WO2025128653A1 - Stat3 degraders and their methods of use - Google Patents

Abstract

The present invention relates to STAT3 degraders and methods of use thereof for treating diseases, disorders, or conditions in patients comprising one or more mutations to serine/threonine kinase 11 (STK11) or KRAS.

Description

STAT3 DEGRADERS AND THEIR METHODS OF USE

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Appl. No. 63/609,145, filed December 12, 2023, the entirety of which is herein incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to STAT3 degraders, and methods of use thereof.

BACKGROUND OF THE INVENTION

[0003] Ubiquitin-Proteasome Pathway (UPP) or Ubiquitin-Proteasome System (UPS) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0004] The UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome- dependent degradation. Bifiinctional compounds composed of a target protein-binding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews, C., Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth, J.S. Jr., Chembiochem, 2005, 6(l):40-46).

[0005] The signal transducer and activator of transcription 3 (STAT3) protein is activated by cytokines and growth factors upon binding to their cognate cell surface receptors resulting in the recruitment and phosphory lation of STAT3 by Janus kinase (JAK), dimerization, nuclear translocation and transcriptional regulation of STAT3 target genes. While in normal cells STAT3 activity is tightly controlled by feedback regulation, in diseases including cancer and auto-immunity, STAT3 activity becomes deregulated by mechanisms that result in persistent activation of STAT3 as evidence by high levels of phosphorylated STAT3 (pSTAT3). Approximately 70% of human cancers including both hematological malignancies and solid tumors exhibit increased levels of pSTAT3. Aberrant activation of STAT3 has been shown to occur through direct mutation of the STAT3 gene, activation of upstream kinases such as JAK or ALK by mutation or translocation, reduced expression of negative regulators such as SOC3 and elevated receptor signaling from overexpression of cytokine and growth factors in the tumor microenvironment.

[0006] Tire mechanisms by which deregulated STAT3 contribute to tumor establishment and progression are multifactorial. Among the target genes regulated by STAT3 are key effectors of several hallmarks of cancer including proliferative signaling (CCND1. CCND2), resisting cell death (BCL2-L1, MCL-1), angiogenesis (VEGF, HIFla), deregulated cellular energetics (MYC), avoiding immune destruction (PD-L1, IFNA) and tumor-promoting inflammation (IL-6). In cancer cell models with strong STAT3 activation such as anaplastic large cell lymphoma (ALCL), genetic knockdown of STAT3 is sufficient to inhibit proliferation and induce apoptosis confirming dependency on STAT3 signaling. In addition to these cancer cell autonomous pathways, activated STAT3 also promotes a suppressive TME through direct regulation of immune cell function and regulation of cancer cell-TME crosstalk. Activation of STAT3 in innate and adaptive immune cells generally favors expansion of immune suppressive cells while reducing the proliferation, maturation and function of cytolytic effector cells. Targeting STAT3 with antisense oligonucleotides that are preferentially taken up by myeloid cells has been shown to reverse immune suppression and restore anti-tumor activity of cytotoxic T cells in mouse syngeneic tumor models. Finally, STAT3 has been shown to be activated in response to both chemo- and targeted therapies such as EGFR inhibitors and contributes to the development of drug -resistance. Collectively these data illustrate the importance of STAT3 signaling to tumor establishment and growth, to tumor-extrinsic immune suppression in the TME and to the development of resistance to standard therapies thereby suggesting that selective degradation of STAT3 may be an effective means to suppress STAT3 signaling for tire treatment of cancer.

[0007] A need exists to develop STAT3 degraders to improve upon the efficacy of STAT3 inhibitors and other therapies and provide cancer therapy.

SUMMARY OF THE INVENTION

[0008] It has been found that STAT3 degraders (e.g., (2-(((5S,8S, 10aR)-3-acetyl-8-(((S)-5-amino-l- (2-chloro-3-(4-(((5J-l-((2S, 4RJ-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3.3-dimethyl-l-oxobutan-2-yl)amino)-4-oxobutyl)phenoxy)- 5-oxopentan-2-yl)carbamoyl)-6-oxodecahydropyrrolo[l,2-a][1.5]diazocin-5-yl)carbamoyl)-lH-indole-5- carbonyl)phosphonic acid (Compound A), and its salts), as described herein, have certain advantages in treating patients comprising (e.g., harboring) one or more mutations to serine/threonine kinase 11 (STK11) or KRAS. [0009] In one aspect, the present invention provides methods and uses for treating a disease, disorder or condition in a patient, comprising administering to the patient a therapeutically effect amount of a STAT3 degrader, as described herein, wherein the patient comprises one or more mutations to serine/threonine kinase 11 (STK11) or KRAS. In some embodiments, tire disease, disorder or condition is cancer. In one aspect, the present invention provides methods and uses for treating a disease, disorder or condition in a patient, comprising administering to the patient a therapeutically effect amount of Compound A, or a pharmaceutically acceptable salt thereof, as described herein, wherein the patient harbors one or more mutations to serine/threonine kinase 11 (STK11) or KRAS. In one aspect, the present invention provides methods and uses for treating a disease, disorder or condition in a patient, comprising administering to the patient a therapeutically effect amount of Compound B, or a phannaceutically acceptable salt thereof, as described herein, wherein the patient harbors one or more mutations to serine/threonine kinase 11 (STK11) or KRAS.

[0010] These and other aspects of this disclosure will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background infonnation and procedures and are each hereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 and FIG. 2 show STK11 mutation is a genomic detenninant of poor clinical outcome with aPD-1 axis in PD-L1 + non-small cell lung cancer (NSCLC), independent of KRAS status.

[0012] FIG. 3 and FIG. 4 show STAT3 degradation leads to anti -tumor response in the STK11 mutant model, not WT; and STAT3 pathway is inhibited comparably in both genotypes.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

1. General Description of Certain Embodiments of the Invention:

[0013] Provided compounds are potent, highly selective heterobifunctional small molecules therapeutic targeting the protein STAT3 and the E3 ligase von Hippel-Lindau protein (VHL) to mediate the selective degradation of STAT3 via the ubiquitin-proteasome system (UPS). Provided compounds have demonstrated inhibition of tumor growth of serine/threonine kinase 11 (STK11) and/or or KRAS mutants. [0014] In some embodiments, the present disclosure provides a method for treating a disease, disorder or condition, comprising administering to the patient a therapeutically effective amount of a STAT3 degrader, as described herein.

[0015] In some embodiments, the present disclosure provides a method for treating a disease, disorder or condition in a patient, comprising administering to the patient a therapeutically effective amount of a STAT3 degrader, as described herein, wherein the patient harbors one or more mutations to serine/threonine kinase 11 (STK11) or KRAS. It will be appreciated that references herein to a patient harboring a particular mutation(s) refers to patients characterized by having (e.g., through a suitable diagnostic test) such mutation(s). In some embodiments, a patient is characterized by having a cancer harboring one or more mutations to serine/threonine kinase 11 (STK11) or KRAS. In some embodiments, a patient treated with a provided method has been diagnosed with a disease, disorder or condition (e.g., cancer) harboring one or more mutations to serine/threonine kinase 11 (STK11) or KRAS.

[0016] In some embodiments, the present disclosure provides a method for treating a disease, disorder or condition in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, as described herein, wherein the patient harbors one or more mutations to serine/threonine kinase 11 (STK11) or KRAS. In some embodiments, the present disclosure provides a method for treating a disease, disorder or condition in a patient, comprising administering to the patient a therapeutically effective amount of Compound B, as described herein, wherein the patient harbors one or more mutations to serine/threonine kinase 11 (STK11) or KRAS.

[0017] In some embodiments, the patient harbors a loss of function mutation in STK11. In some embodiments, the patient harbors an E293* mutation to STK11. In some embodiments, a patient harbors a D53Tfs* 11 mutation to STK11.

[0018] In some embodiments, the patient harbors a gain of function mutation in KRAS. In some embodiments, a patient harbors a G12C mutation to KRAS.

[0019] In some embodiments, the disease, disorder, or condition is cancer. In some embodiments, the disease, disorder, or condition is non-small cell lung cancer.

