MDM2 degraders and their uses

Abstract

The present invention relates to compounds and methods useful for modulating mouse double minute 2 homolog ("MDM2") protein via ubiquitination and / or degradation by compounds according to the present invention. This application relates to novel bifunctional compounds that function to recruit MDM2 protein to E3 ubiquitin ligases for degradation, and methods for their preparation and use. In particular, the disclosure provides bifunctional compounds that find utility as modulators of targeted ubiquitination of MDM2, which are then degraded and / or otherwise inhibited by the bifunctional compounds described herein.

Description

[Technical Field]

[0001] Citation of Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 123,315 (filed December 9, 2020), and U.S. Provisional Application No. 62 / 991,763 (filed March 19, 2020), the contents of each of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention relates to compounds and methods useful for modulating mouse double minute 2 homolog ("MDM2") protein by ubiquitination and / or degradation by compounds according to the invention. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, and methods of using the compositions in the treatment of various disorders. [Background technology]

[0003] Background of the Invention 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 numerous cellular processes, and when deficient or imbalanced, it leads to the pathogenesis of various diseases. Covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0004] There are over 600 E3 ubiquitin ligases that facilitate the ubiquitination of various proteins in vivo, which are divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s. In general, Li et al. (PLOS One, 2008, 3, 1487) entitled "Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling."; Berndsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) entitled "New insights into ubiquitin E3 ligase mechanism"; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) Title "RING domain E3 ubiquitin ligases."; Spratt et al. (Biochem. 2014, 458, 421-437) Title "RBR E3 ubiquitin ligases: new structures, new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) entitled “Roles of F-box proteins in cancer.”

[0005] The UPP plays a key role in the degradation of short-lived regulatory proteins important in a variety of fundamental cellular processes, including cell cycle regulation, cell surface receptor and ion channel regulation, and antigen presentation. The pathway is involved in the pathogenesis of several forms of malignancy, several genetic diseases (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), immune surveillance / viral pathogenesis, and muscle wasting. Many diseases are associated with abnormal UPP and adversely affect the regulation of cell cycle and division, cellular responses to stress and extracellular modulators, neuronal network morphogenesis, cell surface receptors, ion channels, secondary pathways, DNA repair, and organelle biogenesis.

[0006] Abnormalities in this process have recently been implicated in the pathogenesis of several diseases, both congenital and acquired. These diseases fall into two major groups: (a) diseases resulting from loss of function leading to the stabilization of specific proteins, and (b) diseases resulting from gain of function (i.e., aberrant or accelerated degradation of protein targets).

[0007] UPP is used to induce selective protein degradation, including the use of fusion proteins to artificially ubiquitinate target proteins and synthetic small molecule probes to induce proteasome-dependent degradation. Bifunctional compounds consisting of a target protein-binding ligand and an E3 ubiquitin ligase ligand induced proteasome-mediated degradation of selected proteins through recruitment to these E3 ubiquitin ligases and subsequent ubiquitination. These drug-like molecules offer the possibility of temporally controlling protein expression. Such compounds can induce the inactivation of target proteins upon addition to cells or administration to animals or humans, and may be useful as biochemical reagents and provide a new paradigm for disease treatment by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1):40-46). There is a continuing need in the art for effective treatment of diseases, particularly hyperplasia and cancer, such as breast cancer. However, non-specific effects and the inability to target and regulate specific classes of proteins (e.g., transcription factors) together remain obstacles to the development of effective anti-cancer drugs. Therefore, small molecule therapeutic agents that affect E3 ligase-mediated protein degradation and target cancer-related proteins, such as mouse double minute 2 homolog ("MDM2"), hold promise as therapeutic agents. Therefore, there remains a need to find compounds that are MDM2 degraders useful as therapeutic agents. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Li et al. (PLOS One, 2008, 3, 1487) Title: "Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling." [Non-patent document 2] Berndsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) Title: "New insights into ubiquitin E3 ligase mechanism" [Non-patent document 3] Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) Title: "RING domain E3 ubiquitin ligases." [Non-patent document 4] Spratt et al. (Biochem. 2014, 458, 421-437) Title: "RBR E3 ubiquitin ligases: new structures, new insights, new questions." [Non-patent document 5] Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) Title: "Roles of F-box proteins in cancer." [Non-patent document 6] Crews C,Chemistry & Biology,2010,17(6):551-555;Schnnekloth JS Jr.,Chembiochem,2005,6(l):40-46 Summary of the Invention [Means for solving the problem]

[0009] Summary of the Invention The present application relates to novel bifunctional compounds that function to recruit MDM2 protein to E3 ubiquitin ligase for degradation, as well as methods for their preparation and use. In particular, the present disclosure provides bifunctional compounds that find utility as modulators of targeted ubiquitination of MDM2, which are then degraded and / or otherwise inhibited by the bifunctional compounds described herein. Monovalent compounds that find utility as inducers of targeted ubiquitination of MDM2, which are then degraded and / or otherwise inhibited by the monovalent compounds described herein, are also provided. An advantage of the compounds provided herein is that they are capable of a wide variety of pharmacological activities, consistent with MDM2 degradation / inhibition. Additionally, the present disclosure provides methods of using an effective amount of the compounds described herein to treat or alleviate disease conditions, such as cancer, e.g., breast cancer.

[0010] The present application further relates to the targeted degradation of MDM2 protein through the use of bifunctional molecules, including bifunctional molecules that link a cereblon-binding moiety to a ligand that binds to the targeted MDM2 protein.

[0011] It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as degraders of MDM2 protein. Such compounds have the general formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0012] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders, or conditions associated with the regulation of signal transduction pathways involving the MDM2 protein, including those described herein.

[0013] The compounds provided by the present invention are also useful for the study of MDM2 protein in biological and pathological phenomena; for the study of intracellular signaling pathways occurring in body tissues; and for the comparative evaluation of novel MDM2 inhibitors or MDM2 degraders or other regulators of cell cycle, metastasis, angiogenesis, and immune cell escape in vitro or in vivo. DETAILED DESCRIPTION OF THE INVENTION

[0014] Detailed Description of Specific Embodiments 1. General Description of Certain Embodiments of the Invention: The compounds of the present invention, and compositions thereof, are useful as degraders and / or inhibitors of MDM2 protein. In some embodiments, provided compounds degrade and / or inhibit MDM2 protein.

[0015] In certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I: MBM is an MDM2 binding moiety capable of binding to MDM2 protein; L is a divalent moiety linking MBM to DIM; and DIM is a degradation-inducing moiety such as a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom.

[0016] 2. Compounds and Definitions: The compounds of the present invention include those generally described above and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise specified, the following definitions shall apply. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Edition, eds. Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0017] The terms "aliphatic" or "aliphatic group," as used herein, refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted, hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic, bicyclic, bridged bicyclic, or spirocyclic hydrocarbon (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation, but is not aromatic, having one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, saturated or unsaturated, alkyl, alkenyl, alkynyl groups, and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl).

[0018] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system (i.e., carbocyclic or heterocyclic) that is saturated or partially unsaturated and has at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms, or a single atom, or a 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 (other than hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, in which each group is attached to the remainder of the molecule at any suitable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents, such as those described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic rings include: [ka] Examples include:

[0019] The term "lower alkyl" refers to C 1~4 " refers to a straight or branched chain alkyl group of the formula: Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0020] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1~4 The term "alkyl" refers to a straight or branched chain alkyl group.

[0021] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring (e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(as in N-substituted pyrrolidinyl)).

[0022] The term "unsaturated," as used herein, means a moiety having one or more units of unsaturation.

[0023] As used herein, the term "divalent C 1~8 (or C 1~6 ) saturated or unsaturated, straight or branched hydrocarbon chains" refers to straight or branched divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0024] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogens are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0025] 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 with substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0026] As used herein, the term "cyclopropylenyl" refers to the following structure: [ka] The term "cyclopropyl" refers to a divalent cyclopropyl group of the formula:

[0027] The term "halogen" means F, Cl, Br, or I.

[0028] The term "aryl," used alone or as part of a larger moiety, as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, and anthracyl, which may bear one or more substituents. Included within the scope of the term "aryl," as used herein, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0029] The terms "heteroaryl" and "heteroara-," used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a 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 "heteroara-," as used herein, also encompass groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, 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. Heteroaryl groups may be monocyclic or bicyclic. A heteroaryl group may contain one or more oxo (=O) or thioxo (=S) substituents. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted.The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0030] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably 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 having zero to three heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl) or NH (as in pyrrolidinyl). + It may also be NR (as in N-substituted pyrrolidinyl).

[0031] A heterocyclic ring can be attached to its parent group at any heteroatom or carbon atom that results in a stable structure, and any of these ring atoms can 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, 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 alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl). Heterocyclyl groups can be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. Heterocyclic rings can contain one or more oxo (=O) or thioxo (=S) substituents. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions independently are optionally substituted.

[0032] 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 with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0033] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted" means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at each position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0034] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH) 0~4 R ○ ;-(CH2) 0~4 OR ○ ;-O(CH2) 0~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 CH(OR ○ )2;-(CH2) 0~4 SR ○ ;-(CH2) 0~4 Ph (which is R ○ -(CH2) 0~4 O(CH2) 0~1 Ph (which is R ○ -CH=CHPh (which may be substituted with R ○ -(CH2) 0~4 O(CH2) 0~1 -pyridyl (which is R ○ -NO2; -CN; -N3; ​​-(CH2)0~4 N(R ○ )2;-(CH2) 0~4 N(R ○ )C(O)R ○ ;-N(R ○ )C(S)R ○ ;-(CH2) 0~4 N(R ○ )C(O)NR ○ 2;-N(R ○ )C(S)NR ○ 2;-(CH2) 0~4 N(R ○ )C(O)OR ○ ;-N(R ○ )N(R ○ )C(O)R ○ ;-N(R ○ )N(R ○ )C(O)NR ○ 2;-N(R ○ )N(R ○ )C(O)OR ○ ;-(CH2) 0~4 C(O)R ○ ;-C(S)R ○ ;-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 C(O)SR ○ ;-(CH2) 0~4 C(O)OSiR ○ 3;-(CH2) 0~4 OC(O)R ○ ;-OC(O)(CH2) 0~4 SR ○ ;-(CH2) 0~4 SC(O)R ○ ;-(CH2) 0~4 C(O)NR ○ 2;-C(S)NR ○ 2;-C(S)SR ○ ;-SC(S)SR ○ ;-(CH2) 0~4 OC(O)NR ○ 2;-C(O)N(OR ○ )R ○ ;-C(O)C(O)R ○ ;-C(O)CH2C(O)R ○ ;-C(NOR ○ )R○ ;-(CH2) 0~4 SSR ○ ;-(CH2) 0~4 S(O)2R ○ ;-(CH2) 0~4 S(O)2OR ○ ;-(CH2) 0~4 OS(O)2R ○ ;-S(O)2NR ○ 2;-(CH2) 0~4 S(O)R ○ ;-N(R ○ )S(O)NR ○ 2;-N(R ○ )S(O)2R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2;-P(O)2R ○ ;-P(O)R ○ 2;-OP(O)R ○ 2;-OP(O)(OR ○ )2;-SiR ○ 3;-(C 1~4 straight or branched chain alkylene)ON(R ○ )2; or -(C 1~4 straight or branched chain alkylene)C(O)ON(R ○ )2, where each R ○ may be substituted as defined below and independently represent hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R ○ two independent occurrences of together with the atom(s) between them form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0035] R ○(R ○ Suitable monovalent substituents on the ring formed by two independent occurrences of (a ring formed by two independent occurrences of together with the atom between them) are independently halogen, -(CH2) 0~2 R ● ,-(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1~4 straight or branched chain alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0036] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═O, ═S, ═NNR* 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O-, or -S(C(R * 2)) 2~3 S-. Here R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 and an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having an aliphatic or 0-4 heteroatom independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2~3 O-, where R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 It is selected from an aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C which may be substituted as defined below 1~6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † two independent occurrences of together with the atom(s) between them form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] R † Suitable substituents on the aliphatic group are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ●is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and commensurate with 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, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids, inorganic bases, organic acids, and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or formed by using 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of suitable salts include phosphate, 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, and valerate.

[0041] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halides, hydroxides, carbonates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. In some embodiments, provided compounds are purified in salt form for convenience and / or ease of purification, for example, using acidic or basic mobile phases during chromatography. Salt forms of provided compounds formed during chromatographic purification are compared herein and will be readily apparent to those skilled in the art.

[0042] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures of the invention in which hydrogen is replaced by deuterium or tritium, or in which carbon is replaced by methyl ... 13 C or 14 Compounds having the invention in which C is replaced with an enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools according to the invention, as probes in biological assays, or as therapeutic agents.

[0043] As used herein, the term "provided compounds" refers to any genus, subgenus, and / or species described herein.

[0044] As used herein, the term "inhibitor" is defined as a compound that binds and / or inhibits MDM2 protein with measurable affinity. In certain embodiments, an inhibitor has an IC 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. 50 and / or have a binding constant.

[0045] As used herein, the term "degrading agent" is defined as a heterobifunctional compound that binds and / or inhibits both the MDM2 protein and E3 ligase with measurable affinity, resulting in ubiquitination and subsequent degradation of the MDM2 protein. In certain embodiments, the degrading agent has a DC activity 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. 50 As used herein, the term "monovalent" refers to a degrader compound that does not have an E3 ligase binding moiety attached.

[0046] The compounds of the present invention can be tethered to a detectable moiety. It is understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that a detectable moiety can be attached to a provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently linked to a detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing carbonate, amino, thiol, or hydroxyl moieties, to name a few. It is understood that such moieties can be attached directly to a provided compound or via a tethering group such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached via click chemistry. In some embodiments, such moieties can be attached via 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-9 and Sun et al., Bioconjugate Chem., 2006, 17, 52-7.

[0047] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that can be detected, such as primary and secondary labels. Radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), primary labels, such as 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.

[0048] As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a secondary intermediate to generate a detectable signal. For biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. For antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radioactive fluorescence resonance energy transfer (FRET), and the second group generates the signal that is detected.

[0049] As used herein, the terms "fluorescent label," "fluorescent dye," and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include 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, BODIPY530 / 550, BODIPY558 / 568, BODIPY564 / 570, BODIPY576 / 589, BODIPY581 / 591, BODIPY630 / 650, BODIPY650 / 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'-dimethoxy-fluorescein, DM-NERF, eosin, erythrosine, fluorescein, FAM, hydrochloride Examples of suitable dyes include, but are not limited to, roxycoumarin, IRDyes (IRD40, IRD700, IRD800), 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-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

[0050] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection technology.Examples of mass tag include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipeconic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and their derivatives.The synthesis and usefulness of these mass tags are described in U.S. Patent No. 4,650,750, U.S. Patent No. 4,709,016, U.S. Patent No. 5,360,8191, U.S. Patent No. 5,516,931, U.S. Patent No. 5,602,273, U.S. Patent No. 5,604,104, U.S. Patent No. 5,610,020 and U.S. Patent No. 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides of various lengths and base compositions, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, in the appropriate mass range (100-2000 daltons) may be used as mass tags.

[0051] The terms "measurable affinity" and "measurably inhibit," as used herein, refer to a measurable change in MDM2 protein between a sample containing a compound of the present invention or a composition thereof and MDM2 protein and an equivalent sample containing MDM2 protein without the compound or composition thereof present.

