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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07F9/6503—Five-membered rings
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  • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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Definitions

• the present invention relates to compounds and methods useful for the modulation of one or more signal transducers and activators of transcription (“STAT”) via ubiquitination and/or degradation by compounds according to the present invention.
• STAT signal transducers and activators of transcription
• the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
• Ubiquitin-Proteasome Pathway is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.
• E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487) titled“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.
• UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation.
• the pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman’s syndrome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting.
• Many diseases are associated with an abnormal UPP and negatively affect cell cycle and division, the cellular response to stress and to extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair and biogenesis of organelles.
• the UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation.
• Bifunctional compounds composed of a target protein- binding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression.
• Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l):40-46).
• the present application relates novel bifunctional compounds, which function to recruit STAT proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof.
• the present disclosure provides bifunctional compounds, which find utility as modulators of targeted ubiquitination of STAT proteins, which are then degraded and/or otherwise inhibited by the bifunctional compounds as described herein.
• monovalent compounds which find utility as inducers of targeted ubiquitination of STAT proteins, which are then degraded and/or otherwise inhibited by the monovalent compounds as described herein.
• An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation/inhibition of STAT proteins.
• the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as cancer, e.g., breast cancer.
• the present application further relates to targeted degradation of STAT proteins through the use of bifunctional molecules, including bifunctional molecules that link a cereblon-binding moiety to a ligand that binds STAT proteins.
• Compounds of the present invention are useful for treating a variety of diseases, disorders or conditions, associated with regulation of signaling pathways implicating STAT proteins. Such diseases, disorders, or conditions include those described herein.
• Compounds provided by this invention are also useful for the study of STAT proteins in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new STAT inhibitors or STAT degraders or other regulators of cell cycling, metastasis, angiogenesis, and immune cell evasion, in vitro or in vivo.
• FIG.1 shows the binding IC50 ( ⁇ M) of I-1 to both STAT3 and E3 ligase.
• FIG.2 includes images of the results of an AlphaLISA assay (A) and A549 lysates (B) of I-1 indicating efficient ternary complex formation and STAT3 ubiquitination.
• FIG.3 includes graphical images showing the results of an endogenous STAT3-HiBiT live cell assay in A549 (A) with HiBiT signal (% control)(y-axis) over I-103 concentration (nM)(x- axis) at 0.5, 1, 2, 4, 6, 8, 24, and 48 hours and a MSD assay of STAT3 levels in heme cells lines MOLM-16 and SU-DHL-1 at 24 hours (B) with STAT3 protein (% control)(Y-axis) over I-103 concentration (nM)(x-axis).
• FIG. 4 includes images of deep tandem mass tag (TMT) proteomic scatterplots in MOLM-16 (AML) and SU-DHL-1 (ALCL) at 8 hours showing–Log10 p-value (y-axis) and Log2 fold change at 30 nM and 100 nM I-103 in DMSO (x-axis).
• TMT deep tandem mass tag
• FIG. 5 Includes graphical images and tables showing the results of RT-qPCR in SU- DHL-1 cells at 24 hours (A) with mRNA levels (% control) over I-103 concentration (nM)(x-axis) for STAT3, SOCS3, and PDL-1 genes and CellTiterGlo (CTG) cell viability at 4 days (B) with growth inhibition (% control) over I-103 concentration (nM)(x-axis) for MOLM-16 and SU-DHL- 1 cell lines. Also shown are the results of MSD degradation DC50 (nM) in MOLM-16 and SU- DHL-1 cell lines at 24 hours.
• FIG. 6 includes graphical images of MOLM-16 and SU-DHL-1 tumor xenograph results using I-103 for STAT3 and pSTAST3 degradation (A), efficacy in NOD/SCID mice (B) with tumor volume median (mm 3 ) over days (post randomization) for vehicle, 25 mg/kg IP QD, and 50 and 100 mg/kg SC BIW dosing, STAT3 and pSTAT3 degradation (C) with STAT3, and pSTAT3 (relative STAT3/Actin)(left y-axis) and plasma concentration ( ⁇ M)(right y-axis) for vehicle, 25 mpk QD x2 (24 hours post dose), and 50 mpk QD x 1 (48 hours post dose), efficacy in NOD/SCID mice (D) with tumor volume median (mm 3 ) over days (post randomization) for vehicle, 25 mg/kg IP (2 day on/5 day off), 50 mg/kg IP QW, 50 mg/kg IP Q2D, and 50 mg
• FIG.7 depicts the decrease in STAT3 observed at 24 hours treatment with I-103 (A), the time-dependent inhibition of proliferation with I-103 (B), the increase in activated Caspase 3 at 48 hours that leads to cell death with I-103 treatment (C), and increase in subG1 cells observed with I-103 treatment (D).
• FIG.8 depicts that a decrease of STAT3 by 90% using I-103 is necessary to induce SU- DHL-1 apoptosis and inhibit cell growth.
• FIG. 9 depicts a dose response curve showing I-111 degrading mutant STAT3 (STAT D661Y) in HDLM-2 cell lines.
• FIG.10 depicts wash-out study results with I-103 at 24 hours (A) and 48 hours (B).
• FIG.11 depicts degradation results of the reduction of STAT3 in STAT3 mutants using I-83 (3 ⁇ M, 24 hr) in ectopically overexpressed HEK293 cells showing Flag-STAT3 levels (%DMSO)(y-axis) for WT, D661Y (SH2), D661V (SH2), Y640F (SH2), and K392R (DBD) mutants (x-axis).
• %DMSO Flag-STAT3 levels
• FIG.12 depicts a dose response curve showing I-83 degrading mutant STAT3 (STAT D661Y) in HDLM-2 cell lines.
• FIG.13 includes images of deep tandem mass tag (TMT) proteomic scatterplots in SU- DHL-1 (ALCL) at 8 hours showing–Log10 p-value (y-axis) and Log2 fold change at 150 nM, 350 nM, and 3.5 ⁇ M I-174 in DMSO (x-axis).
• TMT deep tandem mass tag
• FIG. 14 depicts dose response curves and DC 50 results showing I-174 and I-94 mediated degradation in multiple ALK+ ALCL cell lines.
• FIG. 15 depicts dose response curves and IC50 results showing I-174 and I-94 repression of STAT3-mediated gene expression in of SOCS3 and PD-L1 in SU-DHL-1 cells.
• FIG. 16 depicts dose response curves showing I-174 and I-94 mediated growth inhibition in multiple ALK+ ALCL cell lines.
• FIG.17 depicts that a decrease of STAT3 by 90% using I-174 and I-94 is necessary to induce SU-DHL-1 apoptosis and inhibit cell growth.
• FIG. 18 depicts wash-out study results with I-174 showing strong growth inhibition and potential cell death after 4 days (24 hours wash-out) and complete growth inhibition and cell death after 4 days (48 hours wash-out) in SU-DHL-1 cells.
• FIG. 19 depicts ALK+ ALCL SU-DHL-1 mouse xenographs and KD results using I- 174 for STAT3 degradation with tumor volume median (mm 3 ) over days (post randomization) for vehicle, 2.5, 5, 10 and 25 mg/kg (mpk) dosing.
• FIG. 20 includes ALK+ ALCL SUP-M2 xenograph results using I-174 for STAT3 degradation with tumor volume median (mm 3 ) over days (post-randomization) for vehicle, 3 mg/kg IV 2d on/5d off, 10 mg/kg IV 2d on/5d off, 30 mg/kg IV 2d on/5d off, and 30 mg/kg IC QW dosing (upper graph) and body weight (g) over day (post-randomization) for animal FD 10 mg/kg 2d on/5d off and 30 mg/kg 2d on/5d off (lower graph).
• FIG.21 depicts dose-response curves in a STAT3-HiBiT live cell assay in A549 cells using I-174 and I-94 with STAT3 protein (% control)(y-axis) over compound concentration (nM)(x-axis) at 0.5, 1, 2, 4, 6, 8, 24, and 48 hours.
• DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
• Compounds of the present invention, and compositions thereof, are useful as degraders and/or inhibitors of one or more STAT proteins.
• a provided compound degrades and/or inhibits one or more of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6.
• the present invention provides a compound of formula I:
• STAT is a STAT binding moiety capable of binding to one or more of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6;
• L is a bivalent moiety that connects STAT to LBM
• LBM is a ligase binding moiety.
• the present invention provides a compound of formula II:
• STAT is a STAT binding moiety capable of binding to one or more of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6;
• L is a bivalent moiety that connects STAT to DIM
• DIM is a degradation inducing moiety.
• aliphatic or“aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,”“cycloaliphatic” or“cycloalkyl”), that has a single point of attachment to the rest of the molecule.
• aliphatic groups contain 1-6 aliphatic carbon atoms.
• aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
• “cycloaliphatic” (or“carbocycle” or“cycloalkyl”) refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
• a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring.
• Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
• bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
• a“bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a“bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
• a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:
• lower alkyl refers to a C1-4 straight or branched alkyl group.
• exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
• lower haloalkyl refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
• heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
• bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
• alkylene refers to a bivalent alkyl group.
• An“alkylene chain” is a polymethylene group, i.e.,–(CH 2 ) n –, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
• a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
• alkenylene refers to a bivalent alkenyl group.
• a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
• cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure: .
• halogen means F, Cl, Br, or I.
• aryl used alone or as part of a larger moiety as in“aralkyl,”“aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
• the term“aryl” may be used interchangeably with the term“aryl ring.”
• “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
• aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
• heteroaryl and“heteroar—,” used alone or as part of a larger moiety e.g., “heteroaralkyl,” or“heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 p electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
• heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
• Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
• heteroaryl and“heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
• Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one.