[0020] In the following disclosure, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise'’ and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0021] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification arc not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

2. Definitions

[0022] As used in the specification and appended claims, unless specified to the contrary, the following terms and abbreviations have the meaning indicated:

[0023] As used herein, the tenns “about” or “approximately” have the meaning of within 20% of a given value or range. In some embodiments, the tenn “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%. 10%. 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

[0024] As used herein, “Compound A” refers to STAT3 degrader (2-(((5S,8S, 10aR)-3-acetyl-8-(((S)- 5-amino-I-(2-chloro-3-(4-(((51-I-((2S.4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-4-oxobutyl)phenoxy)-

5-oxopentan-2-yl)carbamoyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)-lH-indole-5- carbonyl)phosphonic acid, of formula:

In some embodiments, Compound A is provided in solid form. In some embodiments. Compound A is amorphous.

[0025] As used herein, “Compound A ammonium hydrogen salt” (aka “Compound A ammonium salt”) refers to STAT3 degrader ammonium hydrogen (2-(((5S, 8S, 10aR)-3-acetyl-8-(((S)-5-amino-l-(2-chloro-3- (4-(((_lS)-l-((2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-l- yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-4-oxobutyl)phenoxy)-5-oxopentan-2-yl)carbamoyl)-6- oxodecahydropyrrolo[I,2-a][I,5]diazocin-5-yl)carbamoyl)-IH-indole-5-carbonyl)phosphonate, of formula:

In some embodiments, Compound A ammonium hydrogen salt is provided in solid form. In some embodiments, Compound A ammonium hydrogen salt is amorphous.

[0026] As used herein, “Compound B” refers to STAT3 degrader of formula:

or a salt thereof.

[0027] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of tire Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed. Additionally, general principles of organic chemistry arc described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons. New York: 2001, the entire contents of which are hereby incorporated by reference.

[0028] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e.. unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic

hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A carbocyclic ring may include one or more oxo (=0) orthioxo (=S) substituent. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0029] 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 an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherw ise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0030] The term “lower alkyl” refers to a C_1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0031] The term “lower haloalkyl” refers to a C_1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0032] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized fonn of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3.4-dihydro-2//-pyrrolyl). NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl)).

[0033] The tenn "unsaturated." as used herein, means that a moiety has one or more units of unsaturation.

[0034] As used herein, the term “bivalent C_1-8 (or C_1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0035] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)_n-, wherein n is a positive integer, preferably from 1 to 6. from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0036] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0037] As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:

[0038] The term “halogen” means F, Cl, Br, or I. [0039] The term “aryl’’ used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term '’aryl" may be used interchangeably with the tenn “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to. phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and tire like.

[0040] Tire terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 it electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4/7 quinolizmyl. carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl. tetrahydroquinolinyl, tetrahydroisoquinolinyl. and pyrido[2.3-b]-1.4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0041] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical.” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10- membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the tenn "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3.4-dihydro-2H pyrrolyl). NH (as in pyrrolidinyl), or ⁺NR (as in N- substituted pyrrolidinyl).

[0042] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl. diazepinyl. oxazepinyl. thiazepinyl, morpholinyl, and quinuclidinyl. The terms ’‘heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 37Z-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. In some embodiments, a heterocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A heterocyclic ring may include one or more oxo (=0) or thioxo (=S) substituent. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0043] As used herein, the tenn “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties. as herein defined.

[0044] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at evenposition. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0045] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen;

which may be substituted with

which may be substituted with R°; -CH=CHPh, which may be substituted with

pyridyl which may be substituted with

straight or branched alkylene

straight or branched alkylene) wherein

each R° may be substituted as defined below and is independently hydrogen,

membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0046] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen,

SSR* wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from aliphatic, or a 5-6-membered

saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S. [0047] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following:

, wherein each independent occurrence of R* is selected from hydrogen, C_{1 6} aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include:

wherein each independent occurrence of R* is selected from hydrogen, C_1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0048] Suitable substituents on the aliphatic group of R* include halogen, -R", -(haloR*), -OH, -OR*. -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH₂, -NHR*, -NR*₂, or -NO₂, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1-4 aliphatic,

or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0049] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -

wherein each

is independently hydrogen, C_1-6 aliphatic which may be

substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or. notwithstanding the definition above, two independent occurrences of R'. taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0050] 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, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1-4 aliphatic, or a 5-6-membered saturated, partially unsaturated,

or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hcmisulfatc, hcptanoatc, hexanoate, hydroiodidc, 2-hydroxy-cthancsulfonatc, lactobionatc, lactate, laurate, lauryl sulfate, malate, maleate, malonate. methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0052] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Ci 4alkyl)₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. In some embodiments, the provided compounds are purified in salt form for convenience and/or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds formed during chromotagraphic purification are comtemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art.

[0053] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E confonnational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric fonns of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention

[0054] As used herein, the term ‘'provided compound” refers to any genus, subgenus, and/or species set forth herein.

[0055] Tire term “prodrug” refers to a compound that is made more active in vivo. The present compounds can also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry. Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdennal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound. The term “therapeutically acceptable prodrug,” refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

[0056] As used herein, the term “phannaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Phannaceutically acceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J. Phannaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Phannaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methane sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0057] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (C’i ialkyl) i salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. [0058] The term ‘'patient,’’ as used herein, means an animal, preferably a mammal, and most preferably a human. The term “subject,” as used herein, has the same meaning as the term “patient”.

[0059] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g. , in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0060] As used herein, a patient or subject “in need of prevention,” “in need of treatment,” or “in need thereof,” refers to one, who by the judgment of an appropriate medical practitioner (e.g., a doctor, a nurse, or a nurse practitioner in the case of humans: a veterinarian in the case of non-human mammals), would reasonably benefit from a given treatment or therapy.

[0061] A “therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent, such as Compound A, or a pharmaceutically acceptable salt thereof, is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a patient or subject against the onset of a disease, such as a cancer, or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0062] In preferred embodiments, a therapeutically effective amount of the drug, such as Compound A. promotes regression to the point of eliminating the disease. In addition, the terms “effective” and “effectiveness” with regard to a treatment includes both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the Compound A, or a pharmaceutically acceptable salt thereof, to treat the disease in the patient. Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.

[0063] As used herein, the terms “therapeutic benefit” or “benefit from therapy” refers to an improvement in one or more of overall survival, progression-free survival, partial response, complete response, and overall response rate and can also include a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. 3. Description of Exemplary Embodiments

[0064] In some embodiments, the present disclosure provides a method for treating a disease, disorder or condition in a patient, comprising administering to the patient a therapeutically effective amount of a STAT3 degrader, as described herein, wherein the patient harbors one or more mutations to serine/threonine kinase 11 (STK11) or KRAS.

[0065] In some embodiments, the present disclosure provides a method for treating a disease, disorder or condition in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, as described herein, wherein the patient harbors one or more mutations to serine/threonine kinase 11 (STK11) or KRAS. In some embodiments, the present disclosure provides a method for treating a disease, disorder or condition in a patient, comprising administering to the patient a therapeutically effective amount of Compound B. as described herein, wherein the patient harbors one or more mutations to serine/threonine kinase 11 (STK11) or KRAS.

[0066] Serine/threonine kinase 11 (STK11), also known as liver kinase B 1 (LKB 1) or renal carcinoma antigen NY-REN-19 is a member of tire serine/threonine kinase family that regulates cell polarity and functions as a tumor suppressor. KRAS (Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called KRAS, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. In some embodiments, the KRAS protein is a GTPase, a class of enzymes which convert the nucleotide guanosine triphosphate (GTP) into guanosine diphosphate (GDP).

[0067] In some embodiments, a patient harbors an E293* mutation to STK11. In some embodiments, a patient harbors a D53Tfs* ll mutation to STK11. In some embodiments, a patient harbors a G12C mutation to KRAS.

[0068] In some embodiments, the disease, disorder, or condition is cancer. In some embodiments, the disease, disorder, or condition is non-small cell lung cancer.

[0069] In some embodiments, a method of the present invention comprises intravenously administering Compound A as described herein. In some embodiments, a method of the present invention comprises administering a unit dosage form as described herein.

[0070] In some embodiments, a STAT3 degrader is a compound as described in WO 2020/206424, WO 2021/118696. WO 2022/077010. or WO 2023/107706.