[0052] 3. Description of Exemplary Embodiments: As noted above, in certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM is an MDM2 binding moiety capable of binding to MDM2 protein; L is a divalent moiety linking MBM to DIM; and DIM is a degradation-inducing moiety such as a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom. MDM2 binding part (MBM)

[0053] In certain embodiments, the present invention provides a compound of formula I, wherein the MBM is represented by formula I-aaa-1, I-aaa-2, I-aaa-3, I-aaa-4, I-aaa-5, I-aaa-6, I-aaa-7, I-aaa-8, I-aaa-9, I-aaa-10, I-aaa-11, I-aaa-12, I-aaa-13, I-aaa-14, I-aaa-15, I-aaa-16, I-aaa-17, I-aaa-18, I-aaa-19, or I-aaa-20, respectively: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and as described in embodiments herein; X is selected from -CR2-, -O-, -S-, -S(O)-, -S(O)2-, and -NR-; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same atom, optionally taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Y and Z are independently selected from -CR= and -N=; Ring W is a fused ring selected from benzo and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 1 and R 2 is an optionally substituted monocyclic or bicyclic ring independently selected from phenyl, a 5-10 membered aryl, and a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 3 and R 4 are independently hydrogen and C 1-6 alkyl; R 5 is selected from an optionally substituted monocyclic or bicyclic ring selected from phenyl, a 5-10 membered aryl, and a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 6 is selected from hydrogen, —C(O)R, —C(O)OR, and —C(O)NR; R 7 is hydrogen and R A Selected from; Each R A independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 8 is -C(O)R and R A Selected from; R9 is a mono-, bis-, or tri-substituent on ring W, each of the substituents independently being selected from halogen and optionally substituted C 1-6 selected from aliphatic; R 10 is selected from an optionally substituted monocyclic or bicyclic ring selected from phenyl, a 5-10 membered aryl, and a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 11 is -C(O)OR or -C(O)NR2; R 12 and R 13 are independently hydrogen and R A Choose from or: R 12 and R 13 optionally taken together with their intervening atoms, form an optionally substituted 3- to 8-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 14 is R A and; R 15 is -CN; R 16 is R A ,-OR,-(CR2) 0-6 -C(O)R, -(CR2) 0-6 -C(O)OR, -(CR2) 0-6 -C(O)NR2, -(CR2) 0-6 -S(O)2R, -(CR2) 0-6 -N(R)S(O)2R, -(CR2) 0-6 -S(O)2NR2; R 17 is -(CR2) 0-6 -C(O)NR2; R 18 and R 19 are independently hydrogen and R A Selected from; R 20 and R 21are independently hydrogen, R A , halogen and -OR, or: R 20 and R 21 optionally taken together with their intervening atoms to form a fused 5- to 7-membered partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a fused 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 22 , R 23 , R 25 , and R 27 are independently hydrogen, R A , halogen, —C(O)R, —C(O)OR, —C(O)NR2, —NR2, —OR, —S(O)R, —S(O)2R, —S(O)2NR2; R 24 、 R 26 , and R 28 are independently hydrogen, R A , -C(O)R, -C(O)OR, -C(O)NR 2、 selected from -S(O)R, -S(O)R, and -S(O)NR; R 1’ and R 2’ are independently selected from halogen, —C≡CR, —CN, —CF3, and —NO2; R 3’ is -OR; R 4’ , R 5’ , R 6’ are independently hydrogen, halogen, R A , -CN, -CF3, -NR2, -OR, -SR, and -S(O)2R; R 7’ is a mono-, bis-, or tri-substituent, each substituent independently selected from halogen; R 8’ is a mono-, bis-, or tri-substituent, each of which is independently hydrogen, halogen, R A , -CN, -C≡CR, -NO2, and -OR; R 9’ is R A and; Z 1 is selected from hydrogen, halogen, and -OR; R 10’ and R 11’ are independently hydrogen and R A Selected from; R 12’ is selected from —C(O)R, —C(O)OR, —C(O)NR, —OR, —S(O)R, —S(O)NR, and —S(O)R; and R 1’’ is hydrogen and R A is selected from.

[0054] As defined herein and described above, when a formula is indicated using square brackets (e.g. [ka] ), L is attached to a modifiable carbon, oxygen, nitrogen, or sulfur atom within the MBM, including substitution or replacement of defined groups in the MBM.

[0055] In certain embodiments, the present invention provides compounds of formula I, wherein the MBM is represented by formulas I-bbb-1, I-bbb-2, and I-bbb-3, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and as described in embodiments herein; R 1’’ is hydrogen and R A Selected from; Each R A independently, C 1-6an optionally substituted group selected from aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 10 is selected from an optionally substituted monocyclic or bicyclic ring selected from phenyl, a 5-10 membered aryl, and a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 12 and R 13 are each independently hydrogen and R A Choose from or: R 12 and R 13 optionally taken together with their intervening atoms, form an optionally substituted 4-8 membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; A 5 is -C(R 18a )= and -N=; A 6 is -C(R 18b )= and -N=; A 7 is -C(R 18d )= and -N=; R 18a , R 18b , R 18c , and R 18d are each independently hydrogen, halogen, or R A and - selected from OR; Each R is independently hydrogen or C 1-6an optionally substituted group selected from aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring W is an optionally substituted fused ring selected from benzo and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q 1 is an optionally substituted divalent radical selected from alkylenyl, phenylenyl, heteroarylenyl, cycloalkylenyl, and heterocyclenyl.

[0056] As defined above and described herein, X is selected from -CR2-, -O-, -S-, -S(O)-, -S(O)2-, and -NR-.

[0057] In some embodiments, X is -CR2-. In some embodiments, X is -O-. In some embodiments, X is -S-. In some embodiments, X is -S(O)-. In some embodiments, X is -S(O)2-. In some embodiments, X is -NR-. In some embodiments, X is -CH2-.

[0058] In some embodiments, X is selected from those shown in Table 1.

[0059] As defined above and described herein, each R is independently hydrogen or C 1-6an optionally substituted group selected from aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same atom optionally taken together with their intervening atoms form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0060] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1-6 It is aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same atom, optionally taken together with their intervening atoms, form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0061] In some embodiments, R is [ka] In some embodiments, R is [ka] is.

[0062] In some embodiments, R is selected from those shown in Table 1.

[0063] Y and Z are independently selected from -CR= and -N= as defined above and described herein.

[0064] In some embodiments, Y is -CR=. In some embodiments, Y is -N=. In some embodiments, Z is -CR=. In some embodiments, Z is -N=.

[0065] In some embodiments, Y and Z are selected from those shown in Table 1.

[0066] As defined above and described herein, ring W is a fused ring selected from benzo and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0067] In some embodiments, ring W is benzo. In some embodiments, ring W is a 5-6 membered fused heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0068] In some embodiments, ring W is selected from those shown in Table 1.

[0069] R, as defined above and described herein 1 and R 2 is an optionally substituted monocyclic or bicyclic ring independently selected from phenyl, a 5-10 membered aryl, and a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0070] In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 5-10 membered aryl. In some embodiments, R 1is an optionally substituted 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 5-10 membered aryl. In some embodiments, R 1 is an optionally substituted 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0071] In some embodiments, R 1 and R 2 is selected from those shown in Table 1.

[0072] R, as defined above and described herein 3 and R 4 are independently hydrogen and C 1-6 alkyl.

[0073] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C 1-6 In some embodiments, R 3 is methyl. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C 1-6 In some embodiments, R 4 is methyl.

[0074] In some embodiments, R 3 and R 4 is selected from those shown in Table 1.

[0075] R, as defined above and described herein 5 is selected from an optionally substituted monocyclic or bicyclic ring selected from phenyl, a 5- to 10-membered aryl, and a 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0076] In some embodiments, R 5 is optionally substituted phenyl. In some embodiments, R 5 is an optionally substituted 5-10 membered aryl. In some embodiments, R 5 is an optionally substituted 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 5 teeth, [ka] is.

[0077] In some embodiments, R 5 is selected from those shown in Table 1.

[0078] R, as defined above and described herein 6 is selected from hydrogen, —C(O)R, —C(O)OR, and —C(O)NR2.

[0079] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is —C(O)R. In some embodiments, R 6 is —C(O)OR. In some embodiments, R 6 is —C(O)NR. In some embodiments, R 6 teeth, [ka] is.

[0080] In some embodiments, R 6 is selected from those shown in Table 1.

[0081] R, as defined above and described herein 7 is hydrogen and R A is selected from.

[0082] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is R A is.

[0083] In some embodiments, R 7 is selected from those shown in Table 1.

[0084] As generally defined above, each R A independently, C 1~6 An optionally substituted group selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0085] R, as defined above and described herein A is C 1~6 In some embodiments, R is an optionally substituted group selected from aliphatic. A is optionally substituted phenyl. In some embodiments, R A is an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R A is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0086] In some embodiments, R A is selected from those shown in Table 1.

[0087] R, as defined above and described herein 8 is -C(O)R and R A is selected from.

[0088] In some embodiments, R 8 is —C(O)R. In some embodiments, R 8 is R A is.

[0089] In some embodiments, R 8 is selected from those shown in Table 1.

[0090] R, as defined above and described herein 9 is a mono-, bis-, or tri-substituent on ring W, each of the substituents independently being selected from halogen and optionally substituted C 1-6 is selected from aliphatic.

[0091] In some embodiments, R 9is a mono-substituent on ring W. In some embodiments, R 9 is a bis-substituent on ring W. In some embodiments, R 9 is a tri-substituent on ring W. In some embodiments, each R 9 is halogen and optionally substituted C 1-6 In some embodiments, R 9 is chloro.

[0092] In some embodiments, R 9 is selected from those shown in Table 1.

[0093] R, as defined above and described herein 10 is selected from an optionally substituted monocyclic or bicyclic ring selected from phenyl, a 5- to 10-membered aryl, and a 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0094] In some embodiments, R 10 is optionally substituted phenyl. In some embodiments, R 10 is an optionally substituted 5-10 membered aryl. In some embodiments, R 10 is an optionally substituted 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] is.

[0095] In some embodiments, R 10 is selected from those shown in Table 1.

[0096] R, as defined above and described herein 11 is —C(O)OR or —C(O)NR2.

[0097] In some embodiments, R 11 is —C(O)NR. In some embodiments, R 11 is —C(O)OR. In some embodiments, R 11 is —C(O)OH. In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] is.

[0098] In some embodiments, R 11 is selected from those shown in Table 1.

[0099] R, as defined above and described herein 12 and R 13 are independently hydrogen and R A or R 12 and R 13optionally taken together with their intervening atoms, form an optionally substituted 3- to 8-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0100] In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is R A In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is R A In some embodiments, R 12 and R 13 are taken together with their intervening atoms to form an optionally substituted 3-8 membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R 12 and R 13 Let's get together [ka] In some embodiments, R 12 and R 13 Let's get together [ka] Form.

[0101] In some embodiments, R 12 and R 13 is selected from those shown in Table 1.

[0102] R, as defined above and described herein 14 is R A is.

[0103] In some embodiments, R 14 is R A In some embodiments, R 14 teeth, [ka] is.

[0104] In some embodiments, R 14 is selected from those shown in Table 1.

[0105] R, as defined above and described herein 15 is -CN.

[0106] In some embodiments, R 15 is -CN.

[0107] In some embodiments, R 15 is selected from those shown in Table 1.

[0108] R, as defined above and described herein 16 is R A ,-OR,-(CR2) 0-6 -C(O)R, -(CR2) 0-6 -C(O)OR, -(CR2) 0-6 -C(O)NR2, -(CR2) 0-6 -S(O)2R, -(CR2) 0-6 -N(R)S(O)2R, -(CR2) 0-6 -S(O)2NR2.

[0109] In some embodiments, R 16 is R A In some embodiments, R 16 is -OR. In some embodiments, R 16 is -(CR2) 0-6 In some embodiments, R 16 is -(CR2) 0-6 In some embodiments, R 16 is -(CR2) 0-6 In some embodiments, R 16 is -(CR2)0-6 In some embodiments, R 16 is -(CR2) 0-6 -N(R)S(O)R. In some embodiments, R 16 is -(CR2) 0-6 In some embodiments, [ka]

[0110] In some embodiments, R 16 is selected from those shown in Table 1.

[0111] R, as defined above and described herein 17 is -(CR2) 0-6 -C(O)NR2.

[0112] In some embodiments, R 17 is -(CR2) 0-6 In some embodiments, R 17 teeth, [ka] In some embodiments, R 17 teeth, [ka] is.

[0113] In some embodiments, R 17 is selected from those shown in Table 1.

[0114] R, as defined above and described herein 18 and R 19 are independently hydrogen and R A is selected from.

[0115] In some embodiments, R 18is hydrogen. In some embodiments, R 18 is R A In some embodiments, R 18 teeth, [ka] In some embodiments, R 19 is hydrogen. In some embodiments, R 19 is R A In some embodiments, R 18 teeth, [ka] is.

[0116] In some embodiments, R 18 and R 19 is selected from those shown in Table 1.

[0117] R, as defined above and described herein 20 and R 21 are independently hydrogen, R A , halogen and -OR, or R 20 and R 21 optionally taken together with their intervening atoms to form a fused 5- to 7-membered partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a fused 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0118] In some embodiments, R 20 is hydrogen. In some embodiments, R 20 is R A In some embodiments, R 20 is halogen. In some embodiments, R 20 is -OR. In some embodiments, R 20 is -OMe. In some embodiments, R 20is -OiPr. In some embodiments, R 21 is hydrogen. In some embodiments, R 21 is R A In some embodiments, R 21 is halogen. In some embodiments, R 21 is -OR. In some embodiments, R 21 is -OMe. In some embodiments, R 21 is -OiPr. In some embodiments, R 20 and R 21 together with their intervening atoms form a fused 5- to 7-membered partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a fused 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0119] In some embodiments, R 20 and R 21 is selected from those shown in Table 1.

[0120] R, as defined above and described herein 22 , R 23 , R 25 , and R 27 are independently hydrogen, R A , halogen, —C(O)R, —C(O)OR, —C(O)NR2, —NR2, —OR, —S(O)R, —S(O)2R, —S(O)2NR2.

[0121] In some embodiments, R 22 , R 23 , R 25 , and R 27 In some embodiments, one or more of R 22 , R 23 , R 25 , and R 27 One or more of the R A In some embodiments, R22 , R 23 , R 25 , and R 27 In some embodiments, one or more of R 22 , R 23 , R 25 , and R 27 In some embodiments, one or more of R 22 , R 23 , R 25 , and R 27 In some embodiments, one or more of R 22 , R 23 , R 25 , and R 27 In some embodiments, one or more of R 22 , R 23 , R 25 , and R 27 In some embodiments, one or more of R 22 , R 23 , R 25 , and R 27 In some embodiments, one or more of R 22 , R 23 , R 25 , and R 27 In some embodiments, one or more of R 22 , R 23 , R 25 , and R 27 In some embodiments, one or more of R 22 , R 23 , R 25 , and R 27 One or more of the is -S(O)2NR2.

[0122] In some embodiments, R 22 , R 23 , R 25, and R 27 is selected from those shown in Table 1.

[0123] R, as defined above and described herein 24 、 R 26 , and R 28 are independently hydrogen, R A , -C(O)R, -C(O)OR, -C(O)NR 2、 is selected from -S(O)R, -S(O)2R, and -S(O)2NR2.

[0124] In some embodiments, R 24 , R 26 , and R 28 In some embodiments, one or more of R 24 , R 26 , and R 28 One or more of the R A In some embodiments, R 24 , R 26 , and R 28 One or more of the R A In some embodiments, R 24 , R 26 , and R 28 One or more of the R A In some embodiments, R 24 , R 26 , and R 28 In some embodiments, one or more of R 24 , R 26 , and R 28 In some embodiments, one or more of R 24 , R 26 , and R 28 In some embodiments, one or more of R 24 , R 26 , and R 28In some embodiments, one or more of R 24 , R 26 , and R 28 One or more of the is -S(O)2NR2.

[0125] In some embodiments, R 24 , R 26 , and R 28 is selected from those shown in Table 1.

[0126] R, as defined above and described herein 1’ and R 2’ are independently selected from halogen, —C≡CR, —CN, —CF 3 , and —NO 2 .

[0127] In some embodiments, R 1’ is halogen. In some embodiments, R 1’ is -C≡CR. In some embodiments, R 1’ is -CN. In some embodiments, R 1’ is -CF3. In some embodiments, R 1’ is —NO. In some embodiments, R 1’ is chloro. In some embodiments, R 2’ is halogen. In some embodiments, R 2’ is -C≡CR. In some embodiments, R 2’ is -CN. In some embodiments, R 2’ is -CF3. In some embodiments, R 2’ is —NO. In some embodiments, R 2’ is chloro.

[0128] In some embodiments, R 1’ and R 2’ is selected from those shown in Table 1.

[0129] R, as defined above and described herein3’ is -OR.

[0130] In some embodiments, R 3’ is -OR. In some embodiments, R 3’ is -OEt.

[0131] In some embodiments, R 3’ is selected from those shown in Table 1.

[0132] R, as defined above and described herein 4’ , R 5’ , and R 6’ are independently hydrogen, halogen, R A , —CN, —CF 3 , —NR 2 , —OR, —SR, and —S(O) 2 R.

[0133] In some embodiments, R 4’ , R 5’ , and R 6’ In some embodiments, one or more of R 4’ , R 5’ , and R 6’ In some embodiments, one or more of R 4’ , R 5’ , and R 6’ One or more of the R A In some embodiments, R 4’ , R 5’ , and R 6’ In some embodiments, one or more of R 4’ , R 5’ , and R 6’ In some embodiments, one or more of R 4’ , R 5’ , and R 6’ In some embodiments, one or more of R 4’ , R 5’ , and R 6’In some embodiments, one or more of R 4’ , R 5’ , and R 6’ In some embodiments, one or more of R 4’ , R 5’ , and R 6’ In some embodiments, one or more of R 4’ is tert-butyl.

[0134] In some embodiments, R 4’ , R 5’ , and R 6’ is selected from those shown in Table 1.

[0135] R, as defined above and described herein 7’ is a mono-, bis- or tri-substituent, each substituent independently selected from halogen.

[0136] In some embodiments, R 7’ is a mono-substituent. In some embodiments, R 7’ is a bis-substituent. In some embodiments, R 7’ is a tri-substituent. In some embodiments, R 7’ is halogen. In some embodiments, R 7’ is chloro. In some embodiments, R 7’ is fluoro.

[0137] In some embodiments, R 7’ is selected from those shown in Table 1.