• a heteroaryl group may be mono– or bicyclic.
• the term“heteroaryl” may be used interchangeably with the terms“heteroaryl ring,”“heteroaryl group,” or“heteroaromatic,” any of which terms include rings that are optionally substituted.
• the term“heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
• heterocycle As used herein, the terms“heterocycle,”“heterocyclyl,”“heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
• nitrogen includes a substituted nitrogen.
• the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N–substituted pyrrolidinyl).
• a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
• saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
• heterocyclyl refers to groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
• a heterocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring.
• heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
• the term“partially unsaturated” refers to a ring moiety that includes at least one double or triple bond.
• the term“partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
• compounds of the invention may contain“optionally substituted” moieties.
• the term“substituted,” whether preceded by the term“optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
• an“optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every 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 compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
• Suitable monovalent substituents on R° are independently halogen,–(CH 2 ) 0–2 R ⁇ , –(haloR ⁇ ),–(CH 2 )0–2OH,–(CH 2 )0–2OR ⁇ ,–(CH 2 )0–2CH(OR ⁇ )2; -O(haloR ⁇ ),–CN,–N3,–(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 )0–2NHR ⁇ ,–(CH 2 )0–2NR ⁇ 2, etc
• Suitable divalent substituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include:–O(CR * 2)2– 3 O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on the aliphatic group of R * include halogen,–R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ ,–O(haloR ⁇ ),–CN,–C(O)OH,–C(O)OR ⁇ ,–NH 2 ,–NHR ⁇ ,–NR ⁇ 2, or–NO2, wherein each R ⁇ is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic,–CH 2 Ph,–O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on a substitutable nitrogen of an“optionally substituted” group include –R ⁇ , –NR ⁇ 2, –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , – C(O)CH 2 C(O)R ⁇ , -S(O)2R ⁇ , -S(O)2NR ⁇ 2,–C(S)NR ⁇ 2,–C(NH)NR ⁇ 2, or–N(R ⁇ )S(O)2R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted–OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ ,
• Suitable substituents on the aliphatic group of R ⁇ are independently halogen,– R ⁇ , -(haloR ⁇ ),–OH,–OR ⁇ ,–O(haloR ⁇ ),–CN,–C(O)OH,–C(O)OR ⁇ ,–NH 2 ,–NHR ⁇ ,–NR ⁇ 2, or -NO2, wherein each R ⁇ is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic,–CH 2 Ph,–O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are 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, incorporated herein by reference.
• Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
• Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
• organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
• Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1–4alkyl)4 salts.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
• the provided compounds are purified in salt form for convenience and/or ease of purification, e.g., using an acidic or basic mobile phase during chromatography.
• Salts forms of the provided compounds formed during chromotagraphic purification are comtemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art.
• structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. 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.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
• Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention [00066]
• the term“provided compound” refers to any genus, subgenus, and/or species set forth herein.
• prodrug refers to a compound that is made more active in vivo.
• the present compounds can also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003).
• Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound.
• prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
• Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
• a wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
• An example, without limitation, of a prodrug would be a compound which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
• therapeutically acceptable prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
• an inhibitor is defined as a compound that binds to and /or inhibits an STAT protein with measurable affinity.
• an inhibitor has an IC50 and/or binding constant of less than about 50 ⁇ M, less than about 1 ⁇ M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
• a degrader is defined as a heterobifunctional compound that binds to and /or inhibits both an STAT protein and an E3 ligase with measurable affinity resulting in the ubiquitination and subsequent degradation of the STAT protein.
• a degrader has an DC 50 of less than about 50 ⁇ M, less than about 1 ⁇ M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
• the term “monovalent” refers to a degrader compound without an appended E3 ligase binding moiety.
• a compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents.
• a detectable moiety may be attached to a provided compound via a suitable substituent.
• suitable substituent refers to a moiety that is capable of covalent attachment to a detectable moiety.
• moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few.
• moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain.
• such moieties may be attached via click chemistry.
• such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst.
• Methods of using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed.2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.
• the term“detectable moiety” is used interchangeably with the term "label” and relates to any moiety capable of being detected, e.g., primary labels and secondary labels.
• Primary labels such as radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications.
• Detectable moieties also include luminescent and phosphorescent groups.
• secondary label refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal.
• the secondary intermediate may include streptavidin-enzyme conjugates.
• antigen labels secondary intermediates may include antibody-enzyme conjugates.
• fluorescent label refers to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength.
• fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine 6G, carboxy
• mass-tag refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques.
• mass-tags include electrophore release tags such as N-[3-[4’-[(p- Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic Acid, 4’-[2,3,5,6- Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives.
• mass-tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition.
• nucleotides dideoxynucleotides
• oligonucleotides of varying length and base composition oligopeptides, oligosaccharides
• other synthetic polymers of varying length and monomer composition.
• a large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.
• measurable affinity and“measurably inhibit,” as used herein, means a measurable change in a STAT protein activity between a sample comprising a compound of the present invention, or composition thereof, and a STAT protein, and an equivalent sample comprising a STAT protein, in the absence of said compound, or composition thereof.
• the present invention provides a compound of formula I:
• STAT is a STAT protein binding moiety capable of binding to one or more of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6;
• L is a bivalent moiety that connects STAT to LBM
• LBM is a E3 ubiquitin ligase binding moiety.
• the present invention provides a compound of formula I:
• STAT is a STAT3 binding moiety
• L is a bivalent moiety that connects STAT to LBM
• LBM is a cereblon E3 ubiquitin ligase binding moiety.
• the present invention provides a compound of formula II:
• STAT is a STAT protein binding moiety capable of binding to one or more of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6;
• L is a bivalent moiety that connects STAT to DIM
• DIM is a degradation inducing moiety.
• the present invention provides a compound of formula II: II
• STAT is a STAT3 binding moiety
• L is a bivalent moiety that connects STAT to DIM
• DIM is LBM, a lysine mimetic, or a hydrogen atom.
• LBM Ligase Binding Moiety
• LBM is an E3 ligase ligand.
• E3 ligase ligands are well known to one of ordinary skill in the art and include those described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed.2016, 55, 1966, T. Uehara et al.
• brackets e..g, or L is attached to a modifiable carbon
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-a-1, I-a-2, I-a-3, I-a-4, I-a-5, I-a-6, I-a-7, I-a-8, I-a-9, or I-a-10 respectively:
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-b-1, I-b-2, I-b-3, I-b-4, I-b-5, or I-b-6 respectively:
• LBM is In some embodiments, LBM is
• LBM is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• LBM is In some embodiments, LBM is
• LBM is .
• LBM is In some embodiments, LBM is In some embodiments, LBM is
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-c:
• L and STAT are as defined above and described herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–CHCF3–,–SO2–,–S(O)–,–P(O)R–
• X 2 is a carbon atom or silicon atom
• X 3 is a bivalent moiety selected from–CR2–,–NR–,–O–,–S–, or–Si(R2)–;
• 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)(NR2)OR,–P(O)(NR2)2,–Si(OH)2R,–Si(OH)(R)2,–Si(R)3, or an optionally substituted C1-4 aliphatic;
• each R 2 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)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR) 2 , -OP(O)(OR) 2 , -OP(O)(OR) 2 , -OP(O)(OR)(NR 2 ), -OP(O)(NR 2 ) 2 -, -
• Ring B is a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• R 3 is selected from hydrogen, halogen,–OR,–N(R)2, or–SR;
• each R 4 is independently hydrogen, –R 6 , halogen, –CN, –NO 2 , –OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, – C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or–N(R)S(O) 2 R;
• R 5 is hydrogen, C1-4 aliphatic, or–CN
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, 2, 3 or 4;
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• Ring B where a point of attachment of–(R 2 )m is depicted on Ring B, it is intended, and one of ordinary skill in the art would appreciate, that the point of attachment of–(R 2 )m may be on Ring A and may also be at any available carbon or nitrogen atom on Ring A including the ring to which Ring B is fused.
• R 4 or R 5 where -R 2 is attached to a nitrogen atom bound to R 4 or R 5 , R 4 or R 5 is absent and -R 2 takes the place of the R 4 or R 5 group.
• R 3 is absent and -R 2 takes the place of the R 3 group.
• a compound of formula I-c above is provided as a compound of formula I-c ⁇ or formula I-c ⁇ :
• each of STAT, Ring A, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m is as defined above.
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-d:
• L and STAT are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–CHCF 3 –,–SO 2 –,–S(O)–,–
• X 2 is a carbon atom or silicon atom
• X 3 is a bivalent moiety selected from–CR2–,–NR–,–O–,–S–, or–Si(R2)–;
• 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 an optionally substituted C1-4 aliphatic;
• each R 2 is independently hydrogen, deuterium,–R 6 , halogen,–CN,–NO2,–OR, -SR, -N(R)2, - Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR,–C(O)N(R)2, -C(O)N(R)OR, - C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR) 2 , -OP(O)(OR) 2 , -OP(O)(OR)(NR 2 ), -OP(O)(NR 2 ) 2 -, - N(R)C(O)OR, -N(R)C(O)
• Ring A is a bi- or tricyclic ring selected from wherein Ring B is other than
• Ring B is other than benzo, , ,
• Ring B is other than benzo
• Ring B is a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• R 3 is selected from hydrogen, halogen,–OR,–N(R)2, or–SR;
• each R 4 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)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or–N(R)S(O)2R;
• R 5 is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, 2, 3 or 4;
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• the compound of formula I-d above is provided as a compound of formula I-d ⁇ or formula I-d ⁇ :
• each of STAT, Ring A, L, R 1 , R 2 , X 1 , X 2 , X 3 , and m is as defined above.
