STAT Degraders and Their Uses

Abstract

To provide STAT degraders and uses thereof.SOLUTION: The present invention provides compounds, compositions thereof, and methods of using the compositions. In some embodiments, the present invention provides a method of treating a hematologic malignancy selected from LGL leukemia (T cell and NK cell), cutaneous T cell lymphoma (CTCL), peripheral T cell lymphomas (PTCL, all subtypes including ALCL), diffuse large B cell lymphoma (DLBCL), acute myelogenous leukemia, multiple myeloma, and myelofibrosis.SELECTED DRAWING: None

Description

Technical Field

[0001] Citation of Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 830,095, filed Apr. 5, 2019; U.S. Provisional Application No. 62 / 833,331, filed Apr. 12, 2019; U.S. Provisional Application No. 62 / 855,259, filed May 31, 2019; U.S. Provisional Application No. 62 / 860,512, filed Jun. 12, 2019; U.S. Provisional Application No. 62 / 875,362, filed Jul. 17, 2019; U.S. Provisional Application No. 62 / 877,051, filed Jul. 22, 2019; U.S. Provisional Application No. 62 / 887,872, filed Aug. 16, 2019; U.S. Provisional Application No. 62 / 926,127, filed Oct. 25, 2019; U.S. Provisional Application No. 62 / 932,957, filed Nov. 8, 2019; U.S. Provisional Application No. 62 / 944,810, filed Dec. 6, 2019; U.S. Provisional Application No. 62 / 947,310, filed Dec. 12, 2019; U.S. Provisional Application No. 62 / 949,053, filed Dec. 17, 2019; and U.S. Provisional Application No. 62 / 967,921, filed Jan. 30, 2020, the contents of each of which are incorporated herein by reference.

[0002] Field of the Invention The present invention relates to compounds and methods useful for the modulation of one or more signal transducer and activator of transcription (''STAT'') by ubiquitination and / or degradation by a compound according to the invention. The present invention also provides a pharmaceutically acceptable composition comprising a compound of the invention and methods of using said composition in the treatment of various disorders.

Background Art

[0003] Background of the Invention The ubiquitin-proteasome pathway (UPP) is an important pathway that regulates major regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to numerous cellular processes, and when defective or disrupted, it leads to the onset of various diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0004] There are over 600 E3 ubiquitin ligases that facilitate the ubiquitination of various proteins in vivo, and these are divided into four families, namely, HECT-domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s. Generally, see 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. Biol., 2014, 21, 301-307) titled "New insights into ubiquitin E3 ligase mechanism"; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) titled "RING domain E3 ubiquitin ligases."; Spratt et al. (Biochem. 2014, 458, 421-437) titled "RBR E3 ubiquitin ligases: new structures, new insights, new questions."; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) titled "Roles of F-box proteins in cancer."

[0005] The UPP plays a major role in the degradation of short-lived regulatory proteins that are important in various basic cellular processes, including the regulation of the cell cycle, the regulation of cell surface receptors and ion channels, and antigen presentation. The pathway is involved in the pathogenesis of several morphological malignancies, several genetic diseases (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), immune surveillance / viral pathogenesis, and the pathology of muscle wasting. Many diseases are associated with abnormal UPP and have an adverse effect on the regulation of cell cycle and division, stress and cellular response to extracellular modulators, the morphogenesis of neural circuitry, cell surface receptors, ion channels, secondary pathways, DNA repair, and the biogenesis of organelles.

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

[0007] UPP is used to induce selective proteolysis and involves the use of fusion proteins to artificially ubiquitinate target proteins and synthetic small molecule probes to induce proteasome-dependent degradation. Bifunctional compounds consisting of a target protein-binding ligand and an E3 ubiquitin ligase ligand induced proteasome-mediated degradation of selected proteins via recruitment to these E3 ubiquitin ligases and subsequent ubiquitination. These drug-like molecules offer the possibility of transient control of protein expression. Such compounds can induce inactivation of the protein of interest upon addition to cells or administration to animals or humans, can be useful as biochemical reagents, and can provide 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). In the art, there remains a continuing need for effective treatment of diseases, particularly hyperplasia and cancer, such as breast cancer. However, non-specific effects and the inability to target and regulate together specific classes of proteins (e.g., transcription factors) remain obstacles to the development of effective anti-cancer agents. Thus, small molecule therapeutic agents that affect E3 ligase-mediated proteolysis and target cancer-related proteins such as signal transducer and activator of transcription (「STAT」) retain promise as therapeutic agents. Accordingly, there remains a need to find compounds that are useful STAT degraders as therapeutic agents.

PRIOR ART DOCUMENTS

NON-PATENT DOCUMENTS

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NON-PATENT DOCUMENT 1

[0009] Gist of the Invention This application relates to novel bifunctional compounds that function to recruit STAT proteins for degradation by an E3 ubiquitin ligase, as well as methods for their preparation and use. In particular, the present disclosure provides bifunctional compounds that find utility as modulators of targeted ubiquitination of STAT proteins (which are then degraded and / or otherwise inhibited by the bifunctional compounds described herein). Monovalent compounds that find utility as inducers of targeted ubiquitination of STAT proteins (which are then degraded by the monovalent compounds described herein and / or otherwise inhibited) are also provided. The advantage of the compounds provided herein is that a wide variety of pharmacological activities are possible and are compatible with the degradation / inhibition of STAT proteins. Further, the present specification provides methods of using an effective amount of the compounds described herein for the treatment or alleviation of a disease state such as cancer, for example breast cancer.

[0010] This application further relates to the targeted degradation of STAT proteins by the use of bifunctional molecules, including bifunctional molecules that link a cereblon-binding moiety to a ligand that binds to the STAT protein to be targeted.

[0011] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, have been found herein to be effective as STAT protein degraders. Such compounds have the general formula I:

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[0012] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, have also been found herein to be effective as STAT protein degraders. Such compounds have the general formula II:

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[0013] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating various diseases, disorders or conditions associated with the regulation of signal transduction pathways involving STAT proteins. Such diseases, disorders or conditions include those described herein.

[0014] The compounds provided by the present invention are also useful for the study of STAT enzymes in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in body tissues; and the comparative evaluation of novel STAT inhibitors or STAT degraders, or other regulators, of the cell cycle, metastasis, angiogenesis, and immune cell evasion in vitro or in vivo. In embodiments of the present invention, for example, the following items are provided. (Item 1) Formula I: [Chemical formula] A compound of or a pharmaceutically acceptable salt thereof, wherein in Formula I: STAT is a STAT protein binding moiety capable of binding to one or more of STAT3, STAT1, STAT2, STAT4, STAT5A, STAT5B, and STAT6; L is a divalent moiety that binds STAT to LBM; and LBM is an E3 ubiquitin ligase binding moiety, The compound or a pharmaceutically acceptable salt thereof. (Item 2) The compound according to Item 1, wherein LBM is a cereblon E3 ubiquitin ligase binding moiety, a VHL E3 ubiquitin ligase binding moiety, an IAP E3 ubiquitin ligase binding moiety, or an MDM2 E3 ubiquitin ligase binding moiety. (Item 3) LBM is the cereblon E3 ubiquitin ligase binding moiety, and said compound is a compound of formula I-c:

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Brief Description of Drawings

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[0036] Detailed Description of Specific Embodiments 1. General description of specific embodiments of the present invention: The compounds of the present invention, and compositions thereof, are useful as degraders and / or inhibitors of one or more STAT proteins. In some embodiments, the provided compounds degrade and / or inhibit one or more of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6.

[0037] In certain embodiments, the present invention provides a compound of formula I:

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[0038] In certain embodiments, the present invention provides a compound of formula II:

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[0039] 2. Compounds and definitions: The compounds of the present invention generally include those described above, and are further exemplified by the classes, subclasses, and species disclosed herein. When used herein, the following definitions will apply unless otherwise specified. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. Further, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March’s Advanced Organic Chemistry", 5th Edition, eds: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0040] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched-chain, substituted or unsubstituted, hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic (also referred to herein as "carbocyclic", "alicyclic" or "cycloalkyl") and has one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains from 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains from 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains from 1 to 4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains from 1 to 3 aliphatic carbon atoms, and in yet other embodiments, the aliphatic group contains from 1 to 2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic" or "cycloalkyl") means a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic and has one point of attachment to the remainder of the molecule. In some embodiments, the carbocyclic ring can be a 5- to 12-membered bicyclic, bridged bicyclic, or spirocyclic ring. The carbocyclic ring can contain one or more oxo (=O) or thioxo (=S) substituents. Suitable aliphatic groups include, but are not limited to, straight-chain or branched-chain, saturated or unsaturated, alkyl groups, alkenyl groups, alkynyl groups and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl).

[0041] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system (i.e., carbocyclic or heterocyclic), saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is a non-branched chain of multiple atoms, or one atom, or a valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (other than hydrogen). In some embodiments, the bridged bicyclic group has from 7 to 12 ring members and from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art, and examples of such groups are those described below, where each group is attached to the remainder of the molecule at any suitable carbon atom or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more substituents as described for aliphatic groups. Further, or alternatively, any replaceable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include: [Chemical Formula] may be mentioned.

[0042] The term "lower alkyl" refers to a straight-chain or branched-chain alkyl group of C 1~4 . Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0043] The term "lower haloalkyl" refers to a straight-chain or branched-chain alkyl group of C 1~4 that is substituted with one or more halogen atoms.

[0044] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of any basic nitrogen; or a replaceable nitrogen of a heterocyclic ring (e.g., as in N(3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR +(such as in the N-substituted pyrrolidinyl)) to mean one or more of).

[0045] The term "unsaturated", as used herein, means a moiety having one or more unsaturated units.

[0046] As used herein, the term "divalent C 1~8 (or C 1~6 ) saturated or unsaturated, straight-chain or branched hydrocarbon chain" refers to a straight-chain or branched, divalent alkylene chain, alkenylene chain, and alkynylene chain as defined herein.

[0047] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogens are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0048] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group that contains at least one double bond and in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0049] As used herein, the term "cyclopropylenyl" refers to the following structure:

Chemical formula

[0050] The term "halogen" means F, Cl, Br, or I.

[0051] The term "aryl", used alone or as part of a larger moiety such as in "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, at least one ring in the system being aromatic and each ring in the system containing 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the invention, "aryl" refers to an aromatic ring system, examples of which include, but are not limited to, phenyl, biphenyl, naphthyl, and anthracyl, which may have one or more substituents. When the term "term" is used herein, and what is included within its scope are groups in which an aromatic ring is fused to one or more non-aromatic rings (e.g., indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc.).

[0052] The terms "heteroaryl" and "heteroar-" when used alone or as part of a larger moiety (e.g., "heteroalkyl" or "heteroalkoxy") refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-" also, when used herein, encompass groups in which the heteroaromatic ring is fused to one or more aryl rings, cycloaliphatic rings, or heterocyclic rings and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", and any of these terms includes rings that are optionally substituted. The term "heteroalkyl" refers to an alkyl group substituted by a heteroaryl group, where the alkyl portion and the heteroaryl portion are each independently optionally substituted.

[0053] As used herein, the terms "heterocyclic ring", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and are stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moieties, either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably 1 to 4, heteroatoms as defined above. When used with respect to the ring atoms of a heterocyclic ring, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, this nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), + NR (as in N-substituted pyrrolidinyl).

