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 are incorporated herein by reference.

[0002] Field of Invention The present invention relates to compounds and methods useful for the modulation of mouse double minute 2 homolog (“MDM2”) protein by ubiquitination and / or degradation by compounds according to the invention. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using said compositions in the treatment of various disorders. [Background technology]

[0003] Background of the Invention The ubiquitin-proteasome pathway (UPP) is a key pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to many cellular processes and, when deficient or imbalanced, leads to the development 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, and these are in four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multisubunits. Divided into E3. 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) Title "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) entitled “RBR E3 ubiquitin ligases: new structures, new insights, new questions.”; Cancer., 2014, 14, 233-347) See the title "Roles of F-box proteins in cancer."

[0005] UPP plays a major role in the degradation of short-lived regulatory proteins that are important in a variety of fundamental cellular processes, including regulation of the cell cycle, regulation of cell surface receptors and ion channels, and antigen presentation. Fulfill. Its pathways lead to the pathogenesis of several forms of malignancy, the pathogenesis of several genetic disorders (including cystic fibrosis, Angelman's syndrome, and Liddle syndrome), immunosurveillance / viral pathogenesis, and muscle wasting. Involved. Many diseases are associated with abnormal UPPs and are associated with cell cycling and division, cellular responses to stress and extracellular modulators, morphogenesis of neural networks, cell surface receptors, ion channels, secondary pathways, It has a detrimental effect on the regulation of DNA repair and organelle biogenesis.

[0006] Aberrations 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 stabilization of a particular protein, and (b) diseases resulting from gain of function (ie, abnormal or accelerated degradation of protein targets).

[0007] UPP has been used to induce selective proteolysis, 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 target protein-binding ligands and E3 ubiquitin ligase ligands induced proteasome-mediated degradation of selected proteins through their recruitment to E3 ubiquitin ligases and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal regulation of protein expression. Such compounds, upon addition to cells or administration to animals or humans, can induce the inactivation of proteins of interest and can be useful as biochemical reagents and pathogenic or oncogenic proteins. (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l): 40-46). There is a continuing need in the art for effective treatment of disease, particularly hyperplasia and cancer, such as breast cancer. However, non-specific effects and the inability to target and regulate specific classes of proteins (eg, transcription factors) together remain obstacles to the development of effective anticancer agents. Therefore, small-molecule therapeutics that affect E3 ligase-mediated proteolysis to target cancer-associated proteins such as the mouse double minute 2 homolog (“MDM2”) hold therapeutic promise. do. Therefore, there remains a need to find compounds that are MDM2-degrading agents that are 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) titled "New insights into ubiquitin E3 ligase mechanism" [Non-Patent Document 3] Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) titled "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) titled "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 [Outline of the invention] [Means for solving the problem]

[0009] gist of the invention This application relates to novel bifunctional compounds that function to recruit the MDM2 protein to an E3 ubiquitin ligase for degradation, and methods of their preparation and use. In particular, the present disclosure demonstrates utility as modulators of targeted ubiquitination of MDM2, which are then degraded and / or otherwise inhibited by the bifunctional compounds described herein. A bifunctional compound is provided that finds Monovalent compounds that find utility as inducers of targeted ubiquitination of MDM2, which is then degraded and / or otherwise inhibited by monovalent compounds described herein Compounds are also provided. An advantage of the compounds provided herein is that they are capable of a wide variety of pharmacological activities, compatible with degradation / inhibition of MDM2. Further provided herein are methods of using an effective amount of a compound described herein for the treatment or amelioration of a disease state such as cancer, eg breast cancer.

[0010] The present application further relates to 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 the compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as degrading agents for the MDM2 protein. Such compounds have the general formula I: [formation] 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 modulation of signal transduction pathways involving the MDM2 protein. Such diseases, disorders, or conditions include those described herein.

[0013] The compounds provided by the present invention are also useful for studying MDM2 protein in biological and pathological phenomena; studying intracellular signaling pathways occurring in body tissues; and cell cycle, metastasis, angiogenesis in vitro or in vivo. , and for the comparative evaluation of novel MDM2 inhibitors or MDM2-degrading agents, or other regulators of immune cell escape. [Mode for carrying out the invention]

[0014] Detailed description of specific embodiments 1. General Description of Specific Embodiments of the Invention: The compounds of the present invention, and compositions thereof, are useful as degradants 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: [formation] or a pharmaceutically acceptable salt thereof, wherein in Formula I: MBM is an MDM2 binding moiety capable of binding to MDM2 protein; L is the divalent moiety linking MBM to DIM; and DIMs are degradation-inducing moieties such as ligase binding moieties (LBMs), lysine mimetics, or hydrogen atoms.

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

[0017] The term “aliphatic” or “aliphatic group”, as used herein, refers to straight-chain (i.e., unbranched) or branched, substituted or unsubstituted, fully saturated or or a hydrocarbon chain containing one or more units of unsaturation, or a monocyclic, bicyclic, which is fully saturated or contains one or more units of unsaturation but is not aromatic; A bridged bicyclic or spirocyclic hydrocarbon (also referred to herein as "carbocycle", "alicyclic" or "cycloalkyl") with one bond to the rest of the molecule means having a point. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In yet other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in still other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. . In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") is fully saturated or contains one or more units of unsaturation, but aromatic a monocyclic C with no and one point of attachment to the rest of the molecule 3 ~C 6 A hydrocarbon. Suitable aliphatic groups include straight or branched, saturated or unsaturated, alkyl groups, alkenyl groups, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or ( cycloalkyl)alkenyl), but are not limited to these.

[0018] As used herein, the term “bridged bicyclic” refers to any saturated or partially unsaturated bicyclic ring system (i.e., carbocyclic or heterocyclic) having at least one bridge. cyclic). As defined by IUPAC, a "bridge" is an unbranched chain of multiple atoms, or a single atom, or valence bond connecting two bridgeheads, where a "bridgehead" is three Any skeletal atom of the ring system that is bonded to any of the above skeletal atoms (other than hydrogen). In some embodiments, bridged bicyclic groups have 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include groups described below, where each group is attached to the remainder of the molecule at any suitable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are 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 arihashibicycles are: [formation] is mentioned.

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

[0020] The term "lower haloalkyl" means a C 1~4 refers to a straight or branched chain alkyl group.

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

[0022] The term "unsaturated," as used herein, means moieties with 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 chain" means a straight or branched divalent alkylene chain, alkenylene chain, as defined herein, and alkynylene chains.

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

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

[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 group having a total of 5-14 ring members. However, at least one ring in the system is aromatic, and each ring in the system contains from 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 aromatic ring systems including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which contain one Or it may have more substituents. As the term "term" is used herein, and also included within its scope, groups in which an aromatic ring is fused to one or more non-aromatic rings (e.g., indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc.).

[0029] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to 5-10 ring atoms, preferably 5, 6, or 9 ring atoms; 6, 10, or 14 pi-electrons shared in a ring arrangement; and 1 in addition to carbon atoms Refers to groups having ~5 heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized forms of nitrogen or sulfur, and any quaternized forms of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, napthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroara-", as used herein, also refer to heteroaromatic rings 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-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenazinyl. Thiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group 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 are optionally substituted Contains rings. The term "heteroaralkyl" refers to a heteroaryl-substituted alkyl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0030] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and are used interchangeably and are stable 5- to 7-membered a monocyclic, or 7- to 10-membered bicyclic, heterocyclic moiety of is either saturated or partially unsaturated, and in addition to carbon atoms, one or more It preferably has 1 to 4 heteroatoms as defined above. The term "nitrogen" when used in reference to heterocyclic ring atoms includes substituted nitrogens. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be replaced by N(as in 3,4-dihydro-2H-pyrrolyl). ) or NH (as in pyrrolidinyl), + It may be NR (as in N-substituted pyrrolidinyls).

[0031] The heterocyclic ring may 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 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 tetrahydroquinolyl) nil). A heterocyclyl group may be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. A heterocyclic ring may contain one or more oxo (=O) or thioxo (=S) substituents. The term "heterocyclylalkyl" refers to a heterocyclyl-substituted alkyl group, wherein the alkyl and heterocyclyl portions are independently optionally substituted.

[0032] As used herein, the term "partially unsaturated" refers to ring moieties containing at least one double or triple bond. The term "partially unsaturated" is intended to include 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 invention may contain "optionally substituted" moieties. In general, the term "substituted" means that one or more hydrogens on 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 portion of the group and may be substituted at more than one position in any given structure. When can be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to their production, detection, and, in certain embodiments, one or more of the purposes disclosed herein. Refers to compounds that are substantially unchanged when subjected to conditions that permit their recovery, purification, and use for purposes.

[0034] Suitable monovalent substituents on substitutable carbon atoms of "optionally substituted" groups are independently halogen;-(CH 2 ) 0~4 R. ○ ;-(CH 2 ) 0~4 OR ○ ;-O(CH 2 ) 0~4 R. ○ , -O-(CH 2 ) 0~4 C(O)OR ○ ;-(CH 2 ) 0~4 CH(OR ○ ) 2 ;-(CH 2 ) 0~4 SR ○ ;-(CH 2 ) 0~4 Ph (which is R ○ );-(CH 2 ) 0~4 O(CH 2 ) 0~1 Ph (which is R ○ -CH=CHPh (which can be substituted with R ○ );-(CH 2 ) 0~4 O(CH 2 ) 0~1 -pyridyl (which is R ○ );-NO 2 ;-CN;-N 3 ;-(CH 2 ) 0~4 N(R ○ ) 2 ;-(CH 2 ) 0~4 N(R ○ )C(O)R ○ ;-N(R ○ )C(S)R ○ ;-(CH 2 ) 0~4 N(R ○ )C(O)NR ○ 2 ;-N(R ○ )C(S)NR ○ 2 ;-(CH 2 ) 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 ○ ;-(CH 2 ) 0~4 C(O)R ○ ;-C(S)R ○ ;-(CH 2 ) 0~4 C(O)OR ○ ;-(CH 2 ) 0~4 C(O)SR ○ ;-(CH 2 ) 0~4 C(O)OSiR ○ 3 ;-(CH 2 ) 0~4 OC(O)R ○ ;-OC(O)(CH 2 ) 0~4 SR ○ ;-(CH 2 ) 0~4 SC(O)R ○ ;-(CH 2 ) 0~4 C(O)NR ○ 2 ;-C(S)NR ○ 2 ;-C(S)SR ○ ;-SC(S)SR ○ ;-(CH 2 ) 0~4 OC(O)NR ○ 2 ;-C(O)N(OR ○ )R ○ ;-C(O)C(O)R ○ ;-C(O)CH 2 C(O)R ○ ;-C(NOR ○ )R ○ ;-(CH 2 ) 0~4 SSRs ○ ;-(CH 2 ) 0~4 S(O) 2 R. ○ ;-(CH 2 ) 0~4 S(O) 2 OR ○ ;-(CH 2 ) 0~4 OS(O) 2 R. ○ ;-S(O) 2 NR ○ 2 ;-(CH 2 ) 0~4 S(O)R ○ ;-N(R ○ )S(O) 2 NR ○ 2 ;-N(R ○ )S(O) 2 R. ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2 ;-P(O) 2 R. ○ ;-P(O)R ○ 2 ;-OP(O)R ○ 2 ;-OP(O)(OR ○ ) 2 ;-SiR ○ 3 ;-(C 1~4 linear or branched alkylene)O-N(R ○ ) 2 ; or -(C 1~4 linear or branched alkylene)C(O)O-N(R ○ ) 2 , where each R ○ may be substituted as defined below and independently hydrogen, C 1~6 aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, -CH 2 - (5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated or partially unsaturated ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur , or an aryl ring, or notwithstanding the above definition, R ○ two separate occurrences of have, together with the atom(s) between them, from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; It forms a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring, which can be substituted as defined below.

[0035] R. ○ (R ○ Suitable monovalent substituents on a ring formed by joining together two independent occurrences of (with an atom between them) are independently halogen, -(CH 2 ) 0~2 R. ● ,-(halo R ● ), -(CH 2 ) 0~2 OH, -(CH 2 ) 0~2 OR ● , -(CH 2 ) 0~2 CH(OR ● ) 2 ;-O(halo R ● ), -CN, -N 3 , -(CH 2 ) 0~2 C(O)R ● , -(CH 2 ) 0~2 C(O)OH, -(CH 2 ) 0~2 C(O)OR ● , -(CH 2 ) 0~2 SR ● , -(CH 2 ) 0~2 SH, -(CH 2 ) 0~2 NH 2 , -(CH 2 ) 0~2 NHR ● , -(CH 2 ) 0~2 NR ● 2 , -NO 2 , -SiR ● 3 , -OSiR ● 3 , -C(O)SR ● , -(C 1~4 linear or branched alkylene)C(O)OR ● , or -SSR ● , where each R ● is unsubstituted or substituted with only one or more halogens when preceded by "halo", and independently, C 1~4 aliphatic, -CH 2 Ph, -O(CH 2 ) 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. R. ○ Suitable divalent substituents on the saturated carbon atoms of include =O and =S.

[0036] Suitable divalent substituents on saturated carbon atoms of "optionally substituted" groups include: =O, =S, =NNR. * 2 , = NNHC(O)R * , =NNHC(O)OR * , =NNHS(O) 2 R. * ,=NR * , =NOR * , -O(C(R * 2 )) 2~3 O-, or -S(C(R * 2 )) 2~3 S-. where R * Each independent occurrence of is hydrogen, C may be substituted as defined below 1~6 selected from aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; be. 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 is hydrogen, C may be substituted as defined below 1~6 selected from aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; be.

[0037] R. * Suitable substituents on the aliphatic group of include halogen, -R ● ,-(halo R ● ), -OH, -OR ● , -O (halo R ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 , where each R ● is unsubstituted or substituted with only one or more halogens when preceded by "halo", and independently, C 1~4 aliphatic, -CH 2 Ph, -O(CH 2 ) 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.

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

[0039] R. † Suitable substituents on the aliphatic group of are independently halogen, -R ● ,-(halo R ● ), -OH, -OR ● , -O (halo R ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 , where each R ● is unsubstituted or substituted with only one or more halogens when preceded by "halo", and independently, C 1~4 aliphatic, -CH 2 Ph, -O(CH 2 ) 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 capable of producing human and lower toxicants within the scope of sound medical judgment and without undue toxicity, irritation, allergic response, and the like. A salt that is suitable for use in contact with animal tissue 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 this invention include those derived from suitable inorganic acids, inorganic bases, organic acids and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are inorganic acids (e.g. hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric) or organic acids (e.g. acetic, oxalic, maleic, , tartaric acid, citric acid, succinic acid or malonic acid) or 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate Salt, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonic acid salt, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate , phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate, and the like. .

[0041] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1~4 alkyl) 4 salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts are added where appropriate to counterions such as halide, hydroxide, carbonate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate ions. Contains non-toxic ammonium, quaternary ammonium, and amine cations formed using ions. In some embodiments, provided compounds are purified in salt form for convenience and / or ease of purification, eg, using acidic or basic mobile phases during chromatography. Salt forms of provided compounds formed during chromatographic purification are compared herein and are readily apparent to those skilled in the art.

[0042] Unless otherwise stated, structures depicted herein also refer to all isomeric (eg, enantiomers, diastereomers, and geometric (or conformational)) forms of the structure, including each asymmetric center. are meant to include the R and S configurations for, Z and E double bond isomers, and Z and E conformers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds 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. Additionally, 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 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 present 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 a measurable affinity. In certain embodiments, the 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" binds and / or inhibits both the MDM2 protein and the E3 ligase with measurable affinity, leading to the ubiquitination and subsequent It is defined as a heterobifunctional compound that leads to decomposition. In certain embodiments, the degrading agent has less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, about 10 nM, or less than about 1 nM DC 50 have As used herein, the term "monovalent" refers to a resolving agent compound that is not attached to an E3 ligase binding moiety.

[0046] The compounds of the 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 detectable moieties may be attached to a provided compound via suitable substituents. As used herein, the term "suitable substituent" refers to a moiety that can be covalently attached to a detectable moiety. Such moieties are well known to those of skill in the art and include groups containing carbonate, amino, thiol or hydroxyl moieties, to name a few. It is understood that such moieties may be attached directly to a provided compound or via a tethering group such as a divalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached by click chemistry. In some embodiments, such moieties may be attached by 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 are described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-9 and Sun et al., Bioconjugate Chem. Those described are included.