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-e:
• L and STAT are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, or
• R 1 is hydrogen, deuterium, halogen,–CN,–OR,–SR,–S(O)R,–S(O) 2 R,–NR 2 , or an optionally substituted C 1-4 aliphatic;
• each R 2 is independently hydrogen, –R 6 , halogen, –CN, –NO2, –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)NR2, or–N(R)S(O)2R;
• Ring A is a bi- or tricyclic ring selected from
• Ring B is a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• R 3 is selected from hydrogen, halogen,–OR,–N(R)2, or–SR;
• each R 4 is independently hydrogen, –R 6 , halogen, –CN, –NO2, –OR, - SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, – C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or–N(R)S(O)2R;
• R 5 is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, 2, 3 or 4;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• the compound of formula I-e above is provided as a compound of formula I-e ⁇ or formula I-e ⁇ :
• each of STAT, Ring A, L, R 1 , R 2 , X 1 , and m is as defined above.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-f:
• L and STAT are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–CHCF 3 –,–SO 2 –,–S(O)–,–
• X 2 is a carbon atom or silicon atom
• X 3 is a bivalent moiety selected from–CR2–,–NR–,–O–,–S–, or–Si(R2)–;
• R 1 is hydrogen, deuterium, halogen,–CN,–OR,–SR,–S(O)R,–S(O) 2 R,–NR 2 ,–P(O)(OR) 2 ,– P(O)(NR2)OR,–P(O)(NR2)2,–Si(OH)2R,–Si(OH)(R)2,–Si(R)3, or an optionally substituted C1-4 aliphatic;
• Ring C is a mono- or bicyclic ring selected from , ,
• each of 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)2N(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) 2 , -OP(O)(OR) 2 , -OP(O)(OR) 2 , -OP(O)(OR
• Ring D is selected from a 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• 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)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or–N(R)S(O)2R;
• R 5 is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, 2, 3 or 4;
• n 0, 1, 2, 3 or 4;
• p is 0 or 1, wherein when p is 0, the bond connecting Ring C and Ring D is connected to ;
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• a compound of formula I-f above is provided as a compound of formula I-f ⁇ or formula I-f ⁇ :
• each of STAT, Ring C, Ring D, L, L 1 , R 1 , R 2 , R 3a , X 1 , X 2 , X 3 , n, m, and p is as defined above.
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-g:
• L and STAT are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–,
• R 1 is hydrogen, deuterium, halogen,–CN,–OR,–SR,–S(O)R,–S(O)2R,–NR2, or an optionally substituted C1-4 aliphatic;
• Ring C is a mono- or bicyclic ring selected from
• each of R 2 and R 3a is independently hydrogen, –R 6 , halogen, –CN, –NO2, –OR, - SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, – C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or–N(R)S(O)2R;
• Ring D is selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• each R 4 is independently hydrogen, –R 6 , halogen, –CN, –NO2, –OR, - SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -C(O)R, -C(O)OR, – C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or–N(R)S(O)2R;
• R 5 is hydrogen, C1-4 aliphatic, or–CN
• each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, or 2;
• n 0, 1, 2, 3 or 4;
• p is 0 or 1, wherein when p is 0, the bond connecting Ring C and Ring D is connected to
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• a compound of formula I-g above is provided as a compound of formula I-g ⁇ or formula I-g ⁇ :
• each of STAT, Ring C, Ring D, L, R 1 , R 2 , R 3a , X 1 , n, m, and p is as defined above.
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-h:
• L and STAT are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–CHCF 3 –,–SO 2 –,–S(O)–,–
• X 2 is a carbon atom or silicon atom
• X 3 is a bivalent moiety selected from–CR2–,–NR–,–O–,–S–, or–Si(R2)–;
• 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 an optionally substituted C1-4 aliphatic;
• Ring C is a mono- or bicyclic ring selected from , ,
• each or 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)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, – C(O)N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, - C(R) 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) 2 , -OP(O)(OR) 2 , -OP(O)(OR) 2 , -OP(O)(OR) 2 ,
• Ring D is selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R 4 is independently hydrogen, –R 6 , halogen, –CN, –NO2, –OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, – C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -
• R 5 is hydrogen, C1-4 aliphatic, or–CN
• each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, 2, 3 or 4;
• n 0, 1, 2, 3 or 4;
• p is 0 or 1
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• a compound of formula I-h above is provided as a compound of formula I-h ⁇ or formula I-h ⁇ :
• each of STAT, Ring C, Ring D, L, L 1 , R 1 , R 2 , R 3a , X 1 , X 2 , X 3 , m, n, and p is as defined above.
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-i:
• L and STAT are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, or
• R 1 is hydrogen, deuterium, halogen,–CN,–OR,–SR,–S(O)R,–S(O)2R,–NR2, or an optionally substituted C1-4 aliphatic;
• Ring C is a mono- or bicyclic ring selected from , ,
• each of R 2 , R 3a , and R 4 is independently hydrogen,–R 6 , halogen,–CN,–NO 2 ,–OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, – C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or–N(R)S(O) 2 R;
• Ring D is selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• R 5 is hydrogen, C 1-4 aliphatic, or–CN;
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• n 0, 1, or 2;
• n 0, 1, 2, 3, or 4;
• p is 0 or 1
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• a compound of formula I-i above is provided as a compound of formula I-i ⁇ or formula I-i ⁇ :
• each of STAT, Ring C, Ring D, L, R 1 , R 2 , R 3a , X 1 , m, n, and p is as defined above.
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-j:
• L and STAT are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–CHCF 3 –,–SO 2 –,–S(O)–,–
• X 2 is a carbon atom or silicon atom
• X 3 is a bivalent moiety selected from–CR2–,–NR–,–O–,–S–, or–Si(R2)–;
• 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 an optionally substituted C1-4 aliphatic;
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• each R 2 is independently hydrogen, deuterium,–R 6 , halogen,–CN,–NO 2 ,–OR, -SR, -N(R) 2 , - Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR,–C(O)N(R)2, -C(O)N(R)OR, - C(R) 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) 2 , -OP(O)(OR) 2 , -OP(O)(OR) 2 , -OP(O)(OR)(NR 2 ), -OP
• each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each of Ring E, Ring F, and Ring G is independently a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7- membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, , wherein each of Ring E, Ring F, and Ring G is independently and optionally further substituted with 1-2
• attachment of may be on any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the ring to which Ring E or Ring G are fused to Ring F.
• 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 are fused to Ring F.
• a compound of formula I-j above is provided as a compound of formula I-j ⁇ or formula I-j ⁇ :
• each of STAT, Ring E, Ring F, Ring G, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m is as defined above.
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-k:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, or
• R 1 is hydrogen, deuterium, halogen,–CN,–OR,–SR,–S(O)R,–S(O) 2 R,–N(R) 2 , -Si(R) 3 , or an optionally substituted C1-4 aliphatic;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• each R 2 is independently hydrogen, deuterium,–R 6 , halogen,–CN,–NO 2 ,–OR, -SR, -N(R) 2 , - Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR,–C(O)N(R)2, -C(O)N(R)OR, - C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) 2 , or–N(R)S(O) 2 R;
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each of Ring E, Ring F, and Ring G is independently a fused ring selected from 6-membered aryl containing 0-3 nitrogens, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, , wherein each of Ring E, Ring F, and Ring G is independently and optionally further substituted with 1-2 oxo groups; and
• n 0, 1, 2, 3, or 4.
• attachment of may be on any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the ring to which Ring E or Ring G are fused to Ring F.
• a compound of formula I-k above is provided as a compound of formula I-k ⁇ or formula I-k ⁇ :
• each of STAT, L, Ring E, Ring F, Ring G, L, R 1 , R 2 , X 1 , and m is as defined above.
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-l:
• L and STAT are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–CHCF3–,–SO2–,–S(O)–,–P(O)R–
• X 2 is a carbon atom or silicon atom
• X 3 is a bivalent moiety selected from–CR2–,–NR–,–O–,–S–, or–Si(R2)–;
• 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)(NR2)OR,–P(O)(NR2)2,–Si(OH)2R,–Si(OH)(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• each R 2 is independently hydrogen, deuterium,–R 6 , halogen,–CN,–NO2,–OR, -SR, -N(R)2, - Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR,–C(O)N(R)2, -C(O)N(R)OR, - C(R) 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) 2 , -OP(O)(OR) 2 , -OP(O)(OR)(NR 2 ), -OP(O)(NR 2 ) 2 -, - N(
• each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Ring E is a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• Ring H is a fused ring selected from a 7-9 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring E is optionally further substituted with 1-2 oxo groups;
• n 0, 1, 2, 3, or 4.
• a point of attachment of is depicted on Ring E and Ring H, it is intended, and one of ordinary skill in the art would appreciate, that the point of attachment of may 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.
• a compound of formula I-l above is provided as a compound of formula I-l ⁇ or formula I-l ⁇ :
• each of STAT, Ring E, Ring H, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m is as defined above.
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-m:
• L and STAT are as defined above and described in embodiments herein, and wherein:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, or
• R 1 is hydrogen, deuterium, halogen,–CN,–OR,–SR,–S(O)R,–S(O) 2 R,–N(R) 2 , -Si(R) 3 , or an optionally substituted C 1-4 aliphatic;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;
• each R 2 is independently hydrogen, deuterium,–R 6 , halogen,–CN,–NO2,–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)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Ring E is a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• Ring H is a ring selected from a 7-9 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring E is optionally further substituted with 1-2 oxo groups; and
• n 0, 1, 2, 3, or 4.