[0054] A heterocyclic ring can be attached to its parent group at any heteroatom or carbon atom that provides a stable structure, and any of these ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclic ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein, and also include groups in which a heterocyclic ring is fused to one or more aryl rings, heteroaryl rings, or cycloaliphatic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl). In some embodiments, the heterocyclic ring can be a 5- to 12-membered bicyclic, bridged bicyclic, or spirocyclic ring. The heterocyclic ring can contain one or more oxo (=O) or thioxo (=S) substituents. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl portion and the heterocyclyl portion are independently optionally substituted.

[0055] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double bond or triple bond. The term "partially unsaturated" is intended to include rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0056] As described herein, the compounds of the present invention may contain a "optionally substituted" moiety. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have suitable substituents at each substitutable portion of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituents may be the same or different at each position. Combinations of substituents contemplated by the present invention are preferably combinations that result in the formation of stable compounds or compounds that are chemically possible. The term "stable", as used herein, refers to compounds that do not substantially change when subjected to the conditions for their generation, detection, and in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0057] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are, independently, halogen; -(CH2) 0~4 R ○ ; -(CH2) 0~4 OR ○ ; -O(CH2) 0~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ ; -(CH2) 0~4 CH(OR ○ )2; -(CH2) 0~4 SR ○ ; -(CH2) 0~4 Ph (which may be substituted with R ○ ); -(CH2) 0~4 O(CH2) 0~1 Ph (which may be substituted with R ○ ); -CH=CHPh (which may be substituted with R ○ ); -(CH2) 0~4 O(CH2) 0~1 -pyridyl (which may be substituted with R ○which may be replaced by); -NO2; -CN; -N3; -(CH2) 0~4 N(R ○ )2; -(CH2) 0~4 N(R ○ )C(O)R ○ ; -N(R ○ )C(S)R ○ ; -(CH2) 0~4 N(R ○ )C(O)NR ○ 2; -N(R ○ )C(S)NR ○ 2; -(CH2) 0~4 N(R ○ )C(O)OR ○ ; -N(R ○ )N(R ○ )C(O)R ○ ; -N(R ○ )N(R ○ )C(O)NR ○ 2; -N(R ○ )N(R ○ )C(O)OR ○ ; -(CH2) 0~4 C(O)R ○ ; -C(S)R ○ ; -(CH2) 0~4 C(O)OR ○ ; -(CH2) 0~4 C(O)SR ○ ; -(CH2) 0~4 C(O)OSiR ○ 3; -(CH2) 0~4 OC(O)R ○ ; -OC(O)(CH2) 0~4 SR ○ ; -SC(S)SR ○ ; -(CH2) 0~4 SC(O)R ○ ; -(CH2) 0~4 C(O)NR ○ 2; -C(S)NR ○ 2; -C(S)SR ○ ; -(CH2) 0~4 OC(O)NR ○ 2; -C(O)N(OR ○ )R ○ ; -C(O)C(O)R ○ ; -C(O)CH2C(O)R ○;-C(NOR ○ )R ○ ;-(CH2) 0~4 SSR ○ ;-(CH2) 0~4 S(O)2R ○ ;-(CH2) 0~4 S(O)2OR ○ ;-(CH2) 0~4 OS(O)2R ○ ;-S(O)2NR ○ 2;-(CH2) 0~4 S(O)R ○ ;-N(R ○ )S(O)2NR ○ 2;-N(R ○ )S(O)2R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2;-P(O)2R ○ ;-P(O)R ○ 2;-OP(O)R ○ 2;-OP(O)(OR ○ )2;-SiR ○ 3;-(C 1~4 of a linear or branched alkylene)O-N(R ○ )2; or -(C 1~4 of a linear or branched alkylene)C(O)O-N(R ○ )2, wherein each R ○ may be substituted as defined below and independently is hydrogen, C 1~6 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2-(5- to 6-membered heteroaryl ring), or independently a 5- to 6-membered saturated, partially unsaturated, or aryl ring having from 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, or regardless of the above definition, two independent occurrences of R ○ together with the atoms (singly or plurally) between them independently form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having from 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0058] R ○ (R ○ (formed by two independent occurrences of R coming together with an atom between them) Suitable monovalent substituents on the ring are independently halogen, -(CH2) 0~2 R ● , -(haloR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● ),2; -O(haloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● , -(C 1~4 (linear or branched alkylene of C)C(O)OR ● , or -SSR ● , where each R ● is unsubstituted or, if preceded by "halo", substituted by only one or more halogens and is independently selected from C 1~4 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atoms of R ○ include =O and =S.

[0059] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O-, or -S(C(R * 2)) 2~3 S-. Here R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 and an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having an aliphatic or 0-4 heteroatom independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2~3 O-, where R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 It is selected from an aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0060] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1It is a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from N, O, or S.

[0061] Suitable substituents on the nitrogen of the "optionally substituted" group include -R † , -NR † 2, -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † ; where each R † is independently hydrogen, C 1~6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from N, O, or S, or regardless of the above definition, two independent occurrences of R † together with the atom(s) between them form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from N, O, or S.

[0062] Suitable substituents on the aliphatic group of R † are independently halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ●is unsubstituted or, when "halo" precedes, is substituted with only one or more halogens and, independently, C 1~4 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0063] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids, inorganic bases, organic acids, and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or formed by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, 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, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate, etc.

[0064] Suitable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4 alkyl)4 salts. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, among others. Further pharmaceutically acceptable salts, where appropriate, are formed using counterions such as halide ions, hydroxide ions, carbonate ions, sulfate ions, phosphate ions, nitrate ions, lower alkylsulfonate ions, and arylsulfonate ions, and include non-toxic ammonium, quaternary ammonium, and amine cations. In some embodiments, the compounds provided are purified in salt form, for example, using an acidic or basic mobile phase during chromatography, for ease and / or simplicity of purification. Salt forms of the compounds provided that are formed during chromatographic purification are contemplated herein (e.g., diammonium salts) and will be readily apparent to those skilled in the art.

[0065] Unless otherwise indicated, the structures illustrated herein also mean to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of that structure, e.g., the R and S configurations for each chiral center, the Z and E double bond isomers, and the Z and E conformational isomers. Accordingly, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Further, unless otherwise indicated, the structures illustrated herein also mean to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures of the invention where hydrogen is replaced by deuterium or tritium, or carbon is 13 C or 14Compounds having the present invention replaced by carbon enriched with C are within the scope of the present invention. Such compounds are useful, for example, as analytical tools according to the present invention, as probes in biological assays, or as therapeutic agents.

[0066] As used herein, the term "compounds provided" refers to any genus, subgenus, and / or species described herein.

[0067] The term "prodrug" refers to a compound that is more active in vivo. This compound is described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology As described in (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003), it may also exist as a prodrug. A prodrug of a compound described herein is a structurally modified form of this compound that readily undergoes chemical change under physiological conditions to provide this compound. Further, a prodrug can be converted to this compound by chemical or biochemical means in an ex vivo environment. For example, a prodrug can be slowly converted to the compound when placed in a transdermal patch reservoir together with a suitable enzyme or chemical reagent. Prodrugs are often useful because in some situations they can be more easily administered than the compound, i.e., the parent drug. A prodrug can be, for example, bioavailable by oral administration while the parent drug is not. A prodrug can also have improved solubility in a pharmaceutical composition compared to the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on cleavage by hydrolysis or oxidative activation of the prodrug. Examples of prodrugs include, but are not limited to, compounds that are administered as esters ("prodrugs") but are then hydrolyzed by metabolism to the carboxylic acid, which is the active entity. Further examples include peptidyl derivatives of the compounds. The term "therapeutically acceptable prodrug" refers to a prodrug or zwitterion that is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0068] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits STAT proteins with a measurable affinity. In certain embodiments, the inhibitor has an IC 50 and / or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0069] As used herein, the term "degrader" is defined as a heterobifunctional compound that binds and / or inhibits both the STAT protein and the E3 ligase with measurable affinity, resulting in ubiquitination and subsequent degradation of the STAT protein. In certain embodiments, the degrader has a DC of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, about 10 nM, or less than about 1 nM. 50 As used herein, the term "monovalent" refers to a degrader compound that does not have an attached E3 ligase binding moiety.

[0070] The compounds of the invention can be tethered to a detectable moiety. Such compounds are understood to be useful as imaging agents. One of ordinary skill in the art will recognize that the detectable moiety may be attached to the provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently attached to the detectable moiety. Such moieties are well known to those of ordinary skill in the art and include, for example, groups containing a carbonate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety. It is understood that such moieties may be attached directly to the provided compound or via a tethering group such as a divalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached by click chemistry. In some embodiments, such moieties can be attached by 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.

[0071] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and relates to any moiety that can be detected, such as primary and secondary labels. Radioisotopes (e.g., tritium, 32 P, 33 P,35 S, or 14 C), primary labels such as mass tags and fluorescent labels are signal generating reporters that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0072] As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a secondary intermediate for the generation of a detectable signal. For biotin, the secondary intermediate can include a streptavidin-enzyme conjugate. For antigen labels, the secondary intermediate can include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radiative fluorescence resonance energy transfer (FRET), resulting in a signal in which the second group is detected.

[0073] As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to, Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), cascade blue, cascade yellow, coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl, dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, eosin, erythrosin, fluorescein, FAM, hydroxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, lysamine rhodamine B, marina blue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0074] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection techniques. Examples of mass tags include electrospray tags such as N-[3-[4’-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic acid, 4’-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of these mass tags are described in U.S. Patent Nos. 4,650,750, 4,709,016, 5,360,819, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, within a suitable mass range (100 to 2000 daltons) may be used as mass tags.

[0075] As used herein, the terms "measurable affinity" and "measurably inhibits" mean a measurable change in STAT protein activity between a sample containing a compound or composition of the invention and a STAT protein and an equivalent sample containing a STAT protein in the absence of the compound or composition.

[0076] 3. Description of Exemplary Embodiments: As described above, in certain embodiments, the invention provides a compound of formula I:

Chemical formula

[0077] In some embodiments, the present invention provides a compound of formula I:

Chemical formula

[0078] As described above, in certain embodiments, the present invention provides a compound of formula II:

Chemical formula

[0079] In some embodiments, the present invention provides a compound of formula II:

Chemical formula

[0080] In some embodiments, the LBM is an E3 ligase ligand. Such E3 ligase ligands are well known to those skilled in the art and are described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed. 2016, 55, 1966, T. Uehara et al. Nature Chemical Biology 2017, 13, 675, WO 2017 / 176708, US 2017 / 0281784, WO 2017 / 161119, WO 2017 / 176957, WO 2017 / 176958, WO 2015 / 160845, US 2015 / 0291562, WO 2016 / 197032, WO 2016 / 105518, US 2018 / 0009779, WO 2017 / 007612, 2018 / 0134684, WO 2013 / 106643, US 2014 / 0356322, WO 2002 / 020740, US 2002 / 0068063, WO 2012 / 078559, US 2014 / 0302523, WO 2012 / 003281, US 2013 / 0190340, US 2016 / 0022642, WO 2014 / 063061, US 2015 / 0274738, WO 2016 / 118666, US 2016 / 0214972, WO 2016 / 149668, US 2016 / 0272639, WO 2016 / 169989, US 2018 / 0118733, WO 2016 / 197114, US 2018 / 0147202, WO 2017 / 011371, US 2017 / 0008904, WO 2017 / 011590, US 2017 / 0037004, WO 2017 / 079267, US 2017 / 0121321, WO 2017 / 117473, WO 2017 / 117474, WO 2013 / 106646, WO 2014 / 108452, WO 2017 / 197036, WO 2017 / 197046, WO 2017 / 197051, WO 2017 / 197055, and WO 2017 / 197056, the entirety of each of which is incorporated herein by reference.

