g, yield 70%). LC-MS (ESI ⁺ ): m/z 202.1 (M+H) ⁺ .

[00379] 6-Bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (7.4)

[00380] 5-Bromo-N1-methylbenzene-1,2-diamine (14 g, 69.3 mmol) was dissolved in THF (200 mL), CDI (13.4 g, 83.2 mmol) was added. The mixture was heated under reflux for about 2 h under N ₂ atmosphere. When LCMS showed that the starting material was consumed, the solvent was evaporated and the resulting crude material was purified by silica gel column chromatography (EA:PE = 1:2) to give the title product 6-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (10 g, yield 63%). 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.0 (s, 1H), 7.33 (s, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 3.26 (s, 3H). LC-MS (ESI ⁺ ): m/z 228.1 (M+H) ⁺ .

[00381] 3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (7.5)

[00382] To a solution of 6-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (5.0 g, 22.1 mmol) in THF was added t-BuOK (2.48 g, 22.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min, then 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (6.9 g, 22.1 mmol) was added and the reaction mixture was stirred at room temperature overnight. Then, the mixture was concentrated and the residue was purified by silica gel column chromatography (EtOAc:DCM = 1:1); obtaining the title product 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (3.7 g, yield 37%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.48-7.47 (d, J=2.0 Hz, 1H), 7.21-7.16 (m, 3H), 7.02-6.99 (d, J=8.4 Hz, 1H), 6.87-6.84 (m, 2H), 5.55-5.51 (dd, J ₁ =6.4 Hz, J ₂ =14.2 Hz, 1H), 4.84-4.73 (q, J=14.4 Hz, 2H), 3.72 (s, 3H), 3.34 (s, 3H), 3.08-3.00 (m, 1H), 2.84-2.67 (m, 2H), 2.09-2.04 (m, 1H). LC-MS (ESI ⁺ ): m/z 459.4 (M+H) ⁺ .

[00383] 3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (7,6)

[00384] To a solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (1.5 g, 3.28 mmol) in toluene (30 mL) was added methanesulfonic acid (10 mL). The reaction mixture was heated to 110 °C for about 2 h under N ₂ . The reaction mixture was cooled to room temperature, then the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (20 mL) and washed with H ₂ O (10 mL) and brine (10 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ . The solid was filtered and the filtrate was concentrated, the residue was purified by silica gel column chromatography (EtOAc:DCM = 1:1) to give the title product 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.8 g, yield 72%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.22 (dd, J=10.4, 2.0 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 5.41-5.36 (m, 1H), 3.34 (s, 3H), 2.92-2.85 (m, 1H), 2.74-2.60 (m, 2H), 2.05-1.99 (m, 1H). LC-MS (ESI ⁺ ): m/z 339.2 (M+H) ⁺ .

[00385] tert-Butyl (2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate (7.9)

[00386] A mixture of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (200 mg, 0.592 mmol), tert-butyl (2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)carbamate (430 mg, 1.78 mmol), Pd( _PPh3 ) _2Cl2 (34 mg, 0.0474 mmol), CuI (18 _mg , 0.0947 mmol) and DMF (15 mL) was purged with _N2 for 10 min. TEA (598 mg, 5.92 mmol) was then added to the mixture under _N2 . The mixture was heated to 110 °C under N ₂ atmosphere and stirred for 3 h. To the mixture was added H ₂ O (50 mL) and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ . The solid was filtered and the filtrate was concentrated, the residue was purified by silica gel column chromatography (DCM/EA = 1/1 + 1% THF) to give tert-butyl (2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate (100 mg, 34% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (s, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.13 (s, 1H), 6.75 (d, J=8.2 Hz, 1H), 5.20 (dd, J=12.6, 5.4 Hz, 1H), 4.44 (s, 2H), 3.77-3.75 (m, 2H), 3.69-3.67 (m, 2H), 3.57 (t, J=5.2 Hz, 2H), 3.43 (s, 3H), 3.34 (d, J=5.2 Hz, 2H), 2.88-2.70 (m, 2H), 2.27-2.22 (m, 2H), 1.44 (s, 9H). LC-MS (ESI ⁺ ): m/z 401.1 (M-Boc+H) ⁺

[00387] tert-Butyl (2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propoxy)ethoxy)ethyl)carbamate (7,10)

[00388] A solution of tert-butyl (2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate (40 mg, 0.0800 mmol), Pd/C (10%, 4 mg) in EtOAc (10 mL) was stirred overnight at room temperature under H ₂ atmosphere. The mixture was filtered, concentrated and purified by prep-HPLC to give tert-butyl (2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propoxy)ethoxy)ethyl)carbamate (10 mg, 25% yield) as a white solid.