[0071] In certain embodiments, a provided STAT3 degrader is a compound of formula II-r”-l :

or a pharmaceutically acceptable salt thereof, wherein:

X⁴’. X⁵’, and X^6, are each independently a bivalent moiety selected from a covalent bond. -CR₂-, -C(O)-, -

each R is independently hydrogen, or an optionally substituted group selected from C_1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4- 11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R groups are attached, independently selected from nitrogen, oxygen, and sulfur;

R⁶’ is hydrogen or R^A; each R^A is independently an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring D’ is selected from phenyl, a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R⁷’ is hydrogen,

-NRS(O)₂R; p is 0, 1, 2, 3, or 4;

L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C_1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -CRF-, - CF2-, -C(O)-, -S-, -S(O)-, -S(O)₂-, -SiR₂-, -Si(OH)R-, -Si(OH)₂-, -P(O)OR-, -P(O)R-, or -P(O)NR₂- , wherein: each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

L¹ ’ is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C_{1 -5} hydrocarbon chain, wherein 0-3 methylene units of L¹ are independently replaced by -O-, -NR-, -CRF-, -CF₂-, - C(O)-, -S-, -S(O)-, or -S(O)₂-;

X' is an optionally substituted -(CH₂)_X-, wherein 1-2 methylenes ofX’ is optionally replaced with a bivalent group selected from -NR-, -N(COR)-, -N(CO₂R)-. -N(SO₂R)-, -N(CONR₂)-, and -N(SO₂NR₂)-, wherein: x is 1, 2, 3, 4, or 5;

Y’ is an optionally substituted -(CH₂)_y-, wherein: y is 1, 2, or 3;

R³’ is hydrogen or R^A;

Ring M’ is an optionally substituted bivalent ring selected from phenylenyl, naphthylenyl, a 5- 10 membered heteroaryl enyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-11 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Q' is a bivalent moiety selected from -O-, -CR₂-, -CF₂-, -CFR-, -C(O)-, -OCR₂-, and -C(S)-;

R^al and R^a2 are each independently hydrogen or R^A; Ring Z’ is a bivalent ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R^z’ is hydrogen, R^A, halogen, -CN, -NO2, -OR, -SR, -NR₂,

S1R₃, -S(O)₂R, -S(O)₂NR₂ -S(O)R, -C(O)R, -C(O)OR, -C(O)NR₂. -C(O)NROR, -CR₂NRC(O)R, - CR₂NRC(O)NR₂, -OC(O)R, -OC(O)NR₂, -OP(O)R₂, -OP(O)(OR)₂, -OP(O)(OR)NR₂, - OP(O)(NR₂)₂, -NRC(O)OR, -NRC(O)R, -NRC(O)NR₂, -NRS(O)₂R, -NP(O)R₂, -NRP(O)(OR)₂, - NRP(O)(OR)NR₂, -NRP(O)(NR₂)₂, or -NRS(O)₂R; z is 0, 1, 2, 3, or 4; and n is 0 or 1.

[0072] In some embodiments, a provided STAT3 degrader is a compound of formula II-r”-l, wherein

Ring D’ is phenyl, p is 1, R⁷’ is . n is 1, and Q^? is -C(O)- as shown, to provide a compound of formula II-r”-2:

or a pharmaceutically acceptable salt thereof, wherein each ofX⁴’, X⁵’, X⁶’, R³’, R⁶’, L, , Ring M’, Ring

Z', X’, Y’, R^al, R^a2, R^z’, and z is as defined above and described in embodiments herein, both singly and in combination.

[0073] In some embodiments, a provided STAT3 degrader is a compound of formula II-r”-l, wherein

Ring D’ is phenyl, p is 1, R⁷’ is , n is 1. and , and Q’ are -C(O)-

as shown, to provide a compound of formula II-r”-3:

or a pharmaceutically acceptable salt thereof, wherein each of

and z is as defined above and described in embodiments herein, both singly and in combination.

[0074] In some embodiments, a provided STAT3 degrader is a compound of formula

wherein

Ring D" is phenyl, p is 1

is

and Q^? are -C(O)- as shown, to provide a compound of formula Il-r ’-4:

or a pharmaceutically acceptable salt thereof, wherein each of

and z is as defined above and described in embodiments herein, both singly and in combination. [0075] In some embodiments, a provided STAT3 degrader is a compound of formula II-r”-l, wherein

-C(O)- as shown, to provide a compound of formula II-r”-5:

or a pharmaceutically acceptable salt thereof, wherein each of X⁴’, X⁵’, X⁶’, R³’, R⁶’, L, L¹ ’, Ring Z’, X’, Y', R^a1, R^a2, R^z’, and z is as defined above and described in embodiments herein, both singly and in combination.

[0076] In some embodiments, a provided STAT3 degrader is a compound of formula wherein

Ring D’ is phenyl, p is 1, R⁷’ is Ring Z’ is phenylenyl, and X⁴’. X⁵’,

and Q^: are -C(O)- as shown, to provide a compound of formula II-r’’-6:

or a pharmaceutically acceptable salt thereof, wherein each of X⁴’, X⁵’, X⁶’, R³’, R⁶’, L, Ring M’, X’, Y’,

R^al, R^a2, R^z’, and z is as defined above and described in embodiments herein, both singly and in combination.

[0077] In certain embodiments, a provided STAT3 degrader is a compound of formula II-r ’-8:

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is a bivalent moiety selected from a covalent bond, -CR₂-, -C(O)-, -C(S)-, -CR(CF₃)-, -P(O)OR-, -P(O)R-

X² is a carbon atom or silicon atom;

X³ is a bivalent moiety selected from -CR₂-, -NR-, -O-, -S-, or -SiR₂-;

R¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O)₂R, -NR₂, -P(O)(OR)₂. -P(O)NR₂OR, -P(O)(NR₂)₂, -Si(OH)₂R, -Si(OH)R₂, -S1R3. or an optionally substituted C1-4 aliphatic; each R is independently hydrogen, or an optionally substituted group selected from C1.6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered hctcroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4- 11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R groups are attached, independently selected from nitrogen, oxygen, and sulfur; each R² is independently hydrogen, R^A, halogen, -CN, -NO₂, -OR, -SR, -NR₂, SiR₃, -S(O)₂R, -S(O)₂NR₂ -S(O)R, -C(O)R, -C(O)OR, -C(O)NR₂. -C(O)NROR, -CR₂NRC(O)R, - CR₂NRC(O)NR₂, -OC(O)R, -OC(O)NR₂, -OP(O)R₂, -OP(O)(OR)₂, -OP(O)(OR)NR₂, - OP(O)(NR₂)₂, -NRC(O)OR, -NRC(O)R, -NRC(O)NR₂, -NRS(O)₂R, -NP(O)R₂, -NRP(O)(OR)₂, - NRP(O)(OR)NR₂, -NRP(O)(NR₂)₂, or -NRS(O)₂R; each R^A is independently an optionally substituted group selected from Ci-e aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A is a bicyclic or tricyclic ring selected from

Ring B is a fused ring selected from benzo, 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R³ is selected from hydrogen, halogen, -OR, -NR₂, or -SR; each R⁴ is independently hydrogen, R^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)NROR, -OC(O)R, -OC(O)NR₂, -NRC(O)OR, -NRC(O)R, -NRC(O)NR₂, or - NRS(O)₂R;

R⁵ is hydrogen, C _1-4 aliphatic, or -CN; m is 0, 1, 2, 3 or 4;

L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -CRF-, - CF₂-, -C(0)-, -S-, -S(0)-, -S(0)₂-, -S1R₂-, -Si(OH)R-, -SI(OH)₂-, -P(O)OR-, -P(O)R-, or -P(O)NR₂- , wherein: each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl. a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

L¹ ’ is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C_1.5 hydrocarbon chain, wherein 0-3 methylene units of L¹' are independently replaced by -O-, -NR-, -CRF-, -CF₂-, -C(O)-, -S-, -S(O)-, or -S(O)₂-;

L²’ is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1.5 hydrocarbon chain, wherein 0-3 methylene units of L²’ are independently replaced by -O-, -NR-, -CRF-, -CF₂-, -C(O)-, -S-, -S(O)-, or -S(O)₂-;

R³’ is hydrogen or R^A;