[0081] As defined herein and as described below, the formula uses square brackets, for example, [Chemical formula] When illustrated as such, L is bonded to a modifiable carbon, oxygen, or nitrogen atom within DIM or LBM and includes substitution or replacement of the defined groups in DIM or LBM.

[0082] In certain embodiments, the present invention provides that LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby each of the formulas 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: [Chemical formula] a compound of or a pharmaceutically acceptable salt thereof, or each of the formulas 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: [Chemical formula] a compound of, or each of the formulas 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: [Chemical formula] a compound of formula I forming a pharmaceutically acceptable salt thereof, wherein L and STAT are as defined above and as described in the embodiments herein, and the variables [Chemical formula] , each of X, X1, X2, Y, R1, R3, R3', R4, R5, t, m, and n is as defined and described in WO 2017 / 007612 and US 2018 / 0134684, the entirety of each of which is incorporated herein by reference.

[0083] In certain embodiments, the invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby the compounds of formula I-b-1, I-b-2, I-b-3, I-b-4, I-b-5, or I-b-6, respectively:

Chemical formula

Chemical formula

[0084] In some embodiments, the LBM is

Chemical formula

Chemical formula

Chemical formula

[0085] In some embodiments, the LBM is

Chemical formula

Chemical formula

Chemical formula

[0086] In some embodiments, LBM is

Chemical formula

Chemical formula

Chemical formula

[0087] In certain embodiments, 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:

Chemical formula

Chemical formula

Chem.

Chem.

[0088] -(R 2 ) m When the attachment point of -(R 2 ) m It is intended, and one of ordinary skill in the art will understand, that the point of attachment of -R 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). 2 But R 4 or R 5 If bonded to a nitrogen atom bonded to R 4 or R 5 does not exist, and -R 2 But R 4 group or R 5 Occupies the -R group position. 2 But R 3 If attached to a carbon atom that is bonded to R 3 does not exist, and -R 2 But R 3 Occupies the base position.

[0089] In some embodiments, the compound of formula Ic above has formula I-c' or formula I-c'': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I-c′ and formula I-c″: STAT, ring A, L, L 1 , R 1 , R 2 , X 1 , X 2 , X 3 , and m are each as defined above.

[0090] In certain embodiments, the invention provides a compound of formula I, wherein LBM is the E3 ubiquitin ligase (cereblon) binding moiety, thereby forming a compound of formula I-d:

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0091] -(R 2 ) m If the point of attachment of -(R 2 ) m is shown on ring B, it is intended that the point of attachment of -(R 2 ) m may be on ring A and also may be on any available carbon or nitrogen atom on ring A (including the ring to which ring B is fused), and this is understood by those skilled in the art. -R 2 If -R 4 is attached to the nitrogen atom to which R 5 or R 4 is attached, R 4 or R 5 is absent, and -R 2 occupies the position of the R 4 group or the R 5 group. -R 2 If -R 3 is attached to the carbon atom to which R 3 is attached, R 3 is absent, and -R 2 occupies the position of the R 3 group.

[0092] In some embodiments, the compound of formula I-d is provided as a compound of formula I-d’ or formula I-d’’:

Chemical formula

[0093] In certain embodiments, the present invention provides a compound of Formula I, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby forming a compound of Formula I-e: [Chemical Formula] wherein in Formula I-e, L and STAT are as defined above and as described in the embodiments herein, and: X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or a divalent moiety selected from [Chemical Formula] ; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C 1~4 aliphatic; each R 2 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)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; Ring A is a bicyclic or tricyclic ring selected from [Chemical Formula] [Chemical Formula] [Chemical Formula] wherein Ring B is a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic ring, a 5- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 is selected from hydrogen, halogen, -OR, -N(R)2, or -SR; Each R 4 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)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 a group selected from the group consisting of C 1~6 aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is optionally substituted; m is 0, 1, 2, 3 or 4; and each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is selected from the group consisting of C 1~6 aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: The two R groups on the same nitrogen, optionally together with the atoms between them, form, in addition to this nitrogen, a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0094] -(R 2 ) m If the point of attachment of -(R 2 ) m is shown on ring B, it is intended that the point of attachment of -(R 2 ) 4 may be on ring A and also may be at any available carbon or nitrogen atom on ring A (including the ring to which ring B is fused), and this will be understood by those skilled in the art. -R 2 When -R 4 is attached to the nitrogen atom to which R 5 or R 4 is attached, R 5 or R 2 is absent, and -R 4 occupies the position of the R 5 group or the R 2 When -R 3 is attached to the carbon atom to which R 3 is attached, R 2 is absent, and -R 3 occupies the position of the R

[0095] In some embodiments, the compound of formula I-e is provided as a compound of formula I-e' or formula I-e'':

Chemical formula

[0096] In certain embodiments, the invention provides a compound of Formula I, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, such that Formula I-f:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0097]

Chemical formula

Chemical formula

[0098] In certain embodiments, 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:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0099] In some embodiments, the compound of formula I-g is a compound of formula I-g' or formula I-g'':

Chemical formula

Chemical formula

[0100] In certain embodiments, the present invention is such that LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby formula I-h:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0101] In some embodiments, the compound of formula I-h is of formula I-h' or formula I-h'':

Chemical formula

Chemical formula

[0102] In certain embodiments, the 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:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0103] In some embodiments, the compound of formula I-i is of formula I-i' or formula I-i'':

Chemical formula

[0104] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a binding moiety for the E3 ubiquitin ligase (cereblon), thereby forming a compound of formula I-j:

Chemical formula

Chemical formula

[0105]

Chemical formula

Chemical formula

[0106] -(R 2 ) m when the bonding point of -(R 2 ) m is shown on ring E, ring F, or ring G, it is intended that the bonding point of -(R

[0107]

Chemical formula

Chemical formula

[0108] In some embodiments, the compound of formula I-j is a compound of formula I-j' or formula I-j'':

Chemical formula

[0109] In certain embodiments, the present invention provides a compound of formula I in which LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby forming a compound of formula I-k:

Chemical formula

Chemical formula

[0110]

Chem.

Chem.

[0111] -(R 2 ) m When the bonding point of is shown on ring E, ring F, or ring G, -(R 2 ) m it is intended that the bonding point of can be on any available carbon or nitrogen atom on ring E, ring F, or ring G (including the carbon atoms in which ring E or ring G is fused to ring F), and those skilled in the art will understand this.

[0112] In some embodiments, the compound of formula I-k is provided as a compound of formula I-k' or formula I-k'':

Chem.

[0113] In certain embodiments, the present invention provides that LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby formula I-l:

Chem.

Chemical formula

[0114]

Chem.

Chem.

Chem.

Chem.

[0115] -(R 2 ) m When the bonding point of -(R 2 ) m is shown on rings E and H, it is intended that the bonding point of -(R

[0116]

Chem.

Chem.

Chem.

Chem.

[0117] In some embodiments, the compound of Formula I-l is provided as a compound of Formula I-l' or Formula I-l'':

Chemical formula

[0118] In certain embodiments, 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:

Chemical formula

Chemical formula

[0119]

Chemical formula

Chemical formula

[0120] -(R 2 ) m may be on any available carbon or nitrogen atom (including the carbon atoms where ring E and ring H are fused) on ring E or ring H, and those skilled in the art will understand this. 2 ) m When the bonding point of -(R

[0121]

Chemical formula

Chemical formula

[0122] In some embodiments, the compound of formula I-m is a compound of formula I-m' or formula I-m'':

Chemical formula

[0123] In some embodiments, the compound of formula I-m is a compound of formula I-m-1:

Chemical formula

[0124] In certain embodiments, 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:

Chemical formula

Chemical formula

[0125]

Chemical Structure

Chemical Structure

[0126] -(R 2 ) m If the point of attachment of -(R 2 ) m is shown on rings I, J, and K, the point of attachment of -(R

[0127]

Chemical formula

Chemical formula

[0128] In some embodiments, the compound of formula I-n is provided as a compound of formula I-n' or formula I-n'':

Chemical formula

[0129] In certain embodiments, the present invention provides a compound of formula I-o: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein in formula I-o: X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or [Chemical formula] a divalent moiety selected from; R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted C 1~4 aliphatic; each R is independently hydrogen or an optionally substituted group, the optionally substituted group being selected from C 1~6 aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, together with the atoms between them, form, in addition to this nitrogen, a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms 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)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R; Each R 6 is independently a group selected from the group consisting of a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is optionally substituted; 1~6 and is optionally substituted with a group selected from the group consisting of a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each of rings I and J is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic ring, a 5- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring K is a fused ring selected from a 6- to 12-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, where ring H is optionally further substituted with 1 to 2 oxo groups; and m is 0, 1, 2, 3, or 4.

[0130]

Chemical formula

Chemical formula

[0131] -(R 2 ) mWhen the junction points are shown on Ring I, Ring J, and Ring K, -(R 2 ) m It is intended that the junction points can be on any available carbon or nitrogen atom on Ring I, Ring J, or Ring K (including the carbon atoms where Ring I, Ring J, and Ring K are fused), and those skilled in the art will understand this.

[0132]

Chemical formula

Chemical formula

[0133] In some embodiments, the compound of formula I-o is provided as a compound of formula I-o' or formula I-o'':

Chemical formula

[0134] In some embodiments, the compound of formula I-o is provided as a compound of formula I-o-1:

Chemical formula

[0135] In certain embodiments, the present invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby Formula I-o-2 or I-o-3:

Chemical formula

[0136]

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0137] -(R 2 ) m When the bond of -(R 2 ) m is shown on ring E, ring F, or ring G, it is intended that the bond of -(R

[0138]

Chemical formula

Chemical formula

Chemical formula

[0139] is defined above and as described herein, X 1is a divalent moiety selected from a covalent bond, -CH2-, -C(R)2-, -C(O)-, -C(S)-, -CH(R)-, -CH(CF3)-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, -S(O)-, -S(O)2-, or

Chem.

[0140] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 is -CH2-. 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)(NR2)-. In some embodiments, X 1 is -S(O)-. In some embodiments, X 1 is -S(O)2-. In some embodiments, X 1 is

Chem.

[0141] In some embodiments, X 1 is selected from those illustrated in Table 1 below.

[0142] As defined above and as described herein, X 2 is a carbon atom or a silicon atom.

[0143] In some embodiments, X 2 is a carbon atom. In some embodiments, X 2 is a silicon atom.

[0144] In some embodiments, X 2 is selected from those illustrated in Table 1 below.

[0145] As defined above and as described herein, X 3 is a divalent moiety selected from -CH2-, -C(R)2-, -N(R)-, -CF2-, -CHF-, -S-, -CH(R)-, -Si(R2)-, or -O-.

[0146] In some embodiments, X 3 is -CH2-. 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(R2)-. In some embodiments, X 3 is -O-.

[0147] In some embodiments, X 3 is selected from those illustrated in Table 1 below.