[0138] R, as defined above and described herein 8’ is a mono-, bis-, or tri-substituent, each of which is independently hydrogen, halogen, R A , —CN, —C≡CR, —NO2, and —OR.

[0139] In some embodiments, R 8’ is a mono-substituent. In some embodiments, R 8’ is a bis-substituent. In some embodiments, R 8’ is a tri-substituent. In some embodiments, R 8’ is hydrogen. In some embodiments, R 8’ is halogen. In some embodiments, R 8’ is R A In some embodiments, R 8’ is -CN. In some embodiments, R 8’ is -C≡CR. In some embodiments, R 8’ is —NO. In some embodiments, R 8’ is -OR. In some embodiments, R 8’ is chloro. In some embodiments, R 8’ is fluoro.

[0140] In some embodiments, R 8’ is selected from those shown in Table 1.

[0141] R, as defined above and described herein 9’ is R A is.

[0142] In some embodiments, R 9’ is R A is.

[0143] In some embodiments, R 9’ is selected from those shown in Table 1.

[0144] As defined above and described herein, Z 1 is selected from hydrogen, halogen, and —OR.

[0145] In some embodiments, Z 1 is hydrogen. In some embodiments, Z 1is halogen. In some embodiments, Z 1 is -OR.

[0146] R, as defined above and described herein 10’ and R 11’ are independently hydrogen and R A is selected from.

[0147] In some embodiments, R 10’ is hydrogen. In some embodiments, R 10’ is R A In some embodiments, R 11’ is hydrogen. In some embodiments, R 11’ is R A is.

[0148] In some embodiments, R 10’ and R 11’ is selected from those shown in Table 1.

[0149] R, as defined above and described herein 12’ is selected from —C(O)R, —C(O)OR, —C(O)NR, —OR, —S(O)R, —S(O)NR, and —S(O)R;

[0150] In some embodiments, R 12’ is —C(O)R. In some embodiments, R 12’ is —C(O)OR. In some embodiments, R 12’ is —C(O)NR. In some embodiments, R 12’ is -OR. In some embodiments, R 12’ is —S(O)R. In some embodiments, R 12’ is —S(O)NR. In some embodiments, R 12’ is -S(O)R.

[0151] In some embodiments, R 12’is selected from those shown in Table 1.

[0152] R, as defined above and described herein 1’’ is hydrogen and R A is selected from.

[0153] In some embodiments, R 1’’ is hydrogen. In some embodiments, R 1’’ is R A In some embodiments, R 1’’ is -n-pentyl. In some embodiments, R 1’’ is -n-hexyl.

[0154] In some embodiments, R 1’’ is selected from those shown in Table 1.

[0155] As defined above and described herein, A 5 is -C(R 18a )= and -N=.

[0156] In some embodiments, A 5 is -C(R 18a )=. In some embodiments, A 5 is -N=.

[0157] In some embodiments, A 5 is selected from those shown in Table 1.

[0158] As defined above and described herein, A 6 is -C(R 18b )= and -N=.

[0159] In some embodiments, A 6 is -C(R 18b )=. In some embodiments, A 6 is -N=.

[0160] In some embodiments, A 6 is selected from those shown in Table 1.

[0161] As defined above and described herein, A 7 is -C(R 18d )= and -N=.

[0162] In some embodiments, A 7 is -C(R 18d )=. In some embodiments, A 7 is -N=.

[0163] In some embodiments, A 7 is selected from those shown in Table 1.

[0164] R, as defined above and described herein 18a , R 18b , R 18c , and R 18d are each independently hydrogen, halogen, or R A and -OR.

[0165] In some embodiments, R 18a , R 18b , R 18c , and R 18d In some embodiments, one or more of R 18a , R 18b , R 18c , and R 18d In some embodiments, one or more of R 18a , R 18b , R 18c , and R 18d One or more of the R A In some embodiments, R 18a , R 18b , R 18c , and R 18d In some embodiments, one or more of R18c is chloro.

[0166] In some embodiments, R 18a , R 18b , R 18c , and R 18d is selected from those shown in Table 1.

[0167] Q, as defined above and described herein 1 is an optionally substituted divalent radical selected from alkylenyl, phenylenyl, heteroarylenyl, cycloalkylenyl, and heterocyclenyl.

[0168] In some embodiments, Q 1 is optionally substituted alkylenyl. In some embodiments, Q 1 is optionally substituted phenylenyl. In some embodiments, Q 1 is optionally substituted heteroarylenyl. In some embodiments, Q 1 is optionally substituted cycloalkylenyl. In some embodiments, Q 1 is optionally substituted heterocyclenyl. In some embodiments, Q 1 teeth, [ka] In some embodiments, Q 1 teeth, [ka] In some embodiments, Q 1 teeth, [ka] In some embodiments, Q 1 teeth, [ka] In some embodiments, Q 1 teeth, [ka] In some embodiments, Q 1 teeth, [ka] In some embodiments, Q 1 teeth, [ka] In some embodiments, Q 1 teeth, [ka] In some embodiments, Q 1 teeth, [ka] In some embodiments, Q 1 teeth, [ka] In some embodiments, Q 1 teeth, [ka] is.

[0169] In some embodiments, Q 1 is selected from those shown in Table 1.

[0170] In some embodiments, the MBM [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] In some embodiments, the MBM is [ka] is. Ligase binding moiety (LBM)

[0171] In some embodiments, the LBM is an E3 ligase ligand.

[0172] As defined herein and described below, when a formula is indicated using square brackets (e.g., [ka] ), L is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom in DIM or LBM, including substitution or replacement of defined groups in DIM or LBM.

[0173] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and described herein; X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1-4 It is aliphatic; Each R2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring A is [ka] [ka] [ka] is a bicyclic or tricyclic ring selected from Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are independently hydrogen, -R 6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1-4 aliphatic, or -CN; Each R 6 independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond or C 1-3 wherein one to two methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, optionally taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0174] -(R 2 )m When the point of attachment of is shown on ring B, -(R 2 ) m It is contemplated, and one of ordinary skill in the art will understand, that the point of attachment of R may be on ring A or any available carbon or nitrogen atom on ring A, including the ring to which ring B is fused. 4 or R 5 -R on the nitrogen atom bonded to 2 If R is bonded 4 or R 5 does not exist, and -R 2 R 4 or R 5 Substitute for the base. R 3 -R to the carbon atom bonded to 2 If R is bonded 3 does not exist, and -R 2 R 3 It takes the place of the base.

[0175] In some embodiments, the compound of formula Ia above has formula I-a' or formula I-a'': [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, ring A, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 and m are each as defined above.

[0176] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein; X 1is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1-4 It is aliphatic; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring A is [ka] (Ring B is other than imidazo or benzo). [ka] (Ring B is other than benzo), [ka] (Ring B is other than benzo), [ka] (Ring B is other than benzo), [ka] [ka] [ka] is a bicyclic or tricyclic ring selected from Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1-4 aliphatic, or -CN; Each R 6independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; and Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, optionally taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0177] -(R 2 ) m When the point of attachment of is shown on ring B, -(R 2 ) m It is contemplated, and one of ordinary skill in the art will understand, that the point of attachment of R may be on ring A or any available carbon or nitrogen atom on ring A, including the ring to which ring B is fused. 4 or R 5 -R on the nitrogen atom bonded to 2 If R is bonded 4 or R 5 does not exist, and -R 2 R 4 or R 5 Substitute for the base. R 3 -R to the carbon atom bonded to 2 If R is bonded 3 does not exist, and -R 2 R 3 It takes the place of the base.

[0178] In some embodiments, the compound of formula Ib above has formula I-b' or formula I-b: [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, ring A, L, R 1 , R 2 , X 1 , X 2 , X 3 and m are each as defined above.

[0179] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein; X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1-4 It is aliphatic; Each R 2 are independently hydrogen, R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; Ring A is [ka] [ka] is a bicyclic or tricyclic ring selected from Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1-4 aliphatic, or -CN; Each R 6 independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; and Each R is independently hydrogen or C 1-6an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, optionally taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0180] -(R 2 ) m When the point of attachment of is shown on ring B, -(R 2 ) m It is contemplated, and one of ordinary skill in the art will understand, that the point of attachment of R may be on ring A or any available carbon or nitrogen atom on ring A, including the ring to which ring B is fused. 4 or R 5 -R on the nitrogen atom bonded to 2 If R is bonded 4 or R 5 does not exist, and -R 2 R 4 or R 5 Substitute for the base. R 3 -R to the carbon atom bonded to 2 If R is bonded 3 does not exist, and -R 2 R 3 It takes the place of the base.

[0181] In some embodiments, the compound of formula Ic above has the formula I-c' or formula I-c'': [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, ring A, L, R 1 , R 2 , X 1 , and m are as defined above.

[0182] In certain embodiments, the present invention provides a method for treating a ubiquitin ligase (cereblon)-binding moiety, wherein the LBM is an E3 ubiquitin ligase (cereblon)-binding moiety, such as a ubiquitin ligase (LBM) having formula Id: [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein; X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1-4 It is aliphatic; Ring C is [ka] [ka] is a monocyclic or bicyclic ring selected from: R 2 and R 3a each independently represents hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR , -C(O)N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2 , -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R )C(O)N(R)2, -N(R)S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2) 2、 or -N(R)S(O)R; Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7-membered saturated or partially unsaturated carbocyclyl, a 5-7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1-4 aliphatic, or -CN; Each R 6 independently, C 1-6an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond or C 1-3 wherein one to two methylene units of said chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1, and when p is 0, the bond connecting ring C and ring D is [ka] is connected to; and Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, optionally taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0183] In some embodiments, the compound of formula Id above has formula I-d' or formula I-d'': [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, ring C, ring D, L, L 1 , R 1 , R 2 , R 3a , X 1 , X 2 , X 3 , n, m, and p are as defined above.

[0184] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein; X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1-4 It is aliphatic; Ring C is [ka] [ka] is a monocyclic or bicyclic ring selected from: R 2 and R 3a each independently represents hydrogen, -R 6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7-membered saturated or partially unsaturated carbocyclyl, a 5-7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1-4 aliphatic, or -CN; Each R 6 independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0 or 1, and when p is 0, the bond connecting ring C and ring D is [ka] is connected to; and Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, optionally taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0185] In some embodiments, the compound of formula Ie above can be represented by formula I-e' or formula I-e'': [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, ring C, ring D, L, R 1 , R 2 , R 3a , X 1 , n, m, and p are as defined above.

[0186] In certain embodiments, the present invention provides a method for treating a ubiquitin ligase (cereblon) comprising administering to a mammalian subject the invention, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, such that the LBM has the formula If: [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein; X 1is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1-4 It is aliphatic; Ring C is [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from: Each or R 2 and R 3a are independently hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7-membered saturated or partially unsaturated carbocyclyl, a 5-7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 4 are independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1-4 aliphatic, or -CN; Each R 6 independently, C 1-6an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond or C 1-3 wherein one to two methylene units of said chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0 or 1; and Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, optionally taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0187] In some embodiments, the compound of formula If above can be represented by formula If' or formula If: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, ring C, ring D, L, L 1 , R1 , R 2 , R 3a , X 1 , X 2 , X 3 , m, n, and p are as defined above.

[0188] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... the invention, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a fibronectin-binding moiety of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein; X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1-4 It is aliphatic; Ring C is [ka] [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from: R 2 , R 3a , and R 4each independently represents hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; Ring D is selected from a 6-membered aryl, a 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7-membered saturated or partially unsaturated carbocyclyl, a 5-7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 5 is hydrogen, C 1-4 aliphatic, or -CN; Each R 6 independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1 or 2; n is 0, 1, 2, 3, or 4; p is 0 or 1; and Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same nitrogen, optionally taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0189] In some embodiments, the compound of formula Ig above has formula I-g' or formula I-g'': [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, ring C, ring D, L, R 1 , R 2 , R 3a , X 1 , m, n, and p are as defined above.

[0190] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein; X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1-4 It is aliphatic; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1-6an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of ring E, ring F, and ring G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each of ring E, ring F, and ring G is independently optionally further substituted with 1 to 2 oxo groups; L 1 is a covalent bond or C 1-3 wherein one to two methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0191] [ka] is shown on ring E, ring F or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on ring E, ring F, or ring G, including the ring in which ring E or ring G is fused to ring F.

[0192] -(R2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

[0193] [ka] is shown on ring E, ring F or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

[0194] In some embodiments, the compound of formula Ih above can be represented by formula I-h' or formula I-h'': [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, ring E, ring F, ring G, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 and m are each as defined above.

[0195] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein; X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or optionally substituted C 1-4 It is aliphatic; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -C(R )2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R; Each R 6 independently, C 1-6an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of ring E, ring F, and ring G is independently a fused ring selected from a 6-membered aryl containing 0-3 nitrogen atoms, a 5-7-membered saturated or partially unsaturated carbocyclyl, a 5-7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each of ring E, ring F, and ring G is independently optionally further substituted with 1-2 oxo groups; and m is 0, 1, 2, 3 or 4.

[0196] [ka] is shown on ring E, ring F or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on ring E, ring F, or ring G, including the ring in which ring E or ring G is fused to ring F.

[0197] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

[0198] In some embodiments, the compound of formula Ii above has formula I-i' or formula I-i'': [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, L, Ring E, Ring F, Ring G, L, R 1 , R 2 , X 1 , and m are as defined above.

[0199] In certain embodiments, the present invention provides a method for the preparation of a ubiquitin ligase (cereblon)-binding moiety, wherein the LBM is an E3 ubiquitin ligase (cereblon)-binding moiety, such that the LBM has the formula Ik: [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein; X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1-4 It is aliphatic; Each R is independently hydrogen or C1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring H is a fused ring selected from a 7- to 9-membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and Ring E is optionally further substituted with 1 to 2 oxo groups; L 1 is a covalent bond or C 1-3 wherein one to two methylene units of said chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3 or 4.

[0200] [ka] is shown on ring E or ring H, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0201] -(R 2 ) m When the attachment points of -(R 2 ) mIt is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0202] [ka] are shown on ring E and ring H, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0203] In some embodiments, the compound of formula Ik above has formula I-k' or formula I-k'': [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, ring E, ring H, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 and m are each as defined above.

[0204] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein; X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or optionally substituted C 1-4 It is aliphatic; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -C(R )2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R; Each R 6 independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring H is a ring selected from 7-9 membered saturated or partially unsaturated carbocyclyl or heterocyclyl rings having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and Ring E is optionally further substituted with 1-2 oxo groups; and m is 0, 1, 2, 3 or 4.

[0205] [ka] is shown on ring E or ring H, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0206] -(R 2 ) m When the attachment points of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0207] [ka] are shown on ring E and ring H, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

[0208] In some embodiments, the compound of formula II above can be represented by formula II' or formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, ring E, ring H, L, R 1 , R 2 , X 1 , and m are as defined above.

[0209] In some embodiments, the compound of formula Im above has the formula Im-1: [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, L, Tamaki E, X 1 , R 1 , R 2 , and m are as defined above.

[0210] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 is a covalent bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: X 2 is a carbon atom or a silicon atom; X 3 is a divalent moiety selected from -CR2-, -NR-, -O-, -S-, or -Si(R2)-; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, or optionally substituted C 1-4 It is aliphatic; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O )N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R )S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of ring I and ring J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring K is a fused ring selected from a 6- to 12-membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and Ring H is optionally further substituted with 1 to 2 oxo groups; L 1 is a covalent bond or C 1-3wherein one to two methylene units of said chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2-, or -(C)=CH-; and m is 0, 1, 2, 3 or 4.

[0211] [ka] are shown on ring I, ring J, and ring K, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0212] -(R 2 ) m When the attachment points of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0213] [ka] are shown on ring I, ring J, and ring K, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0214] In some embodiments, the compound of formula In above can be represented by formula In' or formula In: [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, Ring I, Ring J, Ring K, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 and m are each as defined above.

[0215] In certain embodiments, the present invention provides compounds of formula Io: [ka] or a pharmaceutically acceptable salt thereof, wherein: X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or optionally substituted C 1-4 It is aliphatic; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -C(R )2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R; Each R 6 independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of ring I and ring J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring K is a fused ring selected from a 6- to 12-membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and Ring H is optionally further substituted with 1-2 oxo groups; and m is 0, 1, 2, 3 or 4.

[0216] [ka] are shown on ring I, ring J, and ring K, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0217] -(R 2 ) m When the attachment points of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0218] [ka] are shown on ring I, ring J, and ring K, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atoms to which Ring I, Ring J, and Ring K are fused.

[0219] In some embodiments, the compound of formula Io above can be represented by formula I-o' or formula I-o'': [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, Ring I, Ring J, Ring K, L, R 1 , R 2 , X 1 , and m are as defined above.

[0220] In some embodiments, the compound of formula Io above has formula Io-1: [ka] or a pharmaceutically acceptable salt thereof, wherein: MBM, L, Ring I, Ring K, X 1 , R 1 , R 2 , and m are as defined above.