[0047] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and relates to any moiety that can be detected, eg, primary and secondary labels. radioisotopes (e.g. tritium, 32 P. 33P. 35 S, or 14 C), mass tags, and primary labels such as 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 secondary intermediates for the production of a detectable signal. For biotin, secondary intermediates may include streptavidin-enzyme conjugates. For antigen labels, secondary intermediates may include antibody-enzyme conjugates. 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 produces a signal that is detected.

[0049] As used herein, the terms "fluorescent label," "fluorochrome," and "fluorophore" refer to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength. Examples of fluorescent labels include Alexa Fluor dyes (Alexa Fluor350, Alexa Fluor488, Alexa Fluor532, Alexa Fluor546, Alexa Fluor568, Alexa Fluor594, Alexa Fluor633, Alexa Fluor660 and Alexa Fluor680), 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 (RO X) , 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, hydroxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, lissaminerhodamine 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, Texas Red-X, including but not limited to.

[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 techniques. Examples of mass tags are N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipeconic acid, 4'-[2,3,5,6- Electrophore emitting tags such as tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and their derivatives. The synthesis and utility of these mass tags are described in U.S. Pat. there is Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides of varying length and base composition, and other synthetic polymers of varying length and monomer composition. not. A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, of 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 sample containing a compound of the invention or composition thereof and MDM2 protein and the compound Means a measurable change in MDM2 protein between an equivalent sample containing MDM2 protein in the absence of the composition.

[0052] 3. Description of exemplary embodiments: As noted above, in certain embodiments, the present invention provides formula I: [formation] or a pharmaceutically acceptable salt thereof, wherein MBM is an MDM2 binding moiety capable of binding to MDM2 protein; L is a divalent moiety that links MBM to DIM; and DIMs are degradation-inducing moieties such as ligase binding moieties (LBMs), lysine mimetics, or hydrogen atoms. MDM2 binding moiety (MBM)

[0053] In certain embodiments, the invention is a compound of formula I, wherein MBM is represented by each of formulas 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: [formation] [formation] [formation] [formation] or a pharmaceutically acceptable salt thereof, wherein L and DIM are defined above and as described in the embodiments herein; X is -CR 2 -, -O-, -S-, -S(O)-, -S(O) 2 selected from -, and -NR-; Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and nitrogen, oxygen and optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from sulfur, or: the two R groups on the same atom, optionally together with their intervening atoms, plus the atom to which they are attached, are independently selected from nitrogen, oxygen and sulfur 0-3 It forms a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring with 1 heteroatom. 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 independently selected from phenyl, 5-10 membered aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; is a monocyclic or bicyclic ring substituted according to; R. 3 and R 4 are independently hydrogen and C 1-6 selected from alkyl; R. 5 is optionally substituted selected from phenyl, 5-10 membered aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. selected from monocyclic or bicyclic rings; R. 6 is hydrogen, -C(O)R, -C(O)OR, and -C(O)NR 2 selected from; R. 7 is hydrogen and R A selected from; Each R A independently, C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and nitrogen, oxygen and optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from sulfur: R. 8 is -C(O)R and R A selected from; R. 9 is a mono-, bis- or tri-substituent on ring W, and each of the substituents is independently halogen and optionally substituted C 1-6 selected from the aliphatic; R. 10is optionally substituted selected from phenyl, 5-10 membered aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. selected from monocyclic or bicyclic rings; R. 11 is -C(O)OR or -C(O)NR 2 is; R. 12 and R 13 are independently hydrogen and R A or selected from: R. 12 and R 13 is independently selected from optionally substituted 3- to 8-membered saturated, partially unsaturated, carbocyclic or nitrogen, oxygen and sulfur optionally with their intervening atoms 1 forming a heterocyclic ring with ~3 heteroatoms; R. 14 is R A is; R. 15 is -CN; R. 16 is R A , -OR, -(CR 2 ) 0-6 -C(O)R, -(CR 2 ) 0-6 -C(O)OR, -(CR 2 ) 0-6 -C(O)NR 2 , -(CR 2 ) 0-6 -S(O) 2 R, -(CR 2 ) 0-6 -N(R)S(O) 2 R, -(CR 2 ) 0-6 -S(O) 2 NR 2 selected from; R. 17 is -(CR 2 ) 0-6 -C(O)NR 2 selected from; R. 18 and R 19 are independently hydrogen and R A selected from; R. 20 and R 21 are independently hydrogen, R A , halogen and -OR, or: R. 20 and R 21 optionally with those intervening atoms, has 1 to 3 heteroatoms independently selected from fused 5- to 7-membered partially unsaturated carbocyclic or nitrogen, oxygen and sulfur forming a heterocyclic ring or a fused 5-6 membered heteroaryl ring having 1-3 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)NR 2 , -NR 2 , -OR, -S(O)R, -S(O) 2 R, -S(O) 2 NR 2 selected from; R. 24 、 R. 26 , and R 28 are independently hydrogen, R A , -C(O)R, -C(O)OR, -C(O)NR 2、 -S(O)R, -S(O) 2 R, and -S(O) 2 NR 2 selected from; R. 1’ and R 2’ is independently halogen, -C≡CR, -CN, -CF 3 , and -NO 2 selected from; R. 3’ is -OR; R. 4’ , R 5’ , R 6’ are independently hydrogen, halogen, R A , -CN, -CF 3 , -NR 2 , -OR, -SR, and -S(O) 2 selected from R; R. 7’ is a mono-, bis- or tri-substituent, each substituent being independently selected from halogen; R. 8’ is a mono-, bis- or tri-substituent and each substituent is independently hydrogen, halogen, R A , -CN, -C≡CR, -NO 2 , and -OR; R. 9’ is R A is; 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 -C(O)R, -C(O)OR, -C(O)NR 2 , -OR, -S(O) 2 R, -S(O) 2 NR 2 , and -S(O)R; and R. 1’’ is hydrogen and R A is selected from

[0054] As defined herein and described above, where square brackets are used to denote a formula (e.g. [formation] ), L is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom within the MBM, including substitution or replacement of defined groups within the MBM.

[0055] In certain embodiments, the invention relates to compounds of Formula I, wherein MBM is each of Formulas I-bbb-1, I-bbb-2, and I-bbb-3: [formation] [formation] or a pharmaceutically acceptable salt thereof, wherein L and DIM are defined above and as described in the embodiments herein; R. 1’’ is hydrogen and R A selected from; Each R A independently, C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and nitrogen, oxygen and optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from sulfur: R. 10 is optionally substituted selected from phenyl, 5-10 membered aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. selected from monocyclic or bicyclic rings; R. 12 and R 13 are each independently hydrogen and R A or selected from: R. 12 and R 13 is independently selected from optionally substituted 4- to 8-membered saturated, partially unsaturated, carbocyclic or nitrogen, oxygen and sulfur optionally with their intervening atoms 1 forming a heterocyclic ring with ~3 heteroatoms; 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, R A and -OR selected from; Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and nitrogen, oxygen and an optionally substituted group selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from 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. Yes; and Q. 1 is an optionally substituted divalent group selected from alkylenyl, phenylenyl, heteroarylenyl, cycloalkylenyl and heterocyclenyl.

[0056] X, as defined above and described herein, is -CR 2 -, -O-, -S-, -S(O)-, -S(O) 2-, and -NR-.

[0057] In some embodiments, X is -CR 2 -is. 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 -is. In some embodiments, X is -NR-. In some embodiments, X is -CH 2 -is.

[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 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and nitrogen, oxygen and optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from sulfur, or two R on the same atom The groups have, in addition to the atoms to which they are attached, optionally together with their intervening atoms, 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. Forms ~7 membered saturated, partially unsaturated or heteroaryl rings.

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

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

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

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

[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 benzo and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. is a fused ring selected from

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

[0070] In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 5- to 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 1 teeth, [formation] is. In some embodiments, R 1 teeth, [formation] is. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 5- to 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, [formation] is. In some embodiments, R 2 teeth, [formation] is. In some embodiments, R 2 teeth, [formation] is.

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

[0072] As defined above and described herein, R 3 and R 4 are independently hydrogen and C 1-6 selected from alkyl;

[0073] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C 1-6 is alkyl. In some embodiments, R 3 is methyl. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C 1-6 is alkyl. 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] As defined above and described herein, R 5 is optionally substituted selected from phenyl, 5-10 membered aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. are selected from monocyclic or bicyclic rings.

[0076] In some embodiments, R 5 is optionally substituted phenyl. In some embodiments, R 5 is an optionally substituted 5- to 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, [formation] is.

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

[0078] As defined above and described herein, R 6 is hydrogen, -C(O)R, -C(O)OR, and -C(O)NR 2 is selected from

[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 2 is. In some embodiments, R 6 teeth, [formation] is.

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

[0081] As defined above and described herein, R 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 defined generally above, each R A independently, C 1~6 a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur; and An optionally substituted group selected from 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0085] As defined above and described herein, R A is C 1~6 It is an optionally substituted group selected from aliphatic. In some embodiments, R 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 It is a ring. In some embodiments, R A is an optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

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

[0087] As defined above and described herein, R 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] As defined above and described herein, R 9 is a mono-, bis- or tri-substituent on ring W, and each of the substituents is independently halogen and optionally substituted C 1-6 selected from the aliphatic

[0091] In some embodiments, R 9 is a monosubstituent 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 selected from the aliphatic In some embodiments, R 9 is chloro.

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

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

[0094] In some embodiments, R 10 is optionally substituted phenyl. In some embodiments, R 10 is an optionally substituted 5- to 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, [formation] is. In some embodiments, R 10 teeth, [formation] is.

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

[0096] As defined above and described herein, R 11 is -C(O)OR or -C(O)NR 2 is.

[0097] In some embodiments, R 11 is -C(O)NR 2 is. In some embodiments, R 11 is -C(O)OR. In some embodiments, R 11 is -C(O)OH. In some embodiments, R 11 teeth, [formation] is. In some embodiments, R 11 teeth, [formation] is. In some embodiments, R 11 teeth, [formation] is. In some embodiments, R 11 teeth, [formation] is. In some embodiments, R 11 teeth, [formation] is.

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

[0099] As defined above and described herein, R 12 and R 13 are independently hydrogen and R A or is selected from R 12 and R 13 is independently selected from optionally substituted 3- to 8-membered saturated, partially unsaturated, carbocyclic or nitrogen, oxygen and sulfur optionally with their intervening atoms 1 Forms a heterocyclic ring with ~3 heteroatoms.

[0100] In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is R A is. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is R A is. In some embodiments, R 12 and R 13 is, together with those intervening atoms, 1-3 optionally substituted 3-8 membered saturated, partially unsaturated, carbocyclic or independently selected from nitrogen, oxygen and sulfur It forms a heterocyclic ring with heteroatoms. In some embodiments, R 12 and R 13 get together [formation] to form In some embodiments, R 12 and R13 get together [formation] to form

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

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

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

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

[0105] As defined above and described herein, R 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] As defined above and described herein, R 16 is R A , -OR, -(CR 2 ) 0-6 -C(O)R, -(CR 2 ) 0-6 -C(O)OR, -(CR 2 ) 0-6 -C(O)NR 2 , -(CR 2 ) 0-6 -S(O) 2 R, -(CR 2 ) 0-6 -N(R)S(O) 2 R, -(CR 2 ) 0-6 -S(O) 2 NR 2 is selected from

[0109] In some embodiments, R 16 is R A is. In some embodiments, R 16 is -OR. In some embodiments, R 16 is -(CR 2 ) 0-6 -C(O)R. In some embodiments, R 16 is -(CR 2 ) 0-6 -C(O)OR. In some embodiments, R 16 is -(CR 2 ) 0-6 -C(O)NR 2 is. In some embodiments, R 16 is -(CR 2 ) 0-6 -S(O) 2 is R. In some embodiments, R 16 is -(CR 2 ) 0-6 -N(R)S(O) 2 is R. In some embodiments, R 16 is -(CR 2 ) 0-6 -S(O) 2 NR 2 is. In some embodiments, [formation]

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

[0111] As defined above and described herein, R 17 is -(CR 2 ) 0-6 -C(O)NR 2 is selected from

[0112] In some embodiments, R 17 is -(CR 2 ) 0-6 -C(O)NR 2 is. In some embodiments, R 17 teeth, [formation] is. In some embodiments, R 17 teeth, [formation] is.

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

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

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

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

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

[0118] In some embodiments, R 20 is hydrogen. In some embodiments, R 20 is R A is. In some embodiments, R 20 is a halogen. In some embodiments, R 20 is -OR. In some embodiments, R 20 is -OMe. In some embodiments, R 20 is -OiPr. In some embodiments, R 21 is hydrogen. In some embodiments, R 21 is R A is. In some embodiments, R 21 is a 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 is, together with those intervening atoms, 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 form a fused 5-6 membered heteroaryl ring having 1-3 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] As defined above and described herein, R 22 , R 23 , R 25 , and R 27 are independently hydrogen, R A , Halogen, -C(O)R, -C(O)OR, -C(O)NR 2 , -NR 2 , -OR, -S(O)R, -S(O) 2 R, -S(O) 2 NR 2 is selected from

[0121] In some embodiments, R 22 , R 23 , R 25 , and R 27 one or more of are hydrogen. In some embodiments, R 22 , R 23 , R 25 , and R 27 one or more of the R A is. In some embodiments, R 22 , R 23 , R 25 , and R 27 one or more of are halogens. In some embodiments, R 22 , R 23 , R 25 , and R 27 one or more of are -C(O)R. In some embodiments, R 22 , R 23 , R 25 , and R 27 one or more of are -C(O)OR. In some embodiments, R 22 , R 23 , R 25 , and R 27 one or more of -C(O)NR 2 is. In some embodiments, R 22 , R 23 , R 25 , and R 27 one or more of -NR 2 is. In some embodiments, R 22 , R 23 , R 25 , and R 27 one or more of are -OR. In some embodiments, R 22 , R 23 , R 25 , and R 27 one or more of are -S(O)R. In some embodiments, R 22 , R 23 , R 25 , and R 27 one or more of -S(O) 2 is R. In some embodiments, R 22 , R 23 , R 25 , and R 27 one or more of -S(O) 2 NR 2 is.

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

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

[0124] In some embodiments, R 24 , R 26 , and R 28 one or more of are hydrogen. In some embodiments, R 24 , R 26 , and R 28 one or more of the R A is. In some embodiments, R 24 , R 26 , and R 28 one or more of the R A -C(O)R. In some embodiments, R 24 , R 26 , and R 28 one or more of the R A is. In some embodiments, R 24 , R 26 , and R 28 one or more of are -C(O)OR. In some embodiments, R 24 , R 26 , and R 28 one or more of -C(O)NR 2 is. In some embodiments, R 24 , R 26 , and R 28 one or more of are -S(O)R. In some embodiments, R 24 , R 26 , and R 28 one or more of -S(O) 2 is R. In some embodiments, R 24 , R 26 , and R 28 one or more of -S(O) 2 NR 2 is.

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

[0126] As defined above and described herein, R 1’ and R 2’ is independently halogen, -C≡CR, -CN, -CF 3 , and -NO 2 is selected from

[0127] In some embodiments, R 1’ is a halogen. In some embodiments, R 1’ is -C≡CR. In some embodiments, R 1’ is -CN. In some embodiments, R 1’ is -CF 3 is. In some embodiments, R 1’ Ha-NO 2 is. In some embodiments, R 1’ is chloro. In some embodiments, R 2’ is a halogen. In some embodiments, R 2’ is -C≡CR. In some embodiments, R 2’ is -CN. In some embodiments, R 2’ is -CF 3 is. In some embodiments, R 2’ -NO 2 is. 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] As defined above and described herein, R 3’ 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] As defined above and described herein, R 4’ , R 5’ , and R 6’ are independently hydrogen, halogen, R A , -CN, -CF 3 , -NR 2 , -OR, -SR, and -S(O) 2 Selected from R.