[0148] As defined above and as described herein, R 1is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, optionally substituted C 1~4 is aliphatic, or R 1 and X 1 or X 4 together with the atoms therebetween form a 5- to 7-membered saturated, partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0149] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is deuterium. In some embodiments, R 1 is halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -OR. In some embodiments, R 1 is -SR. In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is -S(O)2R. In some embodiments, R 1 is -NR2. 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 -P(O)(NR2)2. In some embodiments, R 1 is -Si(OH)2R. In some embodiments, R 1 is -Si(OH)(R)2. In some embodiments, R 1 is -Si(R)3. In some embodiments, R 1 is optionally substituted C 1~4 is aliphatic. In some embodiments, R1 and X 1 or X 4 together with the atoms therebetween form a 5- to 7-membered saturated, partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0150] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0151] As defined above and as described herein, each R is independently hydrogen, deuterium, or an optionally substituted group, and this optionally substituted group is selected from a 4- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 3 heteroatoms independently selected from C 1~6 aliphatic, phenyl, boron, nitrogen, oxygen, silicon, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or two R groups on the same nitrogen together with the atoms therebetween form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur in addition to this nitrogen.

[0152] In some embodiments, R is hydrogen. In some embodiments, R is deuterium. In some embodiments, R is an optionally substituted C 1~6It is aliphatic. In some embodiments, R is phenyl optionally substituted. In some embodiments, R is a 4- to 7-membered saturated or partially unsaturated heterocyclic optionally substituted having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R is a 5- to 6-membered heteroaryl ring optionally substituted having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, two R groups on the same nitrogen, together with the atoms between them, form, in addition to this nitrogen, a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0153] In some embodiments, R is selected from those illustrated in Table 1 below.

[0154] As defined above and as described herein, R 2 and R 3a each independently is hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -Si(OH)2R, -Si(OH)R2, -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)2N(R)C(O)R, -C(R)2N(R)C(O)NR2, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2-, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2, or -N(R)S(O)2R.

[0155] In some embodiments, R 2 and R 3ais independently hydrogen. In some embodiments, R 2 and R 3a are independently deuterium. In some embodiments, R 2 and R 3a are independently -R 6 . In some embodiments, R 2 and R 3a are independently halogen. In some embodiments, R 2 and R 3a are independently -CN. In some embodiments, R 2 and R 3a are independently -NO2. In some embodiments, R 2 and R 3a are independently -OR. In some embodiments, R 2 and R 3a are independently -Si(OH)2R. In some embodiments, R 2 and R 3a are independently -Si(OH)R2. In some embodiments, R 2 and R 3a are independently -SR. In some embodiments, R 2 and R 3a are independently -NR2. In some embodiments, R 2 and R 3a are independently -SiR3. In some embodiments, R 2 and R 3a are independently -S(O)2R. In some embodiments, R 2 and R 3a are independently -S(O)2NR2. In some embodiments, R 2 and R 3a are independently -S(O)R. In some embodiments, R 2 and R 3a are independently -C(O)R. In some embodiments, R 2 and R 3ais independently -C(O)OR. In some embodiments, R 2 and R 3a are independently -C(O)NR2. In some embodiments, R 2 and R 3a are independently -C(O)N(R)OR. In some embodiments, R 2 and R 3a are independently -C(R)2N(R)C(O)R. In some embodiments, R 2 and R 3a are independently -C(R)2N(R)C(O)NR2. In some embodiments, R 2 and R 3a are independently -OC(O)R. In some embodiments, R 2 and R 3a are independently -OC(O)NR2. In some embodiments, R 2 and R 3a are independently -OP(O)R2. In some embodiments, R 2 and R 3a are independently -OP(O)(OR)2. In some embodiments, R 2 and R 3a are independently -OP(O)(OR)NR2. In some embodiments, R 2 and R 3a are independently -OP(O)(NR2)2-. In some embodiments, R 2 and R 3a are independently -N(R)C(O)OR. In some embodiments, R 2 and R 3a are independently -N(R)C(O)R. In some embodiments, R 2 and R 3a are independently -N(R)C(O)NR2. In some embodiments, R 2 and R 3a are independently -NP(O)R2. In some embodiments, R 2 and R 3ais 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)2R.

[0156] In some embodiments, R 2 and R 3a is independently -OH. In some embodiments, R 2 and R 3a is independently -NH2. In some embodiments, R 2 and R 3a is independently -CH2NH2. In some embodiments, R 2 and R 3a is independently -CH2NHCOMe. In some embodiments, R 2 and R 3a is independently -CH2NHCONHMe. 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 -SiMe2OH. In some embodiments, R 2 and R 3a is independently -SiMe(OH)2. In some embodiments, R 2 and R 3a is independently

Chemical Formula

[0157] In some embodiments, R 2 or R 3a is selected from those illustrated in Table 1 below.

[0158] As defined above and as described herein, R 3is hydrogen, deuterium, halogen, -CN, -NO2, -OR, -NR2, -SR, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NR(OR), -OC(O)R, -OC(O)NR2, -OP(O)(OR)2, -OP(O)(NR2)2, -OP(O)(OR)NR2, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)NR2, -N(R)S(O)2R, -N(R)S(O)2NR2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -P(O)(OR)2, -P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, or -Si(R)3.

[0159] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is -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)2R. 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. In some embodiments, R 3 is -C(O)NR(OR). In some embodiments, R 3 is -OC(O)R. In some embodiments, R3 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 -N(R)C(O)NR2. In some embodiments, R 3 is -N(R)S(O)2R. In some embodiments, 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)(NR2)OR. In some embodiments, R 3 is -P(O)(NR2)2. In some embodiments, R 3 is -Si(OH)2R. In some embodiments, R 3 is -Si(OH)(R)2. In some embodiments, R 3 is -Si(R)3.

[0160] In some embodiments, R 3 is methyl. In some embodiments, R 3 is -OCH3. In some embodiments, R 3 is chloro.

[0161] In some embodiments, R 3 is selected from those illustrated in Table 1 below.

[0162] is defined above and, as described herein, each R 4 is independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -P(O)(OR)2, -P(O)(NR2)OR, or -P(O)(NR2)2.

[0163] In some embodiments, 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)NR2. In some embodiments, R 4 is -C(O)N(R)OR. In some embodiments, R 4 is -OC(O)R. In some embodiments, R 4is -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)NR2. In some embodiments, R 4 is -N(R)S(O)2R. In some embodiments, R 4 is -P(O)(OR)2. In some embodiments, R 4 is -P(O)(NR2)OR. In some embodiments, R 4 is -P(O)(NR2)2.

[0164] In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is cyclopropyl.

[0165] In some embodiments, R 4 is selected from those illustrated in Table 1 below.

[0166] As defined above and as described herein, R 5 is hydrogen, deuterium, optionally substituted C 1~4 aliphatic, or -CN.

[0167] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5 is optionally substituted C 1~4 aliphatic. In some embodiments, R 5 is -CN.

[0168] In some embodiments, R 5 is selected from those illustrated in Table 1 below.

[0169] As defined above and as described herein, each R 6 is independently a group selected from the group consisting of a C 1~6 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from aliphatic, phenyl, boron, nitrogen, oxygen, silicon, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, which is a group optionally substituted.

[0170] In some embodiments, R 6 is optionally substituted C 1~6 aliphatic. In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R 6 is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[0171] In some embodiments, R 6 is selected from those illustrated in Table 1 below.

[0172] As defined above and as described herein, ring A is

Chemical formula

[0173] In some embodiments, ring A is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0174] In some embodiments, ring A is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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Chemical formula

Chemical formula

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Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0175] In some embodiments, ring A is selected from those illustrated in Table 1 below.

[0176] As defined above and as described herein, ring B is a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic ring, a 5- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a fused ring selected from a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0177] In some embodiments, ring B is a fused 6-membered aryl. In some embodiments, ring B is a fused 6-membered heteroaryl containing 1 to 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 carbocyclic ring. In some embodiments, ring B is a fused 5- to 7-membered saturated or partially saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring B is a fused 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[0178] In some embodiments, ring B is [Chemical Formula] It is. In some embodiments, ring B is [Chemical Formula] is. In some embodiments, ring B is

Chemical formula

Chemical formula

Chemical formula

[0179] In some embodiments, each ring B is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0180] In some embodiments, ring B is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0181] In some embodiments, ring B is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0182] In some embodiments, ring B is [Chemical formula] is as follows. In some embodiments, ring B is [Chemical formula] is as follows. In some embodiments, ring B is [Chemical formula] is as follows. In some embodiments, ring B is [Chemical formula] is as follows. In some embodiments, ring B is [Chemical formula] is as follows.

[0183] In some embodiments, ring B is [Chemical formula] selected from

[0184] In some embodiments, ring B is selected from those illustrated in Table 1 below.

[0185] defined above and, as described herein, ring C is [Chemical formula] [Chemical formula] a monocyclic or bicyclic ring selected from

[0186] In some embodiments, ring C is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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Chemical formula

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Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

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Chem.

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Chem.

Chem.

[0187] In some embodiments, ring C is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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Chemical formula

Chemical formula

Chemical formula

[0188] In some embodiments, ring C is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0189] In some embodiments, ring C is

Chemical formula

[0190] In some embodiments, ring C is [Chemical formula] selected from

[0191] In some embodiments, ring C is selected from those illustrated in Table 1 below.

[0192] As defined above and as described herein, ring D is a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic ring, a 5- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0193] In some embodiments, ring D is a 6-membered aryl. In some embodiments, ring D is a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring D is a 5- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, ring D is a 5- to 7-membered saturated or partially saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring D is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[0194] In some embodiments, ring D is selected from those illustrated in Table 1 below.

[0195] As defined above and as described herein, each of ring E, ring F, and ring G is independently a fused ring selected from a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic ring, a 5- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each of ring E, ring F, and ring G is independently optionally further substituted with 1 to 2 oxo groups.

[0196] In some embodiments, each of ring E, ring F, and ring G is independently a 6-membered aryl. In some embodiments, each of ring E, ring F, and ring G is independently a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each of ring E, ring F, and ring G is independently a 5- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, each of ring E, ring F, and ring G is independently a 5- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, each of ring E, ring F, and ring G is independently a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each of ring E, ring F, and ring G is independently optionally further substituted with 1 to 2 oxo groups.

[0197] In some embodiments, ring F is

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0198] In some embodiments, ring F is

Chemical formula

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[0199] In some embodiments, each of ring E and ring G is independently [Chemical formula] is. In some embodiments, each of ring E and ring G is independently [Chemical formula] is. In some embodiments, each of ring E and ring G is independently [Chemical formula] is. In some embodiments, each of ring E and ring G is independently [Chemical formula] is. In some embodiments, ring E and ring G are independently [Chemical formula] is.

[0200] In some embodiments, ring E and ring G are independently [Chemical formula] is. In some embodiments, ring E and ring G are independently [Chemical formula] is. In some embodiments, ring E and ring G are independently [Chemical formula] It is. In some embodiments, ring E and ring G are independently,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0201] In some embodiments, ring E and ring G are independently,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0202] In some embodiments, ring E, ring F, and ring G are

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

[0203] In some embodiments, ring E, ring F, and ring G are

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0204] In some embodiments, ring E, ring F, and ring G are selected from those illustrated in Table 1 below.