[00389] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.88 (s, 1H), 6, 72 (d, J=8.0 Hz, 1H), 5.20 (dd, J=12.6, 5.3 Hz, 1H), 3.63-3.55 (m, 6H), 3.49 (t, J=6.4 Hz, 2H), 3.43 (s, 3H), 3.33 (d, J=5 ,3 Hz, 2H), 3.00-2.78 (m, 4H), 2.27-2.22 (m, 2H), 2.03-1.98 (m, 2H), 1.44 (s, 9H). LC-MS (ESI ⁺ ): m/z 405.2 (M-Boc+H) ⁺

[00390] 3-(5-(3-(2-(2-Aminoethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (7.11)

[00391] To a solution of tert-butyl (2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propoxy)ethoxy)ethyl)carbamate (100 mg, 0.248 mmol) in DCM (10 mL) was added TFA (5 mL). The mixture was stirred for 2 h at room temperature. The mixture was concentrated to give the TFA salt of 3-(5-(3-(2-(2-aminoethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (100 mg, 100% yield) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 7.77 (broad s, 3H), 7.03-7.00 (m, 2H), 6.88-6.86 (m, 1H), 5.35 (dd, J=12.8, 5.4 Hz, 1H), 3.61-3.56 (m, 4H), 3.54-3.52 (m, 2H), 3.41 (t, J=6.5 Hz, 2H), 3.33 (s, 3H), 3.00-2.86 (m, 3H), 2.74-2.60 (m, 4H), 2.02-1.97 (m, 1H), 1.86-1.79 (m, 2H). LC-MS (ESI ⁺ ): m/z 405.1 (M+H) ⁺

[00392] 2-((S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propoxy)ethoxy)ethyl)acetamide (I-35)

[00393] A mixture of TFA salt and 3-(5-(3-(2-(2-aminoethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (20 mg, 0.0495 mmol), HATU (28 mg, 0.0743 mmol), (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (22 mg, 0.0545 mmol), DIPEA (19 mg, 0.149 mmol) in DCM (15 mL) was stirred at room temperature for 1 Then _H2O (10 mL) was added to the mixture and the mixture was extracted with DCM (10 mL x ₃ ). The organic layers were dried over anhydrous _Na2SO4 . The solid was filtered and the filtrate was concentrated. Then, the obtained residue was purified by silica gel column chromatography (DCM/MeOH = 10/1) and prep-HPLC to give 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propoxy)ethoxy)ethyl)acetamide (10 mg, yield 26%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 8.28 (t, J=5.7 Hz, 1H), 7.49-7.41 (dd, J=24.0, 8.6 Hz, 4H), 7.03 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.86 (d, J=7.9 Hz, 1H), 5.33 (dd, J=12.6, 5.2 Hz, 1H), 4.50 (dd, J=8.0, 6.0 Hz, 1H), 3.56-3.46 (m, 6H), 3.40 (t, J=6.4 Hz, 2H), 3.30 (s, 3H), 3.30-3.17 (m, 4H), 2.90-2.85 (m, 1H), 2.71-2.63 (m, 4H), 2.59 (s, 3H), 2.40 (s, 3H), 2.00-1.98 (m, 1H), 1.85-1.78 (m, 2H), 1.61 (s, 3H). LC-MS (ESI ⁺ ): m/z 787.2 (M+H) ⁺ .