Ring M" is an optionally substituted bivalent ring selected from phenylenyl, naphthylenyl, a 5-10 membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-11 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Q’ is a bivalent moiety selected from -O-, -CR₂-, -CF₂-, -CFR-, -C(O)-, -OCR₂-, and -C(S)-;

R^al and R^a2 are each independently hydrogen or R^A;

Y‘ is an optionally substituted -(CH₂)_y-, wherein: y is 1. 2, or 3;

Ring W’ is an optionally substituted ring selected from a 5-9 membered saturated or partially unsaturated heterocyclyl;

Ring U’ is a ring selected from phenyl, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur:

R^u’ is hydrogen, R^A, halogen, -CN, -NO₂, -OR, -SR, -NR₂,

SiR₃, -S(O)₂R, -S(O)₂NR₂. -S(O)R, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)NROR, -CR₂NRC(O)R, - CR₂NRC(O)NR₂, -OC(O)R, -OC(O)NR₂, -OP(O)R₂, -OP(O)(OR)₂, -OP(O)(OR)NR₂, - OP(O)(NR₂)₂, -NRC(O)OR. -NRC(O)R, -NRC(O)NR₂, -NRS(O)₂R, -NP(O)R₂, -NRP(O)(OR)₂, - NRP(O)(OR)NR₂. -NRP(O)(NR₂)₂, or -NRS(O)₂R; u is 0, 1, 2, 3, or 4;

Ring Z’ is a bivalent ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R^z? is hydrogen, R^A. halogen. -CN. -NO₂, -OR, -SR, -NR₂,

SIR₃, -S(O)₂R, -S(O)₂NR₂. -S(O)R, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)NROR, -CR₂NRC(O)R, - CR₂NRC(O)NR₂, -OC(O)R, -OC(O)NR₂, -OP(O)R₂, -OP(O)(OR)₂, -OP(O)(OR)NR₂, - OP(O)(NR₂)₂, -NRC(O)OR -NRC(O)R, -NRC(O)NR₂, -NRS(O)₂R, -NP(O)R₂, -NRP(O)(OR)₂, - NRP(O)(OR)NR₂. -NRP(O)(NR₂)₂, or -NRS(O)₂R; z is 0, 1. 2, 3, or 4; and n is 0 or 1.

[0078] In some embodiments, a provided STAT3 degrader is a compound of formula Il-r ’’-8, wherein

X\ X², X³, R¹. and Ring

heterocyclyl, and Q’ is -C(O)- as shown, to provide a compound of formula II-r”-9:

II-r’ -9 or a pharmaceutically acceptable salt thereof, wherein each of R², m, L, L¹’, L²’, Ring M’, Ring U’, Ring Z”, R³”, R^a1, R^a2, R^u”, u, R^z’, and z is as defined above and described in embodiments herein, both singly and in combination.

[0079] In some embodiments, a provided STAT3 degrader is a compound of formula II-r”-8, wherein

X’, X², X³, R¹, and Ring

Ring W’ is an 8-membered heterocyclyl, Ring M’ is

, and Q’ is -C(O)- as shown, to provide a compound of formula

II-r”-10:

II-i ’-lO or a pharmaceutically acceptable salt thereof, wherein each of R², m, L, L¹ ’ , L²’ , Ring U' , Ring Z ’ , R³ ’ , R^a1 , R^a2, R^u', u, R^z', and z is as defined above and described in embodiments herein, both singly and in combination.

[0080] In some embodiments, a provided STAT3 degrader is a compound of formula Il-r ’’-8, wherein

X’, X², X³, R¹. and Ring

heterocyclyl, L² i

, Ring U’ is phenyl, and Q’ is -C(O)- as shown, to provide a compound of formula Il-r ”-11 :

or a pharmaceutically acceptable salt thereof, wherein each of R², m. L, L¹’, Ring M’, Ring Z’, R³’. R^a1, R^a2, R^u’, u, R^z’. and z is as defined above and described in embodiments herein, both singly and in combination.

[0081] In some embodiments, a provided STAT3 degrader is a compound of formula II-r”-8, wherein

X’, X², X³, R‘, and Ring

, Ring W’ is an 8 -membered

O heterocyclyl, L¹’ is

Ring Z’ is cyclohexyl, z is 0, and Q’ is -C(O)- as shown, to provide a compound of formula II-r”-12:

II-r ”-12 or a pharmaceutically acceptable salt thereof, wherein each of R², m, L, L²’, Ring M’, Ring U’, R³’, R^al, R^a2, R^u’, and u is as defined above and described in embodiments herein, both singly and in combination. [0082] As defined above and described herein, X⁴’, X⁵', and X⁶’ are each independently a bivalent moiety selected from a covalent bond. -CR₂-, -C(O)-, -C(S)-, -O-, -S(O)-, -S(O)₂-.

[0083] In some embodiments, X⁴’ is a covalent bond. In some embodiments, X⁴’ is -CR₂-. In some embodiments, X⁴ is -C(O)- . In some embodiments, X⁴’ is -C(S)- . In some embodiments, X⁴’ is -O-. In some embodiments, X⁴' is -S(O)-. In some embodiments, X⁴’ is -S(O)₂-. In some embodiments, X⁴' is

, In some embodiments, X⁵’ is a covalent bond. In some embodiments, X⁵' is -CR₂-. In some embodiments, X⁵’ is -C(O)-. In some embodiments, X” is -C(S)-. In some embodiments, X⁵’ is -O-. In some embodiments, X^5? is -S(O)-. In some embodiments, X^5? is -S(O)₂-

. In some embodiments. X⁵’ is

. In some embodiments, X’’ is

. In some embodiments,

X^b’ is a covalent bond. In some embodiments. X⁶’ is -CR₂-. In some embodiments, X⁶’ is -C(O)-. In some embodiments, X^b’ is -C(S)-. In some embodiments, X⁶’ is -O-. In some embodiments, X⁶’ is -S(O)-. In some embodiments, X⁶’ is -S(O)₂-. In some embodiments, X⁶’ is

. In some embodiments, X⁶’ is

, In some embodiments, X⁶’ is

[0084] As defined above and described herein, each R^A is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0085] In some embodiments, R^A is an optionally substituted Ci-e aliphatic. In some embodiments,

R^A is an optionally substituted phenyl. In some embodiments, R^A is an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^A is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^A is

In some embodiments, R^A is -CH2CO2R. In some embodiments, R^A is -CH2OCO2R. In some embodiments, R^A is -CH2C(O)NR₂.

[0086] As defined above and described herein, R^b’ is hydrogen or R^A.

[0087] In some embodiments, R⁶’ is hydrogen. In some embodiments, R⁶’ is R^A. In some embodiments, R⁵’ is ethyl hi some embodiments, R⁶’ is isopropyl. In some embodiments, R⁶’ is neopropyl. In some embodiments, R⁶’ is tert-butyl. In some embodiments, R⁶’ is cyclopropyl. In some embodiments, R^b? is cyclobutyl. In some embodiments, R^b? is cyclopentyl. In some embodiments. R⁶’ is cyclohexyl.

[0088] As defined above and described herein, R⁷’ is hydrogen, R^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)NROR, -OC(O)R, -OC(O)NR₂, -NRC(O)OR, -NRC(O)R, -NRC(O)NR₂, or -NRS(O)₂R.

[0089] In some embodiments, R⁷’ is hydrogen. In some embodiments, R⁷’ is R^A. In some embodiments. R⁷’ is halogen. In some embodiments. R⁷’ is -CN. In some embodiments. R⁷’ is -NO2. In some embodiments, R⁷’ is -OR. In some embodiments, R⁷’ is -SR. In some embodiments, R⁷’ is -NR₂. In some embodiments, R⁷’ is -S(O)₂R. In some embodiments, R⁷’ is -S(O)₂NR₂. In some embodiments, R⁷’ is -S(O)R. In some embodiments, R⁷' is -C(O)R. In some embodiments, R⁷' is -C(O)OR. In some embodiments, R⁷’ is -C(O)NR₂. In some embodiments, R⁷’ is

-C(O)NROR. In some embodiments, R⁷’ is -OC(O)R. In some embodiments. R⁷' is -OC(O)NR₂. In some embodiments. R⁷’ is -NRC(O)OR. In some embodiments, R⁷’ is -NRC(O)R. In some embodiments, R^7? is -NRC(O)NR₂. In some embodiments, R⁷’ is

-NRS(0)₂R. In some embodiments,

[0090] As defined above and described herein, p is 0, 1, 2, 3, or 4.