[0205] As defined above and as described herein, ring H is a ring selected from 7- to 9-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, where ring E is optionally further substituted with 1 to 2 oxo groups.

[0206] In some embodiments, ring H is a ring selected from 7- to 9-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, where ring H is optionally further substituted with 1 to 2 oxo groups.

[0207] In some embodiments, ring H is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0208] In some embodiments, ring E and ring H are [Chemistry] is.

[0209] In some embodiments, ring E and ring H are selected from those illustrated in Table 1 below.

[0210] As defined above and as described herein, each of ring I and ring J is independently a 6-membered aryl, a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic ring, a 5- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or a fused ring selected from a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0211] In some embodiments, each of ring I and ring J is independently a 6-membered aryl. In some embodiments, each of ring I and ring J is independently a 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, each of ring I and ring J is independently a 5- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, each of ring I and ring J is independently a 5- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, each of ring I and ring J is independently a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0212] In some embodiments, each of ring I and ring J is independently [Chemistry] is. In some embodiments, each of ring I and ring J is independently

Chem.

Chem.

Chem.

Chem.

[0213] In some embodiments, Ring I and Ring J are independently

Chem.

Chem.

Chem.

[0214] as defined above and as described herein, Ring K is a fused ring selected from 6- to 12-membered saturated or partially unsaturated carbocyclic or heterocyclic rings having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, where Ring H is optionally further substituted with 1 to 2 oxo groups.

[0215] In some embodiments, ring K is a fused ring selected from 6- to 12-membered saturated or partially unsaturated carbocyclyls. In some embodiments, ring K is a 6- to 12-membered saturated or partially unsaturated heterocyclyl ring having 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring K is optionally further substituted with 1 to 2 oxo groups.

[0216] In some embodiments, ring K is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0217] In some embodiments, ring I, ring J, and ring K are [Chemistry] is.

[0218] In some embodiments, ring I, ring J, and ring K are selected from those illustrated in Table 1 below.

[0219] as defined above and as described herein, L 1 is a covalent bond, or C 1~3is a divalent linear or branched saturated or unsaturated hydrocarbon chain, where one or two methylene units of this chain are independently replaced, as necessary, by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -S(O)2- or -(C)=CH-;

[0220] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is C 1~3 aliphatic. In some embodiments, L 1 is -CH2-. In some embodiments, L 1 is -C(D)(H)-. In some embodiments, L 1 is -C(D)2-. In some embodiments, L 1 is -CH2CH2-. In some embodiments, L 1 is -NR-. In some embodiments, L 1 is -CH2NR-. In some embodiments, L 1 is or -O-. In some embodiments, L 1 is -CH2O-. In some embodiments, L 1 is -S-. In some embodiments, L 1 is -OC(O)-. In some embodiments, L 1 is -C(O)O-. In some embodiments, L 1 is -C(O)-. In some embodiments, L 1 is -S(O)-. In some embodiments, L 1 is -S(O)2-. In some embodiments, L 1 is -NRS(O)2-. In some embodiments, L 1 is -S(O)2NR-. In some embodiments, L 1 is -NRC(O)-. In some embodiments, L 1 is -C(O)NR-.

[0221] In some embodiments, ring L 1 is selected from those illustrated in Table 1 below .

[0222] as defined above and as described herein [Chemical formula] is a single bond or a double bond.

[0223] In some embodiments [Chemical formula] is a single bond. In some embodiments [Chemical formula] is a double bond.

[0224] In some embodiments [Chemical formula] is selected from those illustrated in Table 1 below

[0225] As defined above and as described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0226] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13. In some embodiments, m is 14. In some embodiments, m is 15. In some embodiments, m is 16.

[0227] In some embodiments, m is selected from those illustrated in Table 1 below.

[0228] As defined above and as described herein, n is 0, 1, 2, 3 or 4.

[0229] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0230] In some embodiments, n is selected from those illustrated in Table 1 below.

[0231] As defined above and as described herein, p is 0 or 1.

[0232] In some embodiments, p is 0. In some embodiments, p is 1.

[0233] In some embodiments, p is selected from those illustrated in Table 1 below.

[0234] In some embodiments, the LBM is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0235] In certain embodiments, the invention provides a compound of formula I, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, such that the compound forms a compound of formula I-p-1, I-p-2, or I-p-3:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0236] In some embodiments, the invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby the compounds of formula I form, respectively, a compound of formula I-q-1, I-q-2, I-q-3, or I-q-4:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0237] In some embodiments, the invention provides that the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby the compounds of formula I form, respectively, a compound of formula I-r-1 or I-r-3:

Chemical formula

Chemical formula

Chemical formula

[0238] In certain embodiments, the present invention provides a compound of formula I which forms 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:

Chemical formula

Chemical formula

Chem.

[0239] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby a compound of formula I-t:

Chem.

[0240] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby a compound of formula I-t-1:

Chem.

[0241] In some embodiments, the LBM is the IAP E³ ubiquitin ligase binding moiety described in Varfolomeev, E. et al., IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB activation, and TNFα-Dependent Apoptosis, Cell, 2007, 131(4): 669-81, for example,

Chem.

Chem.

Chem.

[0242] In certain embodiments, the invention provides a compound of formula I, wherein the LBM is the 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:

Chem.

Chem.

[0243] In certain embodiments, the invention provides a compound of Formula I, wherein the LBM is the VHL E3 ubiquitin ligase binding moiety, and thereby forms a compound of Formula I-v-1, I-v-2, I-v-3, I-v-4, I-v-5 or I-v-6:

Chemical formula

Chemical formula

[0244] As used herein, the illustration of square brackets around any LBM

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

[0245] In certain embodiments, the present invention provides that the LBM is the VHL E3 ubiquitin ligase binding moiety, whereby, respectively, Formula I-w-1, I-w-2, or I-w-3:

Chem.

[0246] In certain embodiments, the present invention provides that the LBM is the CRBN or VHL E3 ubiquitin ligase binding moiety, whereby, respectively, Formula I-x-1, I-x-2, I-x-3, I-x-4, I-x-5, I-x-6, or I-x-7:

Chem.

Chem.

[0247] In certain embodiments, the present invention is such that LBM is a CRBN E3 ubiquitin ligase binding moiety, whereby, respectively, formulae 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:

Chemical formula

Chemical formula

[0248] In certain embodiments, the invention provides that the LBM is the MDM2 (i.e., human double minute 2 or HDM2) E3 ligase binding moiety, whereby each of the compounds of Formulae 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:

Chemical formula

Chemical formula

Chemical formula

[0249] In certain embodiments, the present invention provides a compound of Formula I, wherein the LBM is an IAP E3 ubiquitin ligase binding moiety, whereby the compound forms a compound of Formula I-z-1, I-z-2, I-z-3, or I-z-4:

Chemical formula

[0250] In certain embodiments, the present invention provides a compound of Formula I, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, a DCAF15 E3 ubiquitin ligase binding moiety, or a VHL E3 ubiquitin ligase binding moiety; whereby the compound forms a compound of Formula I-aa-1, I-aa-2, or I-aa-3:

Chemical formula

Chemical formula

Chemical formula

[0251] In certain embodiments, the invention provides a compound of formula I-aa, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby forming a compound of formula I-aa'-1 or I-aa''-1:

Chemical formula

[0252] As defined above and as described herein, each of X 1 , X 2a , and X 3a is independently a covalent bond, -CH2-, -C(O)-, -C(S)-, or

Chemical formula

[0253] In some embodiments, X 1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or

Chemical formula

[0254] In some embodiments, X 1 is selected from those illustrated in Table 1 below.

[0255] In some embodiments, X 2a is a covalent bond, -CH2-, -C(O)-, -C(S)-, or

Chemical formula

[0256] In some embodiments, X 2a is selected from those illustrated in Table 1 below.

[0257] In some embodiments, X 3a is a covalent bond, -CH2-, -C(O)-, -C(S)-, or

Chemical formula

[0258] In some embodiments, X 3a is selected from those illustrated in Table 1 below.

[0259] As defined above and as described herein, each of X 4 and X 5 is independently a divalent moiety selected from -CH2-, -C(O)-, -C(S)-, or

Chemical formula

[0260] In some embodiments, X 4a is -CH2-, -C(O)-, -C(S)-, or

Chemical formula

[0261] In some embodiments, X 4a is selected from those illustrated in Table 1 below.

[0262] In some embodiments, X 5a is -CH2-, -C(O)-, -C(S)-, or

Chemical formula

[0263] In some embodiments, X 5a is selected from those illustrated in Table 1 below.

[0264] As defined above and as described herein, R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or optionally substituted C 1~4 is aliphatic.

[0265] In some embodiments, R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or optionally substituted C 1~4 is aliphatic.

[0266] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0267] As defined above and as described herein, R 2 R 3b and R 4a each 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)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.

[0268] In some embodiments, R 2 is hydrogen, -R 6, a halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[0269] In some embodiments, R 2 is selected from those illustrated in Table 1 below.

[0270] In some embodiments, R 3b is hydrogen, -R 6 , a halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[0271] In some embodiments, R 3b is methyl.

[0272] In some embodiments, R 3b is selected from those illustrated in Table 1 below.

[0273] In some embodiments, R 4a is hydrogen, -R 6 , a halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[0274] In some embodiments, R 4a is methyl.

[0275] In some embodiments, R 4a is selected from those illustrated in Table 1 below.

[0276] As defined above and as described herein, R 5a is hydrogen or C 1~6 is aliphatic.

[0277] In some embodiments, R 5a is t-butyl.

[0278] In some embodiments, R 5a is selected from those illustrated in Table 1 below.

[0279] As defined above and as described herein, each R 6 is independently a group selected from the group consisting of C 1~6 aliphatic, phenyl, nitrogen, oxygen, and sulfur, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is optionally substituted.

[0280] In some embodiments, R 6 is an optionally substituted C 1~6 aliphatic group. In some embodiments, R 6 is an optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 6 is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0281] In some embodiments, R 6 is selected from those illustrated in Table 1 below.

[0282] As defined above and as described herein, ring A a is a fused ring selected from 6-membered aryl containing from 0 to 2 nitrogen atoms, 5- to 7-membered partially saturated carbocyclic ring, 5- to 7-membered partially saturated heterocyclic ring having from 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-membered heteroaryl having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0283] In some embodiments, ring A a is a fused 6-membered aryl containing from 0 to 2 nitrogen atoms. In some embodiments, ring A a is a fused 5- to 7-membered partially saturated carbocyclic ring. In some embodiments, ring A a is a fused 5- to 7-membered partially saturated heterocyclic ring having from 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, ring A a is a fused 5-membered heteroaryl having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0284] In some embodiments, ring A a is fused phenyl.

[0285] In some embodiments, ring A a is selected from those illustrated in Table 1 below.

[0286] As defined above and as described herein, ring B a is selected from 6-membered aryl containing from 0 to 2 nitrogen atoms, or 8- to 10-membered bicyclic heteroaryl having from 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0287] In some embodiments, ring B a is a 6-membered aryl containing 0 to 2 nitrogen atoms. In some embodiments, ring B a is an 8- to 10-membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0288] In some embodiments, ring B a is

Chemical formula

[0289] In some embodiments, ring B a is selected from those illustrated in Table 1 below.