[00394] Example 8. 2-((S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propoxy)ethoxy)ethyl)acetamide (I-36)

[00395] A mixture of TFA salt and 3-(4-(3-(2-(2-aminoethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (20 mg, 0.0495 mmol), HATU (28 mg, 0.0743 mmol), (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (22 mg, 0.0545 mmol), DIPEA (19 mg, 0.149 mmol) and DCM (15 mL) was stirred for 1 h at room temperature. temperature. Then H ₂ O (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL x 3). The organic layers were dried over anhydrous Na ₂ SO ₄ . The solid was filtered and the filtrate was concentrated. Then, the obtained residue was purified by silica gel column chromatography (DCM/MeOH = 10/1) and prep-HPLC to give 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propoxy)ethoxy)ethyl)acetamide (8 mg, yield 21%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 8.28 (t, J=5.4 Hz, 1H), 7.48 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.7 Hz, 2H), 6.96-6.92 (m, 2H), 6.87-6.85 (m, 1H), 5.36 (dd, J=12.5, 5.3 Hz, 1H), 4.50 (dd, J=8.0, 6.1 Hz, 1H), 3.57-3.54 (m, 7H), 3.50-3.45 (m, 4H), 3.29-3.17 (m, 4H), 2.96-2.84 (m, 3H), 2.71-2.63 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 2.00-1.97 (m, 1H), 1.96-1.79 (m, 2H), 1.61 (s, 3H). LC-MS (ESI ⁺ ): m/z 787.2 (M+H) ⁺ .

[00396] Example 9: Synthesis 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1 ,4]diazepin-6-yl)-N-(2-(2-( 2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethoxy)ethoxy)ethyl)acetamide (I-38)

[00397] tert-Butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (9,2)

[00398] To a stirred solution of 2-(2-(2-aminoethoxy)ethoxy)ethan-1-ol (1.0 g, 6.72 mmol) in DCM (25 mL) was added (Boc) _2O (1.92 g, 13.5 mmol), TEA (1.36 g, 13.5 mmol) at rt. The reaction mixture was stirred at rt for 2 h. At this time, TLC (10% MeOH/90% DCM, silica gel plate) showed complete consumption of the starting material. The mixture was concentrated in vacuo to give tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (1.7 g, crude) as a yellow oil, the crude product was used directly without further purification.

[00399] 2,2-Dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl-4-methylbenzenesulfonate (9.3)

[00400] To a stirred solution of tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (1.7 g, 6.82 mmol) in DCM (10 mL) was added TEA (1.7 g, 16.83 mmol) at rt. To the above reaction mixture was added TsCl (1.9 g, 9.97 mmol) in DCM (5 mL) dropwise at 0 °C. After addition, the reaction mixture was stirred at rt overnight. TLC (10% MeOH/90% DCM, silica gel plate) showed that the starting material was consumed. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 5% - 80%) to give 2,2-dimethyl 4-oxo-3,8,11-trioxa-5-azatridecan-13-yl-4-methylbenzenesulfonate (2.4 g, 87.3%) as a yellow oil. LC-MS (ESI ⁺ ): m/z 404.2 (M+H) ⁺ .

[00401] (2-Nitrophenyl)glutamine (9.5)

[00402] To a stirred solution of 1-fluoro-2-nitrobenzene (10 g, 0.069 mol) in EtOH (150 mL) was added glutamine (14.7 g, 0.104 mol) _{, K2CO3} (33.4 g, 0.242 mol) at rt. The reaction mixture was heated at 95 °C overnight. The reaction mixture was cooled to rt. The pH of the reaction mixture was adjusted to = 3~4. Then, a yellow solid was formed. The solid was collected by filtration, dried under vacuum to give the title product (2-nitrophenyl)glutamine (4.5 g, 25% yield) as a yellow solid.

[00403] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.30 (s, 1H), 8.34 (d, J=7.4 Hz, 1H), 8.10 (dd, J=8 ,6, 1.5 Hz, 1H), 7.65-7.46 (m, 1H), 7.33 (s, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.86-6.67 (m, 2H), 4.49 (dd, J=12.7, 5.7 Hz, 1H ), 2.26-2.01 (m, 4H).