• a compound of formula I-m above is provided as a compound of formula I-m ⁇ or formula I-m ⁇ :
• each of STAT, Ring E, Ring H, L, R 1 , R 2 , X 1 , and m is as defined above.
• a compound of formula I-m above is provided as a compound of formula I-m-1:
• each of STAT, L, Ring E, X 1 , R 1 , R 2 , and m is as defined above.
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-n:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–CHCF 3 –,–SO 2 –,–S(O)–,–
• X 2 is a carbon atom or silicon atom
• X 3 is a bivalent moiety selected from–CR2–,–NR–,–O–,–S–, or–Si(R2)–;
• R 1 is hydrogen, deuterium, halogen,–CN,–OR,–SR,–S(O)R,–S(O)2R,–NR2,–P(O)(OR)2,– P(O)(NR 2 )OR,–P(O)(NR 2 ) 2 ,–Si(OH) 2 R,–Si(OH)(R) 2 ,–Si(R) 3 , or an optionally substituted C 1-4 aliphatic;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• each R 2 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)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -OP(O)R2, - OP(O)(OR) 2 , -OP(O)(OR) 2 , -OP(O)(OR) 2 , -OP(O)(OR)(NR 2 ), -OP(O)(NR 2 ) 2 -, -
• each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each of Ring I and J is independently a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1- 4 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• Ring K is a fused ring selected from a 6-12 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring H is optionally further substituted with 1- 2 oxo groups;
• attachment of may 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.
• attachment of may 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.
• a compound of formula I-n above is provided as a compound of formula I-n ⁇ or formula I-n ⁇ :
• each of STAT, Ring I, Ring J, Ring K, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m is as defined above.
• the present invention provides a compound of formula I-o:
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, or
• R 1 is hydrogen, deuterium, halogen,–CN,–OR,–SR,–S(O)R,–S(O)2R,–N(R)2, -Si(R)3, or an optionally substituted C 1-4 aliphatic; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• each R 2 is independently hydrogen, deuterium,–R 6 , halogen,–CN,–NO2,–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)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or–N(R)S(O)2R;
• each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each of Ring I and J is independently a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1- 4 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• Ring K is a fused ring selected from a 6-12 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring H is optionally further substituted with 1- 2 oxo groups; and
• n 0, 1, 2, 3, or 4.
• Ring K it is intended, and one of ordinary skill in the art would appreciate, that the point of attachment of may 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.
• a compound of formula I-o above is provided as a compound of formula I-o ⁇ or formula I-o ⁇ :
• each of STAT, Ring I, Ring J, Ring K, L, R 1 , R 2 , X 1 , and m is as defined above.
• a compound of formula I-o above is provided as a compound of formula I-o-1: .
• each of STAT, L, Ring I, Ring K, X 1 , R 1 , R 2 , and m is as defined above.
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-o-2 or I-o-3:
• L and STAT are as defined above and described in embodiments herein, and wherein:
• each R 2 is independently hydrogen, deuterium,–R 6 , halogen,–CN,–NO2,–OR, -SR, -NR2, - SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR,–C(O)NR2, -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)(OR)NR 2 , -OP(O)(OR)NR 2 , -OP(O)(OR)NR 2 , -OP(O)(OR)NR 2 , -OP
• each R 6 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each of Ring E, Ring F, and Ring G is independently a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7- membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein each of Ring E, Ring F, and Ring G is independently and optionally further substituted with 1-2 oxo groups
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• R 4 , R 10 , R 11 , R 15 , W 1 , W 2 , and X is as defined in WO 2019/099868, the entirety of each of which is herein incorporated by reference.
• Ring E 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 are fused to Ring F.
• X 1 is a bivalent moiety selected from a covalent bond,–CH 2 –,–C(R)2–,–C(O)–,–C(S)–,–CH(R)–,–CH(CF3)–,–P(O)(OR)–,–P(O)(R)–,–
• X 1 is a covalent bond. In some embodiments, X 1 is–CH 2 –. In some embodiments, X 1 is–C(R) 2 –. In some embodiments, X 1 is–C(O)–. In some embodiments, X 1 is–C(S)–. In some embodiments, X 1 is–CH(R)–. In some embodiments, X 1 is–CH(CF3)–. 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
• X 1 is
• X 1 is s elected from those depicted in Table 1, below.
• X 2 is a carbon atom or silicon atom.
• X 2 is a carbon atom. In some embodiments, X 2 is a silicon atom.
• X 2 is selected from those depicted in Table 1, below.
• X 3 is a bivalent moiety selected from–CH 2 –, –C(R)2–,–N(R)–,–CF2–,–CHF–,–S–,–CH(R)–,–Si(R2)–, or–O–.
• X 3 is–CH 2 –. In some embodiments, X 1 is–C(R) 2 –. In some embodiments, X 3 is–N(R)–. In some embodiments, X 3 is–CF2–. 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–.
• X 3 is selected from those depicted in Table 1, below.
• R 1 is hydrogen, deuterium, halogen,–CN,– OR,–SR,–S(O)R,–S(O)2R,–NR2,–P(O)(OR)2,–P(O)(NR2)OR,–P(O)(NR2)2,–Si(OH)2R,– Si(OH)(R) 2 ,–Si(R) 3 , an optionally substituted C 1-4 aliphatic, or R 1 and X 1 or X 4 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur.
• R 1 is hydrogen. In some embodiments, R 1 is deuterium. In some embodiments, R 1 is halogen. In some embodiments, R 1 is–CN. In some embodiments, R 1 is–OR. In some embodiments, R 1 is–SR. In some embodiments, R 1 is–S(O)R. In some embodiments, R 1 is–S(O) 2 R. In some embodiments, R 1 is–NR 2 . In some embodiments, R 1 is– P(O)(OR)2. In some embodiments, R 1 is–P(O)(NR2)OR. In some embodiments, R 1 is about P(O)(NR2)2. In some embodiments, R 1 is–Si(OH)2R.
• R 1 is–Si(OH)(R)2. In some embodiments, R 1 is–Si(R) 3 . In some embodiments, R 1 is an optionally substituted C 1-4 aliphatic. In some embodiments, R 1 and X 1 or X 4 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur.
• R 1 is selected from those depicted in Table 1, below.
• each R is independently hydrogen, deuterium, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from boron, nitrogen, oxygen, silicon, and sulfur.
• R is hydrogen. In some embodiments, R is deuterium. In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R is optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.
• two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from boron, nitrogen, oxygen, silicon, and sulfur.
• R is selected from those depicted in Table 1, below.
• each of R 2 and R 3a is independently hydrogen, deuterium, –R 6 , halogen, –CN, –NO2, –OR, –Si(OH)2R, –Si(OH)R2, -SR, -NR2, - 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) 2 , -OP(O)(OR) 2 , -OP(O)(OR)NR2, -OP(O)
• 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 is independently–R 6 . 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 . In some embodiments, R 2 and R 3a is independently–OR. In some embodiments, R 2 and R 3a is independently–Si(OH)2R. In some embodiments, R 2 and R 3a is independently–Si(OH)R2. In some embodiments, R 2 and R 3a is independently–SR.
• R 2 and R 3a is independently -NR 2 . In some embodiments, R 2 and R 3a is independently –SiR3. In some embodiments, R 2 and R 3a is independently -S(O)2R. In some embodiments, R 2 and R 3a is independently -S(O)2NR2. 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)NR2. In some embodiments, R 2 and R 3a is independently–C(O)N(R)OR.
• R 2 and R 3a is independently -C(R)2N(R)C(O)R. In some embodiments, R 2 and R 3a is independently - C(R) 2 N(R)C(O)NR 2 . 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)NR2. In some embodiments, R 2 and R 3a is independently -OP(O)R2. In some embodiments, R 2 and R 3a is independently -OP(O)(OR)2. In some embodiments, R 2 and R 3a is independently -OP(O)(OR)NR 2 .
• R 2 and R 3a is independently -OP(O)(NR 2 ) 2 -. 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)NR2. In some embodiments, R 2 and R 3a is independently -NP(O)R 2 . In some embodiments, R 2 and R 3a is independently -N(R)P(O)(OR) 2 . In some embodiments, R 2 and R 3a is independently -N(R)P(O)(OR)NR2. In some embodiments, R 2 and R 3a is independently -N(R)P(O)(NR2)2. In some embodiments, R 2 and R 3a is independently –N(R)S(O) 2 R.
• R 2 and R 3a is independently–OH. In some embodiments, R 2 and R 3a is independently–NH 2 . In some embodiments, R 2 and R 3a is independently -CH 2 NH 2 . 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 is independently -SiMe3. In some embodiments, R 2 and R 3a is independently–SiMe 2 OH.
• R 2 and R 3a is independently–SiMe(OH) 2 . In some embodiments R 2 and R 3a is independently . In some embodiments, R 2 and R 3a is independently Br. In some embodiments, R 2 and R 3a is independently Cl. In some embodiments, R 2 and R 3a is independently F. In some embodiments, R 2 and R 3a is independently Me. In some embodiments, R 2 and R 3a is independently–NHMe. In some embodiments, R 2 and R 3a is independently–NMe 2 . In some embodiments, R 2 and R 3a is independently–NHCO 2 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.
• R 2 and R 3a is independently -NHCO2tBu. In some embodiments, R 2 and R 3a is independently -CO 2 tBu. In some embodiments, R 2 and R 3a is independently -OMe. In some embodiments, R 2 and R 3a is independently–CF3.
• R 2 or R 3a is selected from those depicted in Table 1, below.