[0290] As defined above and as described herein, ring C a is selected from a 6-membered aryl containing 0 to 2 nitrogen atoms, or a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0291] In some embodiments, ring C a is a 6-membered aryl containing 0 to 2 nitrogen atoms. In some embodiments, ring C a is a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0292] In some embodiments, ring C a is

Chemical formula

[0293] In some embodiments, ring C a is selected from those illustrated in Table 1 below.

[0294] As defined above and as described herein, m is 0, 1, 2, 3, or 4.

[0295] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0296] In some embodiments, m is selected from those illustrated in Table 1 below.

[0297] In some embodiments, o is selected from those illustrated in Table 1 below.

[0298] As defined above and as described herein, o is 0, 1, 2, 3, or 4.

[0299] In some embodiments, 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.

[0300] In some embodiments, o is selected from those illustrated in Table 1 below.

[0301] As defined above and as described herein, q is 0, 1, 2, 3, or 4.

[0302] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0303] In some embodiments, q is selected from those illustrated in Table 1 below.

[0304] As defined above and as described herein, each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is a C 1~6 selected independently from aliphatic, phenyl, nitrogen, oxygen, and sulfur, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms selected independently from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms selected independently from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, optionally together with the atoms between them, in addition to this nitrogen, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms selected independently from nitrogen, oxygen, and sulfur.

[0305] In some embodiments, R is hydrogen. In some embodiments, R is phenyl. In some embodiments, R is a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms selected independently from nitrogen, oxygen, and sulfur. In some embodiments, R is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms selected independently from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen, optionally together with the atoms between them, in addition to this nitrogen, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms selected independently from nitrogen, oxygen, and sulfur.

[0306] In some embodiments, R is selected from those illustrated in Table 1 below.

[0307] In certain embodiments, the invention is such that the LBM is the VHL binding moiety, whereby Formula I-ab: [Chemical formula] Provided is a compound of formula I which forms a compound of formula I or a pharmaceutically acceptable salt thereof, wherein in formula I-ab, L and STAT are as defined above and as described in the embodiments herein, and the variables R9, R 10 and R 11 and R 14a and R 15 each is as described and defined in WO 2017 / 030814, WO 2016 / 118666, and US 2017 / 0327469, the entirety of each of which is incorporated herein by reference.

[0308] In certain embodiments, the invention provides a compound of formula I which forms a compound of formula I-ac-1 or I-ac-2:

Chemical formula

[0309] In certain embodiments, the invention provides a compound of formula I which forms a compound of formula I-ad:

Chemical formula

[0310] In certain embodiments, the invention provides a compound of formula I which forms a compound of formula I-ae:

Chemical formula

[0311] In certain embodiments, the invention provides a compound of formula I which forms a compound of formula I-af:

Chemical formula

[0312] In certain embodiments, the invention provides a compound of formula I which forms a compound of formula I-ag: [Chemical formula] Provided is a compound of formula I which forms a compound of or a pharmaceutically acceptable salt thereof, as described and defined in Spradin, J.N. et al., bioRxiv (doi: https: / / doi.org / 10.1101 / 436998), the entirety of each of which is incorporated herein by reference.

[0313] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an RNF4 binding moiety, whereby formula I-ah: [Chemical formula] Provided is a compound of formula I which forms a compound of or a pharmaceutically acceptable salt thereof, as described and defined in Ward, C.C., et al., bioRxiv (doi: https: / / doi.org / 10.1101 / 439125), the entirety of each of which is incorporated herein by reference.

[0314] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety, whereby formula I-aay-1 or I-aay-2: [Chemical formula] Provided is a compound of formula I which forms a compound of or a pharmaceutically acceptable salt thereof, wherein in formula I-aay-1 and I-aay-2, L and STAT are as defined above and as described in the embodiments herein, and the variable R 1 , R 2 , R 3 , X, and Y are each as defined and described in WO 2019 / 084026, the entirety of each of which is incorporated herein by reference.

[0315] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety, whereby formula I-aaz-1 or I-aaz-2: [Chemistry] [Chemistry] Compounds of formula I or pharmaceutically acceptable salts thereof, wherein in formulae I-aaz-1 and I-aaz-2, L and STAT are as defined above and as described in the embodiments herein, and the variable R 1 , R 3 , and each of Y is as defined and described in WO 2019 / 084030, the entire content of which is incorporated herein by reference.

[0316] In certain embodiments, the invention provides compounds of formula I, or pharmaceutically acceptable salts thereof, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety, whereby formulae I-aaaa-1, I-aaaa-2, I-aaaa-3, or I-aaaa-4: [Chemistry] [Chemistry] Compounds of formula I, or pharmaceutically acceptable salts thereof, wherein in formulae I-aaaa-1, I-aaaa-2, I-aaaa-3, and I-aaaa-4, L and STAT are as defined above and as described herein, and the variables R 4 , R 10 , R 11 , R 15 , R 16 , R 17 , W 1 , W 2 , and each of X is as defined in WO 2019 / 099868, which is incorporated herein by reference in its entirety, and [Chemistry] is, as defined in WO 2018 / 237026, R 17 or R16 is bonded at the binding site of R 12 , and as a result,

Chemical formula

[0317] In some embodiments, LBM is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0318] In certain embodiments, the invention provides a compound of Formula I, wherein the LBM is an E3 ubiquitin ligase (cereblon) binding moiety, thereby forming a compound of Formula I-bbbb:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0319] As defined above and as described herein, each X 1 is independently -CH2-, -O-, -NR-, -CF2-, [Chemical formula] , -C(O)-, -C(S)-, or [Chemical formula] is as follows.

[0320] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 is -CH2-. In some embodiments, X 1 is -O-. In some embodiments, X 1 is -NR-. In some embodiments, X 1 is -CF2-. In some embodiments, X 1 is [Chemical formula] is as follows. In some embodiments, X 1 is -C(O)-. In some embodiments, X 1 is -C(S)-. In some embodiments, X 1 is [Chemical formula] is as follows.

[0321] In certain embodiments, X 1 is selected from those shown in the compounds of Table 1.

[0322] As defined above and as described herein, X 2 and X 3 are independently, -CH2-, -C(O)-, -C(S)-, or [Chemical formula] is as follows.

[0323] In some embodiments, X 2and X 3 is independently -CH2-. In some embodiments, X 2 and X 3 is independently -C(O)-. In some embodiments, X 2 and X 3 is independently -C(S)-. In some embodiments, X 2 and X 3 is independently [Chemical formula] is as follows.

[0324] In certain embodiments, X 2 and X 3 is independently selected from those shown in the compounds of Table 1.

[0325] As defined above and as described herein, Z 1 and Z 2 is independently a carbon atom or a nitrogen atom.

[0326] In some embodiments, Z 1 and Z 2 is independently a carbon atom. In some embodiments, Z 1 and Z 2 is independently a carbon atom.

[0327] In certain embodiments, Z 1 and Z 2 is independently selected from those shown in the compounds of Table 1.

[0328] As defined above and as described herein, ring A x is a fused ring selected from benzo or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0329] In some embodiments, ring A xis benzo. In some embodiments, ring A x is a 5- to 6-membered heteroaryl ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0330] In some embodiments, ring A x is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0331] In certain embodiments, ring A x is selected from those shown in the compounds of Table 1.

[0332] As defined above and as described herein, L x is a covalent bond, or a divalent straight-chain or branched-chain saturated or unsaturated hydrocarbon chain of C 1~3 wherein one or two methylene units of this chain are independently replaced, as needed, by -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, or -S(O)2-.

[0333] In some embodiments, L x is a covalent bond. In some embodiments, L x is C 1~3is a divalent linear or branched saturated or unsaturated hydrocarbon chain, where one to two methylene units of this chain are independently replaced, as needed, by -O-, -S-, -C(O)-, -C(S)-, -CR2-, -CRF-, -CF2-, -NR-, or -S(O)2-.

[0334] In some embodiments, L x is -C(O)-.

[0335] In certain embodiments, L x is selected from those shown in the compounds of Table 1.

[0336] As defined above and as described herein, each R x is independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -Si(OR)R2, and -SiR3, or two Rs x are optionally taken together to form an optionally substituted 5- to 8-membered partially unsaturated or aryl fused ring having from 0 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0337] In some embodiments, R x is hydrogen. In some embodiments, R x is deuterium. In some embodiments, R x is R z . In some embodiments, R x is halogen. In some embodiments, Rx 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 -NR2. In some embodiments, R x is -S(O)2R. 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. In some embodiments, R x is -CF3. In some embodiments, R x is -CR2(OR). In some embodiments, R x is -CR2(NR2). In some embodiments, R x is -C(O)R. In some embodiments, R x is -C(O)OR. In some embodiments, R x is -C(O)NR2. 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. In some embodiments, R x is -N(R)C(O)OR. In some embodiments, R x is -N(R)C(O)R. In some embodiments, R x is -N(R)C(O)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 xis -OP(O)(OR)2. In some embodiments, R x is -OP(O)(OR)NR2. In some embodiments, R x is -OP(O)(NR2)2. In some embodiments, R x is -Si(OR)R2. In some embodiments, R x is -SiR3. In some embodiments, two Rs x optionally together form a 5- to 8-membered partially unsaturated or aryl fused ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is optionally substituted.

[0338] In some embodiments, R x is fluoro. In some embodiments, R x is bromo. In some embodiments, R x is methyl. In some embodiments, R x is -OH. In some embodiments, R x is -NH2. In some embodiments, R x is -NHCH3. In some embodiments, R x is -N(CH3)2. In some embodiments, R x is -NHCH(CH3)2. In some embodiments, R x is -NHSO2CH3. In some embodiments, R x is -CH2OH. In some embodiments, R x is -CH2NH2. In some embodiments, R x is -C(O)NH2. In some embodiments, R x is -C(O)NHCH3. In some embodiments, R x is

Chemical formula

[0339] In certain embodiments, each R x is independently selected from those shown in the compounds of Table 1.

[0340] As defined above and as described herein, each R is independently selected from hydrogen or an optionally substituted group, and the optionally substituted group is a C 1~6 4- to 7-membered saturated or partially unsaturated heterocyclic having one to two heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same carbon or nitrogen optionally together with the atoms between them form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having zero to three heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to this carbon or nitrogen.

[0341] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C 1~6 aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic having one to two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl ring having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same carbon or nitrogen optionally together with the atoms between them form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having zero to three heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to this carbon or nitrogen.

[0342] As defined above and as described herein, R y is

Chemical formula

[0343] In some embodiments, R y is

Chem.

[0344] In certain embodiments, R y is selected from those shown in the compounds of Table 1.

[0345] As defined above and as described herein, ring B x is phenyl, a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic ring, or a heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein ring B x is further optionally substituted with 1 to 2 oxo groups.

[0346] In some embodiments, ring B x is phenyl. In some embodiments, ring B x is a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic ring, or a heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B x is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B x is further optionally substituted with 1 to 2 oxo groups.

[0347] In some embodiments, ring B x is

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0348] In certain embodiments, ring B x is selected from those shown in the compounds of Table 1.

[0349] As defined above and as described herein, each R w is independently hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, and -SiR3.