[00404] tert-Butyl-(2-nitrophenyl)glutamate (9.6)

[00405] To a stirred solution of (2-nitrophenyl)glutamine (2.72 g, 10.2 mmol) in DMF (100 mL) was added 2-bromo-2-methylpropane (41.87 g, 305.6 mol), benzyltriethylammonium (3.49 g, 15.3 mol), K ₂ CO ₃ (28.2 mg, 204 mmol) at rt in a tightly capped glass tube. The reaction mixture was then heated to 52 °C for 12 h. TLC (50% EtOAc/50% DCM, silica gel plate) showed that the starting material was consumed. H ₂ O (500 mL) was added, the mixture was cooled to rt and extracted with EtOAc (250 mL x 3). The combined organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography (DCM/EtOAc = 5% - 80%) to give the desired compound tert-butyl (2-nitrophenyl) glutaminate (1.95 g, 59.1% yield) as a yellow solid. LCMS (ESI ⁺ ): m/z 324.1 (M+H) ⁺ .

[00406] tert-Butyl-(2-aminophenyl)glutamate (9.7)

[00407] To a stirred solution of tert-butyl (2-nitrophenyl)glutaminate (1.89 g, 5.85 mmol) in EtOAc (40 mL) was added Pd/C (200 mg) at rt. The reaction mixture was degassed and purged with hydrogen several times. The reaction mixture was then stirred at rt for 1 h under H ₂ atmosphere. TLC (50% EtOAc/50% DCM, silica gel plate) showed that the starting material was consumed. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/EtOAc = 5% - 80%) to give the desired compound tert-butyl (2-aminophenyl)glutaminate (1.8 g, 100%) as a yellow oil. LC-MS (ESI ⁺ ): m/z 294.2 (M+H) ⁺ .

[00408] tert-Butyl 5-amino-5-oxo-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pentanoate (9.8)

[00409] To a stirred solution of tert-butyl (2-aminophenyl) glutaminate (1.7 g, 5.8 mmol) in THF (60 mL) was added CDI (1.88 g, 11.6 mol) at rt. The reaction mixture was stirred at rt for 12 h. TLC (50% EtOAc/50% DCM, silica gel plate) showed that the starting material was consumed. _H2O (50 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine, dried and concentrated in vacuo. The mixture was purified by column chromatography (DCM/EtOAc = 5% - 80%) to give the desired compound tert-butyl 5-amino-5-oxo-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pentanoate (1.31 g, yield 70.8%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.92 (s, 1H), 7.22 (s, 1H), 7.06-6.94 (m, 4H), 6.73 (s, 1H), 4.94 (dd, J=10.8, 4.9 Hz, 1H), 2.40-2.30 (m, 1H), 2.24 (ddd, J=19.5, 9.0, 5.3 Hz, 1H), 2.03 (td, J=8.7, 4.5 Hz, 1H), 1.90 (ddd, J=15.1, 9.5, 5.4 Hz, 1H), 1.35 (s, 9H). LC-MS (ESI ⁺ ): m/z 320.1 (M+H) ⁺ .

[00410] tert-Butyl 5-amino-2-(3-(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxopentanoate (9.9)

[00411] To a stirred solution of tert-butyl 5-amino-5-oxo-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pentanoate (300 mg, 0.940 mmol) in DMFA (30 mL) was added 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl-4-methylbenzenesulfonate (9.3, 530.6 mg, 1.32 mmol), K ₂ CO ₃ (181.7 mg, 1.32 mmol) at rt. The reaction mixture was heated to 69 °C for 12 h. TLC (10% MeOH/90% DCM, silica gel plate) showed that the starting material was consumed. H ₂ O (50 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried and concentrated in vacuo. The mixture was purified by reverse phase column chromatography (MeOH/ _H2O = 5% - 80%) to give tert-butyl 5-amino-2-(3-(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxopentanoate (298 mg, 57.6%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.25 (d, J=7.6 Hz, 1H), 7.21 (s, 1H), 7.05 (qd, J=9.1, 4.4 Hz, 3H), 6.73 (s, 2H), 5.00 (dd, J=10.6, 5.0 Hz, 1H), 4.00 (t, J=5.6 Hz, 2H), 3.67 (t, J=5.6 Hz, 2H), 3.51 (dd, J=5.8, 3.6 Hz, 2H), 3.43 (dd, J=5.7, 3.6 Hz, 2H), 3.34 (s, 1H), 3.30 (d, J=5.2 Hz, 1H), 3.02 (dd, J=11.9, 6.0 Hz, 2H), 2.42-2.18 (m, 2H), 2.03 (ddd, J=15.8, 11.3, 4.4 Hz, 1H), 1.91 (ddd, J=15.2, 9.4, 5.5 Hz, 1H), 1.47 (s, 9H), 1.23 (s, 9H). LC-MS (ESI ⁺ ): m/z 551.3 (M+H) ⁺ .