[0091] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0092] As defined above and described herein, L¹ ' is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C_1-5 hydrocarbon chain, wherein 0-3 methylene units of L¹’ are independently replaced by -O-, -NR-, -CRF-, -CF₂-, -C(O)-, -S-, -S(O)-, or -S(O)₂-.

[0093] In some embodiments, L¹’ is covalent bond. In some embodiments, L¹’ is a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of L¹’ are independently replaced by -O-, -NR-, -CRF-, -CF2-. -C(O)-, -S-, -S(O)-, or -S(O)₂-. In some embodiments, L¹' is

In some embodiments, L¹’ is

. In some embodiments. L¹' is In some embodiments. L¹’ is

[0094] As defined above and described herein, L²’ is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C_1.5 hydrocarbon chain, wherein 0-3 methylene units of L²’ are independently replaced by -O-, -NR-, -CRF-, -CF₂-, -C(O)-, -S-, -S(O)-, or -S(O)₂-.

[0095] In some embodiments, L²’ is covalent bond. In some embodiments, L²' is a bivalent, saturated or partially unsaturated, straight or branched C1-5 hydrocarbon chain, wherein 0-3 methylene units of L^2? are independently replaced by -O-, -NR-, -CRF-, -CF₂-, -C(O)-, -S-, -S(O)-, or -S(O)₂-. In some embodiments.

[0096] As defined above and described herein, Q’ is a bivalent moiety selected from -O-, -CR₂-, -CF₂- , -CFR-, -C(O)-, -OCR₂-, and -C(S)-.

[0097] In some embodiments, Q^, is -O-. In some embodiments, Q’ is -CR₂-. In some embodiments, Q' is -OCR₂-. In some embodiments, Q’ is -CF₂-. In some embodiments, Q’ is -CFR-. In some embodiments, Q is -C(O)-. In some embodiments, Q is -C(S)-.

[0098] As defined above and described herein, X’ is an optionally substituted -(CH₂)_X-, wherein 1-2 methylenes of X’ is optionally replaced with a bivalent group selected from -NR-, -N(COR)-, -N(CO₂R)-, -N(SO₂R)-, -N(CONR₂)-, and -N(SO₂NR₂)-.

[0099] In some embodiments, X’ is an optionally substituted -(CH₂)_X-. In some embodiments, X' is an optionally substituted -(CH₂)_X-, wherein 1-2 methylenes of X’ is replaced with a bivalent group selected from -NR-, -N(COR)-, -N(CO₂R)-, -N(SO₂R)-, -N(CONR₂)-, and -N(SO₂NR₂)-. In some embodiments, X^?

.

[00100] As defined above and described herein, x is 0, 1, 2, 3, 4, or 5.

[00101] In some embodiments, x is 0. In some embodiments, x is 1 . In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5.

[00102] As defined above and described herein, Y’ is an optionally substituted -(CH₂)_y-.

[00103] In some embodiments, Y' is an optionally substituted -(CH₂)_y-. In some embodiments, Y’ is -

CH₂-. In some embodiments,

[00104] As defined above and described herein, y is 0, 1, 2, or 3.

[00105] In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3.

[00106] As defined above and described herein, R³’ is hydrogen or R^A.

[00107] In some embodiments, R³’ is hydrogen. In some embodiments, R³’ is R^A. In some embodiments,

[00108] As defined above and described herein, R^al and R^a2 are each independently hydrogen, R^A, - CH2CO2R, or -CH2OCO2R.

[00109] In some embodiments, R^al is hydrogen. In some embodiments, R^al is R^A. In some embodiments, R^al is -CH2CO₂R. In some embodiments, R^al is -CH2OCO₂R. In some embodiments, R^a2 is hydrogen. In some embodiments, R^a2 is R^A. In some embodiments, R^a2 is -CH2CO2R. In some embodiments, R^a2 is -CH2OCO2R.

[00110] As defined above and described herein, Ring M’ is an optionally substituted bivalent ring selected from phenylenyl, naphthylenyl, a 5-10 membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-11 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[00111] In some embodiments, Ring M’ is an optionally substituted phenylenyl. In some embodiments, Ring M’ is an optionally substituted naphthylenyl. In some embodiments, Ring M’ is an optionally substituted 5-10 membered heteroarylenyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments. Ring M’ is an optionally substituted 5-11 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, Ring M’ is an optionally substituted 5-11 membered saturated or partially unsaturated heterocyclylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring M’ is

[00112] As defined above and described herein, Ring D’ is selected from phenyl, a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[00113] In some embodiments, Ring D’ is phenyl. In some embodiments, Ring D’ is 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring D’ is 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[00114] As defined above and described herein, Ring W’ is an optionally substituted ring selected from a 5-9 membered saturated or partially unsaturated heterocyclyl.

[00115] In some embodiments, Ring W’ is an optionally substituted ring selected from a 5-9 membered saturated or partially unsaturated heterocyclyl. In some embodiments. Ring W’ is a 8- membered saturated heterocyclyl.

[00116] As defined above and described herein. Ring U’ is a ring selected from phenyl, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00117] In some embodiments, Ring U' is phenyl. In some embodiments, Ring U’ is a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring U’ is a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00118] As defined above and described herein, R^u’ is hydrogen, R^A, halogen, -CN, -NO₂, -OR, - SR, -NR₂, -SiR₃, -S(O)₂R, -S(O)₂NR₂, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)NROR, - CR₂NRC(O)R, -CR₂NRC(O)NR₂. -OC(O)R, -OC(O)NR₂, -OP(O)R₂. -OP(O)(OR)₂, -OP(O)(OR)NR₂, - OP(O)(NR₂)₂. -NRC(O)OR, -NRC(O)R, -NRC(O)NR₂, -NRS(O)₂R, -NP(O)R₂, -NRP(O)(OR)₂, - NRP(O)(OR)NR₂, -NRP(O)(NR₂)₂, or -NRS(O)₂R.

[00119] In some embodiments, R^u’ is hydrogen. In some embodiments, R^u’ is R^A. In some embodiments, R^u’ is halogen. In some embodiments, R^u’ is -CN. In some embodiments, R^u' is -NO₂. In some embodiments, R^u’ is -OR. In some embodiments, R^u’ is -SR. In some embodiments, R¹¹’ is -NR₂. In some embodiments. R^u’ is -SiR₃. In some embodiments, R^u' is -S(O)₂R. In some embodiments, R^u’ is -S(O)₂NR₂. In some embodiments, R^u’ is -S(O)R. In some embodiments. R^ir is -C(O)R. In some embodiments, R^u’ is -C(O)OR. In some embodiments, R^u’ is -C(O)NR₂. In some embodiments, R^u’ is -C(O)NROR. In some embodiments, R^u’ is -CR₂NRC(O)R. In some embodiments, R^u’ is - CR₂NRC(O)NR₂. In some embodiments, R^u’ is -OC(O)R. In some embodiments, R^u’ is -OC(O)NR₂. In some embodiments, R^u’ is -OP(O)R₂. In some embodiments, R^u’ is -OP(O)(OR)₂. In some embodiments, R^u? is -OP(O)(OR)NR₂. In some embodiments, R^u’ is -OP(O)(NR₂)₂. In some embodiments. R^u’ is - NRC(O)OR. In some embodiments, R^u’ is -NRC(O)R. In some embodiments, R^u’ is -NRC(O)NR₂. In some embodiments, R^u’ is -NRS(O)₂R. In some embodiments, R^u’ is -NP(O)R₂. In some embodiments, R^u’ is -NRP(O)(OR)₂. In some embodiments, R^u’ is -NRP(O)(OR)NR₂. In some embodiments, R^u’ is - NRP(O)(NR₂)₂. In some embodiments, R^u’ is -NRS(O)₂R. In some embodiments, R^u’ is -iPr. In some embodiments, R^u’ is -S(O)₂iPr. In some embodiments, R^u’ is -S(O)₂CH₃. [00120] As defined above and described herein, u is 0, 1, 2, 3, or 4.

[00121] In some embodiments, u is 0. In some embodiments, u is 1 . In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4.