[0350] In some embodiments, R w is hydrogen. In some embodiments, R wis 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 -NR2. 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. In some embodiments, R w is -CF3. In some embodiments, R w is -CR2(OR). In some embodiments, R w is -CR2(NR2). In some embodiments, R w is -C(O)R. In some embodiments, R w is -C(O)OR. In some embodiments, R w is -C(O)NR2. 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. In some embodiments, R w is -N(R)C(O)R. In some embodiments, R w is -N(R)C(O)NR2. In some embodiments, R w is -N(R)S(O)2R. In some embodiments, Rw 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)(NR2)2. In some embodiments, R w is -SiR3.

[0351] In certain embodiments, R w is selected from those shown in the compounds of Table 1.

[0352] As defined above and as described herein, each R z is independently a group selected from C 1~6 aliphatic, phenyl, nitrogen, oxygen, and sulfur, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected therefrom, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is a substituted group as needed.

[0353] In some embodiments, R z is optionally substituted C 1~6 aliphatic. In some embodiments, R z is optionally substituted phenyl. In some embodiments, R z is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R z is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0354] In some embodiments, R z is

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0355] In certain embodiments, R z is selected from those shown in the compounds of Table 1.

[0356] as defined above and as described herein,

Chem.

[0357] In some embodiments,

Chem.

[0358] In certain embodiments, [Chemical formula] is selected from those shown in the compounds of Table 1.

[0359] As defined above and as described herein, w is 0, 1, 2, 3, or 4.

[0360] In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4.

[0361] In certain embodiments, w is selected from those shown in the compounds of Table 1.

[0362] As defined above and as described herein, x is 0, 1, 2, 3, or 4.

[0363] In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, m is 2. In some embodiments, x is 3. In some embodiments, x is 4.

[0364] In certain embodiments, x is selected from those shown in the compounds of Table 1.

[0365] As defined above and as described herein, y is 0, 1, or 2.

[0366] In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.

[0367] In certain embodiments, y is selected from those shown for the compounds of Table 1.

[0368] In some embodiments, the present invention relates to ring A x is benzo, y is 1, X 1 is -CH2-, X 2 and X 3 is -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, of formula I-bbbb-1:

Chemical formula

[0369] In some embodiments, the present invention relates to ring A x is imidazolyl, y is 1, X 1 is -CH2-, X 2 and X 3 is -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, of formula I-bbbb-2:

Chemical formula

[0370] In some embodiments, the present invention relates to ring A x is imidazolyl, y is 1, X 1 is -CH2-, X 2 and X 3 is -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, Formula I-bbbb-3:

Chemical formula

[0371] In some embodiments, the present invention relates to ring A x is oxazolyl, y is 1, X 1 is -CH2-, X 2 and X 3 is -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, Formula I-bbbb-4:

Chemical formula

[0372] In some embodiments, the present invention relates to ring A x is benzo, y is 0, X 2 and X3 is -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, of formula I - bbbb - 5:

Chemical formula

[0373] In some embodiments, the present invention provides that 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, of formula I - bbbb - 6:

Chemical formula

[0374] In some embodiments, the present invention provides that 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, of formula I - bbbb - 7: [Chemistry] To provide a compound of formula I-bbbb or a pharmaceutically acceptable salt thereof, in formula I-bbbb-7, STAT, L, L x , R, R x , R y , and each of x is, both alone and in combination, as defined above and as described in the embodiments herein.

[0375] In some embodiments, the present invention provides that 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, formula I-bbbb-8: [Chemistry] To provide a compound of formula I-bbbb or a pharmaceutically acceptable salt thereof, in formula I-bbbb-8, STAT, L, L x , R x , R y , and each of x is, both alone and in combination, as defined above and as described in the embodiments herein.

[0376] In some embodiments, the present invention provides that ring A x is benzo, y is 1, X 1 is [Chemistry] and X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, formula I-bbbb-9: [Chemistry] Provided is a compound of formula I-bbbb or a pharmaceutically acceptable salt thereof, wherein in formula I-bbbb-9, STAT, L, L x , R x , R y , and each of x is, both alone and in combination, as defined above and as described in the embodiments herein.

[0377] In some embodiments, the present invention provides a compound of formula I-bbbb, wherein ring A x is pyridyl, y is 1, X 1 is -CH2-, X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, of formula I-bbbb-10:

Chemical formula

[0378] In some embodiments, the present invention provides a compound of formula I-bbbb, wherein ring A x is pyridyl, y is 1, X 1 is -CH2-, X 2 and X 3 are -C(O)-, and Z 1 and Z 2 are carbon atoms as shown, of formula I-bbbb-11:

Chemical formula

[0379] In some embodiments, the 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, of formula I-bbbb-12:

Chemical formula

[0380] In some embodiments, LBM is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0381] In some embodiments, LBM is selected from those in Table 1.

[0382] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an RPN13 binding moiety, thereby forming a compound of Formula I-cccc:

Chemical formula

[0383] In certain embodiments, 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 which is incorporated herein by reference), thereby forming a compound of Formula I-dddd-1 or I-dddd-2:

Chemical formula

[0384] In certain embodiments, the invention provides compounds of formula I, wherein LBM is a CRBN binding moiety, whereby formula I-eeee:

Chemical formula

[0385] In certain embodiments, the invention provides compounds of formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety, whereby formulae I-ffff-1, I-ffff-2, I-ffff-3 or I-ffff-4:

Chemical formula

[0386] In certain embodiments, the invention provides formula II:

Chemical formula

[0387] In some embodiments, DIM is LBM as described above and herein. In some embodiments, DIM is a lysine mimetic. In some embodiments, 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 by the action of a lysine mimetic. In some embodiments, when a compound of Formula II binds to STAT1, the lysine-mimicking moiety causes ubiquitination, thereby marking STAT1 for degradation through the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula II binds to STAT2, the lysine-mimicking moiety causes ubiquitination, thereby marking STAT2 for degradation through the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula II binds to STAT3, the lysine-mimicking moiety causes ubiquitination, thereby marking STAT3 for degradation through the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula II binds to STAT4, the lysine-mimicking moiety causes ubiquitination, thereby marking STAT4 for degradation through the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula II binds to STAT5A, the lysine-mimicking moiety causes ubiquitination, thereby marking STAT5A for degradation through the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula II binds to STAT5B, the lysine-mimicking moiety causes ubiquitination, thereby marking STAT5B for degradation through the ubiquitin-proteasome pathway (UPP). In some embodiments, when a compound of Formula II binds to STAT6, the lysine-mimicking moiety causes ubiquitination, thereby marking STAT6 for degradation through the ubiquitin-proteasome pathway (UPP).

[0388] In some embodiments, DIM is

Chemical formula

Chemical formula

Chemical formula

[0389] In some embodiments, DIM is selected from those illustrated in Table 1A below.

[0390] In some embodiments, the present invention provides a compound of formula I as a compound of formula II-a:

Chemical formula

[0391] In some embodiments, the present invention provides a compound of formula I as a compound of formula II-b:

Chemical formula

[0392] In some embodiments, the present invention provides a compound of formula I as a compound of formula II-c:

Chemical formula

[0393] In certain embodiments, the invention provides that DIM is a lysine mimetic

Chemical formula

Chemical formula

Chemical formula

[0394] In some embodiments, DIM is a hydrogen atom. In some embodiments, 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 a provided compound where DIM is a hydrogen atom. In some embodiments, when a compound of Formula II binds to STAT1, the moiety that is hydrogen causes ubiquitination, thereby marking STAT1 for the ubiquitin proteasome (UPP). In some embodiments, when a compound of Formula II binds to STAT2, the moiety that is hydrogen causes ubiquitination, thereby marking STAT2 for the ubiquitin proteasome (UPP). In some embodiments, when a compound of Formula II binds to STAT3, the moiety that is hydrogen causes ubiquitination, thereby marking STAT3 for the ubiquitin proteasome (UPP). In some embodiments, when a compound of Formula II binds to STAT4, the moiety that is hydrogen causes ubiquitination, thereby marking STAT4 for the ubiquitin proteasome (UPP). In some embodiments, when a compound of Formula II binds to STAT5A, the moiety that is hydrogen causes ubiquitination, thereby marking STAT5A for the ubiquitin proteasome (UPP). In some embodiments, when a compound of Formula II binds to STAT5B, the moiety that is hydrogen causes ubiquitination, thereby marking STAT5B for the ubiquitin proteasome (UPP). In some embodiments, when a compound of Formula II binds to STAT6, the moiety that is hydrogen causes ubiquitination, thereby marking STAT6 for the ubiquitin proteasome (UPP).

[0395] In some embodiments, DIM is selected from those illustrated in Table 1A below.

[0396] In some embodiments, the invention provides a compound of Formula II, wherein DIM is a hydrogen atom, thereby forming a compound of Formula II-d-4: [Chemical Formula] In Formula II-d-4, each of STAT and L is, independently and in combination, as defined above and as described in the embodiments herein. STAT binding moiety (STAT)

[0397] As defined above and as described herein, STAT is a STAT binding moiety capable of binding to one or more of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6.

[0398] In some embodiments, STAT is a STAT binding moiety capable of binding to STAT1. In some embodiments, STAT is a STAT binding moiety capable of binding to STAT2. In some embodiments, STAT is a STAT binding moiety capable of binding to STAT3. In some embodiments, STAT is a STAT binding moiety capable of binding to STAT4. In some embodiments, STAT is a STAT binding moiety capable of binding to STAT5A. In some embodiments, STAT is a STAT binding moiety capable of binding to STAT5B. In some embodiments, STAT is a STAT binding moiety capable of binding to STAT6.

[0399] As defined herein and as described below, the formula uses square brackets, for example, [Chemical Formula] When illustrated as such, L is attached to a modifiable carbon, oxygen, or nitrogen atom within STAT and includes substitution or replacement of the defined groups in STAT.

[0400] In certain embodiments, the invention provides a compound of formula I or formula II, wherein STAT is a STAT3 binding moiety, whereby formula I-ai or II-e:

Chemical formula

Chemical formula

[0401] In certain embodiments, the invention provides a compound of formula I or formula II, wherein STAT is a STAT3 binding moiety, whereby formula I-aj or II-f:

Chemical formula

[0402] In certain embodiments, the invention provides a compound of formula I or formula II, wherein STAT is a STAT3 binding moiety, whereby formula I-ak or II-g:

Chemical formula

[0403] In some embodiments, the present invention provides that the STAT is a compound as described in US 2006 / 0247318, for example,

Chemical formula

Chemical formula

[0404] In certain embodiments, the present invention provides that the STAT is a STAT3 binding moiety, whereby formula I-al or II-i:

Chemical formula

[0405] In certain embodiments, the present invention provides that the STAT is a STAT3 binding moiety, whereby formula I-am or II-j: [Chemical] Provided are compounds of formula I or formula II which form a compound of or a pharmaceutically acceptable salt thereof, wherein in formulae I-am and II-j, L and LBM or DIM are as defined above and as described in the embodiments herein, and each of the variables A, B, Z, n, and m is as described and defined in WO 2007 / 042912 and US 7,786,142, the entireties of each of which are incorporated herein by reference.