[0133] In some embodiments, R 4’ , R 5’ , and R 6’ one or more of are hydrogen. In some embodiments, R 4’ , R 5’ , and R 6’ one or more of are halogens. In some embodiments, R 4’ , R 5’ , and R 6’ one or more of the R A is. In some embodiments, R 4’ , R 5’ , and R 6’ one or more of is -CN. In some embodiments, R 4’ , R 5’ , and R 6’ one or more of -CF 3 is. In some embodiments, R 4’ , R 5’ , and R 6’ one or more of -NR 2 is. In some embodiments, R 4’ , R 5’ , and R6’ one or more of are -OR. In some embodiments, R 4’ , R 5’ , and R 6’ one or more of is -SR. In some embodiments, R 4’ , R 5’ , and R 6’ one or more of -S(O) 2 is R. In some embodiments, 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] As defined above and described herein, R 7’ is a mono-, bis- or tri-substituent, each substituent being 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 a 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] As defined above and described herein, R 8’ is a mono-, bis- or tri-substituent and each substituent is independently hydrogen, halogen, R A , -CN, -C≡CR, -NO 2 , 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 a halogen. In some embodiments, R 8’ is R A is. In some embodiments, R 8’ is -CN. In some embodiments, R 8’ is -C≡CR. In some embodiments, R 8’ -NO 2 is. 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] As defined above and described herein, R 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 1 is a halogen. In some embodiments Z 1 is -OR.

[0146] As defined above and described herein, R 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 is. 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] As defined above and described herein, R 12’ is -C(O)R, -C(O)OR, -C(O)NR 2 , -OR, -S(O) 2 R, -S(O) 2 NR 2 , 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 2 is. In some embodiments, R 12’ is -OR. In some embodiments, R 12’ is -S(O) 2 is R. In some embodiments, R 12’ is -S(O) 2 NR 2 is. In some embodiments, R 12’ is -S(O)R.

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

[0152] As defined above and described herein, R 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 is. 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] As defined above and described herein, R 18a , R 18b , R 18c , and R 18d are each independently hydrogen, halogen, R A and -OR.

[0165] In some embodiments, R 18a , R 18b , R 18c , and R 18d one or more of are hydrogen. In some embodiments, R 18a , R 18b , R 18c , and R 18d one or more of are halogens. In some embodiments, R 18a , R 18b , R 18c , and R 18d one or more of the R A is. In some embodiments, R 18a , R 18b , R 18c , and R 18d one or more of are -OR. In some embodiments, R 18c is chloro.

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

[0167] As defined above and described herein, Q 1 is an optionally substituted divalent group 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 an optionally substituted heteroarylenyl. In some embodiments, Q 1 is an optionally substituted cycloalkylenyl. In some embodiments, Q 1 is an optionally substituted heterocyclenyl. In some embodiments, Q 1 teeth, [formation] is. In some embodiments, Q 1 teeth, [formation] is. In some embodiments, Q 1 teeth, [formation] is. In some embodiments, Q 1 teeth, [formation] is. In some embodiments, Q 1 teeth, [formation] is. In some embodiments, Q 1 teeth, [formation] is. In some embodiments, Q 1 teeth, [formation] is. In some embodiments, Q 1 teeth, [formation] is. In some embodiments, Q 1 teeth, [formation] is. In some embodiments, Q 1 teeth, [formation] is. In some embodiments, Q 1 teeth, [formation] is.

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

[0170] In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. In some embodiments, MBM is [formation] is. ligase binding moiety (LBM)

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

[0172] As defined herein and described below, where square brackets are used to denote a formula (e.g. [formation] ), L is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom within DIM or LBM including substitution or replacement of defined groups in DIM or LBM.

[0173] In certain embodiments, the present invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing formula I-a: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described herein; X 1 is a covalent bond, -CH 2 -, -CHCF 3 -, -SO 2 -, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; X 2 is a carbon or silicon atom; X 3 is -CR 2 -, -NR-, -O-, -S-, or -Si(R 2 )- is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -N(R) 2 , -P(O)(OR) 2 , -P(O)(NR 2 )OR, -P(O)(NR 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , or C, substituted as appropriate 1-4 is aliphatic; Each R 2 are independently hydrogen, deuterium, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -Si(R) 3 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(R)C(O)N(R) 2 , -OC(O)R, -OC(O)N(R) 2 , -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)(NR 2 ), -OP(O)(NR 2 ) 2 -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) 2 , -N(R)S(O) 2 R, -NP(O)R 2 , -N(R)P(O)(OR) 2 , -N(R)P(O)(OR)(NR 2 ), -N(R)P(O)(NR 2 ) 2 , or -N(R)S(O) 2 is R; Ring A is [formation] [formation] [formation] a bicyclic or tricyclic ring selected from Ring B is 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen or sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen , a 5-7 membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from silicon or sulfur, or 1-4 independently selected from nitrogen, oxygen or sulfur a fused ring selected from 5-membered heteroaryl having 1 heteroatom; R. 3 is hydrogen, halogen, -OR, -N(R) 2 , or selected from -SR; Each R 4 is independently hydrogen, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or -N(R)S(O) 2 is R; R. 5 is hydrogen, C 1-4 is aliphatic, or -CN; Each R 6 independently, C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and nitrogen, oxygen and an optionally substituted group selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from sulfur; L. 1 is a covalent bond or C 1-3 is a divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 2 methylene units of the chain are independently optionally -O-, -C(O)-, -C(S)-, -C(R) 2 -, -CH(R)-, -C(F) 2 -, -N(R)-, -S(O) 2 - or replaced by -(C)=CH-; m is 0, 1, 2, 3 or 4; Each R is independently hydrogen or C 1-6 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur, and independently selected from nitrogen, oxygen and sulfur is an optionally substituted group selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms, or: Two R groups on the same nitrogen optionally together with their intervening atoms have, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur It forms a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring.

[0174] -(R 2 ) m If the point of attachment of is shown on ring B, -(R 2 ) m The point of attachment of may be on Ring A, or any available carbon or nitrogen atom on Ring A, including the ring to which Ring B is fused. will understand. R. 4 or R 5 -R to the nitrogen atom attached to 2 is bound, then R 4 or R 5 does not exist and -R 2 is R 4 or R 5 replace the base. R. 3 -R to the carbon atom attached to 2 is bound, then R 3 does not exist and -R 2 is R 3 replace the base.

[0175] In some embodiments, the compound of Formula I-a above has Formula I-a' or Formula I-a'': [formation] 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 that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing formula I-b: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; , X 1 is a covalent bond, -CH 2 -, -CHCF 3 -, -SO 2 -, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; X 2 is a carbon or silicon atom; X 3 is -CR 2 -, -NR-, -O-, -S-, or -Si(R 2 )- is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -N(R) 2 , -P(O)(OR) 2 , -P(O)(NR 2 )OR, -P(O)(NR 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , or C, substituted as appropriate 1-4 is aliphatic; Each R 2 are independently hydrogen, deuterium, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -Si(R) 3 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(R)C(O)N(R) 2 , -OC(O)R, -OC(O)N(R) 2 , -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)(NR 2 ), -OP(O)(NR 2 ) 2 -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) 2 , -N(R)S(O) 2 R, -NP(O)R 2 , -N(R)P(O)(OR) 2 , -N(R)P(O)(OR)(NR 2 ), -N(R)P(O)(NR 2 ) 2 , or -N(R)S(O) 2 is R; Ring A is [formation] (Ring B is other than imidazo or benzo), [formation] (ring B is other than benzo), [formation] (ring B is other than benzo), [formation] (ring B is other than benzo), [formation] [formation] [formation] a bicyclic or tricyclic ring selected from Ring B is 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen or sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen , a 5-7 membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from silicon or sulfur, or 1-4 independently selected from nitrogen, oxygen or sulfur a fused ring selected from 5-membered heteroaryl having 1 heteroatom; R. 3 is hydrogen, halogen, -OR, -N(R) 2 , or selected from -SR; Each R 4 is independently hydrogen, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or -N(R)S(O) 2 is R; R. 5 is hydrogen, C 1-4 is aliphatic, or -CN; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, oxygen and heterocyclic rings having 1-2 heteroatoms independently selected from oxygen and sulfur; optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms selected from; m is 0, 1, 2, 3 or 4; and Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen optionally together with their intervening atoms have, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur It forms a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring.

[0177] -(R 2 ) m If the point of attachment of is shown on ring B, -(R 2 ) m The point of attachment of may be on Ring A, or any available carbon or nitrogen atom on Ring A, including the ring to which Ring B is fused. will understand. R. 4 or R 5 -R to the nitrogen atom attached to 2 is bound, then R4 or R 5 does not exist and -R 2 is R 4 or R 5 replace the base. R. 3 -R to the carbon atom attached to 2 is bound, then R 3 does not exist and -R 2 is R 3 replace the base.

[0178] In some embodiments, the compound of Formula I-b above has Formula I-b′ or Formula I-b″: [formation] 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 that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing formula I-c: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; , X 1 is a covalent bond, -CH 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -NR 2 , or C, substituted as appropriate 1-4 is aliphatic; Each R 2 are independently hydrogen, R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or -N(R)S(O) 2 is R; Ring A is [formation] [formation] a bicyclic or tricyclic ring selected from Ring B is 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen and sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen , a 5-7 membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from silicon or sulfur, or 1-4 independently selected from nitrogen, oxygen or sulfur a fused ring selected from 5-membered heteroaryl having 1 heteroatom; R. 3 is hydrogen, halogen, -OR, -N(R) 2 , or selected from -SR; Each R 4 is independently hydrogen, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or -N(R)S(O) 2 is R; R. 5 is hydrogen, C 1-4 is aliphatic, or -CN; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, oxygen and heterocyclic rings having 1-2 heteroatoms independently selected from oxygen and sulfur; optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms selected from; m is 0, 1, 2, 3 or 4; and Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen optionally together with their intervening atoms have, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur It forms a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring.

[0180] -(R 2 ) m If the point of attachment of is shown on ring B, -(R 2 ) m The point of attachment of may be on Ring A, or any available carbon or nitrogen atom on Ring A, including the ring to which Ring B is fused. will understand. R. 4 or R 5 -R to the nitrogen atom attached to 2 is bound, then R 4 or R 5 does not exist and -R 2 is R 4 or R 5 replace the base. R. 3 -R to the carbon atom attached to 2 is bound, then R 3 does not exist and -R 2 is R 3 replace the base.

[0181] In some embodiments, the compound of Formula I-c above has Formula I-c′ or Formula I-c″: [formation] 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 that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing formula I-d: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; , X 1 is a covalent bond, -CH 2 -, -CHCF 3 -, -SO 2 -, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; X 2 is a carbon or silicon atom; X 3 is -CR 2 -, -NR-, -O-, -S-, or -Si(R 2 )- is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -NR 2 , -P(O)(OR) 2 , -P(O)(NR 2 )OR, -P(O)(NR 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , or C, substituted as appropriate 1-4 is aliphatic; Ring C is [formation] [formation] is a monocyclic or bicyclic ring selected from; R. 2 and R 3a is independently hydrogen, deuterium, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -Si(R) 3 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(R)C(O)N(R) 2 , -OC(O)R, -OC(O)N(R) 2 , -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)(NR 2 ), -OP(O)(NR 2 ) 2 -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) 2 , -N(R)S(O) 2 R, -NP(O)R 2 , -N(R)P(O)(OR) 2 , -N(R)P(O)(OR)(NR 2 ), -N(R)P(O)(NR 2 ) 2、 or -N(R)S(O) 2 is R; Ring D is 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen and sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen , a 5-7 membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from silicon or sulfur, or 1-4 independently selected from nitrogen, oxygen or sulfur selected from 5-membered heteroaryls having 1 heteroatom; Each R 4 is independently hydrogen, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or -N(R)S(O) 2 is R; R. 5 is hydrogen, C 1-4 is aliphatic, or -CN; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, oxygen and heterocyclic rings having 1-2 heteroatoms independently selected from oxygen and sulfur; optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms selected from; L. 1 is a covalent bond or C 1-3 is a divalent straight or branched saturated or unsaturated hydrocarbon chain, and 1 to 2 methylene units of said chain are independently optionally -O-, -C(O)- , -C(S)-, -C(R) 2 -, -CH(R)-, -C(F) 2 -, -N(R)-, -S(O) 2 - or replaced by -(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 [formation] linked to; and Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen optionally together with their intervening atoms have, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur It forms a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring.

[0183] In some embodiments, the compound of Formula I-d above has Formula I-d' or Formula I-d'': [formation] [formation] 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 each as defined above.

[0184] In certain embodiments, the invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a compound of formula I-e: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; , X 1 is a covalent bond, -CH 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -NR 2 , or C, substituted as appropriate 1-4 is aliphatic; Ring C is [formation] [formation] is a monocyclic or bicyclic ring selected from; R. 2 and R 3a is independently hydrogen, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or -N(R)S(O) 2 is R; Ring D is 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen and sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen , a 5-7 membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from silicon or sulfur, or 1-4 independently selected from nitrogen, oxygen or sulfur selected from 5-membered heteroaryls having 1 heteroatom; Each R 4 is independently hydrogen, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or -N(R)S(O) 2 is R; R. 5 is hydrogen, C 1-4 is aliphatic, or -CN; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, oxygen and heterocyclic rings having 1-2 heteroatoms independently selected from oxygen and sulfur; optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms selected from; 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 [formation] linked to; and Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen optionally together with their intervening atoms have, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur It forms a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring.

[0185] In some embodiments, the compound of formula I-e above has formula I-e' or formula I-e'': [formation] [formation] 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 each as defined above.

[0186] In certain embodiments, the present invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing formulas I-f: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; , X 1 is a covalent bond, -CH 2 -, -CHCF 3 -, -SO 2 -, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; X 2 is a carbon or silicon atom; X 3 is -CR 2 -, -NR-, -O-, -S-, or -Si(R 2 )- is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -NR 2 , -P(O)(OR) 2 , -P(O)(NR 2 )OR, -P(O)(NR 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , or C, substituted as appropriate 1-4 is aliphatic; Ring C is [formation] [formation] [formation] [formation] is a monocyclic or bicyclic ring selected from; each or R 2 and R 3a are independently hydrogen, deuterium, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -Si(R) 3 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(R)C(O)N(R) 2 , -OC(O)R, -OC(O)N(R) 2 , -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)(NR 2 ), -OP(O)(NR 2 ) 2 -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) 2 , -N(R)S(O) 2 R, -NP(O)R 2 , -N(R)P(O)(OR) 2 , -N(R)P(O)(OR)(NR 2 ), -N(R)P(O)(NR 2 ) 2 , or -N(R)S(O) 2 is R; Ring D is 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen and sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen , a 5-7 membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from silicon or sulfur, or 1-4 independently selected from nitrogen, oxygen or sulfur selected from 5-membered heteroaryls having 1 heteroatom; Each R 4 is independently hydrogen, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or -N(R)S(O) 2 is R; R. 5 is hydrogen, C 1-4 is aliphatic, or -CN; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, oxygen and heterocyclic rings having 1-2 heteroatoms independently selected from oxygen and sulfur; optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms selected from; L. 1 is a covalent bond or C 1-3 is a divalent straight or branched saturated or unsaturated hydrocarbon chain, and 1 to 2 methylene units of said chain are independently optionally -O-, -C(O)- , -C(S)-, -C(R) 2 -, -CH(R)-, -C(F) 2 -, -N(R)-, -S(O) 2 - or replaced by -(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 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen optionally together with their intervening atoms have, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur It forms a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring.

[0187] In some embodiments, the compound of Formula I-f above has Formula I-f' or Formula I-f'': [formation] [formation] 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 , m, n, and p are as defined above.