• R 3 is hydrogen, deuterium, halogen,–CN,– NO2,–OR,–NR2,–SR,–S(O)2R,–S(O)2NR2,–S(O)R,–C(O)R,–C(O)OR,–C(O)NR2,– C(O)NR(OR),–OC(O)R,–OC(O)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)NR2,–N(R)S(O)2R,–N(R)S(O)2NR2,–N(R)P(O)(OR)2, –N(R)P(O)(OR)2, –N(R)P(O)(OR)2, –
• R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is halogen. In some embodiments, R 3 is–CN. In some embodiments, R 3 is–NO2. In some embodiments, R 3 is–OR. In some embodiments, R 3 is–NR2. In some embodiments, R 3 is–SR. In some embodiments, R 3 is–S(O) 2 R. In some embodiments, R 3 is– S(O)2NR2. 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)NR2.
• R 3 is–C(O)NR(OR). In some embodiments, R 3 is–OC(O)R. In some embodiments, R 3 is– OC(O)NR2. In some embodiments, R 3 is–OP(O)(OR)2. In some embodiments, R 3 is– OP(O)(NR2)2. In some embodiments, R 3 is–OP(O)(OR)NR2. 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 about N(R)C(O)NR 2 . In some embodiments, R 3 is–N(R)S(O) 2 R.
• R 3 is– N(R)S(O)2NR2. In some embodiments, R 3 is–N(R)P(O)(OR)2. In some embodiments, R 3 is– N(R)P(O)(OR)NR2. In some embodiments, R 3 is–P(O)(OR)2. In some embodiments, R 3 is– P(O)(NR 2 )OR. In some embodiments, R 3 is–P(O)(NR 2 ) 2 . In some embodiments, R 3 is–Si(OH) 2 R. In some embodiments, R 3 is aboutSi(OH)(R)2. In some embodiments, R 3 is–Si(R)3.
• R 3 is methyl. In some embodiments, R 3 is–OCH3. In some embodiments, R 3 is chloro.
• R 3 is selected from those depicted in Table 1, below.
• each R 4 is independently hydrogen, deuterium, –R 6 , halogen,–CN,–NO 2 ,–OR, -SR, -NR 2 ,–S(O) 2 R,–S(O) 2 NR 2, –S(O)R,–C(O)R,–C(O)OR,– C(O)NR 2 , –C(O)N(R)OR, –OC(O)R, –OC(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR2,–N(R)S(O)2R,–P(O)(OR)2,–P(O)(NR2)OR, or–P(O)(NR2)2.
• R 4 is hydrogen. In some embodiments, R 4 is–R 6 . In some embodiments, R 4 is halogen. In some embodiments, R 4 is–CN. In some embodiments, R 4 is– NO2. In some embodiments, R 4 is–OR. In some embodiments, R 4 is–SR. In some embodiments, R 4 is–NR2. In some embodiments, R 4 is–S(O)2R. In some embodiments, R 4 is–S(O)2NR2. 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 .
• 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)NR2. In some embodiments, R 4 is–N(R)C(O)OR. In some embodiments, R 4 is–N(R)C(O)R. In some embodiments, R 4 is–N(R)C(O)NR 2 . In some embodiments, R 4 is–N(R)S(O) 2 R. In some embodiments, R 4 is–P(O)(OR) 2 . In some embodiments, R 4 is–P(O)(NR 2 )OR. In some embodiments, R 4 is–P(O)(NR2)2.
• R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is cyclopropyl.
• R 4 is selected from those depicted in Table 1, below.
• R 5 is hydrogen, deuterium, an optionally substitute C 1-4 aliphatic, or–CN.
• R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5 is an optionally substituted C1-4 aliphatic. In some embodiments, R 5 is– CN.
• R 5 is selected from those depicted in Table 1, below.
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.
• R 6 is an optionally substituted C 1-6 aliphatic. In some embodiments, R 6 is an optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring 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.
• R 6 is selected from those depicted in Table 1, below.
• Ring A is a bi- or tricyclic ring selected from
• Ring A is In some embodiments, Ring A is
• Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is in some embodiments, Ring A is
• Ring A In some embodiments, Ring A is
• Ring A is . In some embodiments, Ring A is In some embodiments, Ring A is . In some embodiments,
• Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some
• Ring A is In some embodiments, Ring A is In some embodiments, Ring A is . In some
• Ring A is In some embodiments, Ring A is . In
• Ring A is . In some embodiments, Ring A is
• Ring A is In some embodiments, Ring A is
• Ring A is . In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments,
• Ring A is . In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In
• Ring A is In some embodiments, Ring A is In some embodiments, Ring A is . In some embodiments,
• Ring A is In some embodiments, Ring A is
• Ring A is In some embodiments, Ring A is . In
• Ring A is In some embodiments, Ring A is
• Ring A is . In some embodiments, Ring A is
• Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is in some embodiments, Ring A is
• Ring A is In some embodiments, Ring A is . In some embodiments, Ring A is
• Ring A is In some embodiments, Ring A is . In some embodiments, Ring A is In some embodiments,
• Ring A is .
• Ring A is selected from those depicted in Table 1, below.
• Ring B is a fused ring selected from 6- membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• 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 to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring B is fused 5 to 7-membered saturated or partially saturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, Ring B is fused 5-membered heteroaryl with 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.
• Ring B is . In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring
• Ring B is In some embodiments, Ring B is [000179] In some embodiments, each Ring B is In some embodiments, each Ring B is In some embodiments, each Ring B is . In some embodiments, each Ring B is . In some embodiments, Ring B is .
• Ring B is . In some embodiments, Ring B is
• Ring B is . In some embodiments, Ring B
• Ring B is In some embodiments, Ring B is
• Ring B is . In some embodiments, Ring B is In some embodiments, Ring B is . In some embodiments, Ring B is In some embodiments, Ring B is . In some embodiments, Ring B is In some embodiments, Ring B is . In some embodiments, Ring B is In some embodiments, Ring B is
• Ring B is In some embodiments, Ring B is . In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is in some embodiments, Ring B is
• Ring B is selected from , ,
• Ring B is selected from those depicted in Table 1, below.
• Ring C is a mono- or bicyclic ring selected
• Ring C is . In some embodiments, Ring C is
• Ring C is In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments,
• Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is .
• Ring C is In some embodiments, Ring C is . In some embodiments, Ring C is In some embodiments, Ring C is . In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is . In some embodiments,
• Ring C is In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is . In some embodiments, Ring C is
• Ring C is In some embodiments, Ring C is
• Ring C is In some embodiments,
• Ring C is . In some embodiments, Ring C is In some
• Ring C is
• Ring C is a mono- or bicyclic ring selected from
• Ring C is selected from
• Ring C is selected from ,
• Ring C is selected from those depicted in Table 1, below.
• Ring D is a ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• Ring D is a 6-membered aryl. In some embodiments, Ring D is a 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring D is a 5 to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring D is 5 to 7-membered saturated or partially saturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, Ring D is 5-membered heteroaryl with 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.
• Ring D is selected from those depicted in Table 1, below.
• each of Ring E, Ring F, and Ring G is independently a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein each of Ring E, Ring F, and Ring G is independently and optionally further substituted with 1-2 oxo groups.
• 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 to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, each Ring E, Ring F, and Ring G is independently a 5 to 7-membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.
• each Ring E, Ring F, and Ring G is independently a 5-membered heteroaryl with 1- 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, each of Ring E, Ring F, and Ring G is independently and optionally further substituted with 1-2 oxo groups.
• Ring F is . In some embodiments, Ring
• Ring F is In some embodiments, Ring F is In some embodiments, Ring F is In some embodiments, Ring F is In some embodiments, Ring F is In some embodiments, Ring F is In some
• Ring F is In some embodiments, Ring F is
• Ring F is In some embodiments, Ring F is . In some embodiments, Ring F is a
• Ring F is In some embodiments,
• Ring F is . In some embodiments, Ring F is
• Ring F is In some embodiments, Ring F is In some embodiments,
• Ring F is . In some embodiments, Ring F is
• Ring F is In some embodiments, Ring F is In some embodiments,
• Ring F is In some embodiments, Ring F is . In some embodiments, Ring F is In some (R
• Ring F is
• Ring F is . In some embodiments, Ring F is . In some embodiments, Ring F is . In some embodiments, Ring F is . In some
• Ring F is . In some embodiments, Ring F is
• Ring F is In some embodiments,
• Ring F is . In some embodiments, Ring F is
• Ring F is In some embodiments, Ring F is In some embodiments,
• Ring F is . In some embodiments, Ring F is
• Ring F is . In some embodiments, Ring F is . In some embodiments, Ring F is . In some embodiments, Ring F is . In some embodiments, Ring F is
• Ring F is . In some embodiments,
• Ring F is . In some embodiments, Ring F is
• each Ring E and Ring G is independently In some embodiments, each Ring E and Ring G is independently In some embodiments, each Ring E and Ring G is independently . In some embodiments, each Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently [000200] In some embodiments, Ring E and Ring G is independently is . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring
• Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently . In some embodiments, Ring E and Ring G is independently
• Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiment, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is
• Ring E, Ring F, and Ring G is
• Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is
• Ring E, Ring F, and Ring G is
• Ring E, Ring F, and Ring G is
• Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is
• Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is In some embodiments, Ring E, Ring F, and Ring G is In some embodiments, Ring E, Ring F, and Ring G is In some embodiments, Ring E, Ring F, and Ring G is
• Ring E, Ring F, and Ring G is In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is In some embodiments, Ring E, Ring F, and Ring G is In some embodiments, Ring E, Ring F, and Ring G is In some embodiments, Ring E, Ring F, and Ring G is In some embodiments, Ring E, Ring F, and Ring G is
• Ring E, Ring F, and Ring G is In some embodiments, Ring E, Ring F, and Ring G is In some embodiments, Ring E, Ring F, and Ring G is In some embodiments, Ring E, Ring F, and Ring G is In some embodiments, Ring E, Ring F, and Ring G is . In some embodiments, Ring E, Ring F, and Ring G is
• Ring E, Ring F, and Ring G is selected from those depicted in Table 1, below.