[00412] 5-Amino-2-(3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) -5-oxopentanoic acid (9,10)

[00413] To a stirred solution of tert-butyl 5-amino-2-(3-(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxopentanoate (395 mg, 0.536 mmol) in DCM (5 mL) was added TFA (5 mL) at rt. The reaction mixture was stirred at rt for 1 h. TLC (10% MeOH/90% DCM, silica gel plate) showed that the starting material was consumed. The mixture was concentrated in vacuo. The mixture was purified by reversed-phase HPLC (MeOH/ _H2O = 5% - 80%) to give 5-amino-2-(3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxopentanoic acid (215.1 mg, 89.2%) as a colorless oil. LC-MS (ESI ⁺ ): m/z 396.2 (M+H) ⁺ .

[00414] 5-Amino-2-(3-(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-1-yl)-5-oxopentanoic acid (9.11)

[00415] To a stirred solution of 5-amino-2-(3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxopentanoic acid (650 mg, 1.646 mmol) in DCM (20 mL) was added (Boc) _2O (533.2 mg, 2.468 mmol), TEA (249.3 mg, 2.468 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. TLC (10% MeOH/90% DCM, silica gel plate) showed that the starting material was consumed. The mixture was concentrated in vacuo. The mixture was purified by reversed-phase HPLC (MeOH/ _H2O = 5% - 80%) to give 5-amino-2-(3-(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxopentanoic acid (435.1 mg, 53.5%) as a colorless oil. LC-MS (ESI ⁺ ): m/z 495.2 (M+H) ⁺ .

[00416] tert-Butyl-(2-(2-(2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1 -yl)ethoxy)ethoxy)ethyl)carbamate (9.12)

[00417] To a stirred solution of 5-amino-2-(3-(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxopentanoic acid (500 mg, 1.01 mmol) in dioxane (10 mL) were added CDI (245.9 mg, 1.518 mol) and DMAP (2 mg, 0.016 mol) at rt under nitrogen atmosphere. The reaction mixture was then heated at 100 °C for 5 h. At the end of this time, TLC (10% MeOH/90% DCM, silica gel plate) showed complete consumption of the starting material. The mixture was concentrated in vacuo. The mixture was purified by reverse phase column chromatography ( _CH3CN / _H2O = 5%-80%) to give tert-butyl (2-(2-(2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethoxy)ethoxy)ethyl)carbamate (297.1 mg, 61.7%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 7.26 (d, J=7.3 Hz, 1H), 7.06 (ddt, J=15.3, 7.5, 7.0 Hz, 3H), 6.72 (s, 1H), 5.37 (dd, J=12.7, 5.3 Hz, 1H), 4.00 (t, J=5.6 Hz, 2H), 3.68 (t, J=5.6 Hz, 2H), 3.52 (dd, J=5.8, 3.5 Hz, 2H), 3.44 (dd, J=5.7, 3.6 Hz, 2H), 3.35-3.26 (m, 2H), 3.06-2.99 (m, 2H), 2.97-2.85 (m, 1H), 2.78-2.58 (m, 2H), 2.01 (dd, J=11.3, 6.1 Hz, 1H), 1.36 (s, 9H). LC-MS (ESI ⁺ ): m/z 477.2 (M+H) ⁺ .