[0221] In certain embodiments, the present invention provides a method for treating a leukemia, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a leukemia, a leukemia, or a leukemia of formula Io-2 or Io-3: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein; Each R 2 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N R2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S (O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1-6an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of ring E, ring F, and ring G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each of ring E, ring F, and ring G is independently optionally further substituted with 1 to 2 oxo groups; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond or C 1-3 wherein one to two methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; and R4 , R 10 , R 11 , R 15 , W 1 , W 2 and X are as defined in WO 2019 / 099868, each of which is incorporated by reference in its entirety.

[0222] [ka] is shown on ring E, ring F or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on ring E, ring F, or ring G, including the ring in which ring E or ring G is fused to ring F.

[0223] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

[0224] [ka] is shown on ring E, ring F or ring G, [ka] It is intended, and one of ordinary skill in the art will understand, that the point of attachment of may be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom at which Ring E or Ring G is fused to Ring F.

[0225] As noted above, in another aspect, in certain embodiments, the present invention provides compounds of formula I-ii: [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and described in embodiments herein, and wherein: Ring M is, [ka] Selected from; X 1 , X 6 , and X 7 each independently represents a covalent bond, —CH—, —CHCF—, —SO—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR—, —C(O)—, —C(S)—, or [ka] is a divalent moiety selected from: X 3 and X 5 each is independently a divalent moiety selected from a covalent bond, -CR2-, -NR-, -O-, -S-, or -SiR2-; X 4 teeth, [ka] is a trivalent moiety selected from: Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 3a are independently hydrogen, deuterium, -R6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N R2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S (O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7 are independently hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR 2、 -P(O)(OR) 2、 -P(O)(NR2)OR, -P(O)(NR2) 2、 -Si(OH)R 2、 -Si(OH)2R, -SiR3, or optionally substituted C 1-4 Is aliphatic; or R 7 and X 1 or X 3 together with their intervening atoms form a 5- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur; Two R on the same carbon 7groups, optionally taken together with their intervening atoms, form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; Two R on adjacent carbon atoms 7 groups, optionally taken together with their intervening atoms, form a 3- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 7- to 13-membered saturated, partially unsaturated, bridged heterocyclic or spiro heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; Ring D is selected from a 6-10 membered aryl or heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7 membered saturated or partially unsaturated carbocyclyl, a 5-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L 1 is a covalent bond or C 1-3 wherein one to two methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3 or 4.

[0226] X, as defined above and described herein 1 is a covalent bond, -CH 2、 -C(R)2-, -C(O)-, -C(S)-, -CH(R)-, -CH(CF3)-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S(O)-, -S(O)2-, or [ka] is a divalent moiety selected from

[0227] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 is -CH-. In some embodiments, X 1 is -C(R)-. 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)—. 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)(NR2)-. In some embodiments, X 1 is —S(O)—. In some embodiments, X 1 is -S(O)-. In some embodiments, X 1 teeth, [ka] is.

[0228] In some embodiments, X 1 is selected from those shown in Table 1 below.

[0229] X, as defined above and described herein 2 is a carbon atom or a silicon atom.

[0230] In some embodiments, X 2 is a carbon atom. In some embodiments, X 2 is a silicon atom.

[0231] In some embodiments, X 2 is selected from those shown in Table 1 below.

[0232] X, as defined above and described herein 3 is a divalent moiety selected from -CH2-, -C(R)2-, -N(R)-, -CF2-, -CHF-, -S-, -CH(R)-, -Si(R2)-, or -O-.

[0233] In some embodiments, X 3 is -CH-. In some embodiments, X 1 is -C(R)-. In some embodiments, X 3 is -N(R)-. In some embodiments, X 3 is -CF-. 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 —Si(R)—. In some embodiments, X 3 is -O-.

[0234] In some embodiments, X 3 is selected from those shown in Table 1 below.

[0235] R, as defined above and described herein 1 represents hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, optionally substituted C 1-4 aliphatic or R 1 and X 1 or X 4together with their intervening atoms form a 5- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0236] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is deuterium. In some embodiments, R 1 is 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)R. In some embodiments, R 1 is -NR2. In some embodiments, R 1 is -P(O)(OR). In some embodiments, R 1 is -P(O)(NR2)OR. In some embodiments, R 1 is —P(O)(NR) . In some embodiments, R 1 is —Si(OH)R. In some embodiments, R 1 is —Si(OH)(R). In some embodiments, R 1 is —Si(R). In some embodiments, R 1 is replaced by C 1-4 In some embodiments, R 1 and X 1 or X 4 together with their intervening atoms form a 5- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0237] In some embodiments, R 1 is selected from those shown in Table 1 below.

[0238] Each R is independently hydrogen, deuterium, or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or: Two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0239] In some embodiments, R is hydrogen. In some embodiments, R is deuterium. In some embodiments, R is optionally substituted C 1-6 It is aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0240] In some embodiments, R is selected from those shown in Table 1 below.

[0241] R, as defined above and described herein 2 and R 3aeach independently represents hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -Si(OH)2R, -Si(OH)R 2、 -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR 2、 -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)NR 2、 -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R) C(O)NR2, -N(R)S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R.

[0242] In some embodiments, R 2 and R 3a are independently hydrogen. In some embodiments, R 2 and R 3a is independently deuterium. In some embodiments, R 2 and R 3a is independently -R 6 In some embodiments, R 2 and R 3a are independently halogen. In some embodiments, R 2 and R 3a is independently —CN. In some embodiments, R 2 and R 3a is independently —NO. In some embodiments, R 2 and R 3a is independently -OR. In some embodiments, R 2 and R 3a are independently —Si(OH)R. In some embodiments, R 2 and R 3a are independently —Si(OH)R. In some embodiments, R 2 and R3a is independently -SR. In some embodiments, R 2 and R 3a is independently -NR. In some embodiments, R 2 and R 3a is independently -SiR. In some embodiments, R 2 and R 3a is independently —S(O)R. In some embodiments, R 2 and R 3a is independently —S(O)NR. In some embodiments, R 2 and R 3a is independently —S(O)R. In some embodiments, R 2 and R 3a is independently —C(O)R. In some embodiments, R 2 and R 3a is independently —C(O)OR. In some embodiments, R 2 and R 3a is independently —C(O)NR. In some embodiments, R 2 and R 3a is independently —C(O)N(R)OR. In some embodiments, R 2 and R 3a is independently —C(R)N(R)C(O)R. In some embodiments, R 2 and R 3a is independently —C(R)N(R)C(O)NR. In some embodiments, R 2 and R 3a is independently —OC(O)R. In some embodiments, R 2 and R 3a is independently —OC(O)NR. In some embodiments, R 2 and R 3a is independently —OP(O)R. In some embodiments, R 2 and R 3a is independently -OP(O)(OR). In some embodiments, R 2 and R 3ais independently -OP(O)(OR)NR. In some embodiments, R 2 and R 3a are independently -OP(O)(NR)-. In some embodiments, R 2 and R 3a is independently —N(R)C(O)OR. In some embodiments, R 2 and R 3a is independently —N(R)C(O)R. In some embodiments, R 2 and R 3a are independently —N(R)C(O)NR. In some embodiments, R 2 and R 3a is independently -NP(O)R. In some embodiments, R 2 and R 3a is independently —N(R)P(O)(OR). In some embodiments, R 2 and R 3a are independently —N(R)P(O)(OR)NR. In some embodiments, R 2 and R 3a is independently —N(R)P(O)(NR). In some embodiments, R 2 and R 3a are independently -N(R)S(O)R.

[0243] In some embodiments, R 2 and R 3a is independently —OH. In some embodiments, R 2 and R 3a is independently —NH. In some embodiments, R 2 and R 3a is independently —CH NH . In some embodiments, R 2 and R 3a is independently —CHNHCOMe. In some embodiments, R 2 and R 3a is independently —CHNHCONHMe. In some embodiments, R 2 and R 3ais independently -NHCOMe. In some embodiments, R 2 and R 3a is independently -NHCONHEt. In some embodiments, R 2 and R 3a is independently -SiMe. In some embodiments, R 2 and R 3a is independently —SiMeOH. In some embodiments, R 2 and R 3a is independently —SiMe(OH). In some embodiments, R 2 and R 3a is independent [ka] In some embodiments, R 2 and R 3a is independently Br. In some embodiments, R 2 and R 3a is independently Cl. In some embodiments, R 2 and R 3a is independently F. In some embodiments, R 2 and R 3a is independently Me. In some embodiments, R 2 and R 3a is independently -NHMe. In some embodiments, R 2 and R 3a is independently -NMe. In some embodiments, R 2 and R 3a is independently -NHCOEt. In some embodiments, R 2 and R 3a is independently —CN. In some embodiments, R 2 and R 3a is independently -CHPh. In some embodiments, R 2 and R 3a is independently -NHCO2tBu. In some embodiments, R 2 and R 3ais independently -CO2tBu. In some embodiments, R 2 and R 3a is independently -OMe. In some embodiments, R 2 and R 3a are independently -CF3.

[0244] In some embodiments, R 2 or R 3a is selected from those shown in Table 1 below.

[0245] R, as defined above and described herein 3 represents hydrogen, deuterium, halogen, -CN, -NO2, -OR, -NR2, -SR, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NR(OR), -OC(O)R, -OC(O)NR2, -OP(O)(OR)2, -OP(O)(NR2)2, -OP(O)(OR)NR2, -N(R )C(O)R, -N(R)C(O)OR, -N(R)C(O)NR2, -N(R)S(O)2R, -N(R)S(O)2NR2, -N(R)P(O)(OR)2, -N(R)P(O )(OR)NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, or -Si(R)3.

[0246] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is —NO. In some embodiments, R 3 is -OR. In some embodiments, R 3 is -NR2. In some embodiments, R 3 is -SR. In some embodiments, R 3is —S(O)R. In some embodiments, R 3 is —S(O)NR. 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. 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. In some embodiments, R 3 is -OP(O)(OR). In some embodiments, R 3 is -OP(O)(NR). In some embodiments, R 3 is -OP(O)(OR)NR. 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. In some embodiments, R 3 is —N(R)S(O)R. In some embodiments, R 3 is —N(R)S(O)NR. In some embodiments, R 3 is —N(R)P(O)(OR). In some embodiments, R 3 is —N(R)P(O)(OR)NR. In some embodiments, R 3 is -P(O)(OR). In some embodiments, R 3 is -P(O)(NR2)OR. In some embodiments, R 3 is —P(O)(NR) . In some embodiments, R 3 is —Si(OH)R. In some embodiments, R 3 is —Si(OH)(R). In some embodiments, R3 is -Si(R)3.

[0247] In some embodiments, R 3 is methyl. In some embodiments, R 3 is —OCH. In some embodiments, R 3 is chloro.

[0248] In some embodiments, R 3 is selected from those shown in Table 1 below.

[0249] As defined above and described herein, each R 4 are independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2.

[0250] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 -R 6 In some embodiments, R 4 is halogen. In some embodiments, R 4 is -CN. In some embodiments, R 4 is —NO. In some embodiments, R 4 is -OR. In some embodiments, R 4 is -SR. In some embodiments, R 4 is -NR2. In some embodiments, R 4 is —S(O)R. In some embodiments, R 4 is —S(O)NR. In some embodiments, R 4is -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. 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. 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. In some embodiments, R 4 is —N(R)S(O)R. In some embodiments, R 4 is -P(O)(OR). In some embodiments, R 4 is -P(O)(NR2)OR. In some embodiments, R 4 is -P(O)(NR2)2.

[0251] In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is cyclopropyl.

[0252] In some embodiments, R 4 is selected from those shown in Table 1 below.

[0253] R, as defined above and described herein 5 is hydrogen, deuterium, optionally substituted C 1-4 It is aliphatic, or -CN.

[0254] In some embodiments, R 5 is hydrogen. In some embodiments, R5 is deuterium. In some embodiments, R 5 is replaced by C 1-4 In some embodiments, R 5 is -CN.

[0255] In some embodiments, R 5 is selected from those shown in Table 1 below.

[0256] As defined above and described herein, each R 6 independently, C 1-6 An optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0257] In some embodiments, R 6 is replaced by C 1-6 In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 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 having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur.

[0258] In some embodiments, R 6 is selected from those shown in Table 1 below.

[0259] As generally defined above, each R 7are independently hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -P(O)(R)2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)R2, -Si(OH)2R, -SiR3, or optionally substituted C 1-4 aliphatic or R 7 and X 1 or X 3 together with their intervening atoms form a 5- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or two R on the same carbon 7 groups, optionally taken together with their intervening atoms, form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; Two R on adjacent carbon atoms 7 The groups, optionally taken together with their intervening atoms, form a 3- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 7- to 13-membered saturated, partially unsaturated, bridged heterocyclic or spiro heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[0260] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is halogen. In some embodiments, R 7 is -CN. In some embodiments, R 7 is -OR. In some embodiments, R 7 is -SR. In some embodiments, R 7 is -S(O)R. In some embodiments, R 7 is —S(O)R. In some embodiments, R7 is -NR2. In some embodiments, R 7 is —Si(R). In some embodiments, R 7 is -P(O)(R). In some embodiments, R 7 is -P(O)(OR). In some embodiments, R 7 is -P(O)(NR2)OR. In some embodiments, R 7 is —P(O)(NR) . In some embodiments, R 7 is —Si(OH)R. In some embodiments, R 7 is —Si(OH)R. In some embodiments, R 7 is replaced by C 1-4 In some embodiments, R 7 and X 1 or X 3 are taken together with their intervening atoms to form a 5- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, two R on the same carbon 7 The groups, optionally taken together with their intervening atoms, form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, two R groups on adjacent carbon atoms may be 7 The groups, optionally taken together with their intervening atoms, form a 3- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, two R groups on adjacent carbon atoms may be bonded to each other. 7 The groups, optionally taken together with their intervening atoms, form a 7- to 13-membered saturated, partially unsaturated, bridged, or spiroheterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[0261] In some embodiments, R7 is hydrogen, halogen, -CN, -OR, -NR2, or C 1-4 In some embodiments, R 7 is hydrogen, halogen, -CN, or C 1-4 In some embodiments, R 7 is fluoro. In some embodiments, two R on the same carbon 7 The groups, optionally taken together with their intervening atoms, form a 3- or 4-membered spiro-fused ring.

[0262] In some embodiments, R 7 is selected from those shown in Table 1 below.

[0263] As defined above and described herein, ring A is [ka] [ka] is a bicyclic or tricyclic ring selected from:

[0264] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0265] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0266] In some embodiments, ring A is selected from those shown in Table 1 below.

[0267] As defined above and described herein, Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-7-membered saturated or partially unsaturated carbocyclyl, a 5-7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0268] In some embodiments, ring B is a fused 6-membered aryl. In some embodiments, ring B is a fused 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is a fused 5-7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring B is a fused 5-7-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring B is a fused 5-membered heteroaryl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[0269] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0270] In some embodiments, each ring B is [ka] In some embodiments, each ring B is [ka] In some embodiments, each ring B is [ka] In some embodiments, each ring B is [ka] In some embodiments, ring B is [ka] is.

[0271] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0272] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0273] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0274] In some embodiments, ring B is [ka] [ka] is selected from.

[0275] In some embodiments, ring B is selected from those shown in Table 1 below.

[0276] As defined above and described herein, Ring C is [ka] is a monocyclic or bicyclic ring selected from:

[0277] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] is.

[0278] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] is.

[0279] In some embodiments, ring C is [ka] [ka] [ka] [ka] [ka] is a monocyclic or bicyclic ring selected from:

[0280] In some embodiments, ring C is [ka] is selected from.

[0281] In some embodiments, ring C is [ka] is selected from.

[0282] In some embodiments, ring C is selected from those shown in Table 1 below.

[0283] As defined above and described herein, Ring D is selected from a 6-10 membered aryl or heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-7 membered saturated or partially unsaturated carbocyclyl, a 5-7 membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0284] In some embodiments, ring D is a 6- to 10-membered aryl. In some embodiments, ring D is a 6- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring D is a 5- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring D is a 5- to 7-membered saturated or partially saturated heterocyclyl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring D is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[0285] In some embodiments, Ring D is isoquinoline. In some embodiments, Ring D is imidazo[1,2-a]pyridine.

[0286] In some embodiments, ring D is selected from those shown in Table 1 below.

[0287] As defined above and described herein, each of rings E, F, and G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each of rings E, F, and G is independently optionally further substituted with 1 to 2 oxo groups.

[0288] In some embodiments, each ring E, ring F, and ring G is independently a 6-membered aryl. In some embodiments, each ring E, ring F, and ring G is independently a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each ring E, ring F, and ring G is independently a 5 to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, each ring E, ring F, and ring G is independently a 5 to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, each ring E, ring F, and ring G is independently a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each of ring E, ring F, and ring G is independently optionally further substituted with 1 to 2 oxo groups.

[0289] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] is.