• Ring H is a ring selected from a 7-9 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring E is optionally further substituted with 1-2 oxo groups.
• Ring H is a ring selected from a 7-9 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring H is optionally further substituted with 1-2 oxo groups.
• Ring some embodiments, Ring
• Ring H is . In some embodiments, Ring H is . In some
• Ring H is . In some embodiments, Ring H is . In some embodiments, Ring H is In some embodiments, Ring H is In some
• Ring H is . In some embodiments, Ring H is
• Ring H is some
• Ring H is . In some embodiments, Ring H is
• Ring H is .
• Ring H is . In some embodiments, Ring H is
• Ring H is In some embodiments,
• Ring H is In some embodiments, Ring H is . In some embodiments, Ring H is . In some embodiments, Ring H is . In some
• Ring H is In some embodiments, Ring H is
• Ring H is
• Ring E and Ring H is
• Ring E and Ring H is selected from those depicted in Table 1, below.
• each of Ring I and Ring J is independently a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur [000211] In some embodiments, each of Ring I and Ring J is independently a 6-membered aryl.
• 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 to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, each of Ring I and Ring J is independently a 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, each of Ring I and Ring J is independently a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.
• each Ring I and Ring J is independently
• each Ring I and Ring J is independently
• each Ring I and Ring J is independently
• each Ring I and Ring J is independently
• Ring I and Ring J is independently
• Ring I and Ring J is independently is
• Ring I and Ring J is independently In some embodiments,
• Ring I and Ring J is independently
• Ring K is a fused ring selected from a 6-12 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring H is optionally further substituted with 1-2 oxo groups.
• Ring K is a fused ring selected from a 6-12 membered saturated or partially unsaturated carbocyclyl.
• Ring K is a 6-12 membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.
• Ring K is optionally further substituted with 1-2 oxo groups.
• Ring K is . In some embodiments, Ring
• Ring K is In
• Ring K is . In some embodiments, Ring K is
• Ring K is In some embodiments,
• Ring K is . In some embodiments, Ring K is
• Ring K is . some embodiments, Ring K is In some embodiments, Ring K is
• Ring K is .
• Ring K is In some embodiments, Ring K is
• Ring K is
• Ring I, Ring J, and Ring K is
• Ring I, Ring J, and Ring K is selected from those depicted in Table 1, below.
• L 1 is a covalent bond. In some embodiments, L 1 is a C 1-3 aliphatic. In some embodiments, L 1 is–CH 2 –. In some embodiments, L 1 is–C(D)(H)-. In some embodiments, L 1 is -C(D)2–. In some embodiments, L 1 is–CH 2 CH 2 –. In some embodiments, L 1 is–NR–. In some embodiments, L 1 is–CH 2 NR–. In some embodiments, L 1 is or–O–. In some embodiments, L 1 is–CH 2 O–. In some embodiments, L 1 is–S–. In some embodiments, L 1 is - OC(O)-.
• 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-,. In some embodiments, L 1 is - NRS(O) 2 -. In some embodiments, L 1 is -S(O) 2 NR-. In some embodiments, L 1 is -NRC(O)-. In some embodiments, L 1 is -C(O)NR-.
• Ring L 1 is selected from those depicted in Table 1, below.
• m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.
• m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13. In some embodiments, m is 14. In some embodiments, m is 15. In some embodiments, m is 16.
• m is selected from those depicted in Table 1, below.
• n 0, 1, 2, 3 or 4.
• n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.
• n is selected from those depicted in Table 1, below.
• p is 0 or 1.
• p is 0. In some embodiments, p is 1.
• p is selected from those depicted in Table 1, below.
• LBM is . In some embodiments, LBM is . In some embodiments, LBM is In some
• LBM is . In some embodiments, LBM is . In some embodiments, LBM is In some
• LBM is In some embodiments, LBM is
• LBM is . In some embodiments,
• LBM is In some embodiments, LBM is
• LBM is .
• LBM is . In some embodiments, LBM is . In some embodiments, LBM is . In some embodiments, LBM is . In some
• LBM is In some embodiments.
• LBM is . In some embodiments, LBM is
• LBM is In some embodiments,
• LBM is In some embodiments, LBM is In some
• LBM is N
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-p-1, I-p-2, or I-p-3 respectively:
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-q-1, I-q-2, I-q-3, or I-q-4, respectively:
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-r-1 or I-r-3, respectively:
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-s-1, I-s-2, I-s-3, I-s-4, I-s-5, I-s-6, I-s-7, or I-s-8:
• L and STAT are as defined above and described in embodiments herein, and wherein each of the variables Ar, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, L, x, y, and is as described and defined in WO 2017/161119, the entirety of each of
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-t:
• the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-t-1:
• LBM is a IAP E3 Ubiquitin ligase binding moiety recited in Varfolomeev, E. et al., IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-kB activation, and TNFa-Dependent Apoptosis, Cell, 2007, 131(4): 669-81, such as, for example:
• the present invention provides a compound of Formula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-u-1, I-u-2, I-u-3, I-u-4, or I-u-5 respectively:
• the present invention provides a compound of Formula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-v-1, I-v-2, I-v-3, I-v-4, I-v-5 or I-v-6 respectively:
• brackets around any LBM means that the moiety is covalently attached to said LBM at any available modifiable carbon, nitrogen, oxygen, or sulfur atom.
• available modifiable carbon, nitrogen, oxygen, or sulfur atoms in the following LBM compound structure are depicted below, wherein each wavy bond defines the point of attachment to said
• the present invention provides a compound of Formula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-w-1, I-w-2, or I-w-3 respectively:
• the present invention provides a compound of Formula I, wherein LBM is a CRBN or VHL E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-x-1, I-x-2, I-x-3, I-x-4, I-x-5, I-x-6, or I-x-7 respectively:
• the present invention provides a compound of Formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-x ⁇ -1, I-x ⁇ -1, I-x ⁇ -2, I-x ⁇ -2, I-x ⁇ -3, I-x ⁇ -3, I-x ⁇ -4, I-x ⁇ -4, I-x ⁇ -7 or I-x ⁇ -7 respectively:
• the present invention provides a compound of Formula I, wherein LBM is a MDM2 (i.e. human double minute 2 or HDM2) E3 ligase binding moiety thereby forming a compound of formula I-y-1, I-y-2, I-y-3, I-y-4, I-y-5, I-y-6, I-y-7, I-y-8, I-y-9, I-y-10, I-y-11, I-y-12, I-y-13, I-y-14, I-y-15, I-y-16, I-y-17, or I-y-18 respectively:
• MDM2 i.e. human double minute 2 or HDM2
• the present invention provides a compound of Formula I, wherein LBM is an IAP E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-z-1, I-z-2, I-z-3, or I-z-4 respectively:
• the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety, a DCAF15 E3 ubiquitin ligase binding moiety, or a VHL E3 ubiquitin ligase binding moiety; thereby forming a compound of formula I-aa-1, I-aa-2, or I-aa-3:
• L and STAT is as defined above and described in embodiments herein, and wherein:
• each of X 1 , X 2a , and X 3a is independently a bivalent moiety selected from a covalent bond,–CH 2 –
• each of X 4 and X 5 is independently a bivalent moiety selected from–CH 2 –,–C(O)–,–C(S)–, or
• R 1 is hydrogen, deuterium, halogen, –CN, –OR, –SR, –S(O)R,–S(O) 2 R,–NR 2 , or an optionally substituted C 1-4 aliphatic;
• each of R 2 , R 3b , and R 4a is independently hydrogen,–R 6 , halogen,–CN,–NO 2 ,–OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, –C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or –N(R)S(O) 2 R;
• R 5a is hydrogen or C1-6 aliphatic
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Ring A a is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7- membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5- membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
• Ring B a is selected from 6-membered aryl containing 0-2 nitrogen atoms or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• Ring C a is a selected from 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; m is 0, 1, 2, 3 or 4;
• o 0, 1, 2, 3 or 4;
• q 0, 1, 2, 3 or 4;
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• the present invention provides a compound of Formula I-aa, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-aa ⁇ -1 or I-aa ⁇ -1:
• each of X 1 , X 2a , and X 3a is independently a
• bivalent moiety selected from a covalent bond,–CH 2 –,–C(O)–,–C(S)–, or .
• X 1 is a covalent bond,–CH 2 –,–C(O)–,–C(S)–, .
• X 1 is selected from those depicted in Table 1, below.
• X 2a is a covalent bond,–CH 2 –,–C(O)–,–C(S)–, or .
• X 2a is selected from those depicted in Table 1, below.
• X 3a is a covalent bond,–CH 2 –,–C(O)–,–C(S)–, or
• X 3a is selected from those depicted in Table 1, below .
• each of X 4 and X 5 is independently a bivalent moiety selected from–CH 2 –,–C(O)–,–C(S)–, or
• X 4a is–CH 2 –,–C(O)–,–C(S)–, or .
• X 4a is selected from those depicted in Table 1, below.
• X 5a is–CH 2 –,–C(O)–,–C(S)–, or
• X 5a is selected from those depicted in Table 1, below.
• R 1 is hydrogen, deuterium, halogen,–CN,– OR,–SR,–S(O)R,–S(O)2R,–NR2, or an optionally substituted C1-4 aliphatic.