[0188] In certain embodiments, the present invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing formula I-g: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; , X 1 is a covalent bond, -CH 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -NR 2 , or C, substituted as appropriate 1-4 is aliphatic; Ring C is [formation] [formation] [formation] [formation] [formation] is a monocyclic or bicyclic ring selected from; R. 2 , R 3a , and R 4 is independently hydrogen, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or -N(R)S(O) 2 is R; Ring D is 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen and sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen , a 5-7 membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from silicon or sulfur, or 1-4 independently selected from nitrogen, oxygen or sulfur selected from 5-membered heteroaryls having 1 heteroatom; R. 5 is hydrogen, C 1-4 is aliphatic, or -CN; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, oxygen and heterocyclic rings having 1-2 heteroatoms independently selected from oxygen and sulfur; optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms selected from; 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 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen optionally together with their intervening atoms have, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur It forms a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring.

[0189] In some embodiments, the compound of Formula I-g above has Formula I-g' or Formula I-g'': [formation] 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 that LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing formula I-h: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; , X 1 is a covalent bond, -CH 2 -, -CHCF 3 -, -SO 2 -, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; X 2 is a carbon or silicon atom; X 3 is -CR 2 -, -NR-, -O-, -S-, or -Si(R 2 )- is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -N(R) 2 , -P(O)(OR) 2 , -P(O)(NR 2 )OR, -P(O)(NR 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , or C, substituted as appropriate 1-4 is aliphatic; Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen, together with their intervening atoms, are 4- to 7-membered having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. forming a saturated, partially unsaturated or heteroaryl ring; Each R 2 are independently hydrogen, deuterium, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -Si(R) 3 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(R)C(O)N(R) 2 , -OC(O)R, -OC(O)N(R) 2 , -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)(NR 2 ), -OP(O)(NR 2 ) 2 -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) 2 , -N(R)S(O) 2 R, -NP(O)R 2 , -N(R)P(O)(OR) 2 , -N(R)P(O)(OR)(NR 2 ), -N(R)P(O)(NR 2 ) 2 , or -N(R)S(O) 2 is R; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, oxygen and heterocyclic rings having 1-2 heteroatoms independently selected from oxygen and sulfur; optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms selected from; Each of ring E, ring F, and ring G is independently a 6-membered heteroaryl containing 1-4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen or sulfur, 5-7 membered a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen, silicon or sulfur; or nitrogen, oxygen or a condensed ring selected from 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from sulfur, wherein each of ring E, ring F and ring G is independently optionally 1 is further substituted with ~2 oxo groups; L. 1 is a covalent bond or C 1-3 is a divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 2 methylene units of the chain are independently optionally -O-, -C(O)-, -C(S)-, -C(R) 2 -, -CH(R)-, -C(F) 2 -, -N(R)-, -S(O) 2 - or is replaced by -(C)=CH-; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0191] [formation] is shown on ring E, ring F or ring G, [formation] It is contemplated that the point of attachment of may be on any available carbon or nitrogen atom on ring E, ring F or ring G, including rings where ring E or ring G is fused to ring F. , will be understood by those skilled in the art.

[0192] -(R 2 ) m is shown on ring E, ring F or ring G, -(R 2 ) m It is contemplated 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 to which ring E or ring G is fused to ring F. , will be understood by those skilled in the art.

[0193] [formation] is shown on ring E, ring F or ring G, [formation] It is contemplated that the point of attachment of may be on any available carbon or nitrogen atom on ring E, ring F or ring G, including the carbon atom to which ring E or ring G is fused to ring F. and will be understood by those skilled in the art.

[0194] In some embodiments, the compound of formula I-h above has formula I-h' or formula I-h'': [formation] 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 that LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing formula I-i: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; , X 1 is a covalent bond, -CH 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -N(R) 2 , -Si(R) 3 , or C, substituted as appropriate 1-4 is aliphatic; Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen, together with their intervening atoms, are 4- to 7-membered having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. forming a saturated, partially unsaturated or heteroaryl ring; Each R 2 are independently hydrogen, deuterium, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -Si(R) 3 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(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) 2 is R; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, oxygen and heterocyclic rings having 1-2 heteroatoms independently selected from oxygen and sulfur; optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms selected from; Each of Ring E, Ring F, and Ring G is independently 6-membered aryl containing 0 to 3 nitrogens, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen, silicon, or sulfur a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur a fused ring selected from 5-membered heteroaryl, wherein each of ring E, ring F and ring G is independently optionally further substituted with 1 to 2 oxo groups; and m is 0, 1, 2, 3 or 4;

[0196] [formation] is shown on ring E, ring F or ring G, [formation] It is contemplated that the point of attachment of may be on any available carbon or nitrogen atom on ring E, ring F or ring G, including rings where ring E or ring G is fused to ring F. , will be understood by those skilled in the art.

[0197] -(R 2 ) m is shown on ring E, ring F or ring G, -(R 2 ) m It is contemplated 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 to which ring E or ring G is fused to ring F. , will be understood by those skilled in the art.

[0198] In some embodiments, the compound of formula I-i above has formula I-i' or formula I-i'': [formation] [formation] 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 invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a compound of formula I-k: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; , X 1 is a covalent bond, -CH2 -, -CHCF 3 -, -SO 2 -, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; X 2 is a carbon or silicon atom; X 3 is -CR 2 -, -NR-, -O-, -S-, or -Si(R 2 )- is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -N(R) 2 , -P(O)(OR) 2 , -P(O)(NR 2 )OR, -P(O)(NR 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , or C, substituted as appropriate 1-4 is aliphatic; Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen, together with their intervening atoms, are 4- to 7-membered having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. forming a saturated, partially unsaturated or heteroaryl ring; Each R 2 are independently hydrogen, deuterium, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -Si(R) 3 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(R)C(O)N(R) 2 , -OC(O)R, -OC(O)N(R) 2 , -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)(NR 2 ), -OP(O)(NR 2 ) 2 -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) 2 , -N(R)S(O) 2 R, -NP(O)R 2 , -N(R)P(O)(OR) 2 , -N(R)P(O)(OR)(NR 2 ), -N(R)P(O)(NR 2 ) 2 , or -N(R)S(O) 2 is R; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, oxygen and heterocyclic rings having 1-2 heteroatoms independently selected from oxygen and sulfur; optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms selected from; Ring E is 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen or sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen , a 5-7 membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from silicon or sulfur, or 1-4 independently selected from nitrogen, oxygen or sulfur a fused ring selected from 5-membered heteroaryl having 1 heteroatom; Ring H is a fused ring selected from 7- to 9-membered saturated or partially unsaturated carbocyclyl or heterocyclyl rings having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur. , ring E is optionally further substituted with 1-2 oxo groups; L. 1 is a covalent bond or C 1-3 is a divalent straight or branched saturated or unsaturated hydrocarbon chain, and 1 to 2 methylene units of said chain are independently optionally -O-, -C(O)- , -C(S)-, -C(R) 2 -, -CH(R)-, -C(F) 2 -, -N(R)-, -S(O) 2 - or replaced by -(C)=CH-; m is 0, 1, 2, 3 or 4;

[0200] [formation] If the point of attachment of is shown on ring E or ring H, [formation] It is contemplated that the point of attachment of can be on 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, as understood by those skilled in the art would do.

[0201] -(R 2 ) m is shown on ring E and ring H, -(R 2 ) m It is contemplated that the point of attachment of can be on 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, as understood by those skilled in the art would do.

[0202] [formation] is indicated on ring E and ring H, [formation] It is contemplated that the point of attachment of can be on 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, as understood by those skilled in the art would do.

[0203] In some embodiments, the compound of formula I-k above has formula I-k' or formula I-k'': [formation] 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 that LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing formula I-l: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; , X 1 is a covalent bond, -CH 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -N(R) 2 , -Si(R) 3 , or C, substituted as appropriate 1-4 is aliphatic; Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen, together with their intervening atoms, are 4- to 7-membered having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. forming a saturated, partially unsaturated or heteroaryl ring; Each R 2 are independently hydrogen, deuterium, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -Si(R) 3 , -S(O) 2 R, -S(O) 2 N(R)2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(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) 2 is R; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, oxygen and heterocyclic rings having 1-2 heteroatoms independently selected from oxygen and sulfur; optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms selected from; Ring E is 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen or sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen , a 5-7 membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from silicon or sulfur, or 1-4 independently selected from nitrogen, oxygen or sulfur a fused ring selected from 5-membered heteroaryl having 1 heteroatom; Ring H is a ring selected from 7- to 9-membered saturated or partially unsaturated carbocyclyl or heterocyclyl rings having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur; Ring E is optionally further substituted with 1-2 oxo groups; and m is 0, 1, 2, 3 or 4;

[0205] [formation] If the point of attachment of is shown on ring E or ring H, [formation] It is contemplated that the point of attachment of can be on 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, as understood by those skilled in the art would do.

[0206] -(R 2 ) m is shown on ring E and ring H, -(R 2 ) m It is contemplated that the point of attachment of can be on 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, as understood by those skilled in the art would do.

[0207] [formation] is indicated on ring E and ring H, [formation] It is contemplated that the point of attachment of can be on 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, as understood by those skilled in the art would do.

[0208] In some embodiments, the compound of Formula I-l above has Formula I-l' or Formula I-l'': [formation] 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 I-m above has formula I-m-1: [formation] or a pharmaceutically acceptable salt thereof, wherein: MBM, L, ring E, X 1 , R 1 , R 2 , and m are as defined above.

[0210] In certain embodiments, the present invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing formula I-n: [formation] providing a compound of Formula I that forms a compound of or a pharmaceutically acceptable salt thereof, wherein X 1 is a covalent bond, -CH 2 -, -CHCF 3 -, -SO 2 -, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; X 2 is a carbon or silicon atom; X 3 is -CR 2 -, -NR-, -O-, -S-, or -Si(R 2 )- is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -NR 2 , -P(O)(OR) 2 , -P(O)(NR 2 )OR, -P(O)(NR 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , or C, substituted as appropriate 1-4 is aliphatic; Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen, together with their intervening atoms, are 4- to 7-membered having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. forming a saturated, partially unsaturated or heteroaryl ring; Each R 2 are independently hydrogen, deuterium, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -Si(R) 3 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(R)C(O)N(R) 2 , -OC(O)R, -OC(O)N(R) 2 , -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)(NR 2 ), -OP(O)(NR 2 ) 2 -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) 2 , -N(R)S(O) 2 R, -NP(O)R 2 , -N(R)P(O)(OR) 2 , -N(R)P(O)(OR)(NR 2 ), -N(R)P(O)(NR 2 ) 2 , or -N(R)S(O) 2 is R; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected; Each of Ring I and Ring J is independently a 6-membered heteroaryl, a 5- to 7-membered saturated or partially unsaturated ring containing 1-4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen and sulfur. a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from saturated carbocyclyl, boron, nitrogen, oxygen, silicon or sulfur; or independently from nitrogen, oxygen or sulfur is a fused ring selected from 5-membered heteroaryl having 1 to 4 heteroatoms selected as; Ring K is a fused ring selected from 6- to 12-membered saturated or partially unsaturated carbocyclyl or heterocyclyl rings having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur; , ring H is optionally further substituted with 1-2 oxo groups; L. 1 is a covalent bond or C 1-3 is a divalent straight or branched saturated or unsaturated hydrocarbon chain, and 1 to 2 methylene units of said chain are independently optionally -O-, -C(O)- , -C(S)-, -C(R) 2 -, -CH(R)-, -C(F) 2 -, -N(R)-, -S(O) 2 - or is replaced by -(C)=CH-; and m is 0, 1, 2, 3 or 4;

[0211] [formation] is indicated on ring I, ring J, and ring K, [formation] can be on any available carbon or nitrogen atom on ring I, ring J, or ring K, including the carbon atom to which ring I, ring J, and ring K are fused; is intended and will be understood by those skilled in the art.

[0212] -(R 2 ) m is shown on ring I, ring J, and ring K, -(R 2 ) m can be on any available carbon or nitrogen atom on ring I, ring J, or ring K, including the carbon atom to which ring I, ring J, and ring K are fused; is intended and will be understood by those skilled in the art.

[0213] [formation] is indicated on ring I, ring J, and ring K, [formation] can be on any available carbon or nitrogen atom on ring I, ring J, or ring K, including the carbon atom to which ring I, ring J, and ring K are fused; is intended and will be understood by those skilled in the art.

[0214] In some embodiments, the compound of formula I-n above has formula I-n' or formula I-n'': [formation] 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 I-o: [formation] or a pharmaceutically acceptable salt thereof, wherein X 1 is a covalent bond, -CH 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -N(R) 2 , -Si(R) 3 , or C, substituted as appropriate 1-4 is aliphatic; Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen, together with their intervening atoms, are 4- to 7-membered having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. forming a saturated, partially unsaturated or heteroaryl ring; Each R 2 are independently hydrogen, deuterium, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -N(R) 2 , -Si(R) 3 , -S(O) 2 R, -S(O) 2 N(R) 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(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) 2 is R; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, oxygen and heterocyclic rings having 1-2 heteroatoms independently selected from oxygen and sulfur; optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms selected from; Each of Ring I and Ring J is independently a 6-membered heteroaryl, a 5- to 7-membered saturated or partially unsaturated ring containing 1-4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen or sulfur. a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from saturated carbocyclyl, boron, nitrogen, oxygen, silicon or sulfur; or independently from nitrogen, oxygen or sulfur is a fused ring selected from 5-membered heteroaryl having 1 to 4 heteroatoms selected as; Ring K is a fused ring selected from 6- to 12-membered saturated or partially unsaturated carbocyclyl or heterocyclyl rings having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur; , ring H is optionally further substituted with 1-2 oxo groups; and m is 0, 1, 2, 3 or 4;

[0216] [formation] is indicated on ring I, ring J, and ring K, [formation] can be on any available carbon or nitrogen atom on ring I, ring J, or ring K, including the carbon atom to which ring I, ring J, and ring K are fused; is intended and will be understood by those skilled in the art.

[0217] -(R 2 ) m is shown on ring I, ring J, and ring K, -(R 2 ) m can be on any available carbon or nitrogen atom on ring I, ring J, or ring K, including the carbon atom to which ring I, ring J, and ring K are fused; is intended and will be understood by those skilled in the art.

[0218] [formation] is indicated on ring I, ring J, and ring K, [formation] can be on any available carbon or nitrogen atom on ring I, ring J, or ring K, including the carbon atom to which ring I, ring J, and ring K are fused; is intended and will be understood by those skilled in the art.

[0219] In some embodiments, the compound of formula I-o above has formula I-o' or formula I-o'': [formation] 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 I-o above is of formula I-o-1: [formation] 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 invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a compound of formula I-o-2 or I-o-3: [formation] [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; , Each R 2 are independently hydrogen, deuterium, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -SiR 3 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(R)C(O)N(R) 2 , -OC(O)R, -OC(O)N(R) 2 , -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR 2 , -OP(O)(NR 2 ) 2 -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -NP(O)R 2 , -N(R)P(O)(OR) 2 , -N(R)P(O)(OR)NR 2 , -N(R)P(O)(NR 2 ) 2 , or -N(R)S(O) 2 is R; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, oxygen and heterocyclic rings having 1-2 heteroatoms independently selected from oxygen and sulfur; optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms selected from; Each of ring E, ring F, and ring G is independently a 6-membered heteroaryl containing 1-4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen or sulfur, 5-7 membered saturated or partially unsaturated carbocyclyl, 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or nitrogen, oxygen or a condensed ring selected from 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from sulfur, wherein each of ring E, ring F and ring G is independently optionally 1 to further substituted with two oxo groups; Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen, together with their intervening atoms, are 4- to 7-membered having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. forming a saturated, partially unsaturated or heteroaryl ring; L. 1 is a covalent bond or C 1-3 is a divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 2 methylene units of the chain are independently optionally -O-, -C(O)-, -C(S)-, -C(R) 2 -, -CH(R)-, -C(F) 2 -, -N(R)-, -S-, -S(O) 2 - or replaced by -(C)=CH-; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; and R. 4 , R 10 , R 11 , R 15 , W 1 , W 2 and X are as defined in WO2019 / 099868, each of which is incorporated herein by reference in its entirety.

[0222] [formation] is shown on ring E, ring F or ring G, [formation] It is contemplated that the point of attachment of may be on any available carbon or nitrogen atom on ring E, ring F or ring G, including rings where ring E or ring G is fused to ring F. , will be understood by those skilled in the art.