[0406] In some embodiments, the present invention relates to a STAT being a compound described in WO 2007 / 136858, such as S31-201 (shown in Figure 7), NSC-59263 (shown in Figure 8), NSC-42067 (shown in Figure 9), Formula A (shown in Figure 10), Formula B (shown in Figure 11), Formula C (shown in Figure 12A), Formula D (Figure 12B), Formula E (Figure 12C), Formula F (Figure 12D), NSC 75912 (shown in Figure 50), NSC 11421 (shown in Figure 49), NSC 91529 (shown in Figure 51), NSC 263435 (shown in Figure 48), HL2-006-1 (shown in Figure 13), HL2-006-2 (shown in Figure 14), HL2-006-3 (shown in Figure 15), HL2-006-4 (shown in Figure 16), HL2-006-5 (shown in Figure 17), HL2-011-1 (shown in Figure 18), HL2-011-2 (shown in Figure 19), HL2-01 1-3 (shown in Figure 20), HL2-011-4 (shown in Figure 21), HL2-011-5 (shown in Figure 22), BG2069-1 (shown in Figure 23), HL2-011-6 (shown in Figure 24), HL2-011-7 (shown in Figure 25), HL2-005 (shown in Figure 26), HL2-OO3 (shown in Figure 27), BG2066 (shown in Figure 28), BG2074 (shown in Figure 29), BG3004 (shown in Figure 30), BG3006A (shown in Figure 31), BG3006B (shown in Figure 32), BG3006D (shown in Figure 33), BG3009 (shown in Figure 34), RPM381 (shown in Figure 35), RPM384 (shown in Figure 35), RPM385 (shown in Figure 35), RPM405 (shown in Figure 36), RPM411 (shown in Figure 36), RPM407 (shown in Figure 37), RPM412 (shown in Figure 37), RPM408 (shown in Figure 38), RPM410 (shown in Figure 38), RPM415 (shown in Figure 39), RPM416 (shown in Figure 39), RPM418 (shown in Figure 40), RPM418-A (shown in Figure 40), RPM427 (shown in Figure 41), RPM431 (shown in Figure 42), RPM432 (shown in Figure 43), RPM444 (shown in Figure 44), RPM448 (shown in Figure 44), RPM445 (shown in Figure 45), RPM447 (shown in Figure 45), RPM452 (shown in Figure 46), and a compound of formula I or formula II or a pharmaceutically acceptable salt thereof which is a STAT3 binding moiety selected from RPM202, wherein [Chemical formula] is attached to a carbon, oxygen, nitrogen, or sulfur atom which can be modified.

[0407] In certain embodiments, the invention is a STAT which is a STAT3 or STAT5 binding moiety, whereby formula I-an or II-k: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-an and II-k, L and LBM or DIM are as defined above and in embodiments herein, and each of the variables R1, R2, X, and Z are as described and defined in U.S. Pat. No. 7,960,434, the entirety of each of which is incorporated herein by reference.

[0408] In some embodiments, the present invention relates to a compound in which the STAT is a compound described in US 2006 / 0247318, such as [ka] or a pharmaceutically acceptable salt thereof, wherein the STAT3 binding moiety is selected from the group consisting of: [ka] is attached to a modifiable carbon, nitrogen, or oxygen atom.

[0409] In certain embodiments, the present invention provides a compound wherein the STAT is a STAT3 or STAT5 binding moiety, whereby the compound has formula I-ap or II-m: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas I-ap and II-m, L and LBM or DIM are as defined above and as described in embodiments herein, and variable R 1 , R 2 Each of A, X1, and Y is as described and defined in US 8,263,599, the entirety of each of which is incorporated herein by reference.

[0410] In certain embodiments, the present invention provides compounds wherein the STAT is a STAT3 binding moiety, whereby the compound has formula I-aq or II-n: [Chemical formula] Provided are compounds of formula I or formula II which form a compound of or a pharmaceutically acceptable salt thereof, wherein in formulae I-aq and II-n, L and LBM or DIM are as defined above and as described in the embodiments herein, and the variable R 1 , R 1’ , R 2 , R 3 , R 6 , AA, and each of n are as described and defined in WO 2008 / 067270, the entirety of which is incorporated herein by reference.

[0411] In certain embodiments, the present invention provides that the STAT is a STAT1, STAT3 or STAT5 binding moiety, whereby formulae I-ar-1, I-ar-2, I-ar-3, I-ar-4, II-o-1, II-o-2, II-o-3, or II-o-4: [Chemical formula] [Chemical formula] Provided are compounds of formula I or formula II which form a compound of or a pharmaceutically acceptable salt thereof, wherein in formulae I-ar-1, I-ar-2, I-ar-3, I-ar-4, II-o-1, II-o-2, II-o-3, and II-o-4, L and LBM or DIM are as defined above and as described in the embodiments herein, and the variables R, R 1 , R 2 , R 3 , R 3a , R 3b , R 4 , x, and each of y are as described and defined in WO 2008 / 156644 and US 2011 / 0144043, the entirety of which is incorporated herein by reference.

[0412] In some embodiments, the invention provides a compound of formula I or formula II or a pharmaceutically acceptable salt thereof, wherein STAT is a STAT3 binding moiety selected from the compounds described in WO 2009 / 032338, such as aplatoxin A, aplatoxin B, aplatoxin C, E-dehydroaplatoxin A, aplatoxin D, aplatoxin E, and analogs thereof as described, where

Chemical formula

[0413] In certain embodiments, the invention provides a compound of formula I or formula II, wherein STAT is a STAT3 binding moiety, thereby forming a compound of formula I-as or II-p:

Chemical formula

[0414] In certain embodiments, the invention provides a compound of formula I-at or II-q, wherein STAT is a STAT3 binding moiety, thereby

Chemical formula

[0415] In certain embodiments, the invention provides a compound of formula I or formula II which forms a compound of the formula or a pharmaceutically acceptable salt thereof, wherein STAT is a STAT3 binding moiety, whereby formula I-au or II-r:

Chemical formula

[0416] In certain embodiments, the invention provides a compound of formula II which forms a compound of the formula or a pharmaceutically acceptable salt thereof, wherein STAT is a STAT3 binding moiety, whereby formula II-r’-1, II-r’-2, II-r’-3, or II-r’-4:

Chemical formula

Chemical formula

Chemical formula

[0417] In some embodiments, R x is hydrogen. In some embodiments, R x is methanesulfonyl. In some embodiments, R x is isopropyl. In some embodiments, R x is isobutyl.

[0418] In certain embodiments, the present invention provides a compound of formula I or formula II, wherein STAT is a STAT3 binding moiety, thereby forming a compound of formula I-av or II-s:

Chemical formula

[0419] In certain embodiments, the invention provides a compound of Formula II, wherein STAT is a STAT3 binding moiety, such that Formula II-s'-1, II-s'-2, or II-s'-3:

Chemical formula

[0420] In certain embodiments, the invention provides a compound of Formula II-r'':

Chemical formula

[0421] In certain embodiments, the invention provides Formula II-r''-1:

Chemical formula

Chemical formula

[0422] In some embodiments, the present invention is such that ring D’ is phenyl, p is 1, and R 7 ’ is [Chemical formula] wherein n is 1 and Q’ is -C(O)- as shown, of formula II-r’’-2: [Chemical formula] There is provided a compound of formula II-r’’-1, or a pharmaceutically acceptable salt thereof, wherein in formula II-r’’-2, X 4 ’, X 5 ’, X 6 ’, R 3 ’, R 6 ’, L, L 1 ’, ring M’, ring Z’, X’, Y’, R a1 , R a2 , R z ’ and z are each, independently and in combination, as defined above and as described in the embodiments herein.

[0423] In some embodiments, the present invention provides that ring D’ is phenyl, p is 1, R 7 ’ is [Chemical formula] wherein R 3 ’ is [Chemical formula] wherein n is 1 and X 4 ’, X 5 ’ and Q’ are -C(O)- as shown, of formula II-r’’-3: [Chemical formula] There is provided a compound of formula II-r’’-1, or a pharmaceutically acceptable salt thereof, wherein in formula II-r’’-3, X 6 ’, R 6 ’, L, L 1 ’, ring M’, ring Z’, X’, Y’, R a1 , R a2, R z Each of ’ and z is, both alone and in combination, as defined above and as described in the embodiments herein.

[0424] In some embodiments, the invention is such that ring D’ is phenyl, p is 1, R 7 ’, and

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0425] In some embodiments, the invention is such that ring D’ is phenyl, p is 1, R 7 ’, and

Chemical formula

Chemical formula

Chemical formula

[0426] In some embodiments, the present invention provides that ring D’ is phenyl, p is 1, R 7 ’ is

Chemical formula

Chemical formula

Chemical formula

[0427] In certain embodiments, the present invention provides a compound of formula II-r’’-7:

Chemical formula

[0428] In certain embodiments, the present invention provides a compound of formula II-r''-8:

Chemical formula

Chemical formula

[0429] In some embodiments, the present invention provides that X 1 、X 2 、X 3 、R 1 、and ring A are

Chemical formula

Chemical formula

Chemical formula

[0430] In some embodiments, the present invention provides that X 1 , X 2 , X 3 , R 1 , and ring A are

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0431] In some embodiments, the present invention provides an X 1 , X 2 , X 3 , R 1 , and ring A, where

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0432] In some embodiments, the present invention provides an X 1 , X 2 , X 3 , R 1 , and ring A, where

Chemical formula

Chemical formula

Chem.

Chem.

[0433] In certain embodiments, the invention provides a compound of formula II-s’’:

Chem.

Claims

1. 【Fig. 1393】 【Chemical 1394】 【Chemical 1395】 【Chemical 1396】 【Chemical 1397】 【Chemical 1398】 【Chemical 1399】 A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

2. The compound is 【Chemical 1400】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

3. The compound is 【Chemical 1401】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

4. The compound is 【Chemical 1402】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

5. The compound is 【Chemical 1403】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

6. The compound is 【Chemical 1404】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

7. The compound is 【Chemical 1405】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

8. The compound is 【Chemical 1406】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

9. The compound is 【Chemical 1407】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

10. The compound is 【Chemical 1408】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

11. The compound is 【Chemical 1409】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

12. The compound is 【Chemical 1410】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

13. The compound is 【Chemical 1411】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

14. The compound is 【Chemical 1412】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

15. The compound is 【Chemical 1413】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

16. The compound is 【Chemical 1414】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

17. The compound is 【Chemical 1415】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

18. The compound is 【Chemical 1416】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

19. The compound is 【Chemical 1417】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

20. The compound is 【Chemical 1418】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

21. The compound is 【Chemical 1419】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

22. The compound is 【Chemical 1420】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

23. The compound is 【Chemical 1421】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

24. The compound is 【Chemical 1422】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

25. The compound is 【Chemical 1423】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising the compound according to any one of claims 1 to 25, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

27. A pharmaceutical composition for degrading STAT3 protein in a patient or biological sample, comprising the compound according to any one of claims 1 to 25.

28. A pharmaceutical composition for treating lymphoma in a patient, comprising the compound according to any one of claims 1 to 25.

29. A pharmaceutical composition for treating large granular lymphocytic (LGL) leukemia (T cells and NK cells) in a patient, comprising the compound according to any one of claims 1 to 25.

30. A pharmaceutical composition for treating cutaneous T cell lymphoma (CTCL) in a patient, comprising the compound according to any one of claims 1 to 25.

31. A pharmaceutical composition for treating peripheral T cell lymphoma (PTCL) in a patient, comprising the compound according to any one of claims 1 to 25.

32. A pharmaceutical composition for treating solid tumors in a patient, comprising the compound according to any one of claims 1 to 25.

33. The pharmaceutical composition according to claim 32, wherein the solid tumor is prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyosarcoma, or melanoma.

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