[00122] As defined above and described herein, Ring V’ is an optionally substituted fused ring selected from a 6-membered aryl, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00123] In some embodiments, Ring V’ is an optionally substituted 6-membered aryl. In some embodiments, Ring V’ is an optionally substituted 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring V is an optionally substituted 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments. Ring V is a 6-membered aryl.

[00124] As defined above and described herein, Ring Z’ is a bivalent ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[00125] In some embodiments. Ring Z’ is phenylenyl. In some embodiments, Ring Z’ is a 4-7 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, Ring Z’ is a heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z’ is a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z’ is

. In some embodiments, Ring Z' is

. In some embodiments, Ring Z’ is

.

[00126] As defined above and described herein, R^z' is hydrogen, R^A, halogen, -CN, -NO2, -OR, - SR, -NR₂, -SiR₃, -S(O)₂R, -S(O)₂NR₂, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR₂. -C(O)NROR, - CR₂NRC(O)R, -CR₂NRC(O)NR₂. -OC(O)R, -OC(O)NR₂, -OP(O)R₂. -OP(O)(OR)₂, -OP(O)(OR)NR₂, - OP(O)(NR₂)₂, -NRC(O)OR, -NRC(O)R, -NRC(O)NR₂, -NRS(O)₂R, -NP(O)R₂, -NRP(O)(OR)₂, - NRP(O)(OR)NR₂, -NRP(O)(NR₂)₂, or -NRS(O)₂R.

[00127] In some embodiments, R^z’ is hydrogen. In some embodiments, R^z’ is R^A. In some embodiments, R^z’ is halogen. In some embodiments, R^z’ is -CN. In some embodiments. R^z? is -NO₂. In some embodiments, R^z’ is -OR. In some embodiments, R^z is -SR. In some embodiments, R^z is -NR₂. In some embodiments, R^z’ is -SiR₂. In some embodiments, R^z’ is -S(O)₂R. In some embodiments, R^z’ is -S(O)₂NR₂. In some embodiments, R^z’ is -S(O)R, -C(O)R. In some embodiments, R^z’ is -C(O)OR. In some embodiments, R^z’ is -C(O)NR₂. In some embodiments, R^z’ is -C(O)NROR. In some embodiments, R^z’ is -CR₂NRC(O)R. In some embodiments, R^z’ is -CR₂NRC(O)NR₂. In some embodiments, R^z’ is -OC(O)R. In some embodiments. R^z' is -OC(O)NR₂. In some embodiments, R^z' is -OP(O)R₂. In some embodiments. R^z’ is -OP(O)(OR)₂. In some embodiments, R^z’ is -OP(O)(OR)NR₂. In some embodiments, R^z’ is -OP(O)(NR₂)₂. In some embodiments, R^z’ is -NRC(O)OR. In some embodiments, R^z’ is -NRC(O)R. In some embodiments, R^z’ is -NRC(O)NR₂. In some embodiments, R^z’ is -NRS(O)₂R. In some embodiments, R^z’ is -NP(O)R₂. In some embodiments, R^z’ is -NRP(O)(OR)₂. In some embodiments, R^z’ is -NRP(O)(OR)NR₂. In some embodiments, R^z’ is -NRP(O)(NR₂)₂. hr some embodiments, R^z' is - NRS(O)₂R. In some embodiments, R^z’ is -CH₃. In some embodiments, R^z' is -Cl. In some embodiments, R^z? is -F.

[00128] As defined above and described herein, z is 0, 1, 2, 3 or 4.

[00129] In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4.

[00130] As defined above and described herein, n is 0 or 1.

[00131] In some embodiments, n is 0. In some embodiments, n is 1.

[00132] In some embodiments, L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1.50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -C(D)(H)-, -C(D)₂-, -Cy-, -O-, -N(R)-, -SI(R)₂-, -Si(OH)(R)-, -Si(OH)₂-, -P(O)(OR)-, -P(O)(R)-, - P(O)(NR₂) , -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)₂-, -N(R)S(O)₂-, -S(O)₂N(R)-, -N(R)C(O)-, -

optionally substituted bivalent ring selected from phenyl enyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl. a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered hctcroarylcnyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein r is 0. 1, 2, 3. 4, 5, 6, 7. 8, 9, or 10.

[00133] In some embodiments, each -Cy- is independently an optionally substituted bivalent phenylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic arylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 5-6 membered hctcroarylcnyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00134] In some embodiments, some embodiments, -Cy- is

[00135] In some embodiments,

n some embodiments, -Cy- is

In some embodiments, -Cy- is

In some embodiments. -Cy- is

In some embodiments, -Cy- is

. In some embodiments,

. In some embodiments, -

[00136] In some embodiments, -Cy- is

. In some embodiments, -Cy- is

. In some embodiments. -Cy- is

. In some embodiments,

In some embodiments, -Cy- is

. In some embodiments, -Cy- is

. In some embodiments,

n some em o mens, y s n some em o mens,

. In some embodiments,

[00137] In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, r is 7. In some embodiments, r is 8. In some embodiments, r is 9. In some embodiments, r is 10.

[00138] In some embodiments, L is a covalent bond. In some embodiments, L is

. In some embodiments, L is

In some embodiments, L is

In some embodiments, L is n some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

n some em o men s, s In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In 0

n some em o mens, s

o

n some em o mens, s

,

. In some embodiments, L is

In some embodiments, L is

some embodiments, L is

In some embodiments, L is

. In some embodiments, L is

In some embodiments, L is

. In some

In some embodiments, L is

. In some embodiments, L is

, In some embodiments, L is

In some embodiments, L is

In some embodiments. L is

In some embodiments, L is

n some em o mens, s n some

n some em o mens, s

embodiments, L

In some embodiments, L is

embodiments, L is

. In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

embodiments, L is

In some embodiments, L is

embodiments, L is

In some embodiments, L is

In some embodiments,

In some embodiments, L is

embodiments, L is

In some embodiments, L is

, ,

In some embodiments, L is

In some embodiments. L is

[00140] In some embodiments, X¹ is a covalent bond. In some embodiments, X¹ is -CH2-. In some embodiments, X¹ is -C(R)₂-. In some embodiments, X¹ is -C(O)-. In some embodiments, X¹ is -C(S)-. In some embodiments, X¹ is -CH(R)-. In some embodiments, X¹ is -CH(CF₃)-. In some embodiments, X¹ is -P(O)(OR)-. In some embodiments, X¹ is -P(O)(R)-. In some embodiments, X¹ is -P(O)(NR₂)-. In some embodiments, X¹ is -S(O)-. In some embodiments, X¹ is -S(O)₂-. In some embodiments, X¹ is

[00141] As defined above and described herein, X² is a carbon atom or silicon atom.

[00142] In some embodiments, X² is a carbon atom. In some embodiments, X² is a silicon atom.

[00143] As defined above and described herein, X³ is a bivalent moiety selected from -CH2-, -C(R)₂- , -N(R)-, -CF2-, -CHF-, -S-, -CH(R)-, -Si(R>)-, or-O-.

[00144] In some embodiments, X³ is -CH₂-. In some embodiments, X¹ is -C(R)₂- In some embodiments, X³ is -N(R)-. In some embodiments, X³ is -CF2-. In some embodiments, X³ is -CHF-. In some embodiments, X³ is -S-. In some embodiments, X³ is -CH(R)-. In some embodiments, X³ is - Si(R₂)-. In some embodiments, X³ is -O-.

[00145] As defined above and described herein. R¹ is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)₂R, -NR₂, -P(O)(OR)₂, -P(O)(NR₂)OR -P(O)(NR₂)₂, -SI(OH)₂R, -SI(OH)(R)₃, -SI(R)₃, an optionally substituted C1.4 aliphatic, or R¹ and X¹ or X⁴ are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur.

[00146] In some embodiments, R¹ is hydrogen. In some embodiments. R¹ is deuterium. In some embodiments. R¹ is halogen. In some embodiments. R¹ is -CN. In some embodiments, R¹ is -OR. In some embodiments, R¹ is -SR. In some embodiments, R¹ is -S(O)R. In some embodiments, R¹ is -S(O)₂R. In some embodiments, R¹ is -NR₂. In some embodiments, R¹ is -P(O)(OR)₂. In some embodiments, R¹ is -P(O)(NR₂)OR. In some embodiments, R¹ is -P(O)(NR₂)₂. In some embodiments, R¹ is -Si(OH)₂R. In some embodiments, R¹ is -Si(OH)(R)₂. In some embodiments, R¹ is -Si(R)₃. In some embodiments, R¹ is an optionally substituted C1-4 aliphatic. In some embodiments. R¹ and X¹ or X⁴ are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur.