• R 1 is hydrogen, deuterium, halogen,–CN,–OR,–SR, –S(O)R,–S(O)2R,–NR2, or an optionally substituted C1-4 aliphatic.
• R 1 is selected from those depicted in Table 1, below.
• each of R 2 , R 3b , and R 4a is independently hydrogen, –R 6 , halogen, –CN, –NO2, –OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, – C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or–N(R)S(O) 2 R.
• R 2 is hydrogen, –R 6 , halogen, –CN, –NO2, –OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, – C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or–N(R)S(O)2R.
• R 2 is selected from those depicted in Table 1, below.
• R 3b is hydrogen,–R 6 , halogen,–CN, –NO 2 ,–OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, – C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or–N(R)S(O) 2 R.
• R 3b is methyl
• R 3b is selected from those depicted in Table 1, below.
• R 4a is hydrogen,–R 6 , halogen,–CN,–NO2,–OR, - SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, – C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , or–N(R)S(O)2R.
• R 4a is methyl
• R 4a is selected from those depicted in Table 1, below.
• R 5a is hydrogen or C 1-6 aliphatic.
• R 5a is t-butyl
• R 5a is selected from those depicted in Table 1, below.
• each R 6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 6 is an optionally substituted C1-6 aliphatic group. In some embodiments, R 6 is an optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 6 is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 6 is selected from those depicted in Table 1, below.
• Ring A a is a fused ring selected from 6- membered aryl containing 0-2 nitrogen atoms, 5 to 7-membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.
• Ring A a is a fused 6-membered aryl containing 0-2 nitrogen atoms. In some embodiments Ring A a is a fused 5 to 7-membered partially saturated carbocyclyl. In some embodiments Ring A a is a fused 5 to 7-membered partially saturated heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments Ring A a is a fused 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.
• Ring A a is a fused phenyl.
• Ring A a is selected from those depicted in Table 1, below.
• Ring B a is selected from 6-membered aryl containing 0-2 nitrogen atoms or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Ring B a is a 6-membered aryl containing 0-2 nitrogen atoms. In some embodiments, Ring B a is a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Ring B a is
• Ring B a is selected from those depicted in Table 1, below.
• Ring C a is selected from 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.
• Ring C a is a 6-membered aryl containing 0-2 nitrogen atoms. In some embodiments, Ring C a is a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.
• Ring C a is .
• Ring C a is selected from those depicted in Table 1, below.
• m is 0, 1, 2, 3 or 4.
• m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.
• m is selected from those depicted in Table 1, below.
• o is selected from those depicted in Table 1, below.
• o 0, 1, 2, 3 or 4.
• o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. [000300] In some embodiments, o is selected from those depicted in Table 1, below.
• q is 0, 1, 2, 3 or 4.
• q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.
• q is selected from those depicted in Table 1, below.
• each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• R is hydrogen. In some embodiments, R is phenyl. In some embodiments, R is a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• R is selected from those depicted in Table 1, below.
• the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety thereby forming a compound of formula I-ab:
• the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety thereby forming a compound of formula I-ac-1 or I-ac-2:
• L and STAT are as defined above and described in embodiments herein, and wherein each of the variables X, W 3 , W 5 , R9, R10, R11, R14a, R 14b , R 15 , R 16 , and o is as described and defined in WO 2017/030814, WO 2016/118666, and US 2017/0327469, the entirety of each of which is herein incorporated by reference.
• the present invention provides a compound of formula I, wherein LBM is an IAP binding moiety thereby forming a compound of formula I-ad:
• the present invention provides a compound of formula I, wherein LBM is a MDM2 binding moiety thereby forming a compound of formula I-ae:
• the present invention provides a compound of formula I, wherein LBM is a DCAF16 binding moiety thereby forming a compound of formula I-af:
• the present invention provides a compound of formula I, wherein LBM is a RNF114 binding moiety thereby forming a compound of formula I-ag:
• the present invention provides a compound of formula I, wherein LBM is a RNF4 binding moiety thereby forming a compound of formula I-ah:
• the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety thereby forming a compound of formula I-aay-1 or I-aay- 2:
• the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety thereby forming a compound of formula I-aaz-1 or I-aaz- 2:
• the present invention provides a compound of formula I, wherein LBM is a E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-aaaa-1, I-aaaa-2, I-aaaa-3, or I-aaaa-4:
• LBM is In some embodiments,
• LBM is In some embodiments, LBM is
• LBM is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• LBM is In some embodiments, LBM is
• LBM is In some embodiments, LBM is In some embodiments, LBM is . In some embodiments, LBM is
• LBM is In some embodiments, LBM is
• LBM is . In some embodiments, LBM is
• LBM is . In some embodiments, LBM is
• LBM is In some embodiments, LBM is . In some embodiments, LBM is In some embodiments, LBM is . In some embodiments, LBM is
• LBM is In some embodiments, LBM is . In some embodiments, LBM is . In some embodiments, LBM is . In some embodiments, LBM is
• LBM is .
• LBM is In some embodiments, LBM is
• LBM is In
• LBM is N
• the present invention provides a compound of formula I, wherein LBM is a E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula formula I-bbbb:
• L and STAT are as defined above and described in embodiments herein, wherein:
• each X 1 is independently -CH 2 -, -O-, -NR-, -CF 2 -, , -C(O)-, -C(S)-, or
• X 2 and X 3 are independently -CH 2 -, -C(O)-, -C(S)-, or
• Z 1 and Z 2 are independently a carbon atom or a nitrogen atom
• Ring A x is a fused ring selected from benzo or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• L x is a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -S-, -C(O)-, -C(S)-, -CR 2 -, -CRF-, -CF 2 -, -NR-, or -S(O) 2 -;
• each R x is independently selected from hydrogen, deuterium, R z , halogen, -CN, -NO2, -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)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, - OP(O)(OR) 2 , -OP(O)(OR) 2 , -OP(O)
• R x groups are optionally taken together to form an optionally substituted 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each R is independently selected from hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the carbon or nitrogen, independently selected from nitrogen, oxygen, and sulfur; R y is selected from or hydrogen;
• Ring B x is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 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 is independently selected from hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, - SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2, -S(O)R, -CF 2 R, -CF 3 , -CR 2 (OR), - CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)2, -OP(O)(OR)2, - OP(O)(OR)2, -OP
• each R z is independently selected from an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• x 0, 1, 2, 3 or 4;
• y 0, 1 or 2;
• each X 1 is independently -CH 2 -, -O-, -NR-, -
• X 1 is a covalent bond. In some embodiments, X 1 is -CH 2 -. In some embodiments, X 1 is -O-. In some embodiments, X 1 is -NR-. In some embodiments, X 1 is - CF2-. In some embodiments, X 1 is . In some embodiments, X 1 is -C(O)- . In some
• X 1 is -C(S)- . In some embodiments, X 1 is
• X 1 is selected from those shown in the compounds of Table 1.
• X 2 and X 3 are independently -CH 2 -, -C(O)-, -
• X 2 and X 3 are independently -CH 2 -. In some embodiments, X 2 and X 3 are independently -C(O)-. In some embodiments, X 2 and X 3 are independently -C(S)-. In
• X 2 and X 3 are independently
• X 2 and X 3 are independently selected from those shown in the compounds of Table 1.
• Z 1 and Z 2 are independently a carbon atom or a nitrogen atom.
• Z 1 and Z 2 are independently a carbon atom. In some embodiments, Z 1 and Z 2 are independently a carbon atom.
• Z 1 and Z 2 are independently selected from those shown in the compounds of Table 1.
• Ring A x is fused ring selected from benzo or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Ring A x is benzo. In some embodiments, Ring A x is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [000330] In some embodiments, Ring A x is In some embodiments, Ring A x is
• Ring A x is In some embodiments, Ring
• a x is .
• Ring A x is selected from those shown in the compounds of Table 1.
• L x is a covalent bond or a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, - NR-, or -S(O) 2 -.
• L x is a covalent bond.
• L x is a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF 2 -, -NR-, or -S(O) 2 -.
• L x is -C(O)-.
• L x is selected from those shown in the compounds of Table 1.
• each R x is independently selected from hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, - CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, - C(O)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)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)2, -OP(O)(OR)2, -OP(O)
• R x is hydrogen. In some embodiments, R x is deuterium. In some embodiments, R x is R z . In some embodiments, R x is halogen. In some embodiments, R x is –CN. In some embodiments, R x is -NO2. In some embodiments, R x is–OR. In some embodiments, R x is–SR. In some embodiments, R x is -NR 2 . In some embodiments, R x is -S(O) 2 R. In some embodiments, R x is -S(O)2NR2. In some embodiments, R x is -S(O)R. In some embodiments, R x is -CF2R.
• R x is -CF3. In some embodiments, R x is - CR 2 (OR). In some embodiments, R x is -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 . 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)NR2. In some embodiments, R x is -C(S)NR2.
• 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)NR2. In some embodiments, R x is -N(R)S(O)2R. In some embodiments, R x is - OP(O)R2. In some embodiments, R x is -OP(O)(OR)2,. In some embodiments, R x is - OP(O)(OR)NR 2 . In some embodiments, R x is -OP(O)(NR 2 ) 2 . In some embodiments, R x is - Si(OR)R2.