[0290] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] In some embodiments, ring F is [ka] is.

[0291] In some embodiments, each ring E and ring G is independently: [ka] In some embodiments, each ring E and ring G is independently: [ka] In some embodiments, each ring E and ring G is independently: [ka] In some embodiments, each ring E and ring G is independently: [ka] In some embodiments, ring E and ring G are independently: [ka] is.

[0292] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently. In some embodiments, ring E and ring G are independently [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] is.

[0293] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] In some embodiments, ring E and ring G are independently: [ka] is.

[0294] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, rings E, F and G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] is.

[0295] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] In some embodiments, ring E, ring F, and ring G are [ka] is.

[0296] In some embodiments, ring E, ring F, and ring G are selected from those shown in Table 1 below.

[0297] As defined above and described herein, Ring H is a ring selected from 7-9 membered saturated or partially unsaturated carbocyclyl or heterocyclyl rings having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and Ring E is optionally further substituted with 1-2 oxo groups.

[0298] In some embodiments, Ring H is a ring selected from a 7-9 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and Ring H is optionally further substituted with 1-2 oxo groups.

[0299] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] In some embodiments, ring H is [ka] is.

[0300] In some embodiments, ring E and ring H are [ka] is.

[0301] In some embodiments, ring E and ring H are selected from those shown in Table 1 below.

[0302] As defined above and described herein, each of ring I and ring J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0303] In some embodiments, each of ring I and ring J is independently a 6-membered aryl. In some embodiments, each of ring I and ring J is independently a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each of ring I and ring J is independently a 5 to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, each of ring I and ring J is independently a 5 to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, each of ring I and ring J is independently a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0304] In some embodiments, each ring I and ring J is independently: [ka] In some embodiments, each ring I and ring J is independently: [ka] In some embodiments, each ring I and ring J is independently: [ka] In some embodiments, each ring I and ring J is independently: [ka] In some embodiments, ring I and ring J are independently: [ka] is.

[0305] In some embodiments, ring I and ring J are independently: [ka] In some embodiments, ring I and ring J are independently: [ka] In some embodiments, ring I and ring J are independently: [ka] is.

[0306] As defined above and described herein, ring K is a fused ring selected from a 6- to 12-membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and ring H is optionally further substituted with 1 to 2 oxo groups.

[0307] In some embodiments, ring K is a fused ring selected from a 6- to 12-membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring K is a 6- to 12-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring K is optionally further substituted with 1 to 2 oxo groups.

[0308] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] In some embodiments, ring K is [ka] is.

[0309] In some embodiments, ring I, ring J, and ring K are [ka] is.

[0310] In some embodiments, ring I, ring J, and ring K are selected from those shown in Table 1 below.

[0311] As defined above and described herein, ring M is [ka] is selected from.

[0312] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] In some embodiments, ring M is [ka] is.

[0313] In some embodiments, ring M is selected from those shown in Table 1 below.

[0314] As defined above and described herein, L 1 is a covalent bond or C 1-3 wherein one to two methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-.

[0315] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is C 1-3 In some embodiments, L 1 is -CH-. In some embodiments, L 1 is -C(D)(H)-. In some embodiments, L 1 is -C(D)2-. In some embodiments, L 1 is -CHCH-. In some embodiments, L 1 is -NR-. In some embodiments, L 1 is -CHNR-. In some embodiments, L1 is —O—. In some embodiments, L 1 is —CH2O—. In some embodiments, L 1 is -S-. In some embodiments, L 1 is -OC(O)-. In some embodiments, L 1 is —C(O)O—. In some embodiments, L 1 is —C(O)—. In some embodiments, L 1 is —S(O)—. In some embodiments, L 1 is -S(O)-. In some embodiments, L 1 is -NRS(O)-. In some embodiments, L 1 is -S(O)NR-. In some embodiments, L 1 is -NRC(O)-. In some embodiments, L 1 is —C(O)NR—.

[0316] In some embodiments, ring L 1 is selected from those shown in Table 1 below.

[0317] As defined above and described herein, [ka] is a single or double bond.

[0318] In some embodiments, [ka] is a single bond. In some embodiments, [ka] is a double bond.

[0319] In some embodiments, [ka] is selected from those shown in Table 1 below.

[0320] As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0321] 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. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13. In some embodiments, m is 14. In some embodiments, m is 15. In some embodiments, m is 16.

[0322] In some embodiments, m is selected from those shown in Table 1 below.

[0323] As defined above and described herein, n is 0, 1, 2, 3, or 4.

[0324] 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.

[0325] In some embodiments, n is selected from those shown in Table 1 below.

[0326] As defined above and described herein, p is 0 or 1.

[0327] In some embodiments, p is 0. In some embodiments, p is 1.

[0328] In some embodiments, p is selected from those shown in Table 1 below.

[0329] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0330] In certain embodiments, the present invention provides a method for treating a leukemia, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a leukemia, a leukemia, or a leukemia having the formula Ip-1, Ip-2, or Ip-3, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described herein, and the variable R 1 , R 2 , R 4 , R 5 , R 10 , R 11 , R 14 , R 17 , W 1 , W 2 ,X, [ka] and each of n is as defined in WO2017 / 197051, which is incorporated herein by reference in its entirety; [ka] is R as defined in WO2017 / 197051 12 R at the binding site of 1 , R 1 and R 2 or R 17 is bound to, resulting in [ka] This R 12 It takes the place of a substituent.

[0331] In some embodiments, the present invention provides methods for treating HIV-1-associated ... [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described herein, and the variable R 1 , R 4 , R 10 , R 11 , R 14 , R 16 , W 1 , W 2 ,X, [ka] and each of n is as defined in WO2018 / 237026, the entire contents of each of which are incorporated herein by reference; [ka] is R as defined in WO2018 / 237026 12 R at the binding site of 1 or R 16 is bound to, resulting in [ka] This R 12 It takes the place of a substituent.

[0332] In certain embodiments, the present invention provides a method for the production of LBM comprising the steps of: or HDM2) E3 ligase binding moiety, thereby having the formula Iq-1, Iq-2, Iq-3, Iq-4, Iq-5, Iq-6, Iq-7, Iq-8, Iq-9, Iq-10, Iq-11, Iq-12, Iq-13, Iq-14, Iq-15, Iq-16, Iq-17 or Iq-18, respectively: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and MDM2 are as defined above and as described in embodiments herein, and the variables R1, R2, R3, R4, R5, R 6、 R 7、 R 8、 R 9、 R 10、 R 11、 R 12、 R 13、 R 14、 R 15、 R 16、 R 17、 R 18、 R 19、 R 20、 R 21、 R 22、 R 23、 R 24、 R 25、 R 26、 R 27、R 28、 R 1’、 R 2’、 R 3’、 R 4’、 R 5’、 R 6’、 R 7’、 R 8’、 R 9’、 R 10’、 R 11’、 R 12’、 R 1’’、 Each of A, A', A'', X, Y, and Z is as defined and described in WO2017 / 011371 and US2017 / 008904, each of which is incorporated by reference in its entirety.

[0333] In some embodiments, the compound of formula Iq-1, Iq-2, Iq-3, Iq-4, Iq-5, Iq-6, Iq-7, Iq-8, Iq-9, Iq-10, Iq-11, Iq-12, Iq-13, Iq-14, Iq-15, Iq-16, Iq-17, or Iq-18 can be selected from the group consisting of I-aaa-1, I-aaa-2, I-aaa-3, I-aaa-4, I-aaa-5, I-aaa-6, I-aaa-7, I-aaa-8, I-aaa-9, I-aaa-10, I-aaa-11, I-aaa-12, I-aaa-13, I-aaa-14, I-aaa-15, I-aaa-16, I-aaa-17, I-aaa-18, I-aaa-19, I-aaa-20, I-aaa-21, I-aaa-22, I-aaa-23, I-aaa-24, I-aaa-25, I-aaa-26, I-aaa-27, I-aaa-28, I-aaa-29, I-aaa-30, I-aaa-31, I-aaa-32, I-aaa-33, I-aaa-34, I-aaa-35, I-aaa-36, I-aaa-37, I-aaa-38, I-aaa-39, I-aaa-40, I-aaa-41, I-aaa-42, I-aaa-43, I-aaa-44, I-aaa-45, 4, I-aaa-5, I-aaa-6, I-aaa-7, I-aaa-8, I-aaa-9, I-aaa-10, I-aaa-11, I-aaa-12, I-aaa-13, I-aaa-14, I-aaa-15, I-aaa-16, I-aaa-17, I-aaa-18, I-aaa-19, or I-aaa-20.

[0334] In certain embodiments, the present invention provides a method for the preparation of a nucleotide sequence of formula Iq-19, Iq-20, or Iq-21, respectively, wherein the LBM is an MDM2 (i.e., human double minute 2 or HDM2) E3 ligase binding moiety, thereby providing a nucleotide sequence of formula Iq-19, Iq-20, or Iq-21, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and MDM2 are as defined above and as described in embodiments herein, and the variable R 12c , R 12d , R 13 , R 17 , R18b , R 18c , R 18d , A 5 , A 6 , A 7 , Q 1 Each of Ar and Ar is as defined and described in WO2017 / 176957 and US2019 / 127387, each of which is incorporated by reference in its entirety.

[0335] In some embodiments, the compounds of formula Iq-19, Iq-20, or Iq-21 are defined by the definitions of formula I-bbb-1, I-bbb-2, and I-bbb-3 above.

[0336] In some embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described herein, and the variable R 1 , R 14 , and R 16 each as defined in WO2018 / 237026, the entire contents of which are incorporated herein by reference; [ka] is R as defined in WO2018 / 237026 12 R at the binding site of 1 or R 16 is bound to, resulting in [ka] This R 12 It takes the place of a substituent.

[0337] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in the embodiments herein, and each of the variables A, B, C, W, X, Y, and Z are as described and defined in U.S. Pat. No. 5,721,246, the entirety of each of which is incorporated herein by reference.

[0338] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein, and each of the variables R1, R2, and n are as described and defined in WO2019 / 043214, each of which is incorporated by reference in its entirety.

[0339] In some embodiments, the LBM is an IAP E3 ubiquitin ligase binding moiety, as described in Varfolomeev, E. et al., IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB activation, and TNFα-Dependent Apoptosis, Cell, 2007, 131(4):669-81, e.g., [ka] During the ceremony, [ka] is attached to a modifiable carbon, oxygen, nitrogen, or sulfur atom.

[0340] In certain embodiments, the present invention provides an IAP E3 ubiquitin ligase binding moiety, whereby the LBM is an IAP E3 ubiquitin ligase binding moiety, represented by formula Iu-1, Iu-2, Iu-3, or Iu-4, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein, and the variable R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 each as defined and described in WO2017 / 011590 and US2007 / 037004, each of which is incorporated by reference herein in its entirety.

[0341] In certain embodiments, the present invention provides a method for treating a leukemia where the LBM is an IAP binding moiety, such as a leukemia of formula IV: [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein, and the variables W, Y, Z, R 1 , R 2 , R 3 , R 4 , and R 5 each as described and defined in WO2014 / 044622, US2015 / 0225449, WO2015 / 071393, and US2016 / 0272596, each of which is incorporated by reference in its entirety.

[0342] In certain embodiments, the present invention provides compounds wherein the LBM is an MDM2 binding moiety, such as those of formula Iw: [ka] or a pharmaceutically acceptable salt thereof (as described and defined in Hines, J. et al., Cancer Res. (DOI: 10.1158 / 0008-5472.CAN-18-2918)), each of which is incorporated herein by reference in its entirety.

[0343] In certain embodiments, the present invention provides a compound wherein the LBM is a DCAF16 binding moiety, such that the compound has formula Ix: [ka] or a pharmaceutically acceptable salt thereof (as described and defined in Zhang, X. et al., bioRxiv (doi: https: / / doi.org / 10.1101 / 443804)), each of which is incorporated herein by reference in its entirety.

[0344] In certain embodiments, the present invention provides compounds wherein the LBM is an RNF114 binding moiety, such as a compound of formula Iy: [ka] or a pharmaceutically acceptable salt thereof (as described and defined in Spradin, JNet al., bioRxiv (doi: https: / / doi.org / 10.1101 / 436998)), each of which is incorporated herein by reference in its entirety.

[0345] In certain embodiments, the present invention provides a compound wherein the LBM is an RNF4 binding moiety, such as a compound of formula Iz: [ka] or a pharmaceutically acceptable salt thereof (as described and defined in Ward, CC, et al., bioRxiv (doi: https: / / doi.org / 10.1101 / 439125)), each of which is incorporated herein by reference in its entirety.

[0346] In certain embodiments, the present invention provides a compound wherein the LBM is a VHL binding moiety, whereby the compound has formula I-aa-1 or I-aa-2: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas I-aa-1 and I-aa-2, L and MBM are as defined above and as described in embodiments herein, and variable R 1 , R 2 , R 3 , X, and Y are each as defined and described in WO 2019 / 084026, the entirety of each of which is incorporated herein by reference.

[0347] In certain embodiments, the present invention provides a compound wherein the LBM is a VHL binding moiety, whereby the compound has formula I-aa-3 or I-aa-3: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas I-aa-3 and I-aa-3, L and MBM are as defined above and as described in embodiments herein, and variable R 1 , R 3 and Y are each as defined and described in WO 2019 / 084030, the entirety of each of which is incorporated herein by reference.

[0348] In certain embodiments, the present invention provides a method for treating a fibronectin-binding protein (FBMP) comprising administering to a subject therapies comprising administering to a subject therapies a method for treating a fibronectin-binding protein ... [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas I-bb-1, I-bb-2, I-bb-3, and I-bb-4, L and MBM are as defined above and described herein, and variable R 4 , R 10 , R 11 , R 15 , R 16 , R 17 , W 1 , W 2 and each of X is as defined in WO 2019 / 099868, which is incorporated herein by reference in its entirety; and [ka] is R as defined in WO 2018 / 237026 17 or R 16 To, R 12 binding site, resulting in [ka] But this R 12 Occupy the position of the substituent.

[0349] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0350] In certain embodiments, the present invention provides a method for treating a ubiquitin ligase (cereblon)-binding moiety, whereby the LBM is an E3 ubiquitin ligase (cereblon)-binding moiety, such as represented by formula I-cc: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-cc, L and MBM are as defined above and as described in embodiments herein, and wherein: each X 1 are independently -CH2-, -O-, -NR-, -CF2-, [ka] , -C(O)-, -C(S)-, or [ka] and; X 2 and X 3 are independently -CH2-, -C(O)-, -C(S)-, or [ka] and; Z 1 and Z 2 are independently a carbon atom or a nitrogen atom; Ring A x is a fused ring selected from benzo or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L x is a covalent bond, or C 1~3a divalent linear or branched saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are independently optionally replaced by -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, or -S(O)2-; Each R x are independently hydrogen, deuterium, R z , halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —CF2R, —CF3, —CR2(OR), —CR2(NR2), —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —C(S)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)R2, —OP(O)(OR)2, —OP(O)(OR)NR2, —OP(O)(NR2)2, —Si(OR)R2, and —SiR3; or 2 R's x optionally taken together form an optionally substituted 5- to 8-membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently selected from hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same carbon or nitrogen, optionally taken together with the atoms between them, form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R y teeth, [ka] or hydrogen; Ring B x is phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic, carbocyclic ring, or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein ring B x is further optionally substituted with 1 to 2 oxo groups; Each R w are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, and -SiR3; Each R z independently, C 1~6 selected from optionally substituted groups selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [ka] is a single or double bond; x is 0, 1, 2, 3 or 4; y is 0, 1, or 2; and w is 0, 1, 2, 3 or 4.

[0351] As defined above and described herein, each X 1 are independently -CH2-, -O-, -NR-, -CF2-, [ka] , -C(O)-, -C(S)-, or [ka] is.

[0352] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 is -CH2-. In some embodiments, X 1 is —O—. In some embodiments, X 1 is -NR-. In some embodiments, X 1 In some embodiments, X is —CF—. 1 teeth [ka] In some embodiments, X 1 is —C(O)—. In some embodiments, X 1 is -C(S)-. In some embodiments, X 1 teeth [ka] is.

[0353] In certain embodiments, X 1 is selected from those shown in the compounds of Table 1.

[0354] As defined above and described herein, X 2 and X 3 are independently -CH2-, -C(O)-, -C(S)-, or [ka] is.

[0355] In some embodiments, X 2 and X 3 is independently -CH-. In some embodiments, X 2 and X 3 is independently —C(O)—. In some embodiments, X 2 and X 3 is independently -C(S)-. In some embodiments, X 2 and X 3 is independent, [ka] is.

[0356] In certain embodiments, X 2 and X 3 are independently selected from those shown in the compounds of Table 1.

[0357] As defined above and described herein, Z 1 and Z 2 are independently carbon atoms or nitrogen atoms.

[0358] In some embodiments, Z 1 and Z 2 are independently carbon atoms. In some embodiments, Z 1 and Z 2 are independently carbon atoms.