[0223] -(R 2 ) m is shown on ring E, ring F or ring G, -(R 2 ) m It is contemplated 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 to which ring E or ring G is fused to ring F. , will be understood by those skilled in the art.

[0224] [formation] is shown on ring E, ring F or ring G, [formation] It is contemplated that the point of attachment of may be on any available carbon or nitrogen atom on ring E, ring F or ring G, including the carbon atom to which ring E or ring G is fused to ring F. and will be understood by those skilled in the art.

[0225] As noted above, in another aspect, and in certain embodiments, the present invention provides a compound of formula I-ii: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are as defined above and described in the embodiments herein; Ring M is [formation] selected from; X 1 , X 6 , and X 7 is independently a covalent bond, -CH 2 -, -CHCF 3 -, -SO 2 -, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; X 3 and X 5 is independently a covalent bond, -CR 2 -, -NR-, -O-, -S-, or -SiR 2 - is a divalent moiety selected from; X 4 teeth, [formation] is a trivalent moiety selected from; Each R is independently hydrogen or C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, heterocyclic having 1-2 heteroatoms independently selected from oxygen and sulfur, and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected, or: Two R groups on the same nitrogen, together with their intervening atoms, are 4- to 7-membered having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. forming a saturated, partially unsaturated or heteroaryl ring; Each R 3a are independently hydrogen, deuterium, -R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -SiR 3 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(R)C(O)N(R) 2, -OC(O)R, -OC(O)N(R) 2 , -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR 2 , -OP(O)(NR 2 ) 2 -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -NP(O)R 2 , -N(R)P(O)(OR) 2 , -N(R)P(O)(OR)NR 2 , -N(R)P(O)(NR 2 ) 2 , or -N(R)S(O) 2 is R; Each R 6 independently, C 1-6 aliphatic, phenyl, 4- to 7-membered saturated or partially unsaturated nitrogen, oxygen and heterocyclic rings having 1-2 heteroatoms independently selected from oxygen and sulfur; optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms selected from; Each R 7 are independently hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -NR 2、 -P(O)(OR) 2、 -P(O)(NR 2 )OR, -P(O)(NR 2 ) 2、 -Si(OH)R 2、 -Si(OH) 2 R, -SiR 3 , or C, substituted as appropriate 1-4 is aliphatic; or R. 7 and X 1 or X 3 is, together with those intervening atoms, a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur forming a heterocyclic ring having two Rs on the same carbon 7 The group is a 3- to 6-membered spiro-fused ring having, optionally together with their intervening atoms, 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or forming a 4- to 7-membered heterocyclic ring; two Rs on adjacent carbon atoms 7 The groups, optionally together with their intervening atoms, are 1 to 7 independently selected from 3- to 7-membered saturated, partially unsaturated, carbocyclic rings or boron, nitrogen, oxygen, silicon or sulfur. A heterocyclic ring having 3 heteroatoms, or a 7-13 membered saturated, partially unsaturated, bridged ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur forming a heterocyclic or spiro-heterocyclic ring; Ring D is 6- to 10-membered aryl or heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen , a 5- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 3 heteroatoms independently selected from silicon or sulfur, or 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur is selected from 5-membered heteroaryls having heteroatoms of; L. 1 is a covalent bond or C 1-3 is a divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 2 methylene units of the chain are independently optionally -O-, -C(O)-, -C(S)-, -C(R) 2 -, -CH(R)-, -C(F) 2 -, -N(R)-, -S-, -S(O) 2 - or replaced by -(C)=CH-; n is 0, 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4;

[0226] As defined above and described herein, X 1 is a covalent bond, -CH 2、 -C(R) 2 -, -C(O)-, -C(S)-, -CH(R)-, -CH(CF 3 )-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR 2 )-, -S(O)-, -S(O) 2 -,or [formation] is a divalent moiety selected from

[0227] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 is -CH 2 -is. In some embodiments, X 1 is -C(R) 2 -is. In some embodiments, X 1 is -C(O)-. In some embodiments, X 1 is -C(S)-. In some embodiments, X 1 is -CH(R)-. In some embodiments, X 1 is -CH(CF 3 )-. In some embodiments, X 1 is -P(O)(OR)-. In some embodiments, X 1 is -P(O)(R)-. In some embodiments, X 1 is -P(O)(NR 2 )-. In some embodiments, X 1 is -S(O)-. In some embodiments, X 1 is -S(O) 2 -is. In some embodiments, X 1 teeth, [formation] is.

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

[0229] As defined above and described herein, X 2 is a carbon or 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] As defined above and described herein, X 3 is -CH 2 -, -C(R) 2 -, -N(R)-, -CF 2 -, -CHF-, -S-, -CH(R)-, -Si(R 2 )-, or -O-.

[0233] In some embodiments, X 3 is -CH 2 -is. In some embodiments, X 1 is -C(R) 2 -is. In some embodiments, X 3 is -N(R)-. In some embodiments, X 3 is -CF 2 -is. 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 2 )-. In some embodiments, X 3 is -O-.

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

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

[0236] In some embodiments, R 1 is hydrogen. In some embodiments, R1 is deuterium. In some embodiments, R 1 is a halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -OR. In some embodiments, R 1 is -SR. In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is -S(O) 2 is R. In some embodiments, R 1 is -NR 2 is. In some embodiments, R 1 is -P(O)(OR) 2 is. In some embodiments, R 1 is -P(O)(NR 2 ) OR. In some embodiments, R 1 is -P(O)(NR 2 ) 2 is. In some embodiments, R 1 is -Si(OH) 2 is R. In some embodiments, R 1 is -Si(OH)(R) 2 is. In some embodiments, R 1 is -Si(R) 3 is. In some embodiments, R 1 is C 1-4 Aliphatic. In some embodiments, R 1 and X 1 or X 4 is, together with their intervening atoms, a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; form a formula ring.

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

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

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

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

[0241] As defined above and described herein, R 2 and R 3a is independently hydrogen, deuterium, -R 6 , Halogen, -CN, -NO 2 , -OR, -Si(OH) 2 R, -Si(OH)R 2、 -SR, -NR 2 , -SiR 3 , -S(O) 2 R, -S(O) 2 NR 2、 -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(R)C(O)NR 2、 -OC(O)R, -OC(O)NR 2 , -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR 2 , -OP(O)(NR 2 ) 2 -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -NP(O)R 2 , -N(R)P(O)(OR) 2 , -N(R)P(O)(OR)NR 2 , -N(R)P(O)(NR 2 ) 2 , or -N(R)S(O) 2 is R.

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

[0243] In some embodiments, R 2 and R 3a is independently -OH. In some embodiments, R 2 and R 3a is independently -NH 2 is. In some embodiments, R 2 and R 3a is independently -CH 2 NH 2 is. In some embodiments, R 2 and R 3a is independently -CH 2 NHCOMe. In some embodiments, R 2 and R 3a is independently -CH 2 NHCONHMe. In some embodiments, R 2 and R 3a is independently -NHCOMe. In some embodiments, R 2 and R 3a is independently -NHCONHEt. In some embodiments, R 2 and R 3a Independently - SiMe 3 is. In some embodiments, R 2 and R 3a Independently - SiMe 2 is OH. In some embodiments, R 2 and R 3a is independently -SiMe(OH) 2 is. In some embodiments, R 2 and R 3a independently [formation] is. 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 independently - NMe 2 is. In some embodiments, R 2 and R 3a independently - NHCO 2 is Et. In some embodiments, R 2 and R 3a is independently -CN. In some embodiments, R 2 and R 3a is independently -CH 2 Ph. In some embodiments, R 2 and R 3a independently - NHCO 2 is tBu. In some embodiments, R 2 and R 3a is independently -CO 2 is tBu. In some embodiments, R 2 and R 3a is independently -OMe. In some embodiments, R 2 and R 3a independently - CF 3 is.

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

[0245] As defined above and described herein, R 3 is hydrogen, deuterium, halogen, -CN, -NO 2 , -OR, -NR 2 , -SR, -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)NR(OR), -OC(O)R, -OC(O)NR 2 , -OP(O)(OR) 2 , -OP(O)(NR 2 ) 2 , -OP(O)(OR)NR 2 , -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -N(R)S(O) 2 NR 2 , -N(R)P(O)(OR) 2 , -N(R)P(O)(OR)NR 2 , -P(O)(OR) 2 , -P(O)(NR 2 )OR, -P(O)(NR 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , or -Si(R) 3 is.

[0246] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is a halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 -NO 2 is. In some embodiments, R 3 is -OR. In some embodiments, R 3 is -NR 2 is. In some embodiments, R 3 is -SR. In some embodiments, R 3 is -S(O) 2 is R. In some embodiments, R 3 is -S(O) 2 NR 2 is. In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is -C(O)R. In some embodiments, R 3 is -C(O)OR. In some embodiments, R 3 is -C(O)NR 2 is. In some embodiments, R 3 is -C(O)NR(OR). In some embodiments, R 3 is -OC(O)R. In some embodiments, R 3 is -OC(O)NR 2 is. In some embodiments, R 3 is -OP(O)(OR) 2 is. In some embodiments, R 3 is -OP(O)(NR 2 ) 2 is. In some embodiments, R 3 is -OP(O)(OR)NR 2 is. In some embodiments, R 3 is -N(R)C(O)R. In some embodiments, R 3 is -N(R)C(O)OR. In some embodiments, R 3 is -N(R)C(O)NR 2 is. In some embodiments, R 3 is -N(R)S(O) 2 is R. In some embodiments, R 3 is -N(R)S(O) 2 NR 2 is. In some embodiments, R 3 is -N(R)P(O)(OR) 2 is. In some embodiments, R 3 is -N(R)P(O)(OR)NR 2 is. In some embodiments, R 3 is -P(O)(OR) 2 is. In some embodiments, R 3 is -P(O)(NR 2) OR. In some embodiments, R 3 is -P(O)(NR 2 ) 2 is. In some embodiments, R 3 is -Si(OH) 2 is R. In some embodiments, R 3 is -Si(OH)(R) 2 is. In some embodiments, R 3 is -Si(R) 3 is.

[0247] In some embodiments, R 3 is methyl. In some embodiments, R 3 Ha-OCH 3 is. 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, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -P(O)(OR) 2 , -P(O)(NR 2 )OR, or -P(O)(NR 2 ) 2 is.

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

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

[0254] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5 is C 1-4 Aliphatic. 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 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-3 heteroatoms independently selected from aliphatic, phenyl, boron, nitrogen, oxygen, silicon and sulfur, and boron, nitrogen, oxygen is an optionally substituted group selected from 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from silicon and sulfur.

[0257] In some embodiments, R 6 is C 1-6 Aliphatic. In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 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 6 is an optionally substituted 5-6 membered heteroaryl ring having 1-4 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 defined generally above, each R 7 is independently hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -N(R) 2 , -P(O)(R) 2 , -P(O)(OR) 2 , -P(O)(NR 2 )OR, -P(O)(NR 2 ) 2 , -Si(OH)R 2 , -Si(OH) 2 R, -SiR 3 , or C, substituted as appropriate 1-4 is aliphatic or R 7 and X 1 or X 3 is, together with those intervening atoms, a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur or two R on the same carbon 7 The group is a 3- to 6-membered spiro-fused ring having, optionally together with their intervening atoms, 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or forming a 4- to 7-membered heterocyclic ring; two Rs on adjacent carbon atoms 7 The groups, optionally together with their intervening atoms, are 1 to 7 independently selected from 3- to 7-membered saturated, partially unsaturated, carbocyclic rings or boron, nitrogen, oxygen, silicon or sulfur. A heterocyclic ring having 3 heteroatoms, or a 7-13 membered saturated, partially unsaturated, bridged ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur Forms a heterocyclic or spiro-heterocyclic ring.

[0260] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is a halogen. In some embodiments, R 7 is -CN. In some embodiments, R 7is -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) 2 is R. In some embodiments, R 7 is -NR 2 is. In some embodiments, R 7 is -Si(R) 3 is. In some embodiments, R 7 is -P(O)(R) 2 is. In some embodiments, R 7 is -P(O)(OR) 2 is. In some embodiments, R 7 is -P(O)(NR 2 ) OR. In some embodiments, R 7 is -P(O)(NR 2 ) 2 is. In some embodiments, R 7 is -Si(OH)R 2 is. In some embodiments, R 7 is -Si(OH) 2 is R. In some embodiments, R 7 is C 1-4 Aliphatic. In some embodiments, R 7 and X 1 or X 3 is, together with those intervening atoms, a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur to form a heterocyclic ring with In some embodiments, two R on the same carbon 7 The groups, optionally together with their intervening atoms, are 1-2 independently selected from 3-6 membered spiro-fused rings or 4-7 membered boron, nitrogen, oxygen, silicon or sulfur. to form a heterocyclic ring with heteroatoms. In some embodiments, two R on adjacent carbon atoms 7 The groups, optionally together with their intervening atoms, are 1 to 7 independently selected from 3- to 7-membered saturated, partially unsaturated, carbocyclic rings or boron, nitrogen, oxygen, silicon or sulfur. It forms a heterocyclic ring with 3 heteroatoms. In some embodiments, two R on adjacent carbon atoms 7 The group is a 7- to 13-membered saturated, partially unsaturated group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur optionally together with their intervening atoms. Forms a saturated, bridged heterocyclic ring, or spiro heterocyclic ring.

[0261] In some embodiments, R 7 is hydrogen, halogen, -CN, -OR, -NR 2 , or C 1-4 selected from alkyl; In some embodiments, R 7 is hydrogen, halogen, -CN, or C 1-4 selected from alkyl; In some embodiments, R 7 is fluoro. In some embodiments, two R on the same carbon 7 The groups are optionally combined with their intervening atoms to form 3- or 4-membered spirofused rings.

[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 [formation] [formation] is a bicyclic or tricyclic ring selected from

[0264] In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is.

[0265] In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] is. In some embodiments, Ring A is [formation] 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 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen or sulfur, 5 ~7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur; or a fused ring selected from 5-membered heteroaryl having 1 to 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 saturated 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 boric acid, nitrogen, oxygen, silicon, or sulfur.

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

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

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

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

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

[0274] In some embodiments, ring B is [formation] [formation] 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 [formation] is a monocyclic or bicyclic ring selected from

[0277] In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is.

[0278] In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is. In some embodiments, Ring C is [formation] is.

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

[0280] In some embodiments, Ring C is [formation] is selected from

[0281] In some embodiments, Ring C is [formation] 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 a 6- to 10-membered aryl or heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; ~7-membered saturated or partially unsaturated carbocyclyl, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur; or selected from 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0284] In some embodiments, Ring D is 6-10 membered aryl. In some embodiments, Ring D is a 6-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring D is a 5-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring D is a 5-7 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 boric acid, 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 Ring E, Ring F, and Ring G is independently selected from 6-membered aryl, nitrogen, oxygen, or sulfur 1-4 5-7 having 1-3 heteroatoms independently selected from 6-membered heteroaryl containing 1 heteroatom, 5-7 membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen, silicon or sulfur A fused ring selected from a saturated or partially unsaturated heterocyclyl ring or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; Each of F and ring G is independently optionally further substituted with 1-2 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 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, each ring E, ring F and ring G is independently a 5-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, each ring E, ring F and ring G is independently 5-7 membered with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur. It is a saturated or partially unsaturated heterocyclyl. In some embodiments, each Ring E, Ring F, and Ring G is independently a 5-membered heteroaryl having 1-4 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 1-2 oxo groups.

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

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

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

[0292] In some embodiments, Ring E and Ring G are independently [formation] is. In some embodiments, Ring E and Ring G are independently [formation] is. In some embodiments, Ring E and Ring G are independently [formation] is. In some embodiments, Ring E and Ring G are independently [formation] is. In some embodiments, Ring E and Ring G are independent. In some embodiments, ring E and ring G are independently [formation] is. In some embodiments, Ring E and Ring G are independently [formation] is. In some embodiments, Ring E and Ring G are independently [formation] is.

[0293] In some embodiments, Ring E and Ring G are independently [formation] is. In some embodiments, Ring E and Ring G are independently [formation] is. In some embodiments, Ring E and Ring G are independently [formation] is. In some embodiments, Ring E and Ring G are independently [formation] is. In some embodiments, Ring E and Ring G are independently [formation] is.