• R x is -SiR3. In some embodiments, two R x groups are optionally taken together to form an optionally substituted 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• R x is fluoro. In some embodiments, R x is bromo. In some embodiments, R x is methyl. In some embodiments, R x is -OH. In some embodiments, R x is -NH 2 . In some embodiments, R x is -NHCH3. In some embodiments, R x is -N(CH3)2. In some embodiments, R x is -NHCH(CH 3 ) 2 . In some embodiments, R x is -NHSO 2 CH 3 . In some embodiments, R x is -CH 2 OH. In some embodiments, R x is -CH 2 NH 2 . In some embodiments, R x
• R x is -C(O)NH 2 . In some embodiments, R x is -C(O)NHCH 3 . In some embodiments, R x is
• R x is In some embodiments, R x is . In some embodiments, R x is In some embodiments, R x is . In some embodiments, R x is In some embodiments, R x is .
• R x is
• R x is In some embodiments, R x is .
• each R x is independently selected from those shown in the compounds of Table 1.
• each R is independently selected from hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the carbon or nitrogen, independently selected from nitrogen, oxygen, and sulfur.
• R is hydrogen. In some embodiments, R is an optionally substituted C1-6 aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R y is selected from or hydrogen.
• R y is In some embodiments, R y is hydrogen.
• R y is selected from those shown in the compounds of Table 1.
• Ring B x is phenyl, a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 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.
• Ring B x is phenyl. In some embodiments, Ring B x is a 4-10 membered saturated or partially unsaturated mono- or bicyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur In some embodiments, Ring B x is a 5-6 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 1-2 oxo groups.
• Ring B x is In some embodiments, Ring B x is . In some embodiments, Ring B x is . In some embodiments Ring B x is In some embodiments Ring B x is
• Ring B x is selected from those shown in the compounds of Table 1.
• each R w is independently selected from hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, - CF 2 R, -CF 3 , -CR 2 (OR), -CR 2 (NR 2 ), -C(O)R, -C(O)OR, - C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, - N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(OR)NR2, -OP(O)(NR2)2, and -S
• R w is hydrogen. In some embodiments, R w is deuterium. In some embodiments, R w is R z . In some embodiments, R w is halogen. In some embodiments, R w is –CN. In some embodiments, R w is -NO2. In some embodiments, R w is–OR. In some embodiments, R w is–SR. In some embodiments, R w is -NR 2 . In some embodiments, R w is -S(O)2R. In some embodiments, R w is -S(O)2NR2. In some embodiments, R w is -S(O)R. In some embodiments, R w is -CF2R.
• R w is -CF3. In some embodiments, R w is -CR 2 (OR) . In some embodiments, R w is -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 . 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)NR2. In some embodiments, R w is -N(R)C(O)OR.
• R w is -N(R)C(O)R. In some embodiments, R w is -N(R)C(O)NR 2 . In some embodiments, R w is -N(R)S(O)2R. In some embodiments, R w is -OP(O)R2. In some embodiments, R w is -OP(O)(OR)2. In some embodiments, R w is -OP(O)(OR)NR2. In some embodiments, R w is -OP(O)(NR 2 ) 2 . In some embodiments, R w is -SiR 3 .
• R w is selected from those shown in the compounds of Table 1.
• each R z is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R z is an optionally substituted C1-6 aliphatic. In some embodiments, R z is an optionally substituted phenyl. In some embodiments, R z is an optionally substituted 4-7 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 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R z is In some embodiments, R z
• R z is . In some embodiments, R z is In some embodiments, R z is . In some embodiments, R z is In some embodiments, R z is R z is
• R z is selected from those shown in the compounds of Table 1.
• w is 0, 1, 2, 3 or 4.
• w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4.
• w is selected from those shown in the compounds of Table 1.
• x is 0, 1, 2, 3 or 4.
• x is 0. In some embodiments, x is 1. In some embodiments, m is 2. In some embodiments, x is 3. In some embodiments, x is 4.
• x is selected from those shown in the compounds of Table 1.
• y is 0, 1 or 2.
• y is 0. In some embodiments, y is 1. In some embodiments, y is 2.
• y is selected from those shown in the compounds of Table 1.
• the present invention provides a compound of formula I-bbbb, wherein Ring A x is benzo, y is 1, X 1 is -CH 2 -, X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, to provide a compound of formula I-bbbb-1:
• each of STAT, L, L x , R x , R y , and x is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of formula I-bbbb, wherein Ring A x is imidazolyl, y is 1, X 1 is -CH 2 -, X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, to provide a compound of formula I-bbbb-2:
• the present invention provides a compound of formula I-bbbb, wherein Ring A x is imidazolyl, y is 1, X 1 is -CH 2 -, X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, to provide a compound of formula I-bbbb-3:
• the present invention provides a compound of formula I-bbbb, wherein Ring A x is oxazolyl, y is 1, X 1 is -CH 2 -, X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, to provide a compound of formula I-bbbb-4:
• the present invention provides a compound of formula I-bbbb, wherein Ring A x is benzo, y is 0, X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, to provide a compound of formula I-bbbb-5:
• each of STAT, L, L x , R x , R y , and x is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of formula I-bbbb, wherein Ring A x is benzo, y is 1, X 1 is -O-, X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, to provide a compound of formula I-bbbb-6:
• each of STAT, L, L x , R x , R y , and x is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of formula I-bbbb, wherein Ring A x is benzo, y is 1, X 1 is -NR-, X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, to provide a compound of formula I-bbbb-7:
• each of STAT, L, L x , R, R x , R y , and x is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of formula I-bbbb, wherein Ring A x is benzo, y is 1, X 1 is -CF2-, X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, to provide a compound of formula I-bbbb-8:
• each of STAT, L, L x , R x , R y , and x is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of formula I-bbbb, wherein Ring A x is benzo, y is 1, X 1 i X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, to provide a compound of formula I-bbbb-9:
• each of STAT, L, L x , R x , R y , and x is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of formula I-bbbb, wherein Ring A x is pyridyl, y is 1, X 1 is -CH 2 -, X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, to provide a compound of formula I-bbbb-10:
• each of STAT, L, L x , R x , R y , and x is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of formula I-bbbb, wherein Ring A x is pyridyl, y is 1, X 1 is -CH 2 -, X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, to provide a compound of formula I-bbbb-11:
• each of STAT, L, L x , R x , R y , and x is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of formula I-bbbb, wherein Ring A is benzo, y is 1, X 1 , X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, to provide a compound of formula I-bbbb-12:
• each of STAT, L, L x , R x , R y , and x is as defined above and described in embodiments herein, both singly and in combination.
• LBM is In some embodiments, LBM is . In some embodiments, LBM is In some embodiments,
• LBM is In some embodiments, LBM is . In some embodiments,
• LBM is . In some embodiments, LBM is In some embodiments, LBM is
• LBM is selected from those in Table 1.
• the present invention provides a compound of formula I, wherein LBM is a RPN13 binding moiety thereby forming a compound of formula I-cccc:
• L and STAT are as defined above and described in embodiments herein, and wherein each of the variables A, Y, and Z is as described and defined in WO 2019/165229, the entirety of each of which is herein incorporated by reference.
• the present invention provides a compound of formula I, wherein LBM is a Ubr1 binding moiety as described in Shanmugasundaram, K. et al, J. Bio. Chem. 2019, doi: 10.1074/jbc.AC119.010790, the entirety of each of which is herein incorporated by reference, thereby forming a compound of formula I-dddd-1 or I-dddd-2:
• L and STAT are as defined above and described in embodiments herein.
• the present invention provides a compound of formula I, wherein LBM is a CRBN binding moiety thereby forming a compound of formula I-eeee:
• the present invention provides a compound of formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-ffff-1, I-ffff-2, I-ffff-3 or I-ffff-4:
• the present invention provides a compound of formula II: II
• L and STAT are as described above and herein, and DIM is a degradation inducing moiety selected from LBM, a lysine mimetic, or a hydrogen atom.
• DIM is LBM as described above and herein.
• DIM is a lysine mimetic.
• the covalent attachment of ubiquitin to one or more members of the STAT protein family i.e., STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6 is achieved through the action of a lysine mimetic.
• STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6 is achieved through the action of a lysine mimetic.
• the moiety that mimics a lysine undergoes ubiquitination thereby marking STAT1 for degradation via the Ubiquitin- Proteasome Pathway (UPP).
• UPB Ubiquitin- Proteasome Pathway
• the moiety that mimics a lysine undergoes ubiquitination thereby marking STAT2 for degradation via the Ubiquitin-Proteasome Pathway (UPP).
• the moiety that mimics a lysine undergoes ubiquitination thereby marking STAT3 for degradation via the Ubiquitin-Proteasome Pathway (UPP).
• the moiety that mimics a lysine undergoes ubiquitination thereby marking STAT4 for degradation via the Ubiquitin-Proteasome Pathway (UPP).
• the moiety that mimics a lysine undergoes ubiquitination thereby marking STAT5A for degradation via the Ubiquitin-Proteasome Pathway (UPP).
• the moiety that mimics a lysine upon the binding of a compound of formula II to STAT5B, undergoes ubiquitination thereby marking STAT5B for degradation via the Ubiquitin- Proteasome Pathway (UPP).
• the moiety that mimics a lysine upon the binding of a compound of formula II to STAT6, undergoes ubiquitination thereby marking STAT6 for degradation via the Ubiquitin-Proteasome Pathway (UPP).
• DIM is In some embodiments, DIM is In some embodiments, DIM is
• DIM is selected from those depicted in Table 1A, below.
• the present invention provides the compound of formula I as a compound of formula II-a:
• the present invention provides the compound of formula I as a compound of formula II-b:
• the present invention provides the compound of formula I as a compound of formula II-c:
• the present invention provides a compound of Formula II,
• DIM is a lysine mimetic , or ; thereby forming a compound of Formulae II-d-1, II-d-2, or II- d-3, respectively:

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• Peptides Or Proteins (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Medicinal Preparation (AREA)
• Steroid Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Detergent Compositions (AREA)

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