[0359] In certain embodiments, Z 1 and Z 2 are independently selected from those shown in the compounds of Table 1.

[0360] Ring A, as defined above and described herein xis a fused ring selected from benzo or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0361] In some embodiments, ring A x In some embodiments, ring A is benzo. x is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0362] In some embodiments, ring A x teeth, [ka] In some embodiments, ring A x teeth, [ka] In some embodiments, ring A x teeth, [ka] In some embodiments, ring A x teeth, [ka] is.

[0363] In certain embodiments, ring A x is selected from those shown in the compounds of Table 1.

[0364] As defined above and described herein, L x is a covalent bond, or C 1~3wherein one to two methylene units of the chain are independently optionally replaced by -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, or -S(O)2-.

[0365] In some embodiments, L x is a covalent bond. In some embodiments, L x is C 1~3 wherein one to two methylene units of the chain are independently optionally replaced by -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, or -S(O)2-.

[0366] In some embodiments, L x is -C(O)-.

[0367] In certain embodiments, L x is selected from those shown in the compounds of Table 1.

[0368] As defined above and described herein, each R x are independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -Si(OR)R2, and -SiR3, or two R xare optionally joined together to form an optionally substituted 5- to 8-membered partially unsaturated or aryl fused ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0369] In some embodiments, R x is hydrogen. In some embodiments, R x is deuterium. In some embodiments, R x is R z In some embodiments, R x is halogen. In some embodiments, R x is -CN. In some embodiments, R x is —NO. In some embodiments, R x In some embodiments, R x In some embodiments, R x is -NR2. In some embodiments, R x is —S(O)R. In some embodiments, R x is —S(O)NR. In some embodiments, R x is -S(O)R. In some embodiments, R x is -CF2R. In some embodiments, R x is —CF. In some embodiments, R x is -CR2(OR). In some embodiments, R x is -CR2(NR2). In some embodiments, R x is —C(O)R. In some embodiments, R x is —C(O)OR. In some embodiments, R x is —C(O)NR. In some embodiments, R x is —C(O)N(R)OR. In some embodiments, R x is -OC(O)R. In some embodiments, R xis —OC(O)NR. In some embodiments, R x is —C(S)NR. In some embodiments, R x is —N(R)C(O)OR. In some embodiments, R x is —N(R)C(O)R. In some embodiments, R x is —N(R)C(O)NR. In some embodiments, R x is —N(R)S(O)R. In some embodiments, R x is -OP(O)R. In some embodiments, R x is -OP(O)(OR). In some embodiments, R x is -OP(O)(OR)NR. In some embodiments, R x is -OP(O)(NR). In some embodiments, R x is —Si(OR)R. In some embodiments, R x is -SiR. In some embodiments, two R x are optionally joined together to form an optionally substituted 5- to 8-membered partially unsaturated or aryl fused ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0370] In some embodiments, R x is fluoro. In some embodiments, R x is bromo. In some embodiments, R x is methyl. In some embodiments, R x is —OH. In some embodiments, R x is -NH2. In some embodiments, R x is -NHCH3. In some embodiments, R x is —N(CH). In some embodiments, R x is —NHCH(CH). In some embodiments, R xis —NHSO2CH3. In some embodiments, R x is —CHOH. In some embodiments, R x is —CH 2 NH 2 . In some embodiments, R x is —C(O)NH. In some embodiments, R x is —C(O)NHCH. In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] In some embodiments, R x teeth, [ka] is.

[0371] In certain embodiments, each R x are independently selected from those shown in the compounds of Table 1.

[0372] As defined above and described herein, each R is independently selected from hydrogen or an optionally substituted group, which optionally substituted group is C 1~6 a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same carbon or nitrogen optionally taken together with the atoms between them form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0373] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1~6It is aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same carbon or nitrogen, together with atoms between them, optionally form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the carbon or nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0374] As defined above and described herein, R y teeth, [ka] or hydrogen.

[0375] In some embodiments, R y teeth, [ka] In some embodiments, R y is hydrogen.

[0376] In certain embodiments, R y is selected from those shown in the compounds of Table 1.

[0377] As defined above and described herein, ring B xis phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic, bicyclic, carbocyclic, or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein ring B x is further optionally substituted with 1 to 2 oxo groups.

[0378] In some embodiments, ring B x is phenyl. In some embodiments, ring B x is a 4- to 10-membered saturated or partially unsaturated monocyclic, bicyclic, carbocyclic, or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. x is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B x is further optionally substituted with 1 to 2 oxo groups.

[0379] In some embodiments, ring B x teeth, [ka] In some embodiments, ring B x teeth, [ka] In some embodiments, ring B x teeth, [ka] In some embodiments, ring B x teeth, [ka] In some embodiments, ring Bx teeth, [ka] is.

[0380] In certain embodiments, ring B x is selected from those shown in the compounds of Table 1.

[0381] As defined above and described herein, each R w are independently hydrogen, deuterium, R z , halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —CF2R, —CF3, —CR2(OR), —CR2(NR2), —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)R2, —OP(O)(OR)2, —OP(O)(OR)NR2, —OP(O)(NR2)2, and —SiR3.

[0382] In some embodiments, R w is hydrogen. In some embodiments, R w is deuterium. In some embodiments, R w is R z In some embodiments, R w is halogen. In some embodiments, R w is -CN. In some embodiments, R w is —NO. In some embodiments, R w In some embodiments, R w In some embodiments, R w is -NR2. In some embodiments, R w is —S(O)R. In some embodiments, R wis —S(O)NR. In some embodiments, R w is -S(O)R. In some embodiments, R w is -CF2R. In some embodiments, R w is —CF. In some embodiments, R w is -CR2(OR). In some embodiments, R w is -CR2(NR2). In some embodiments, R w is —C(O)R. In some embodiments, R w is —C(O)OR. In some embodiments, R w is —C(O)NR. In some embodiments, R w is —C(O)N(R)OR. In some embodiments, R w is -OC(O)R. In some embodiments, R w is —OC(O)NR. In some embodiments, R w is —N(R)C(O)OR. In some embodiments, R w is —N(R)C(O)R. In some embodiments, R w is —N(R)C(O)NR. In some embodiments, R w is —N(R)S(O)R. In some embodiments, R w is -OP(O)R. In some embodiments, R w is -OP(O)(OR). In some embodiments, R w is -OP(O)(OR)NR. In some embodiments, R w is -OP(O)(NR). In some embodiments, R w is -SiR3.

[0383] In certain embodiments, R w is selected from those shown in the compounds of Table 1.

[0384] As defined above and described herein, each Rz independently, C 1~6 An optionally substituted group selected from aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0385] In some embodiments, R z is replaced by C 1~6 In some embodiments, R z is optionally substituted phenyl. In some embodiments, R z is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R z is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0386] In some embodiments, R z teeth, [ka] In some embodiments, R z teeth, [ka] In some embodiments, R z teeth, [ka] In some embodiments, R z teeth, [ka] In some embodiments, R z teeth, [ka] In some embodiments, R z teeth, [ka] In some embodiments, R z teeth, [ka] is.

[0387] In certain embodiments, R z is selected from those shown in the compounds of Table 1.

[0388] As defined above and described herein, [ka] is a single or double bond.

[0389] In some embodiments, [ka] is a single bond. In some embodiments, [ka] is a double bond.

[0390] In certain embodiments, [ka] is selected from those shown in the compounds of Table 1.

[0391] As defined above and described herein, w is 0, 1, 2, 3, or 4.

[0392] In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4.

[0393] In certain embodiments, w is selected from those shown in the compounds of Table 1.

[0394] As defined above and described herein, x is 0, 1, 2, 3, or 4.

[0395] In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, m is 2. In some embodiments, x is 3. In some embodiments, x is 4.

[0396] In certain embodiments, x is selected from those shown in the compounds of Table 1.

[0397] As defined above and described herein, y is 0, 1, or 2.

[0398] In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.

[0399] In certain embodiments, y is selected from those shown in the compounds of Table 1.

[0400] In some embodiments, the present invention provides a compound comprising ring A x is benzo, y is 1, and X 1 is -CH2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-cc-1: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-cc-1, MBM, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0401] In some embodiments, the present invention provides a compound comprising ring A x is imidazolyl, y is 1, and X 1 is -CH2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-cc2: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-cc2, MBM, L, L x , and R y Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0402] In some embodiments, the present invention provides a compound comprising ring A x is imidazolyl, y is 1, and X 1 is -CH2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-cc-3: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-cc-3, MBM, L, L x , and R yEach of the is as defined above and described in embodiments herein, both alone and in combination.

[0403] In some embodiments, the present invention provides a compound comprising ring A x is oxazolyl, y is 1, and X 1 is -CH2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-cc-4: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formula I-cc-4, each of MBM and L, both alone and in combination, is as defined above and as described in embodiments herein.

[0404] In some embodiments, the present invention provides a compound comprising ring A x is benzo, y is 0, and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-cc-5: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-cc-5, MBM, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein. is.

[0405] In some embodiments, the present invention provides a compound comprising ring A x is benzo, y is 1, and X 1 is -O- and X 2and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-cc-6: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-cc-6, MBM, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0406] In some embodiments, the present invention provides a compound comprising ring A x is benzo, y is 1, and X 1 is -NR- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-cc-7: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-cc-7, MBM, L, L x , R, R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0407] In some embodiments, the present invention provides a compound comprising ring A x is benzo, y is 1, and X 1 is -CF2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-cc-8: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-cc-8, MBM, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0408] In some embodiments, the present invention provides a compound comprising ring A x is benzo, y is 1, and X 1 but [ka] and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-cc-9: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-cc-9, MBM, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0409] In some embodiments, the present invention provides a compound comprising ring A x is pyridyl, y is 1, and X 1 is -CH2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-cc-10: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-cc-10, MBM, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0410] In some embodiments, the present invention provides a compound comprising ring A x is pyridyl, y is 1, and X 1 is -CH2- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-cc-11: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-cc-11, MBM, L, L x , R x , R y and x, both alone and in combination, are as defined above and as described in embodiments herein.

[0411] In some embodiments, the present invention provides a compound wherein ring A is benzo, y is 1, and X 1 , X 2 and X 3 is -C(O)- and Z 1 and Z 2 and a carbon atom as shown in formula I-cc-12: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-cc-12, MBM, L, L x , R x , R yand x, both alone and in combination, are as defined above and as described in embodiments herein.

[0412] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is.

[0413] In some embodiments, the LBM is selected from those in Table 1 below.

[0414] In certain embodiments, the present invention provides compounds wherein the LBM is an RPN13 binding moiety, whereby the compound has formula I-dd: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formula I-dd, L and MBM are as defined above and in embodiments herein, and each of variables A, Y, and Z are as described and defined in WO 2019 / 165229, the entire contents of each of which are incorporated herein by reference.

[0415] In certain embodiments, the present invention provides a method for the preparation of a Ubr1-binding moiety, wherein the LBM is a Ubr1-binding moiety as described in Shanmugasundaram, K. et al, J. Bio. Chem. 2019, doi:10.1074 / jbc.AC119.010790, each of which is incorporated by reference herein in its entirety, whereby the LBM is represented by formula I-ee-1 or I-ee-2: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas I-ee-1 and I-ee-2, L and MBM are as defined above and as described in embodiments herein.

[0416] In certain embodiments, the present invention provides a method for the treatment of cancer, wherein the LBM is a CRBN binding moiety, thereby , Formula I-ff: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formula I-ff, L and MBM are as defined above and in embodiments herein, and each of the variables R1, R2, R3, R4, R5, Q, X, and n are as described and defined in US 2019 / 276474, the entire contents of each of which are incorporated herein by reference.

[0417] In certain embodiments, the present invention provides a method for the preparation of a CRBN E3 ubiquitin ligase-binding moiety, whereby the LBM is a CRBN E3 ubiquitin ligase-binding moiety of formula I-gg-1, I-gg-2, I-gg-3, or I-gg-4: [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein, and the variables Y, A 1 , and A 3 each as described and defined in WO 2019 / 236483, each of which is incorporated by reference in its entirety.

[0418] In some embodiments, the present invention provides that the MBM is [ka] and thereby formula I-hh-1: [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 , ring A, m, and L, both alone and in combination, are as defined above and described in the embodiments herein.

[0419] In some embodiments, the present invention provides that ring A is [ka] and MBM is as shown. [ka] and thereby formula I-hh-2: [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 Each of , m, and L, both alone and in combination, is as defined above and described in the embodiments herein.

[0420] In some embodiments, the present invention provides that the MBM is [ka] and thereby formula I-hh-3: [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 , ring A, m, and L, both alone and in combination, are as defined above and described in the embodiments herein.

[0421] In some embodiments, the present invention provides that ring A is [ka] and MBM is as shown. [ka] and thereby formula I-hh-4: [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 Each of , m, and L, both alone and in combination, is as defined above and described in the embodiments herein.

[0422] In some embodiments, the present invention provides that the MBM is [ka] and thereby formula I-hh-5: [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 , ring A, m, and L, both alone and in combination, are as defined above and described in the embodiments herein.

[0423] In some embodiments, the present invention provides that ring A is [ka] and MBM is as shown. [ka] and thereby formula I-hh-6: [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 Each of , m, and L, both alone and in combination, is as defined above and described in the embodiments herein.

[0424] In some embodiments, the present invention provides that the MBM is [ka] and thereby formula I-hh-7: [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 , ring A, m, and L, both alone and in combination, are as defined above and described in the embodiments herein.

[0425] In some embodiments, the present invention provides that ring A is [ka] and MBM is as shown. [ka] and thereby formula I-hh-8: [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 Each of , m, and L, both alone and in combination, is as defined above and described in the embodiments herein.

[0426] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (PTA) syndrome, comprising administering to a patient a therapeutically effective amount of MBM, as set forth herein. [ka] and having formula I-ii-1: [ka] or a pharmaceutically acceptable salt thereof, wherein the ring M, the ring D, the ring L, the ring L 1 , R 3a , R 7 , n, and q, both alone and in combination, are as defined above and described in the embodiments herein.

[0427] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (PTA) syndrome, comprising administering to a patient a therapeutically effective amount of MBM, as set forth herein. [ka] and LBM is [ka] and formula I-ii-2: [ka] or a pharmaceutically acceptable salt thereof, wherein L, R 3a , and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0428] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (PTA) syndrome, comprising administering to a patient a therapeutically effective amount of MBM, as set forth herein. [ka] and LBM is [ka] and formula I-ii-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L, R 3a , and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0429] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (PTA) syndrome, comprising administering to a patient a therapeutically effective amount of MBM, as set forth herein. [ka] and formula I-ii-4: [ka] or a pharmaceutically acceptable salt thereof, wherein the ring M, the ring D, the ring L, the ring L 1 , R 3a , R 7 , n, and q, both alone and in combination, are as defined above and described in the embodiments herein.

[0430] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (PTA) syndrome, comprising administering to a patient a therapeutically effective amount of MBM, as set forth herein. [ka] and LBM is [ka] and formula I-ii-5: [ka] or a pharmaceutically acceptable salt thereof, wherein L, R 3a , and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0431] In some embodiments, the present invention provides a method for treating a pulmonary arthritis (PTA) syndrome, comprising administering to a patient a therapeutically effective amount of MBM, as set forth herein. [ka] and LBM is [ka] and formula I-ii-6: [ka] or a pharmaceutically acceptable salt thereof, wherein L, R 3a , and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0432] In some embodiments, the present invention provides a compound of formula I-bbb-4: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1’’ is hydrogen and R A Selected from; Each R A independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 10 is selected from an optionally substituted monocyclic or bicyclic ring selected from phenyl, a 5-10 membered aryl, and a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 12 and R 13 are each independently hydrogen and R A Choose from or: R 12 and R 13 optionally taken together with their intervening atoms, form an optionally substituted 4-8 membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 18b , R 18c , and R 18d are each independently hydrogen, halogen, or R A and - selected from OR; Q 1 is an optionally substituted divalent radical selected from alkylenyl, phenylenyl, heteroarylenyl, cycloalkylenyl, and heterocyclenyl; L is a covalent bond or a divalent saturated or partially unsaturated straight-chain or branched C 1-20a hydrocarbon chain wherein 0 to 6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -C(O)O-, -C(O)-, -S(O)-, -SO2-, -NRSO2-, -SON2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or -NRC(O)O-; Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or partially unsaturated spiroheterocyclylenyl, 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, optionally taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [ka] is a divalent moiety selected from: R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1-4 It is aliphatic; Each R 2 are independently hydrogen, R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; Each R 6 independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A is [ka] [ka] is a bicyclic or tricyclic ring selected from Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R3 is selected from hydrogen, halogen, —OR, —N(R)2, or —SR; Each R 4 are independently hydrogen, R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; R 5 is hydrogen, C 1-4 is aliphatic, or -CN; and m is 0, 1, 2, 3 or 4.

[0433] In some embodiments, the present invention provides compounds of formula I-bbb-4 as any one of the following formulas: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 , ring A, m, L, R 1’’ , R 10 , R 12 , and R 13 Each of the following, both alone and in combination, is as defined above and described in the embodiments herein.