[00418] 3-(3-(2-(2-(2-Aminoethoxy)ethoxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2, 6-dione (9.13)

[00419] To a stirred solution of tert-butyl (2-(2-(2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethoxy)ethoxy)ethyl)carbamate (330 mg, 0.693 mmol) in DCM (5 mL) was added TFA (5 mL) at rt. The reaction mixture was stirred at rt for 1 h. At this time, TLC (10% MeOH/90% DCM, silica gel plate) showed complete consumption of starting material. The mixture was concentrated in vacuo. The residue was dissolved in deionized water and cooled to 0 °C. The mixture was freeze-dried to give 3-(3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (305.1 mg, 89.8%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 7.76 (s, 3H), 7.34-7.22 (m, 1H), 7.18-6.97 (m, 3H), 5.38 (dd, J=12.6, 5.4 Hz, 1H), 4.02 (t, J=5.5 Hz, 2H), 3.70 (t, J=5.5 Hz, 2H), 3.64-3.46 (m, 6H), 2.91 (tt, J=11.3, 5.8 Hz, 3H), 2.71 (ddd, J=36.9, 22.7, 11.0 Hz, 2H), 2.02 (dd, J=8.8, 3.5 Hz, 1H). LC-MS (ESI ⁺ ): m/z 377.1 (M+H) ⁺ .

[00420] 2-((S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1 ,4]diazepin-6-yl)-N-(2-(2- (2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethoxy)ethoxy)ethyl)acetamide (I-38)

[00421] To a stirred solution of 3-(3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (38.5 mg, 0.0786 mol) in DCM (5 mL) were added (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (40.8 mg, 0.102 mol), HATU (38.8 mg, 0.102 mol) and DIPEA (13.2 mg, 0.102 mmol) at rt. The reaction mixture was stirred at rt for 3 h. TLC (10% MeOH/90% DCM, silica gel plate) showed that the starting material was consumed. The mixture was concentrated in vacuo. H ₂ O (5 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried and concentrated in vacuo. The mixture was purified by reverse phase HPLC (MeOH/ _H2O = 5% - 80%) to give 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(2-(2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethoxy)ethoxy)ethyl)acetamide (35.7 mg, 59.9%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 8.24 (t, J=5.6 Hz, 1H), 7.48 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H), 7.25 (d, J=7.3 Hz, 1H), 7.15-6.97 (m, 3H), 5.37 (dd, J=12.9, 5.5 Hz, 1H), 4.51 (t, J=7.0 Hz, 1H), 4.00 (t, J=5.6 Hz, 2H), 3.69 (t, J=5.6 Hz, 2H), 3.59-3.52 (m, 2H), 3.52-3.45 (m, 2H), 3.40 (t, J=5.9 Hz, 2H), 3.32-3.13 (m, 4H), 2.96-2.81 (m, 1H), 2.78-2.62 (m, 2H), 2.59 (s, 3H), 2.41 (s, 3H), 2.06-1.97 (m, 1H), 1.61(s, 3H). LC-MS (ESI ⁺ ): m/z 759.1 (M+H) ⁺ .

[00422] Example 10. 2-((S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1 ,4]diazepin-6-yl)-N-(2-(2-(2-(2 -(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethoxy)ethoxy)ethoxy)ethyl)acetamide (I-37)

[00423] I-37 was prepared according to Example 9, replacing the starting material 9.1 with 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethan-1-ol. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 8.26 (t, J=5.6 Hz, 1H), 7.48 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H), 7.30-7.21 (m, 1H), 7.13-6.97 (m, 3H), 5.37 (dd, J=12.8, 5.4 Hz, 1H), 4.51 (dd, J=7.9, 6.2 Hz, 1H), 3.99 (t, J=5.6 Hz, 2H), 3.68 (t, J=5.5 Hz, 2H), 3.56-3.50 (m, 2H), 3.50-3.40 (m, 8H), 3.33-3.16 (m, 4H), 2.96-2.85 (m, 1H), 2.79-2.63 (m, 2H), 2.59 (s, 3H), 2.41 (s, 3H), 2.05-1.98 (m, 1H), 1.62 (s, 3H). LC-MS (ESI ⁺ ): m/z 803.3 (M+H) ⁺ .