[00147] As defined above and described herein, each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci-e aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[00148] In some embodiments, R is hydrogen. In some embodiments, R is deuterium. In some embodiments, R is optionally substituted Ci-6 aliphatic. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R is optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[00149] As defined above and described herein, each of R² and R^3a is independently hydrogen, deuterium, -R⁶, 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.

[00150] In some embodiments, R² and R^3a is independently hydrogen. In some embodiments, R² and R^3a is independently deuterium. In some embodiments, R² and R^3a is independently -R' In some embodiments, R² and R^3a is independently halogen. In some embodiments, R² and R^3a is independently - CN. In some embodiments, R² and R^3a is independently -NO₂. In some embodiments, R² and R^3a is independently -OR. In some embodiments, R² and R^3a is independently -Si(OH)₂R. In some embodiments, R² and R^3a is independently -Si(OH)R₂. In some embodiments, R² and R^3a is independently -SR. In some embodiments. R² and R^3a is independently -NR₂. In some embodiments, R² and R^3a is independently -SiR₂. In some embodiments, R² and R^3a is independently -S(O)₂R. In some embodiments, R² and R^3a is independently -S(O)₂NR₂. In some embodiments, R² and R^3a is independently -S(O)R. In some embodiments, R² and R^3a is independently -C(O)R. In some embodiments, R² and R^3a is independently - C(O)OR. In some embodiments, R² and R^3a is independently -C(O)NR₂. In some embodiments, R² and R^3a is independently -C(O)N(R)OR. In some embodiments, R² and R^3a is independently - C(R)₂N(R)C(O)R. In some embodiments, R² and R^3a is independently -C(R)₂N(R)C(O)NR₂. In some embodiments, R² and R^3a is independently -OC(O)R. In some embodiments, R² and R^3a is independently -OC(O)NR₂. In some embodiments, R² and R^3a is independently -OP(O)R₂. In some embodiments, R² and R^3a is independently -OP(O)(OR)₂. In some embodiments, R² and R^3a is independently -OP(O)(OR)NR₂. In some embodiments, R² and R^3a is independently -OP(O)(NR₂)₂-. In some embodiments, R² and R^3a is independently -N(R)C(O)OR. In some embodiments, R² and R^3a is independently -N(R)C(O)R. In some embodiments, R² and R^3a is independently -N(R)C(O)NR₂. In some embodiments, R² and R^3a is independently -NP(O)R₂. In some embodiments, R² and R^3a is independently -N(R)P(O)(OR)₂. In some embodiments, R² and R^3a is independently -N(R)P(O)(OR)NR₂. In some embodiments, R² and R^3a is independently -N(R)P(O)(NR₂)₂. In some embodiments, R² and R^3a is independently -N(R)S(O)₂R.

[00151] In some embodiments, R² and R^3a is independently -OH. In some embodiments, R² and R^3a is independently -NHz. In some embodiments, R² and R^3a is independently -CH2NH2. In some embodiments, R² and R^3a is independently -CH₂NHCOMe. In some embodiments, R² and R^3a is independently - CH2NHCONHMe. In some embodiments, R² and R^3a is independently -NHCOMe. In some embodiments, R² and R^3a is independently -NHCONHEt. In some embodiments, R² and R^3a is independently -Si Me?. In some embodiments. R² and R^3a is independently -SiMc₂OH. In some embodiments, R² and R^3a is independently -SiMe(OH)₂. In some embodiments R² and R^3a is independently

In some embodiments, R² and R^3a is independently Br. In some embodiments, R² and R^3a is independently Cl. In some embodiments, R² and R^3a is independently F. In some embodiments, R² and R^3a is independently Me. In some embodiments, R² and R^3a is independently -NHMe. In some embodiments, R² and R^3a is independently -NMe2. In some embodiments, R² and R^3a is independently -NHCCFEt. In some embodiments, R² and R^3a is independently -CN. In some embodiments, R² and R^3a is independently - CH Ph In some embodiments, R² and R^3a is independently -NHCO2/B11. In some embodiments, R² and R^3a is independently -CCEtBu. In some embodiments, R² and R^3a is independently -OMe. In some embodiments, R² and R^3a is independently -CF₃.

[00152] As defined above and described herein, R³ is hydrogen, deuterium, halogen, -CN, -NO2, -OR, -NR₂, -SR, -S(O)₂R, -S(O)₂NR₂ -S(O)R, -C(O)R, -C(O)OR. -C(O)NR₂, -C(O)NR(OR), -OC(O)R, - OC(O)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.

[00153] In some embodiments, R³ is hydrogen. In some embodiments, R³ is deuterium. In some embodiments, R³ is halogen. In some embodiments, R³ is -CN. In some embodiments, R³ is -NO2. In some embodiments, R³ is -OR. In some embodiments, R³ is -NR₂. In some embodiments. R³ is -SR. In some embodiments, R³ is -S(O)₂R. In some embodiments, R³ is -S(O)₂NR₂ In some embodiments, R³ is - S(O)R. In some embodiments, R³ is -C(O)R. In some embodiments, R³ is -C(O)OR. In some embodiments, R³ is -C(O)NR₂. In some embodiments, R³ is -C(O)NR(OR). In some embodiments, R³ is -OC(O)R. In some embodiments, R³ is -OC(O)NR₂. In some embodiments, R³ is -OP(O)(OR)₂. In some embodiments, R³ is -OP(O)(NR₂)₂. In some embodiments, R³ is -OP(O)(OR)NR₂. In some embodiments, R³ is - N(R)C(O)R. In some embodiments, R³ is -N(R)C(O)OR. In some embodiments, R³ is -N(R)C(O)NR₂. In some embodiments, R³ is -N(R)S(O)₂R. In some embodiments, R³ is -N(R)S(O)₂NR₂. In some embodiments, R³ is -N(R)P(O)(OR)₂. In some embodiments, R³ is -N(R)P(O)(OR)NR₂. In some embodiments, R³ is -P(O)(OR)₂. In some embodiments, R³ is -P(O)(NR₂)OR. In some embodiments, R³ is -P(O)(NR₂)₂. In some embodiments, R³ is -Si(OH)₂R. In some embodiments. R³ is -Si(OH)(R)₂. In some embodiments. R³ is -Si(R)3.

[00154] In some embodiments, R³ is methyl. In some embodiments, R³ is -OCH3. In some embodiments, R³ is chloro.

[00155] As defined above and described herein, each R⁴ is independently hydrogen, deuterium, -R⁶, 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.

[00156] In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is -R⁶. In some embodiments, R⁴ is halogen. In some embodiments, R⁴ is -CN. In some embodiments, R⁴ is -NO2. In some embodiments, R⁴ is -OR. In some embodiments, R⁴ is -SR. In some embodiments, R⁴ is -NR₂. In some embodiments, R⁴ is -S(O)₂R. In some embodiments, R⁴ is -S(O)₂NR₂. In some embodiments, R⁴ is - S(O)R. In some embodiments, R⁴ is -C(O)R. In some embodiments, R⁴ is -C(O)OR. In some embodiments. R⁴ is -C(O)NR₂. In some embodiments, R⁴ is -C(O)N(R)OR. In some embodiments, R⁴ is -OC(O)R. In some embodiments, R⁴ is -OC(O)NR₂. In some embodiments, R⁴ is -N(R)C(O)OR. In some embodiments, R⁴ is -N(R)C(O)R. In some embodiments, R⁴ is -N(R)C(O)NR₂. In some embodiments, R⁴ is -N(R)S(O)₂R. In some embodiments, R⁴ is -P(O)(OR)₂. In some embodiments, R⁴ is -P(O)(NR₂)OR. In some embodiments, R⁴ is -P(O)(NR₂)₂.

[00157] In some embodiments, R⁴ is methyl. In some embodiments, R⁴ is ethyl. In some embodiments, R⁴ is cyclopropyl.