[0294] In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is.

[0295] In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] is. In some embodiments, Ring E, Ring F and Ring G are [formation] 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 7- to 9-membered saturated or ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur It is a ring selected from partially unsaturated carbocyclyl or heterocyclyl rings, and ring E is optionally further substituted with 1 to 2 oxo groups.

[0298] In some embodiments, ring H is 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. A ring of choice, wherein ring H is optionally further substituted with 1-2 oxo groups.

[0299] In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is. In some embodiments, Ring H is [formation] is.

[0300] In some embodiments, Ring E and Ring H are [formation] 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 independently contains 1-4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen or sulfur. 6-membered heteroaryl, 5- to 7-membered saturated or partially unsaturated carbocyclyl containing 5- to 7-membered saturated or having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur It is a partially unsaturated heterocyclyl ring or a fused ring selected from 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 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each of Ring I and Ring J is independently a 5-7 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 It is a partially unsaturated heterocyclyl ring. In some embodiments, each of Ring I and Ring J is independently a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

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

[0305] In some embodiments, Ring I and Ring J are independently [formation] is. In some embodiments, Ring I and Ring J are independently [formation] is. In some embodiments, Ring I and Ring J are independently [formation] is.

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

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

[0309] In some embodiments, Ring I, Ring J and Ring K are [formation] 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 [formation] is selected from

[0312] In some embodiments, ring M is [formation] is. In some embodiments, ring M is [formation] is. In some embodiments, ring M is [formation] is. In some embodiments, ring M is [formation] is. In some embodiments, ring M is [formation] is. In some embodiments, ring M is [formation] is. In some embodiments, ring M is [formation] is. In some embodiments, ring M is [formation] is. In some embodiments, ring M is [formation] is. In some embodiments, ring M is [formation] is. In some embodiments, ring M is [formation] 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 is a divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 2 methylene units of the chain are independently optionally -O-, -C(O)-, -C(S)-, -C(R) 2 -, -CH(R)-, -C(F) 2 -, -N(R)-, -S-, -S(O) 2 - or replaced by -(C)=CH-.

[0315] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is C 1-3 Aliphatic. In some embodiments, L 1 is -CH 2 -is. In some embodiments, L 1 is -C(D)(H)-. In some embodiments, L 1 is -C(D) 2 -is. In some embodiments, L 1 is -CH 2 CH 2 -is. In some embodiments, L 1 is -NR-. In some embodiments, L 1 is -CH 2 It is NR-. In some embodiments, L 1 is -O-. In some embodiments, L 1 is -CH 2 It is O-. 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) 2 -is. In some embodiments, L 1 is -NRS(O) 2 -is. In some embodiments, L 1 is -S(O) 2 It is 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, [formation] is a single or double bond.

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

[0319] In some embodiments, [formation] 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 two. In some embodiments, m is three. In some embodiments, m is four. In some embodiments, m is five. In some embodiments, m is 6. In some embodiments, m is seven. In some embodiments, m is eight. In some embodiments, m is nine. In some embodiments, m is ten. In some embodiments, m is 11. In some embodiments, m is twelve. In some embodiments, m is thirteen. In some embodiments, m is 14. In some embodiments, m is fifteen. In some embodiments, m is sixteen.

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

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

[0324] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is two. In some embodiments, n is three. In some embodiments, n is four.

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

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

[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, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is.

[0330] In certain embodiments, the present invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing compounds of formula I-p-1, I-p-2, or I-p-3, respectively: [formation] [formation] 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, [formation] , and n are each as defined in WO2017 / 197051, which is incorporated herein by reference in its entirety; [formation] is R as defined in WO2017 / 197051 12 at the binding site of R 1 , R 1 and R 2 or the ring formed by combining the 17 is coupled to the resulting [formation] is this R 12 substitute for a substituent.

[0331] In some embodiments, the present invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a compound of formula I-p-4, I-p-5, I-p-6, or I-p-7, respectively: [formation] [formation] 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, [formation] , and n are as defined in WO2018 / 237026, each of which is incorporated herein by reference in its entirety, [formation] is R as defined in WO2018 / 237026 12 at the binding site of R 1 or R 16 is coupled to the resulting [formation] is this R 12 substitute for a substituent.

[0332] In certain embodiments, the present invention provides that LBM is MDM2 (i.e., human double minute 2 or or HDM2) E3 ligase binding moieties, thereby providing the formulas I-q-1, I-q-2, I-q-3, I-q-4, I-q-5, I-q-6, I-q-7, I-q-8, I-q- 9, I-q-10, I-q-11, I-q-12, I-q-13, I-q-14, I-q-15, I-q-16, I-q-17 or I-q-18: [formation] [formation] [formation] or a pharmaceutically acceptable salt thereof, wherein L and MDM2 are as defined above and described in the embodiments herein, the variable Thing 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. 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 herein by reference in its entirety. .

[0333] In some embodiments, the formulas I-q-1, I-q-2, I-q-3, I-q-4, I-q-5, I-q-6, I-q-7, I-q-8, I-q-9, I-q-10, I-q- 11, I-q-12, I-q-13, I-q-14, I-q-15, I-q-16, I-q-17, or I-q-18 compounds of formulas I-aaa-1, I-aaa-2, -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 as defined by the definition of I-aaa-20.

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

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

[0336] In some embodiments, the present invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a compound of formula I-r-1 or I-r-3, respectively: [formation] [formation] 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 are as defined in WO2018 / 237026, each of which is incorporated herein by reference in its entirety, [formation] is R as defined in WO2018 / 237026 12 at the binding site of R 1 or R 16 is coupled to the resulting [formation] is this R 12 substitute for a substituent.

[0337] In certain embodiments, the present invention provides that LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a compound of formula I-s: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; Each of A, B, C, W, X, Y, and Z is as described and defined in US 5,721,246, each of which is incorporated herein by reference in its entirety.

[0338] In certain embodiments, the invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a compound of the formula I-t: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; R. 1 , R 2 , and n are as described and defined in WO2019 / 043214, each of which is incorporated herein 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, eg: [formation] During the ceremony, [formation] is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

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

[0341] In certain embodiments, the invention provides that LBM is an IAP binding moiety, thereby providing formulas I-v: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and as described in the embodiments herein; W, Y, Z, R 1 , R 2 , R 3 , R 4 , and R 5 are as described and defined in WO2014 / 044622, US2015 / 0225449. WO2015 / 071393, and US2016 / 0272596, each of which is incorporated herein by reference in its entirety.

[0342] In certain embodiments, the invention provides that LBM is an MDM2 binding moiety, thereby providing formula I-w: [formation] or a pharmaceutically acceptable salt thereof (Hines, J. et al., Cancer Res. (DOI: 10.1158 / 0008-5472. CAN-18-2918). and as defined), each of which is incorporated herein by reference in its entirety.

[0343] In certain embodiments, the invention provides that LBM is a DCAF16 binding moiety, thereby providing formula I-x: [formation] (described and defined in Zhang, X. et al., bioRxiv (doi:https: / / doi.org / 10.1101 / 443804)) as described), each of which is incorporated herein by reference in its entirety.

[0344] In certain embodiments, the present invention provides that LBM is an RNF114 binding moiety, thereby providing formula I-y: [formation] or a pharmaceutically acceptable salt thereof (described and defined in Spradin, J.N. et 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 invention provides that LBM is the RNF4 binding moiety, thereby providing formulas I-z: [formation] (described and defined in Ward, C.C., et al., bioRxiv (doi: https: / / doi.org / 10.1101 / 439125)). as described), each of which is incorporated herein by reference in its entirety.

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

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

[0348] In certain embodiments, the invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing a Four: [formation] providing a compound of formula I, forming a compound of or a pharmaceutically acceptable salt thereof, of formulas I-bb-1, I-bb-2, I-bb-3, and I-bb-4 wherein L and MBM are as defined above and described herein, and the variable R 4 , R 10 , R 11 , R 15 , R 16 , R 17 , W 1 , W 2 , and X are as defined in WO 2019 / 099868, which is incorporated herein by reference in its entirety, and [formation] is an R 17 or R 16 to, R 12 is bound at the binding site of the [formation] but this R 12 Occupy the position of the substituent.

[0349] In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is.

[0350] In certain embodiments, the present invention provides that LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby providing formula I-cc: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and according to embodiments herein As stated, where: each X 1 is independently -CH 2 -, -O-, -NR-, -CF 2 -, [formation] , -C(O)-, -C(S)-, or [formation] is; X 2 and X 3 is independently -CH 2 -, -C(O)-, -C(S)-, or [formation] is; Z. 1 and Z 2 is 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 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L. x is a covalent bond, or C 1~3 is a divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein one to two methylene units of the chain are independently -O-, -S-, -C( O)-, -C(S)-, -CR 2 -, -CRF-, -CF 2 -, -NR-, or -S(O) 2 - has been replaced where necessary; Each R x are independently hydrogen, deuterium, R z , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -CF 2 R, -CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -C(S)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR 2 , -OP(O)(NR 2 ) 2 , -Si(OR)R 2 , and -SiR 3 is selected from; or 2 R's x is an optionally substituted 5- to 8-membered partially unsaturated group having, taken together, 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or forming a fused ring of aryl; Each R is independently selected from hydrogen or an optionally substituted group, wherein the optionally substituted group is C 1~6 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and nitrogen, oxygen, and sulfur is selected from 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from, or: Two R groups on the same carbon or nitrogen, optionally together with atoms between them, are independently selected from nitrogen, oxygen, and sulfur in addition to the carbon or nitrogen. forming an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms; R. y teeth, [formation] or selected from hydrogen; Ring B x is phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic, carbocyclic ring, or 1 to 3 hetero groups independently selected from nitrogen, oxygen, and sulfur. or a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein ring B x is further optionally substituted with 1-2 oxo groups; Each R w are independently hydrogen, deuterium, R z , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -CF 2 R, -CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR 2 , -OP(O)(NR 2 ) 2 , and -SiR 3 selected from; Each R z independently, C 1~6 a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and nitrogen, oxygen, and optionally substituted groups selected from 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from sulfur; [formation] 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 is independently -CH 2 -, -O-, -NR-, -CF 2 -, [formation] , -C(O)-, -C(S)-, or [formation] is.

[0352] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 Ha-CH 2 -is. In some embodiments, X 1 is -O-. In some embodiments, X 1 is -NR-. In some embodiments, X 1 Ha-CF 2 -is. In some embodiments, X 1 teeth [formation] is. In some embodiments, X 1 is -C(O)-. In some embodiments, X 1 is -C(S)-. In some embodiments, X 1 teeth [formation] is.

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

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

[0355] In some embodiments, X 2 and X 3 is independently -CH 2 -is. 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 independently [formation] is.

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

[0357] As defined above and described herein, Z 1 and Z 2 is independently a carbon atom or a nitrogen atom.

[0358] In some embodiments, Z 1 and Z 2is independently a carbon atom. In some embodiments, Z 1 and Z 2 is independently a carbon atom.

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

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

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

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

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

[0364] As defined above and described herein, L x is a covalent bond, or C 1~3 is a divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein one to two methylene units of the chain are independently -O-, -S-, -C(O )-, -C(S)-, -CR 2 -, -CRF-, -CF 2 -, -NR-, or -S(O) 2 - has been replaced where necessary.

[0365] In some embodiments, L x is a covalent bond. In some embodiments, L x is C 1~3 is a divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein one to two methylene units of the chain are independently -O-, -S-, -C( O)-, -C(S)-, -CR 2 -, -CRF-, -CF 2 -, -NR-, or -S(O) 2 - has been replaced where necessary.

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

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

[0368] As defined above and described herein, each R x are independently hydrogen, deuterium, R z , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -CF 2 R, -CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -C(S)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR 2 , -OP(O)(NR 2 ) 2 , -Si(OR)R 2 , and -SiR 3 or two R x is an optionally substituted 5- to 8-membered partially unsaturated group having, taken together, 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Or form a condensed ring of aryl.

[0369] In some embodiments, R x is hydrogen. In some embodiments, R x is deuterium. In some embodiments, R x is R z is. In some embodiments, R x is a halogen. In some embodiments, R x is -CN. In some embodiments, R x Ha-NO 2 is. In some embodiments, R x is -OR. In some embodiments, R x is -SR. In some embodiments, R x Ha-NR 2 is. In some embodiments, R x is -S(O) 2 is R. In some embodiments, R x is -S(O) 2 NR 2 is. In some embodiments, R x is -S(O)R. In some embodiments, R x Ha-CF 2 is R. In some embodiments, R x Ha-CF 3 is. In some embodiments, R x Ha-CR 2 (OR). In some embodiments, R x Ha-CR 2 (NR 2 ). 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 2 is. In some embodiments, R x is -C(O)N(R)OR. In some embodiments, R x is -OC(O)R. In some embodiments, R x is -OC(O)NR 2 is. In some embodiments, R x is-C(S)NR 2 is. 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 2 is. In some embodiments, R x は-N(R)S(O) 2 is R. In some embodiments, R x is -OP(O)R 2 is. In some embodiments, R x -OP(O)(OR) 2 is. In some embodiments, R x is -OP(O)(OR)NR 2 is. In some embodiments, R x is -OP(O)(NR 2 ) 2 is. In some embodiments, R x -Si(OR)R 2 is. In some embodiments, R x Ha-SiR 3 is. In some embodiments, two R x is an optionally substituted 5- to 8-membered partially unsaturated group having, taken together, 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Or form a condensed ring of aryl.

[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 Ha-NH 2is. In some embodiments, R x Ha-NHCH 3 is. In some embodiments, R x は-N(CH 3 ) 2 is. In some embodiments, R x is -NHCH(CH 3 ) 2 is. In some embodiments, R x Ha-NHSO 2 CH 3 is. In some embodiments, R x Ha-CH 2 is OH. In some embodiments, R x Ha-CH 2 NH 2 is. In some embodiments, R x is -C(O)NH 2 is. In some embodiments, R x is -C(O)NHCH 3 is. In some embodiments, R x teeth, [formation] is. In some embodiments, R x teeth, [formation] is. In some embodiments, R x teeth, [formation] is. In some embodiments, R x teeth, [formation] is. In some embodiments, R x teeth, [formation] is. In some embodiments, R x teeth, [formation] is. In some embodiments, R x teeth, [formation] is. In some embodiments, R x teeth, [formation] is. In some embodiments, R x teeth, [formation] is. In some embodiments, R x teeth, [formation] is.

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

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

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

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

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

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

[0377] Ring B, as defined above and described herein x is phenyl, 4- to 10-membered saturated or partially unsaturated monocyclic, bicyclic, carbocyclic, or 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5- to 6-membered heteroaryl ring having 1-4 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 having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur It is a heterocyclic ring. In some embodiments, ring B x is a 5- to 6-membered heteroaryl ring having 1-4 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, [formation] is. In some embodiments, ring B x teeth, [formation] is. In some embodiments, ring B x teeth, [formation] is. In some embodiments, ring B x teeth, [formation] is. In some embodiments, ring B x teeth, [formation] is.

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

[0381] As defined above and described herein, each R w are independently hydrogen, deuterium, R z , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -CF 2 R, -CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, -C(O)NR 2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR 2 , -OP(O)(NR 2 ) 2 , and -SiR 3 is selected from

[0382] In some embodiments, R w is hydrogen. In some embodiments, R w is deuterium. In some embodiments, R w is R z is. In some embodiments, R w is a halogen. In some embodiments, R w is -CN. In some embodiments, R w Ha-NO 2 is. In some embodiments, R w is -OR. In some embodiments, R w is -SR. In some embodiments, R w Ha-NR 2 is. In some embodiments, R w is -S(O) 2 is R. In some embodiments, R w is -S(O) 2 NR 2 is. In some embodiments, R w is -S(O)R. In some embodiments, R w Ha-CF 2 is R. In some embodiments, R w Ha-CF 3 is. In some embodiments, R w Ha-CR 2 (OR). In some embodiments, R w Ha-CR 2 (NR 2 ). 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 2 is. 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 2 is. 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 2 is. In some embodiments, R w は-N(R)S(O) 2 is R. In some embodiments, R w is -OP(O)R 2 is. In some embodiments, R w -OP(O)(OR) 2 is. In some embodiments, R w is -OP(O)(OR)NR 2 is. In some embodiments, R w is -OP(O)(NR 2 ) 2 is. In some embodiments, R w Ha-SiR 3 is.