[00424] Example 11. Degradation of BRD4 in NAMALWA cells

[00425] Materials and cell lines

[00426] Cell information: NAMALWA cells were cultured in RPMI-1640 containing 10% fetal bovine serum (FBS), 2 mM L-glutamine. Cell lysis buffer: protease/phosphatase inhibitor cocktail buffer. Primary antibodies: BRD4, CST, #13440S (1:1,000) and monoclonal mouse beta-actin antibody, Sigma, A5441 (1:10,000). Secondary antibodies: goat anti-mouse (700) Licor, #926-68070 (1:10,000) and goat anti-rabbit (800) Licor #926-32211 (1:10,000).

[00427] Western Blot Protocol

• 2.5E06 NAMALWA cells, 0.9 ml of the suspension of these cells were seeded into each well of a 12-well plate.

• Dilutions of compounds were prepared in DMSO and 0.1 ml was added to the assay plate to final concentrations of 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM, 0.0003 μM, DMSO (negative control) and incubated for 2 h, n=2.

• Cells were centrifuged, cell pellets were washed with cold Dulbecco's phosphate-buffered saline (DPBS) and lysed in 30 µl radioimmune precipitation assay (RIPA) buffer on ice for 30 min without sonication.

• After centrifugation at 14,000 rpm for 10 min, the supernatant was collected and diluted 1/5 to determine the protein concentration (cell experiment) using the bicinchoninic acid method.

• Samples were supplemented with 3X loading buffer and incubated in boiling water for 5 min.

• Samples and protein marker were loaded onto lanes of a 10% Midi gel (140 V, 5.5-6 h) and then semi-dry transferred (25 V, 2.5 A, 13 min) using the Trans-blot Turbo system.

• Membranes were blocked with Odyssey blocking buffer for 1 h at room temperature.

• Membranes were incubated with anti-IRAK4 Abs and anti-beta-actin Abs overnight.

• Secondary goat anti-rabbit 800 and goat anti-mouse 700 antibodies were diluted 1:10,000 with Odyssey buffer containing 0.1% Tween 20. The membranes were incubated for 1 h at room temperature.

• Membranes were scanned using the Odyssey imaging system.

[00428] Table 4 shows the % degradation of BRD4 induced by selected compounds in NAMALWA cells using metobome Western blot analysis. The assays were performed at 8 different inhibitor concentrations according to the protocol: 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM, and 0.0003 μM, with neat DMSO as a negative control. Compound numbers correspond to the compound numbers in Table 1 and the Examples. Compounds with inhibitory activity designated "A" degraded more than 80 percent of the protein; compounds with inhibitory activity designated "B" degraded 60-80 percent of the protein; Compounds with inhibitory activity designated as "C" provided degradation of 40-60 percent of the protein; compounds with inhibitory activity designated as "D" provided degradation of less than 40 percent of the protein.

[00429]

[00430] Although a number of embodiments of the present invention have been described herein, it will be apparent that the foregoing basic examples may be modified to provide other embodiments that utilize the compounds and methods of the present invention. It will therefore be apparent that the scope of the present invention is to be determined by the appended claims rather than by the specific embodiments that are presented by way of example.

Claims (21)

1. Compound of formula I or a pharmaceutically acceptable salt thereof, wherein X ¹ is a divalent moiety selected from -C(O)-; R ¹ is hydrogen; each R ² is independently hydrogen or -R ⁶ ; ring A is , wherein ring B is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms; each R ⁴ is independently hydrogen or -R ⁶ ; each R ⁶ is C _1-6 alkyl; L is a divalent saturated linear C _1-20 hydrocarbon chain where 0-6 methylene units of L are independently replaced by -O- or -NR-; TBM is a target-binding fragment, where the target-binding fragment is a BRD4-binding fragment, where the BRD4-binding fragment is ; m is 0, 1, 2, 3 or 4; And each R independently represents hydrogen. 2. The compound according to claim 1, wherein ring B is phenyl. 3. The compound according to claim 1, wherein R ⁴ is hydrogen. 4. The compound according to claim 1, wherein said compound is selected from Connection number Structure I-9 I-10 I-35 I-36 I-37 I-38 or their pharmaceutically acceptable salts. 5. A pharmaceutical composition for treating a disorder, disease or condition mediated by BRD4, comprising a compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. 6. A method for destroying a target protein in a biological sample, comprising contacting said sample with a compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein said target protein is BRD4.