[0434] In some embodiments, the present invention provides a compound of formula I-bbb-4: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1’’ is hydrogen and RA Selected from; Each R A independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 10 is selected from an optionally substituted monocyclic or bicyclic ring selected from phenyl, a 5-10 membered aryl, and a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 12 and R 13 are each independently hydrogen and R A Choose from or: R 12 and R 13 optionally taken together with their intervening atoms, form an optionally substituted 4-8 membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 18b , R 18c , and R 18d are each independently hydrogen, halogen, or R A and - selected from OR; Q 1 is an optionally substituted divalent radical selected from alkylenyl, phenylenyl, heteroarylenyl, cycloalkylenyl, and heterocyclenyl; L is a covalent bond or a divalent saturated or partially unsaturated straight-chain or branched C 1-20 a hydrocarbon chain wherein 0 to 6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -C(O)O-, -C(O)-, -S(O)-, -SO2-, -NRSO2-, -SON2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or -NRC(O)O-; Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or partially unsaturated spiroheterocyclylenyl, 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, optionally taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Ring M is, [ka] Selected from; X 1 , X 6 , and X 7each independently represents a covalent bond, —CH—, —CHCF—, —SO—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR—, —C(O)—, —C(S)—, or [ka] is a divalent moiety selected from: X 3 and X 5 each is independently a divalent moiety selected from a covalent bond, -CR2-, -NR-, -O-, -S-, or -SiR2-; X 4 teeth, [ka] is a trivalent moiety selected from: Each R 3a are independently hydrogen, deuterium, R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N R2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S (O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R; Each R 6 independently, C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7are independently hydrogen, deuterium, halogen, -CN, -OR, or -SR; -S(O)R, -S(O)2R, -NR 2、 -P(O)(OR) 2、 -P(O)(NR2)OR, -P(O)(NR2) 2、 -Si(OH)R 2、 -Si(OH)2R, -SiR3, or optionally substituted C 1-4 Is aliphatic; or R 7 and X 1 or X 3 together with their intervening atoms form a 5- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur; Two R on the same carbon 7 groups, optionally taken together with their intervening atoms, form a 3- to 6-membered spiro-fused ring or a 4- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; Two R on adjacent carbon atoms 7 groups, optionally taken together with their intervening atoms, form a 3- to 7-membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 7- to 13-membered saturated, partially unsaturated, bridged heterocyclic or spiro heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; Ring D is selected from a 6-10 membered aryl or heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-7 membered saturated or partially unsaturated carbocyclyl, a 5-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or a 5 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 1 is a covalent bond or C 1-3wherein one to two methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S-, -S(O)2-, or -(C)=CH-; n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3 or 4.

[0435] In some embodiments, the present invention provides compounds of formula I-bbb-15 as any one of the following formulas: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 7 , ring D, n, q, L, R 1’’ , R 10 , R 12 , and R 13 Each of the following, both alone and in combination, is as defined above and described in the embodiments herein. Decomposition induction part (DIM)

[0436] In certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as described above and herein, and DIM is a degradation-inducing moiety selected from LBM, a lysine mimetic, or a hydrogen atom.

[0437] In some embodiments, the DIM is LBM as described above and herein. In some embodiments, the DIM is a lysine mimetic. In some embodiments, the covalent binding of ubiquitin to the MDM2 protein is achieved by the action of the lysine mimetic. In some embodiments, when the compound of formula I binds to MDM2, the lysine mimetic moiety undergoes ubiquitination, thereby marking MDM2 for degradation via the ubiquitin-proteasome pathway (UPP).

[0438] In some embodiments, DIM is [ka] In some embodiments, DIM is [ka] In some embodiments, DIM is [ka] is.

[0439] In some embodiments, the DIM is selected from those shown in Table 1 below.

[0440] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein each of STAT and L, both alone and in combination, is as defined above and as described in the embodiments herein.

[0441] In some embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein each of STAT and L, both alone and in combination, is as defined above and as described in the embodiments herein.

[0442] In some embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein each of STAT and L, both alone and in combination, is as defined above and as described in the embodiments herein.

[0443] In certain embodiments, the present invention provides a method for treating a leukemia where DIM is a lysine mimetic. [ka] and thereby forming a compound of formula I-dddd-1, I-dddd-2, or I-dddd-3, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and as described in embodiments herein, and the variable R 1 , R 4 , R 5 , A, B, E, Y, Y', Z, Z', and k are as defined and described in U.S. Pat. No. 7,622,496, each of which is incorporated herein by reference in its entirety. hydrogen atom

[0444] In some embodiments, DIM is a hydrogen atom. In some embodiments, covalent binding of ubiquitin to MDM2 protein is achieved via provided compounds in which DIM is a hydrogen atom. In some embodiments, when the compound of Formula I binds to MDM2, the hydrogen moiety results in ubiquitination, thereby marking STAT1 for degradation via the ubiquitin-proteasome pathway (UPP).

[0445] In some embodiments, the DIM is selected from those shown in Table 1 below.

[0446] In some embodiments, the present invention provides compounds wherein DIM is a hydrogen atom, thereby providing compounds of formula I-dddd-4: [ka] or a pharmaceutically acceptable salt thereof, wherein each of STAT and L, both alone and in combination, is as defined above and as described in the embodiments herein. Linker (L)

[0447] As defined above and described herein, L is a divalent moiety that links MBM to LBM or MBM to DIM.

[0448] In some embodiments, L is a bivalent moiety that links MBM to LBM. In some embodiments, L is a bivalent moiety that links MBM to DIM. In some embodiments, L is a bivalent moiety that links MBM to a lysine mimetic.

[0449] In some embodiments, L is a covalent bond or a divalent saturated or partially unsaturated straight-chain or branched C 1-50is a hydrocarbon chain, and 0 to 6 methylene units of L are independently -C(D)(H)-, -C(D)2-, -Cy-, -O-, -N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, [ka] where: Each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or partially unsaturated spiroheterocyclylenyl, 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, optionally taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0450] In some embodiments, L is selected from those shown in Table 1 below.

[0451] In some embodiments, each -Cy- is independently an optionally substituted bivalent phenylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered bicyclic arylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4- to 7-membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0452] In some embodiments, -Cy- is [ka] is.

[0453] In some embodiments, Cy- is selected from those depicted in Table 1 or Table 1A below.

[0454] In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, r is 7. In some embodiments, r is 8. In some embodiments, r is 9. In some embodiments, r is 10.

[0455] In some embodiments, r is selected from those depicted in Table 1 or Table 1A below.

[0456] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] is.

[0457] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] is.

[0458] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] is.

[0459] In some embodiments, L is selected from those shown in Table 1 or Table 1A below.

[0460] The point of attachment of L to MBM and DIM can be, for example, but not limited to, [ka] If [ka] It can be either of the following.

[0461] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0462] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0463] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0464] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0465] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0466] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0467] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0468] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0469] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0470] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0471] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0472] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0473] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0474] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0475] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0476] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0477] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0478] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0479] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0480] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0481] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0482] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0483] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0484] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0485] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0486] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0487] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0488] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0489] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0490] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0491] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0492] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0493] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0494] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below.

[0495] In some embodiments, a provided compound or a pharmaceutically acceptable salt thereof is MBM [ka] and LBM is selected from any of those in Table A below, and L is selected from any of those in Table B below. [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table B-1] [Table B-2] [Table B-3] [Table B-4] [Table B-5] [Table B-6] [Table B-7] [Table B-8] [Table B-9] [Table B-10] [Table B-11] Table B-12 Table B-13 Table B-14 Table B-15 Table B-16 Table B-17 Table B-18 Table B-19 Table B-20 Table B-21 Table B-22 Table B-23 Table B-24 Table B-25 Table B-26 Table B-27

[0496] In some embodiments, the present invention provides a compound having an MDM2 binding moiety as described and disclosed herein, an LBM as described in Table A above, and a linker as described in Table B above, or a pharmaceutically acceptable salt thereof.

[0497] Exemplary compounds of the present invention are set forth in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47

[0498] In some embodiments, the present invention provides a compound depicted in Table 1 above, or a pharmaceutically acceptable salt thereof. 4. General Methods of Providing the Compounds

[0499] The compounds of the invention may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by methods described in detail in the Examples herein.

[0500] In the following schemes, where particular protecting groups, leaving groups, or transformation conditions are illustrated, one skilled in the art will understand that other protecting groups, leaving groups, and transformation conditions are also suitable and contemplated. Such groups and transformation conditions are described in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M.B. Smith and J. March, 5 th Edition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, RC Larock, 2 nd Edition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T.W. Greene and P.G. M. Buts, 3 rd edition, John Wiley & Sons, 1999, each of which is incorporated herein by reference in its entirety.

[0501] As used herein, the phrase "oxygen protecting group" includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M.Wuts, 3 rdedition, John Wiley & Sons, 1999, the entire contents of each of which are incorporated herein by reference. Suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formates, benzoylformates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoates, 4,4-(ethylenedithio)pentanoates, pivalates (trimethylacetyl), crotonates, 4-methoxycrotonates, benzoates, p-benylbenzoates, 2,4,6-trimethylbenzoates, carbonates (methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

[0502] Amino protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3, which is incorporated herein by reference in its entirety. rd edition, John Wiley & Sons, 1999. Suitable amino-protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allylamines, amides, etc. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0503] In the schemes below, where provided compounds are formed that have a reactive moiety (e.g., an amine, alcohol, etc.), although not shown, it is generally recognized and well known by those skilled in the art that the reactivity of this reactive moiety can be masked by using an appropriate protecting group, which can be subsequently removed in situ or during another synthetic step.

[0504] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 1 below: Scheme 1: Synthesis of compounds of formula I [ka]

[0505] As illustrated in Scheme 1 above, amine A-1 is coupled to acid A-2 using coupling agent HATU in the presence of base DIPEA in DMF to form a compound of Formula I having a linker containing an amide bond. [ka] represent the portion of the linker between MBM and the terminal amino group of A-1, or the position of the linker between DIM and the terminal carboxyl group of A-2, respectively. Furthermore, the amide bond can be formed using coupling reagents known in the art (e.g., but not limited to, DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU).

[0506] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 2 below: Scheme 2: Synthesis of compounds of formula I [ka]

[0507] As illustrated in Scheme 2 above, amine A-1 is coupled to acid A-2 using the coupling agent PyBOP in DMF in the presence of base DIPEA to form a compound of Formula I having a linker containing an amide bond. [ka] represent the portion of the linker between MBM and the terminal amino group of A-1, or the position of the linker between DIM and the terminal carboxyl group of A-2, respectively. Furthermore, the amide bond can be formed using coupling reagents known in the art (e.g., but not limited to, DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU).

[0508] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 3 below: Scheme 3: Synthesis of compounds of formula I [ka]

[0509] As illustrated in Scheme 3 above, acid A-3 is coupled to amine A-4 in DMF using coupling agent HATU in the presence of base DIPEA to form a compound of Formula I having a linker containing an amide bond. [ka] represent the linker portion between MBM and the terminal carboxyl group of A-3, or the linker portion between DIM and the terminal amino group of A-4, respectively. Furthermore, the amide bond can be formed using coupling reagents known in the art (e.g., but not limited to, DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU).

[0510] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 4 below: Scheme 4: Synthesis of compounds of formula I [ka]

[0511] As illustrated in Scheme 4 above, acid A-3 is coupled to amine A-4 in DMF using coupling agent PyBOP in the presence of base DIPEA to form a compound of Formula I having a linker containing an amide bond. [ka] represent the linker portion between MBM and the terminal carboxyl group of A-3, or the linker portion between DIM and the terminal amino group of A-4, respectively. Furthermore, the amide bond can be formed using coupling reagents known in the art (e.g., but not limited to, DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU).

[0512] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 5 below: Scheme 5: Synthesis of compounds of formula I [ka]

[0513] As illustrated in Scheme 5 above, the S-catalysis of fluoride A-6 with amine A-5 N The Ar substitution is carried out in DMF in the presence of the base DIPEA to form compounds of formula I with linkers containing secondary amines. [ka] represents the linker portion between MBM and the terminal amino group of A-5.

[0514] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 6 below: Scheme 6: Synthesis of compounds of formula I [ka]

[0515] As illustrated in Scheme 6 above, the S-conjugation of fluoride A-7 with amine A-8 N The Ar substitution is carried out in DMF in the presence of the base DIPEA to form compounds of formula I with linkers containing secondary amines. [ka] represents the linker portion between DIM and the terminal amino group of A-8. Scheme 7: Synthesis of compounds of formula I [ka]

[0516] As illustrated in Scheme 7 above, reductive alkylation of a mixture of aldehyde A-9 and amine A-10 is carried out in the presence of NaHB(OAc)3 and KOAc in DMF / THF to form compounds of Formula I bearing a linker containing a secondary amine. [ka] represents the linker portion between DIM and the terminal amino group of A-8.

[0517] Those skilled in the art will recognize that various functional groups present in the compounds of the present invention, such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens, and nitriles, can be interconverted by techniques well known in the art, including, but not limited to, reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. March's Advanced Organic Chemistry, 5 thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, each of which is incorporated herein by reference in its entirety. Such interconversions may require one or more of the techniques described above, and certain methods for synthesizing compounds of the invention are described in the examples below.

[0518] 5. Use, Prescription and Administration Pharmaceutically Acceptable Compositions According to another embodiment, the present invention provides 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 an amount effective to measurably degrade and / or inhibit MDM2 protein or a variant thereof in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present invention is an amount effective to measurably degrade and / or inhibit MDM2 protein or a variant thereof in a biological sample or in a patient. In certain 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.

[0519] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0520] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of this invention include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, electrolytes such as salts or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0521] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of this invention or an inhibitory or degradative active metabolite or residue thereof.

[0522] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of the MDM2 protein or a mutant thereof.

[0523] As used herein, the term "degradatively active metabolite or residue thereof" means that the metabolite or residue thereof is also a degrader of the MDM2 protein or a variant thereof.

[0524] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0525] For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, especially in their polyoxyethylated forms, are useful for preparing injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions. Other commonly used surfactants, such as Tween®, Span, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0526] The pharmaceutically acceptable composition of this invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiers and suspending agents.If desired, certain sweeteners, flavorings or coloring agents can also be added.

[0527] Alternatively, the pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0528] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0529] Topical application for the lower intestinal tract may be in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches may also be used.

[0530] For topical application, the provided pharmaceutically acceptable composition can be formulated into 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 paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, the provided pharmaceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0531] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated into an ointment such as petrolatum.

[0532] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0533] Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of this invention are administered with food.

[0534] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated so that a dosage of between 0.01 and 100 mg of compound per kg of body weight per day can be administered to a patient receiving these compositions.

[0535] It should also be understood that the specific dosage and treatment regimen for any particular patient will vary depending on a variety of factors, including the activity of the specific compounds employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also vary depending on the particular compound in the composition.

[0536] Uses of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for degrading and / or inhibiting MDM2 protein activity.

[0537] MDM2 proteins that are degraded and / or inhibited by the compounds and compositions described herein and for which the methods described herein are useful include the mouse double minute 2 homolog ("MDM2") protein, encoded by the MDM2 gene, or the E3 ubiquitin-protein ligase MDM2. MDM2 is a key negative regulator of the p53 tumor suppressor, which is a key mediator of growth arrest, senescence, and apoptosis in response to a wide range of cellular insults. Rapid induction of high p53 protein levels by various stress types prevents inappropriate proliferation of cells with potentially mutagenic damaged DNA. p53 can kill cells through dual transcription-dependent and transcription-independent functions in the nucleus and mitochondria. Cellular p53 protein levels have been demonstrated to be the single most important determinant of its function. In normal, unstressed cells, p53 is a highly unstable protein with a half-life ranging from 5 to 30 minutes, present at very low cellular levels due primarily to continuous degradation mediated by MDM2. Conversely, many cellular stress pathways, such as DNA damage, hypoxia, telomere shortening, and oncogene activation, are characterized by rapid stabilization of p53 via blocking its degradation. MDM2 has emerged as a major cellular antagonist of p53 by limiting the function of the p53 tumor suppressor. (Moll and Petrenko, Mol. Cancer Res. 2003, 1:1001)

[0538] MDM2 is transcriptionally activated by p53 and inhibits p53 activity through at least three mechanisms. (Wu et al., Genes Dev. 1993, 7:1126) First, the MDM2 protein directly binds to the p53 transactivation domain, thereby inhibiting p53-mediated transactivation. Second, the MDM2 protein contains a nuclear export signal sequence, which, upon binding to p53, induces nuclear export of p53 and prevents p53 from binding to target DNA. Third, the MDM2 protein is an E3 ubiquitin ligase, which, upon binding to p53, can promote p53 degradation.