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

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

[0385] In some embodiments, R z is C 1~6 Aliphatic. 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 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R z is an optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

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

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

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

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

[0390] In certain embodiments, [formation] is selected from those shown in Table 1 for compounds.

[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 two. In some embodiments, w is three. In some embodiments, w is four.

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

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

[0395] In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, m is two. In some embodiments, x is three. In some embodiments, x is four.

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

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

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

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

[0400] In some embodiments, the present invention provides ring A x is benzo, y is 1, and X 1 ga-CH 2 - and X 2 and X 3 is -C(O)- and Z 1 and Z 2 is a carbon atom as shown and formula I-cc-1: [formation] 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 described in the embodiments herein.

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

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

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

[0404] In some embodiments, the present invention provides ring A x is benzo, y is 0, and X 2 and X 3 is -C(O)- and Z 1 and Z 2 is a carbon atom as shown and formula I-cc-5: [formation] 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, as defined above and described in the embodiments herein is.

[0405] In some embodiments, the present invention provides ring A x is benzo, y is 1, and X 1 is -O- and X 2 and X 3 is -C(O)- and Z 1 and Z 2 is a carbon atom as shown and formula I-cc-6: [formation] providing a compound of formula I-cc, which provides a compound of 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 described in the embodiments herein.

[0406] In some embodiments, the present invention provides 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 is a carbon atom as shown and formula I-cc-7: [formation] providing a compound of formula I-cc, which provides a compound of 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 described in the embodiments herein.

[0407] In some embodiments, the present invention provides ring A x is benzo, y is 1, and X 1 Ga-CF 2 - and X 2 and X 3 is -C(O)- and Z 1 and Z 2 is a carbon atom as shown and formula I-cc-8: [formation] providing a compound of Formula I-cc, which provides a compound of 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 described in the embodiments herein.

[0408] In some embodiments, the present invention provides ring A x is benzo, y is 1, and X 1 but [formation] and X 2 and X 3 is -C(O)- and Z 1 and Z 2 is a carbon atom as shown and formula I-cc-9: [formation] providing a compound of Formula I-cc, which provides a compound of 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 described in the embodiments herein.

[0409] In some embodiments, the present invention provides ring A x is pyridyl, y is 1, and X 1 ga-CH 2 - and X 2 and X 3 is -C(O)- and Z 1 and Z 2 is a carbon atom as shown and formula I-cc-10: [formation] providing a compound of formula I-cc, which provides a compound of 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 described in the embodiments herein.

[0410] In some embodiments, the present invention provides ring A x is pyridyl, y is 1, and X 1 ga-CH 2 - and X 2 and X 3 is -C(O)- and Z 1 and Z 2 is a carbon atom as shown and formula I-cc-11: [formation] 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 described in the embodiments herein.

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

[0412] In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is. In some embodiments, LBM is [formation] is.

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

[0414] In certain embodiments, the invention provides that LBM is an RPN13 binding moiety, thereby providing a compound of formula I-dd: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and in embodiments herein and each of variables A, Y, and Z are as described and defined in WO 2019 / 165229, each of which is incorporated herein by reference in its entirety. be.

[0415] In certain embodiments, the present invention provides that LBM is characterized by Shanmugusundaram, K. et al, J.Bio.Chem. incorporated herein by reference), thereby providing a Ubr1 binding moiety of the formula I-ee-1 or I-ee-2: [formation] or a pharmaceutically acceptable salt thereof, wherein in formulas I-ee-1 and I-ee-2, L and MBM are defined above, and As described in the embodiments herein.

[0416] In certain embodiments, the invention provides that LBM is the CRBN binding moiety, thereby , the formula I-ff: [formation] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-ff, L and MBM are defined above, and in embodiments herein as described and the variable R 1 , R 2 , R 3 , R 4 , R 5 , Q, X, and n are as described and defined in US 2019 / 276474, each of which is incorporated herein by reference in its entirety.

[0417] In certain embodiments, the invention provides that the LBM is a CRBN E3 ubiquitin ligase binding moiety, thereby providing a compound of the formula I-gg-1, I-gg-2, I-gg-3 or I-gg-4: [formation] or a pharmaceutically acceptable salt thereof, wherein L and MBM are defined above and described in the embodiments herein, and variables Y, A 1 , and A 3 are as described and defined in WO2019 / 236483, each of which is incorporated herein by reference in its entirety.

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

[0420] In some embodiments, the present invention provides that MBM is [formation] and thereby the formula I-hh-3: [formation] providing a compound of formula I-c, which provides a compound of or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 , rings 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 [formation] and the MBM is [formation] and thereby the formula I-hh-4: [formation] providing a compound of formula I-c, which provides a compound of or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 , m, and L, both alone and in combination, are as defined above and described in the embodiments herein.

[0422] In some embodiments, the present invention provides that MBM is [formation] and thereby the formula I-hh-5: [formation] providing a compound of formula I-c, which provides a compound of or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 , rings 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 [formation] and the MBM is [formation] and thereby the formula I-hh-6: [formation] providing a compound of formula I-c, which provides a compound of or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 , m, and L, both alone and in combination, are as defined above and described in the embodiments herein.

[0424] In some embodiments, the present invention provides that MBM is [formation] and thereby the formula I-hh-7: [formation] providing a compound of formula I-c, which provides a compound of or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 , rings 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 [formation] and the MBM is [formation] and thereby the formula I-hh-8: [formation] providing a compound of formula I-c, which provides a compound of or a pharmaceutically acceptable salt thereof, wherein X 1 , R 1 , R 2 , m, and L, both alone and in combination, are as defined above and described in the embodiments herein.

[0426] In some embodiments, the present invention provides that MBM is [formation] of formula I-ii-1: [formation] or a pharmaceutically acceptable salt thereof, wherein ring M, ring D, L, 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 that MBM is [formation] and the LBM is [formation] of formula I-ii-2: [formation] 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 that MBM is [formation] and the LBM is [formation] of formula I-ii-3: [formation] 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 that MBM is [formation] of formula I-ii-4: [formation] or a pharmaceutically acceptable salt thereof, wherein ring M, ring D, L, 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 that MBM is [formation] and the LBM is [formation] of formula I-ii-5: [formation] 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 that MBM is [formation] and the LBM is [formation] and formula I-ii-6: [formation] 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: [formation] or a pharmaceutically acceptable salt thereof, wherein R. 1’’ is hydrogen and R A selected from; Each R A independently, C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and nitrogen, oxygen and optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from sulfur: R. 10 is optionally substituted selected from phenyl, 5-10 membered aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. selected from monocyclic or bicyclic rings; R. 12 and R 13 are each independently hydrogen and R A or selected from: R. 12 and R 13 is independently selected from optionally substituted 4- to 8-membered saturated, partially unsaturated, carbocyclic or nitrogen, oxygen and sulfur optionally with their intervening atoms 1 forming a heterocyclic ring with ~3 heteroatoms; R. 18b , R 18c , and R 18d are each independently hydrogen, halogen, R A and -OR selected from; Q. 1 is an optionally substituted divalent group selected from alkylenyl, phenylenyl, heteroarylenyl, cycloalkylenyl and heterocyclenyl; L is a covalent bond or a divalent saturated or partially unsaturated linear or branched C 1-20 is a hydrocarbon chain, and 0 to 6 methylene units of L are independently -Cy-, -O-, -NR-, -S-, -C(O)O-, -C(O) -, -S(O)-, -SO 2 -, -NRSO 2 -, -SO 2 is replaced by NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or -NRC(O)O-; Each -Cy- is independently 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 heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nyl, nitrogen, oxygen and sulfur, independently selected from nitrogen, oxygen and sulfur 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms, 5-6 having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur optionally selected from membered heteroarylenyl or 8- to 10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; is a substituted bivalent ring; Each R is independently hydrogen or C 1-6 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur, and independently selected from nitrogen, oxygen and sulfur is an optionally substituted group selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms, or: Two R groups on the same nitrogen optionally together with their intervening atoms have, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur forming a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; X 1 is a covalent bond, -CH 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; R. 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -NR 2 , or C, substituted as appropriate 1-4 is aliphatic; Each R 2 are independently hydrogen, R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or -N(R)S(O) 2 is R; Each R 6 independently, C 1-6 a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur; and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected; Ring A is [formation] [formation] is a bicyclic or tricyclic ring selected from; Ring B is 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from 6-membered aryl, nitrogen, oxygen and sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen , a 5-7 membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from silicon or sulfur, or 1-4 independently selected from nitrogen, oxygen or sulfur a fused ring selected from 5-membered heteroaryl having 1 heteroatom; R. 3 is hydrogen, halogen, -OR, -N(R) 2 , or selected from -SR; Each R 4 are independently hydrogen, R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or -N(R)S(O) 2 is R; 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 formula I-bbb-4 as any one of the following formulas: [formation] [formation] [formation] 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 are as defined above and described in the embodiments herein, both alone and in combination.

[0434] In some embodiments, the present invention provides a compound of formula I-bbb-4: [formation] or a pharmaceutically acceptable salt thereof, wherein R. 1’’ is hydrogen and R A selected from; Each R A independently, C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and nitrogen, oxygen and optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from sulfur: R. 10is optionally substituted selected from phenyl, 5-10 membered aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. selected from monocyclic or bicyclic rings; R. 12 and R 13 are each independently hydrogen and R A or selected from: R. 12 and R 13 is independently selected from optionally substituted 4- to 8-membered saturated, partially unsaturated, carbocyclic or nitrogen, oxygen and sulfur optionally with their intervening atoms 1 forming a heterocyclic ring with ~3 heteroatoms; R. 18b , R 18c , and R 18d are each independently hydrogen, halogen, R A and -OR selected from; Q. 1 is an optionally substituted divalent group selected from alkylenyl, phenylenyl, heteroarylenyl, cycloalkylenyl and heterocyclenyl; L is a covalent bond or a divalent saturated or partially unsaturated linear or branched C 1-20 is a hydrocarbon chain, and 0 to 6 methylene units of L are independently -Cy-, -O-, -NR-, -S-, -C(O)O-, -C(O) -, -S(O)-, -SO 2 -, -NRSO 2 -, -SO 2 is replaced by NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or -NRC(O)O-; Each -Cy- is independently 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 heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nyl, nitrogen, oxygen and sulfur, independently selected from nitrogen, oxygen and sulfur 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms, 5-6 having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur optionally selected from membered heteroarylenyl or 8- to 10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; is a substituted bivalent ring; Each R is independently hydrogen or C 1-6 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur, and independently selected from nitrogen, oxygen and sulfur is an optionally substituted group selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms, or: Two R groups on the same nitrogen optionally together with their intervening atoms have, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur forming a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Ring M is [formation] selected from; X 1 , X 6 , and X 7 is independently a covalent bond, -CH 2 -, -CHCF 3 -, -SO 2 -, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR 2 -, -C(O)-, -C(S)-, or [formation] is a divalent moiety selected from; X 3 and X 5 is independently a covalent bond, -CR 2 -, -NR-, -O-, -S-, or -SiR 2 - is a divalent moiety selected from; X 4 teeth, [formation] is a trivalent moiety selected from; Each R 3a are independently hydrogen, deuterium, R 6 , Halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -SiR 3 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -C(R) 2 N(R)C(O)R, -C(R) 2 N(R)C(O)N(R) 2 , -OC(O)R, -OC(O)N(R) 2 , -OP(O)R 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR 2 , -OP(O)(NR 2 ) 2 -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)S(O) 2 R, -NP(O)R 2 , -N(R)P(O)(OR) 2 , -N(R)P(O)(OR)NR 2 , -N(R)P(O)(NR 2 ) 2 , or -N(R)S(O) 2 is R; Each R 6 independently, C 1-6 a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur; and independently from nitrogen, oxygen and sulfur optionally substituted groups selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms selected; Each R 7 is independently hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O) 2 R, -NR 2、 -P(O)(OR) 2、 -P(O)(NR 2 )OR, -P(O)(NR 2 ) 2、 -Si(OH)R 2、 -Si(OH) 2 R, -SiR 3 , or C, substituted as appropriate 1-4 is aliphatic; or R. 7 and X 1 or X 3 is, together with those intervening atoms, a 5- to 7-membered saturated, partially unsaturated, carbocyclic ring or 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur forming a heterocyclic ring having two Rs on the same carbon 7 The group is a 3- to 6-membered spiro-fused ring having, optionally together with their intervening atoms, 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or forming a 4- to 7-membered heterocyclic ring; two Rs on adjacent carbon atoms 7 The groups, optionally together with their intervening atoms, are 1 to 7 independently selected from 3- to 7-membered saturated, partially unsaturated, carbocyclic rings or boron, nitrogen, oxygen, silicon or sulfur. A heterocyclic ring having 3 heteroatoms, or a 7-13 membered saturated, partially unsaturated, bridged ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur forming a heterocyclic or spiro-heterocyclic ring; Ring D is 6- to 10-membered aryl or heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclyl, boron, nitrogen, oxygen , a 5-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from silicon and sulfur, or 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur is selected from 5-membered heteroaryls having heteroatoms of; L. 1 is a covalent bond or C 1-3 is a divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 2 methylene units of the chain are independently optionally -O-, -C(O)-, -C(S)-, -C(R) 2 -, -CH(R)-, -C(F) 2 -, -N(R)-, -S-, -S(O) 2 - or replaced by -(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 formula I-bbb-15 as any one of the following formulas: [formation] [formation] [formation] 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 are as defined above and described in the embodiments herein, both alone and in combination. Degradation Induced Moiety (DIM)

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

[0437] In some embodiments, the DIM is LBM as described above and herein. In some embodiments, DIM is a lysine mimetic. In some embodiments, covalent attachment of ubiquitin to the MDM2 protein is achieved through the action of lysine mimetics. In some embodiments, when a 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, the DIM is [formation] is. In some embodiments, the DIM is [formation] is. In some embodiments, the DIM is [formation] is.

[0439] In some embodiments, DIMs are selected from those shown in Table 1 below.

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

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

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

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

[0444] In some embodiments, DIM is a hydrogen atom. In some embodiments, covalent attachment of the ubiquitin MDM2 protein is achieved via provided compounds in which DIM is a hydrogen atom. In some embodiments, when a 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, DIMs are selected from those shown in Table 1 below.

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

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

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

[0449] In some embodiments, L is a covalent bond or a divalent saturated or partially unsaturated linear or branched C 1-50 is 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)(NR 2 )-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O- , [formation] replaced by, in the formula: Each -Cy- is independently 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 heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur 4- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nyl, nitrogen, oxygen and sulfur, independently selected from nitrogen, oxygen and sulfur 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms, 5-6 having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur optionally selected from membered heteroarylenyl or 8- to 10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; is a substituted bivalent ring; Each R is independently hydrogen or C 1-6 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen and sulfur, and independently selected from nitrogen, oxygen and sulfur is an optionally substituted group selected from 5-6 membered heteroaryl rings having 1-4 heteroatoms, or: Two R groups on the same nitrogen optionally together with their intervening atoms have, in addition to the nitrogen, 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur forming a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring, 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 divalent 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 a 4- to 7-membered optionally substituted heteroatom having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a saturated or partially unsaturated heterocyclylenyl member. In some embodiments, each -Cy- is an optionally substituted 4- to 11-membered optionally substituted heteroatom having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a saturated or partially unsaturated spiroheterocyclylenyl member. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered heteroatom having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a membered bicyclic saturated or partially unsaturated heterocyclylenyl; In some embodiments, each -Cy- is independently a 5- to 6-membered optionally substituted heteroatom having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. is a membered heteroarylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8- to 10-membered heteroatom having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. is a membered bicyclic heteroarylenyl.

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

[0453] In some embodiments, Cy- is selected from those illustrated 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 two. In some embodiments, r is three. In some embodiments, r is four. In some embodiments, r is five. In some embodiments, r is 6. In some embodiments, r is seven. In some embodiments, r is eight. In some embodiments, r is nine. In some embodiments, r is ten.

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

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

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

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

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

[0460] The points of attachment of L to MBM and DIM include, but are not limited to, L [formation] If it is, [formation] can be either

[0461] In some embodiments, a provided compound, or a pharmaceutically acceptable salt thereof, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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, comprises MBM is [formation] 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 invention provides a compound, or a pharmaceutical composition thereof, having an MDM2 binding moiety described and disclosed herein, an LBM described in Table A above, and a linker described in Table B above. provide a commercially acceptable salt.

[0497] Exemplary compounds of the invention are listed 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 compounds illustrated in Table 1 above, or pharmaceutically acceptable salts thereof. 4. General Methods of Providing the Compounds

[0499] The compounds of the present invention are generally prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds and by the methods detailed in the Examples herein. obtain.

[0500] In the schemes below, where particular protecting groups, leaving groups, or transformation conditions are depicted, it will be appreciated by those skilled in the art that other protecting groups, leaving groups, and transformation conditions are also appropriate and are envisioned. to understand. 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, R.C. Larock, 2 nd Edition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T.W.Greene and P.G.M.Wuts, 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, and the like. 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 rd edition, John Wiley & Sons, 1999, each of which is incorporated herein by reference in its entirety. 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 formate, benzoylformate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoic acid. ester, 4,4-(ethylenedithio)pentanoate, pivalate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonate (methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl , allyl and p-nitrobenzyl, etc.). 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 ether. 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. Wuts, 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, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimido, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

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

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

[0505] As illustrated in Scheme 1 above, amine A-1 is coupled to acid A-2 in DMF in the presence of the base DIPEA using the coupling agent HATU to form a linker containing an amide bond. to form a compound of formula I having wavy bond [formation] represents 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. Additionally, the amide bond can be coupled with coupling reagents known in the art (e.g. 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 invention are generally prepared according to Scheme 2 below: Scheme 2: Synthesis of compounds of formula I [formation]

[0507] As illustrated in Scheme 2 above, amine A-1 is coupled to acid A-2 in DMF in the presence of the base DIPEA using the coupling agent PyBOP to create a linker containing an amide bond. to form a compound of formula I having wavy bond [formation] represents 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. Additionally, the amide bond can be coupled with coupling reagents known in the art (e.g. 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 invention are generally prepared according to Scheme 3 below: Scheme 3: Synthesis of compounds of formula I [formation]

[0509] As illustrated in Scheme 3 above, acid A-3 is coupled to amine A-4 in DMF in the presence of the base DIPEA using the coupling agent HATU to form a linker containing an amide bond. to form a compound of formula I having wavy bond [formation] represents the portion of the linker 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. Additionally, the amide bond can be coupled with coupling reagents known in the art (e.g. 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 invention are generally prepared according to Scheme 4 below: Scheme 4: Synthesis of compounds of formula I [formation]

[0511] As illustrated in Scheme 4 above, acid A-3 is coupled to amine A-4 in DMF in the presence of the base DIPEA using the coupling agent PyBOP to form a linker containing an amide bond. to form a compound of formula I having wavy bond [formation] represents the portion of the linker 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. Additionally, the amide bond can be coupled with coupling reagents known in the art (e.g. 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 invention are generally prepared according to Scheme 5 below: Scheme 5: Synthesis of compounds of formula I [formation]

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

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

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

[0516] As illustrated in Scheme 7 above, the reductive alkylation of a mixture of aldehyde A-9 and amine A-10 was performed using NaHB(OAc) 3 and KOAc to form compounds of formula I with a linker containing a secondary amine. wavy bond [formation] represents the portion of the linker between DIM and the terminal amino group of A-8.

[0517] Those skilled in the art will appreciate that the various functional groups present in the compounds of the present invention, including, but not limited to, reduction, oxidation, ester It will be recognized that interconversions can be achieved by techniques well known in the art, including oxidization, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration and hydration. "March's Advanced Organic Chemistry", 5 th Ed., 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 involve one or more of the techniques described above, and certain methods for synthesizing the compounds of the invention are described in the illustrations below.

[0518] 5. Use, Prescription and Administration Pharmaceutically acceptable composition According to another embodiment, the invention provides compositions comprising a compound of the invention, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the composition of the invention is that amount that is effective to measurably degrade and / or inhibit MDM2 protein or variant thereof in a biological sample or in a patient. In certain embodiments, the amount of compound in the composition of the invention is effective to measurably degrade and / or inhibit MDM2 protein or variant thereof in a biological sample or in a patient. be. In certain embodiments, compositions of the invention are formulated for administration to a patient in need of such composition. In some embodiments, the compositions of the invention are formulated for oral administration to a patient.

[0519] The term "patient" as used herein means an animal, preferably a mammal, 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 compounds 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, salt or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, silicate Magnesium acid, polyvinylpyrrolidone, cellulosics, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

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

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

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

[0524] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, intranasally, buccally, intravaginally or by an implantable reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or Including injection techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, a solution in 1,3-butanediol. good too. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0525] For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, especially in their polyoxyethylated forms, are useful in the preparation of injectables because they are natural pharmaceutically acceptable oils such as olive oil or castor oil. . Solutions or suspensions of these oils also include long-chain dispersing agents such as carboxymethylcellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions. It may contain an alcohol diluent or dispersant. Other commonly used surfactants, such as Tween®, Span, and other surfactants commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms. Emulsifying agents or bioavailability enhancing agents can also be used for formulation purposes.

[0526] The pharmaceutically acceptable compositions of this invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. can. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, 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 emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

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

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

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

[0530] For topical application, provided pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the active ingredients suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions are formulated in a suitable lotion or cream containing the active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. obtain. 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 uses, pharmaceutically acceptable compositions provided are either as a micronized suspension in isotonic, pH-adjusted sterile saline or, preferably, with a preservative such as benzylalkonium chloride. It can be formulated as a solution in isotonic, pH-adjusted sterile saline with or without. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in 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 pharmaceutical formulation art and include benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other additives. can be prepared as a solution in saline using conventional solubilizers or dispersants.

[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, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0534] The amount of a compound of the invention that may be combined with the carrier materials to produce a composition in single dosage form will vary depending on the host treated, the particular mode of administration. 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. be.

[0535] Specific dosages and treatment regimens for any particular patient will depend on the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, and the treating physician's It should also be understood that it will depend on a variety of factors, including the severity of the particular disease being determined and treated. The amount of the compound of the invention in the composition will also vary depending on the particular compound in the composition.

[0536] Uses of 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 encoded by the MDM2 gene (“MDM2”); ) protein or that of the E3 ubiquitin-protein ligase MDM2. MDM2 is a key negative regulator of the p53 tumor suppressor. The p53 tumor suppressor is a major mediator of growth arrest, senescence and apoptosis in response to a wide range of cellular damage. Rapid induction of high p53 protein levels by various stress types prevents inappropriate growth of cells with potentially mutagenic damaged DNA. p53 can kill cells through dual transcription-dependent and transcription-independent functions in the nucleus and mitochondria. It has been demonstrated that cellular p53 protein levels are the single most important determinant of its function. In normal, unstressed cells, p53 is a highly labile protein with a half-life ranging from 5 to 30 min, which is highly sensitive, mainly due to continuous degradation mediated by MDM2. Present at a low cellular level. Conversely, many cellular stress pathways, such as DNA damage, hypoxia, telomere shortening and oncogene activation, are characterized by rapid stabilization of p53 through 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 MDM2 inhibits p53 activity by 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 that, 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 and can promote p53 degradation upon binding to p53.

[0539] The activity of compounds utilized in the present invention as degradants and / or inhibitors of MDM2 protein or variants thereof can be assayed in vitro, in vivo or in cell lines. In vitro assays include assays that determine inhibition of any activity and / or subsequent functional consequences of an activated MDM2 protein or variant thereof. An alternative in vitro assay quantifies the ability of inhibitors to bind MDM2 protein. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / MDM2 complex, and determining the amount of radiolabel bound. Alternatively, inhibitor binding can be determined by performing competition experiments in which novel inhibitors are incubated with MDM2 protein bound to a known radioligand. Representative in vitro and in vivo assays useful for assaying MDM2 inhibitors include, 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 STAT protein degradants and / or inhibitors or variants thereof are described in the Examples below.

[0540] Representative small molecule inhibitors targeting 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. 7,737,174; 8,518,984; 8,680,132; 8,629,141; 6,617,346; 7,553,833; 6,916,833; 7,495,007; 7,638,548; 7,576,082; 7,625,895; and 7,083,983; 2005 / 0288287; 2009 / 0143364; 2009 / 0312310; 2006 / 0211718; 2010 / 0048593; 2005 / 0227932; 2006 / 0211757; 2005 / 0137137; 2002 / 0132977; and 2009 / 0030181, each of which is incorporated herein by reference in its entirety.

[0541] As used herein, the terms "treatment," "treat," and "treating" refer to diseases or disorders, or refers to reversing, alleviating, delaying onset of, or inhibiting progression of, one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms develop. 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 (eg, in view of the history of symptoms and / or in view of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, eg, to prevent or delay the recurrence of the symptoms.

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

[0543] As used herein, the term "MDM2-mediated" disorders, diseases, and / or conditions, as used herein, refers to means any disease or other deleterious condition for which is known. Accordingly, another embodiment of the invention relates to treating or reducing the severity of one or more diseases in which the MDM2 protein or variants thereof are 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 disorders, diseases, or conditions are cancer, Neurodegenerative disorders, viral diseases, autoimmune diseases, inflammatory disorders, genetic disorders, hormone-related disorders, metabolic disorders, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases , conditions associated with cell death, thrombin-induced platelet aggregation, liver disease, pathological immune conditions involving T cell activation, cardiovascular disorders, or CNS disorders.

[0545] Diseases and conditions treatable according to the methods of the invention include cancer (see, eg, Vassilev, Trends in Mol. Med. 2007, 13(1):23), diabetes (see, eg, Secchiero et al., Acta Diabeto. 2013, 50:899), cardiovascular diseases, viral diseases (see e.g. Yang et al., Protein&Cell 2013, 4:71), lupus erythematosus (see e.g. Thomasova et al., Neoplasia 2012, 14( 12):1097) and autoimmune diseases such as rheumatoid arthritis (see e.g. Zhang et al., Int. Immunopharm. 2016, 30:69), autoinflammatory syndromes, atherosclerosis (e.g. Ihling et al., J. Pathol. 1998, 185(3):303), psoriasis (see e.g. Assmann et al., Rheumatol. Int. 2010, 30:1273), allergic disorders (e.g. Han et al. al., J. Invest. Dermatol. 2014, 134(10):2521), inflammatory bowel disease (see e.g. Zimmer et al., Digestion 2019, 81:246), inflammation (e.g. Ebrahim et al. 2015, 31(11):1271), acute and chronic gout and gouty arthritis, neuropathy (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 (e.g. Jatiani et al., Genes & Can. 2011, 1(10)). :979), osteoarthritis (see e.g. 9,993,472), proliferative disorders (see e.g. al., Am. J. Surg. 2009, 197(1):43), including symptoms associated with cell death, pathological immune symptoms with T cell activation, and CNS disorders in patients. is not limited to 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 capable of measuring MDM2 protein or variant thereof. It is present in an amount that degrades and / or inhibits activity.

[0546] The compounds of the present invention are useful in the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, Benign or malignant tumors, carcinomas or solid tumors of the skin, bone or thyroid gland, liquid tumors, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, especially colon cancer or colorectal adenoma , head and neck tumors, epidermal hyperplasia, psoriasis, benign prostatic hyperplasia, neoplasia, neoplasia of epithelial character, adenoma, adenocarcinoma, keratocanthoma, epidermoid carcinoma, large cell carcinoma, Non-small cell lung cancer, lymphoma, Hodgkin or non-Hodgkin, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 driven disorder, MyD88 driven disorder MyD88 driven disorder), smoldering indolent multiple myeloma, or hematologic malignancies (leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic leukemia (CLL), Peripheral lymphoma, primary exudative lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic margin limbal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma).

[0547] In some embodiments, the present disclosure relates to benign proliferative disorders such as, 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, pseudobrain tumors, seborrheic keratosis, gastric polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps and Methods of treating cysts, Castleman's disease, chronic ciliary disease, dermatofibroma, trichocyst, pyogenic granuloma, and juvenile polyposis syndrome are provided.

[0548] In another aspect, the disclosure provides methods of treating a condition or disease by administering a therapeutically effective amount of a provided compound to an individual, eg, a human, in need thereof. Diseases or conditions of interest are treatable by degradation of the MDM2 protein, such as cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis, or viral infections. Preventing proliferation of unwanted proliferating cells (e.g., in cancer) in a subject, including administering a therapeutically effective amount of a provided compound to a subject at risk of developing a condition characterized by unwanted proliferating cells A method is also provided. In some embodiments, provided compounds reduce proliferation of unwanted cells by inducing apoptosis in those cells.

[0549] MDM2 hyperactivity can inhibit the function of wild-type p53, resulting in the development of a wide variety of cancers, due to amplification / overexpression or inactivating mutations of the ARF locus. In some embodiments, MDM2 hyperactivity that can be treated according to the methods of the invention is a human cancer. In some embodiments, human cancers that can be treated according to the methods of the present invention are 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 carcinoma, acinar cell carcinoma, acoustic neuroma, acral lentiginous melanoma, hidradenoma acral, 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 tissue sarcoma, osteoblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblast Cellular T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma , biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner's tumor, Brown's tumor, Burkitt's lymphoma, breast cancer, brain tumor, carcinoma, in situ cancer, carcinosarcoma, cartilage tumor, cementoma, myeloma, chondroma, chordoma , choriocarcinoma, choroid plexus papilloma, renal clear cell sarcoma, 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, embryonic carcinoma, endocrine neoplasm, endoderm sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetal inclusion malformation, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglionoma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone, glial tumor, glioblastoma multiforme, glioma, glioma, glucagonoma , gonadoblastoma, granulosacytoma, female adenoblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T cell Lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, renal cancer, laryngeal cancer, malignant lentigo, fatal 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, breast medullary carcinoma, thyroid medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma , metastatic urothelial carcinoma, mixed Müllerian tumor, myxoid tumor, multiple myeloma, muscle 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, ovary carcinoma, pancoast tumor, papillary thyroid carcinoma, paraganglioma, pineoblastoma, pineocytoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasmacytoma multiple embryonal tumor, progenitor 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, striated Myoma, rhabdomyosarcoma, Richter's degeneration, rectal cancer, sarcoma, schwannomatosis, seminoma, Sertoli cell tumor, seminoma, signet ring cell tumor, skin cancer, small blue round cell tumor, small cell carcinoma , soft tissue sarcoma, somatostatin-producing tumor, soot wart, spinal cord tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sézary's disease, small bowel cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, tecoma thyroid cancer, transitional cell carcinoma, pharyngeal cancer, urinary tract cancer, urological cancer, urothelial cancer, uveal melanoma, uterine cancer, verrucous carcinoma, visual tract goma, vulvar cancer, vaginal cancer, Waldenström high gamma Selected from globulinemia, Warthin's tumor, and Wilms tumor.

[0551] In some embodiments, the cancer is a leukemia, such as a leukemia selected from acute monocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed 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 invention provides a method of treating triple-negative breast cancer in a patient in need of treatment for triple-negative breast cancer comprising administering a compound of the invention or a pharmaceutically acceptable salt thereof. A method is provided, comprising:

[0553] In some embodiments, the invention provides a method of treating malignant peripheral nerve sheath tumor (MPNST) in a patient in need of such treatment, comprising a compound of the invention or a pharmaceutical composition thereof A method is provided comprising administering a physiologically acceptable salt.

[0554] In some embodiments, the invention provides a method of treating pancreatic cancer in a patient in need of treatment for pancreatic cancer comprising administering ...

Claims

【Request Item 1】 【Chemistry 1168】 【Chemistry 1169】 【Chemistry 1170】 【Chemistry 1171】 【Chemistry 1172】 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 the group consisting of 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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