[0539] The activity of the compounds utilized in the present invention as degraders and / or inhibitors of MDM2 protein or its mutants can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine inhibition of either the activity of activated MDM2 protein or its mutants and / or the subsequent functional consequences. An alternative in vitro assay quantifies the ability of an inhibitor to bind to MDM2 protein. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / MDM2 complex, and determining the amount of bound radiolabel. Alternatively, inhibitor binding can be determined by performing a competition experiment in which new inhibitors are incubated with MDM2 protein bound to a known radioligand. Representative in vitro and in vivo assays useful for assaying MDM2 inhibitors include those described and disclosed in, for example, Zhange et al., "Fluorescence polarization assay and inhibitor design for MDM2 / p53 interaction," Anal. Biochem. 2004, 333(1):138; Herman et al., "Discovery of Mdm2-MdmX E3 Ligase Inhibitors Using a Cell-Based Ubiquitination Assay," Cancer Discovery. 2011, 1(4):312. Detailed conditions for assaying compounds utilized in the present invention as degraders and / or inhibitors of STAT proteins or their variants are described in the Examples below.

[0540] Representative small molecule inhibitors that target the p53-MDM2 interaction have therapeutic potential for treating cancer and other diseases. Chene, Nat. Rev. Cancer 2003, 3:102 and Vassilev et al., Science 2004, 303:844. Antagonists of the p53-MDM2 interaction are disclosed in U.S. Patents 7,759,383; 7,737,174; 8,518,984; 8,680,132; 8,629,141; 6,617,346; 6,734,302; 7,132,421; 7,425,638; 7,579,368; 7,060,713; 7,553,833; 6,916,833; 7,495,007; 7,638,548; 7,576,082; 7,625,895; and 7,083,983; as well as U.S. Patents 7,759,383; and 2009 / 0030181, each of which is incorporated by reference in its entirety.

[0541] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of the symptoms and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay the recurrence of the symptoms.

[0542] The provided compounds are degraders and / or inhibitors of MDM2 protein and are therefore useful for treating one or more disorders associated with the activity of MDM2 protein. Accordingly, in certain embodiments, the present invention provides a method for treating an MDM2-mediated disorder, comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof.

[0543] As used herein, the term "MDM2-mediated" disorder, disease, and / or condition means any disease or other deleterious condition in which the MDM2 protein or a variant thereof is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which the MDM2 protein or a variant thereof is known to play a role.

[0544] In some embodiments, the present invention provides methods for treating one or more disorders, diseases, and / or conditions, wherein the disorder, disease, or condition is cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a genetic disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, a liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, or a CNS disorder.

[0545] Diseases and conditions treatable according to the methods of the invention include cancer (see, e.g., Vassilev, Trends in Mol. Med. 2007, 13(1):23), diabetes (see, e.g., Secchiero et al., Acta Diabeto. 2013, 50:899), cardiovascular disease, viral diseases (see, e.g., Yang et al., Protein & Cell 2013, 4:71), autoimmune diseases such as lupus erythematosus (see, e.g., Thomasova et al., Neoplasia 2012, 14(12):1097) and rheumatoid arthritis (see, e.g., Zhang et al., Int. Immunopharm. 2016, 30:69), autoinflammatory syndromes, atherosclerosis (see, e.g., Ihling et al., J. Pathol. 1998, 185(3):303), psoriasis (see, e.g., Assmann et al., J. Pathol. 2016, 30:69), and the like. al., Rheumatol. Int. 2010,30:1273), allergic disorders (see, e.g., Han et al., J. Invest. Dermatol. 2014,134(10):2521), inflammatory bowel disease (see, e.g., Zimmer et al., Digestion 2019,81:246), inflammation (see, e.g., Ebrahim et al., Histol. Histopathol. 2015,31(11):1271), acute and chronic gout and gouty arthritis, neuropathies (see, e.g., Engel et al., Brain 2013,136(2):577), metabolic syndrome, immunodeficiency disorders such as AIDS and HIV (see, e.g., Izumi et al., Retrovirology 2009,6:1), destructive bone disorders (see, e.g., Jatiani et al., al., Genes & Can. 2011, 1(10):979), osteoarthritis (see, e.g., No. 9,993,472), proliferative disorders (see, e.g., No. 8,658,170), Waldenstrom's macroglobulinemia, infectious diseases such as sepsis (see, e.g., Kleiman et al., Am. J. Surg. 2009, 197(1):43), conditions associated with cell death, pathological immune conditions involving T cell activation, and CNS disorders in patients.In one embodiment, a human patient is treated with a compound of the invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the compound is present in an amount that measurably degrades and / or inhibits the activity of MDM2 protein or a mutant thereof.

[0546] The compounds of the present invention may be used to treat benign or malignant tumors, carcinomas or solid tumors of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone or thyroid gland, liquid tumors, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, in particular colon cancer or colorectal adenoma, head and neck tumors, epidermal hyperproliferation, psoriasis, benign prostatic hyperplasia, neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's or non-Hodgkin's, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 driven disorder, MyD88 driven disorder. and / or hematological malignancies, including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma.

[0547] In some embodiments, the present disclosure provides methods of treating benign proliferative disorders, including, but not limited to, benign soft tissue tumors, bone tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine neoplasms, nasal polyps, pituitary tumors, prolactinomas, pseudotumor cerebri, seborrheic keratosis, gastric polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps and cysts, Castleman's disease, chronic ciliary body disease, dermatofibromas, pilonidal cysts, pyogenic granulomas, and juvenile polyposis syndrome.

[0548] In another aspect, the present disclosure provides a method for treating a condition or disease by administering a therapeutically effective amount of a provided compound to an individual, e.g., a human, in need thereof. The disease or condition of interest is treatable by degradation of the MDM2 protein, such as cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection. Also provided is a method for preventing the proliferation of unwanted proliferating cells (e.g., in cancer) in a subject at risk of developing a condition characterized by unwanted proliferating cells, comprising administering a therapeutically effective amount of a provided compound to the subject. In some embodiments, the provided compound reduces the proliferation of unwanted cells by inducing apoptosis in those cells.

[0549] MDM2 hyperactivity can be caused by the amplification / overexpression or mutational inactivation of ARF locus, inhibiting the function of wild-type p53, leading to the development of a wide variety of cancers.In some embodiments, the MDM2 hyperactivity that can be treated according to the method of the present invention is human cancer.In some embodiments, the human cancer that can be treated according to the method of the present invention is selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, cutaneous melanoma and ovarian cancer.

[0550] In some embodiments, the cancer is adrenal gland carcinoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acral hidradenoma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia / lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, osteoblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid Rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt lymphoma, breast cancer, brain tumor, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, somatic neuroepithelial tumor, dysplastic carcinoma, embryonal carcinoma, endocrine neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma , esophageal cancer, inclusion malformation fetus, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid carcinoma, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, female adenomatous tumor, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematologic malignancies, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, renal cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, Leydig cell tumor , liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant Triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary breast carcinoma, medullary thyroid carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic urothelial carcinoma, mixed Müllerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, Myxoma, myxosarcoma, nasopharyngeal carcinoma, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid carcinoma, paraganglioma, pineoblastoma, pineocytoma, pituitary adenoma, pituitary tumor, plasmacytoma multiple germinoma, precursor T lymphoblastoma, primary central nervous system lymphoma, primary pleural effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, peritoneal pseudomyxoma, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma,Selected from Richter's transformation, rectal cancer, sarcoma, schwannomatosis, seminoma, Sertoli cell tumor, seminoma, signet ring cell tumor, skin cancer, small round cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatinoma, sooty wart, spinal cord tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary disease, small intestine cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, transitional cell carcinoma, pharyngeal cancer, urinary tract cancer, urothelial cancer, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway gland, vulvar cancer, vaginal cancer, Waldenstrom's hypergammaglobulinemia, Warthin's tumor, and Wilms' tumor.

[0551] In some embodiments, the cancer is a leukemia, e.g., a leukemia selected from acute monocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia (MLL). In another embodiment, the cancer is NUT midline carcinoma. In another embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is lung cancer, such as small cell lung cancer (SCLC). In another embodiment, the cancer is neuroblastoma. In another embodiment, the cancer is Burkitt's lymphoma. In another embodiment, the cancer is cervical cancer. In another embodiment, the cancer is esophageal cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.

[0552] In some embodiments, the present invention provides a method of treating triple-negative breast cancer in a patient in need thereof, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0553] In some embodiments, the present invention provides a method of treating malignant peripheral nerve sheath tumor (MPNST) in a patient in need thereof, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0554] In some embodiments, the present invention provides a method of treating pancreatic cancer in a patient in need thereof, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0555] The compounds according to the present invention are useful in the treatment of inflammatory or obstructive airway diseases, for example, by reducing tissue damage, airway inflammation, bronchial hyperactivity, remodeling or disease progression.The inflammatory or obstructive airway diseases to which the present invention is applicable include asthma of any type or origin, including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection.Treatment of asthma can also be understood as embracing treatment of subjects (for example, those diagnosed or capable of being diagnosed with "wheezing infants" (an established patient category of major medical problems, currently often identified as early or early stage asthma) who show symptoms of wheezing, under the age of 4 or 5 years.

[0556] The compounds according to the present invention are useful in treating heteroimmune diseases. Examples of such heteroimmune diseases include, but are not limited to, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy (e.g., allergy to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, house dust mite, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0557] Prophylactic efficacy in the treatment of asthma is evidenced, for example, by reduced frequency or severity of symptomatic attacks of acute asthma or bronchoconstriction attacks, improved lung function, or improved airway hyperactivity. This may further be evidenced by a reduced need for other symptomatic treatments (e.g., treatments intended to limit or stop symptomatic attacks when they occur, such as anti-inflammatory or bronchodilation therapies). The benefit of prophylaxis in asthma may be particularly evident in subjects prone to "morning depression." "Morning depression" is a recognized symptom of asthma, common to a significant proportion of asthmatics, and characterized by an asthma attack, for example, between 4:00 and 6:00 a.m., i.e., a time usually well removed from any previously administered symptomatic asthma treatment.

[0558] The compounds of the present invention can be used for other inflammatory or obstructive airway diseases and conditions to which the present invention is applicable, including acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD, COAD, or COLD) (including associated chronic bronchitis or dyspnea), emphysema, and exacerbations of airway hyperactivity as a result of other medications (especially other inhaled medications). The present invention is also applicable to the treatment of bronchitis of any type or onset, including, but not limited to, acute, arachidic, keratoconjunctivitis, croupus, chronic, or tuberculous bronchitis. Further inflammatory or obstructive airway diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, generally occupational lung disease, whether chronic or acute, frequently associated with airway obstruction and caused by repeated inhalation of dust) of any type or occurrence, including, for example, aluminum lung disease, anthracosis, asbestosis, stone disease, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

[0559] With regard to their anti-inflammatory activity, particularly with respect to eosinophil activation, the compounds of the present invention are also useful in the treatment of eosinophil-associated disorders, such as eosinophilia, particularly eosinophil-associated disorders of the respiratory tract (e.g., involving pathological eosinophil infiltration of lung tissue), including hypereosinophilia affecting the respiratory tract and / or lungs, as well as eosinophil-associated disorders of the respiratory tract resulting from or associated with, for example, Loffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granulomas, and eosinophil-associated disorders affecting the respiratory tract caused by drug reactions.

[0560] The compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0561] The compounds of the invention may also be used in the treatment of other diseases or conditions, for example, diseases or conditions which have an inflammatory component, for example, diseases and conditions of the eye such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases which involve an autoimmune response or have an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, red blood cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic thrombocytopenia, ... systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic thrombocytopenia, Sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, renal disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (e.g., idiopathic nephrotic syndrome or minimal change nephropathy), and urinary tract infections. Nephrotic syndrome (with or without nephrotic syndrome, including nephrotic change nephropathy), chronic granulomatous disease, endometriosis, leptospirosisRenal disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, ahidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, ocular allergies, silica-induced disease, COPD (reduction of damage, airway inflammation, bronchial hyperactivity, remodeling, or disease progression), pulmonary disease, cystic fibrosis , acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection Diarrhea, 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 abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis It can be used to treat myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0562] In some embodiments, the inflammatory disease that can be treated according to the methods of the present invention is a skin disease, in some embodiments, the inflammatory disease of the skin is selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foli...

Claims

【Request Item 1】 【Chemistry 1168】 【Chemistry 1169】 【Chemistry 1170】 【Chemistry 1171】 【Chemistry 1172】 10. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

2. The compound is 【Chemistry 1173】 or a pharmaceutically acceptable salt thereof.

3. The compound is 【Chemistry 1174】 2. The compound of claim 1, wherein: 【Request Item 4】 【Chemistry 1176】 【Chemistry 1177】 【Chemistry 1178】 【Chemistry 1179】 【Chemistry 1180】 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

5. The compound is 【Chemistry 1181】 or a pharmaceutically acceptable salt thereof.

6. The compound is 【Chemistry 1182】 5. The pharmaceutical composition of claim 4, wherein

7. The pharmaceutical composition of any one of claims 4 to 6, further comprising an additional therapeutic agent.

8. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof for use in a method for degrading MDM2 protein in a patient or a biological sample, the method comprising administering the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to the patient, or contacting the biological sample with the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for treating a disorder, disease or condition mediated by MDM2 in a patient.

10. 10. The composition of claim 9, wherein the composition is administered in combination with an additional therapeutic agent.

11. 10. A pharmaceutical composition comprising a compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for treating a patient, wherein the patient has cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.

12. The composition of claim 11 , wherein the patient has cancer.

13. The cancer may be adrenal gland carcinoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acral hidradenoma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia / lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, osteoblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, vascular Sarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt lymphoma, breast cancer, brain tumor, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, somatic neuroepithelial tumor, dysplastic carcinoma, embryonal carcinoma, endocrine neoplasia Biology, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, inclusion malformation fetus, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid carcinoma, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, female adenomatous tumor, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematologic malignancies, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, renal cancer, laryngeal cancer, lentigo maligna , lethal midline carcinoma, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant Triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary breast carcinoma, medullary thyroid carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic urothelial carcinoma, mixed Müllerian tumor, mucinous tumor, multiple myeloma,Muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid carcinoma, paraganglioma, pineoblastoma, pineocytoma, pituitary adenoma, pituitary tumor, plasmacytoma multiple germinoma, precursor T lymphoblastoma, primary central nervous system lymphoma, primary pleural effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma 13. The composition of claim 12, wherein the cancer is selected from Richter's transformation, rectal cancer, sarcoma, schwannomatosis, seminoma, Sertoli cell tumor, seminoma, signet ring cell tumor, skin cancer, small round cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatinoma, sooty wart, spinal cord tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, transitional cell carcinoma, pharyngeal cancer, urinary tract cancer, urothelial cancer, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway cancer, vulvar cancer, vaginal cancer, Waldenstrom's hypergammaglobulinemia, Warthin's tumor, and Wilms' tumor.

14. 13. The composition of claim 12, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT midline carcinoma, multiple myeloma, small cell lung cancer (SCLC), neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colon cancer, prostate cancer, and breast cancer.

15. The composition according to any one of claims 11 to 14, wherein the composition is administered in combination with an additional therapeutic agent.

16. 10. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder, disease or condition mediated by MDM2 in a patient.

17. 17. The use of claim 16, further comprising an additional therapeutic agent.

18. 17. The use of claim 16, wherein the MDM2-mediated disorder, disease or condition is cancer.

19. The cancer may be adrenal gland carcinoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acral hidradenoma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia / lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, osteoblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, vascular Sarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt lymphoma, breast cancer, brain tumor, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, somatic neuroepithelial tumor, dysplastic carcinoma, embryonal carcinoma, endocrine neoplasia Biology, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, inclusion malformation fetus, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid carcinoma, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, female adenomatous tumor, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematologic malignancies, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, renal cancer, laryngeal cancer, lentigo maligna , lethal midline carcinoma, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant Triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary breast carcinoma, medullary thyroid carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic urothelial carcinoma, mixed Müllerian tumor, mucinous tumor, multiple myeloma,Muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid carcinoma, paraganglioma, pineoblastoma, pineocytoma, pituitary adenoma, pituitary tumor, plasmacytoma multiple germinoma, precursor T lymphoblastoma, primary central nervous system lymphoma, primary pleural effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma 19. The use according to claim 18, wherein the cancer is selected from Richter's transformation, rectal cancer, sarcoma, schwannomatosis, seminoma, Sertoli cell tumor, seminoma, signet ring cell tumor, skin cancer, small round cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatinoma, sooty wart, spinal cord tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sézary's disease, small intestine cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, transitional cell carcinoma, pharyngeal cancer, urinary tract cancer, urothelial cancer, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway cancer, vulvar cancer, vaginal cancer, Waldenstrom's hypergammaglobulinemia, Warthin's tumor, and Wilms' tumor.

20. 19. The use of claim 18, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT midline carcinoma, multiple myeloma, small cell lung cancer (SCLC), neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colon cancer, prostate cancer, and breast cancer.

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