[00158] As defined above and described herein, R⁵ is hydrogen, deuterium, an optionally substitute Ci. 4 aliphatic, or -CN.

[00159] In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is deuterium. In some embodiments, R⁵ is an optionally substituted C14 aliphatic. In some embodiments, R⁵ is -CN.

[00160] As defined above and described herein, each R⁶ is independently an optionally substituted group selected from C_1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. [00161] In some embodiments, R⁶ is an optionally substituted Ci-6 aliphatic. In some embodiments, R⁶ is an optionally substituted phenyl. In some embodiments, R’ is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R⁶ is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

[00162] As defined above and described herein. Ring A is a bi- or tricyclic ring selected from

[00163] In some embodiments, Ring In some embodiments. Ring A is some embodiments, Ring In some embodiments, Ring A is some embodiments, Ring In some embodiments, Ring A is

. , g , g some embodiments, Ring some embodiments, Ring A is some embodiments. Ring In some embodiments. Ring A is

. some embodiments, Ring

some embodiments, Ring A is

, some embodiments, Ring A is

. ,

. ,

some embodiments, Ring

some embodiments, Ring some embodiments, Ring

some embodiments, Ring

some embodiments. Ring

some embodiments. Ring

some embodiments, Ring

, some embodiments,

[00165] As defined above and described herein, Ring B is a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5 -membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[00166] In some embodiments. Ring B is a fused 6-membered and. In some embodiments. Ring B is a fused 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is a fused 5 to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring B is fused 5 to 7-membered saturated or partially saturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments. Ring B is fused 5-membered heteroaryl with 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

[00167] In some embodiments. Ring B is

In some embodiments. Ring B is

[00169] In some embodiments, Ring

In some embodiments, Ring B is

, In some embodiments, Ring B is

, [00171] In some embodiments. Ring

In some embodiments, Ring B is some embodiments, Ring

In some embodiments, Ring B is

some embodiments, Ring

[00173] As defined above and described herein, Ring C is a mono- or bicyclic ring selected from

4. Methods and Uses for Treating Disease

[00174] In some embodiments, the present disclosure provides a method for treating a disease, disorder or condition in a patient, comprising administering to the patient a therapeutically effective amount of a STAT3 degrader, as described herein, wherein the patient harbors one or more mutations to serine/threonine kinase 11 (SIKH) or KRAS. [00175] In some embodiments, the present disclosure provides a method for treating a disease, disorder or condition in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, as described herein, wherein the patient harbors one or more mutations to serine/threonine kinase 11 (STK11) or KRAS. In some embodiments, the present disclosure provides a method for treating a disease, disorder or condition in a patient, comprising administering to the patient a therapeutically effective amount of Compound B. as described herein, wherein the patient harbors one or more mutations to serine/threonine kinase 11 (STK11) or KRAS.

[00176] In some embodiments, the patient harbors an E293* mutation to STK11. In some embodiments, a patient harbors a D53Tfs* 11 mutation to STK11. In some embodiments, a patient harbors a G12C mutation to KRAS.

[00177] In some embodiments, the disease, disorder, or condition is cancer. In some embodiments, the cancer is selected from cancer is selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, skin melanomas, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), pancreatic cancer, non-small cell lung cancer (NSCLC), urothelial cancer, liver cancer, bile duct cancer, kidney cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, and hematological malignancies. In some embodiments, the disease, disorder, or condition is NSCLC. In some embodiments, a cancer is relapsed or refractory cancer. In some embodiments, a cancer is PD1 inhibitor resistant or refractory.

5. Processes and Intermediates

[00178] In some embodiments, the present invention provides a process for preparing Compound A ammonium hydrogen salt. In some embodiments, the process for preparing Compound A ammonium hydrogen salt comprises treating intermediate F:

Intermediate F under suitable salt exchange conditions to fonn Compound A ammonium hydrogen salt.

[00179] In some embodiments, the suitable salt exchange conditions used to prepare Compound A ammonium hydrogen salt from intermediate F include conditions known in the art to exchange a DIPEA salt with an ammonium salt. In some embodiments, the suitable salt exchange conditions include subjecting intermediate F to an ammonium source, such as a solution containing ammonium hydrogen carbonate. In some embodiments, the suitable salt exchange conditions are described in the examples herein, such as Example 1.

[00180] In some embodiments, the process for preparing Compound A ammonium hydrogen salt further comprises preparing Intermediate F. the process comprising treating intermediate D:

with intermediate E:

Intermediate E to form Intermediate F.

[00181] In some embodiments, the process for preparing intermediate F from intemrediates D and F further comprises a base, such DIPEA. In some embodiments, the process for preparing intermediate F from intermediates D and F is described in the examples herein, such as Example 1.

[00182] In some intermediate embodiments, the present invention provides the DIPEA salt of Compound A (intermediate F):

Intermediate F

[00183] The following examples are provided for illustrative purposes only and are not to be construed as limiting this invention in any manner.

EXEMPLIFICATION

Example 1. Synthesis of Compound A

[00184] Compound A can be prepared by methods known to one of ordinary skill in the art, for example, as described in WO 2020/206424, the contents of which, including below intermediates A, B, C, D, and E, are incorporated herein by reference in their entireties.

[00185] Step 1. Preparation of Intermediate C. To a room temperature solution of the amine A. the acid B and 2-chloro-4,6-dimethoxy-1.3,5-triazine (CDMT) in dichloromethane was added 4-methylmorpholine (NMM) slowly. The reaction mixture was stirred at this temperature until complete conversion of A to C is achieved (IPC, reaction conversion monitoring by HPLC). Upon reaction completion, deionized water was added. Tire layers were separated, and the organic phase was successively washed with aqueous solutions of sodium phosphate monobasic, sodium bicarbonate, and sodium chloride. The organic layer was dried over magnesium sulfate and the filtrate was tested for water content (IPC for water content by KF). The organic stream was concentrated down, and the resulting solution was used as is for step 2 (IPC, purity, and assay by HPLC).

[00186] Step 2. Preparation of Intermediate D. To a cold solution of the intermediate C in dichloromcthanc (DCM) was slowly added a solution of hydrochloric acid in dioxane. Tire reaction mixture was warmed to room temperature for at least 5 hours. Upon reaction completion (IPC. reaction monitoring by HPLC), the resulting solid was filtered, rinsed with DCM, and dried (IPC. water content by KF. purity by HPLC, and residual solvents by GC).

[00187] Step 3. Preparation of Intermediate F. To a cold suspension of the HO salt of intermediate D in MeCN w as added N,N-diisopropylethylamine (DIPEA) followed by a solution of intermediate E in N- methylpyrrolidinone (NMP) and a second charge of DIPEA. The reaction mixture w as wanned to room temperature and stirred until complete conversion of intennediate D to F was achieved (IPC, reaction conversion monitoring by HPLC). The reaction mixture was transferred slowly to a room temperature solution of MeCN and the DIPEA salt of Compound A (intermediate F) precipitated. The suspension was then stirred at room temperature for at least 1 hour before filtration. The filtered solid was rinsed with MeCN and dried (IPC, purity by HPLC, residual solvents by GC).

[00188] Step 3’. Preparation of Compound A ammonium hydrogen salt. Intennediate F was purified by reverse phase preparative chromatography using ammonium bicarbonate and MeCN as the eluants (IPC, fraction purity by HPLC). Tire conforming fractions were combined and concentrated. The combined conforming fractions were concentrated (IPC, purity by HPLC) and lyophilized to yield Compound A ammonium hydrogen salt (IPC, water content by KF, residual solvent (MeCN) by GC, residual solvent (NMP and DIPEA) by GC).

Example 2. STAT3 degrader inhibits tumor growth in patient-derived xenograft models of STK11 (LBK1) mutant anti PD1 refractory non-small cell lung cancer (NSCLC)

[00189] Overall survival of KRAS-driven patient-derived xenografts (PDX) of STK11 (LBK1) mutants were evaluated, and STK11 mutation was shown to be a genomic detenninant of poor clinical outcome, independent of KRAS status (FIG. 1 and FIG. 2).

[00190] Using KRAS-driven PDX with mutations in STK11 (LBK1) were used to assess the efficacy of a STAT3 degrader in vivo. In vivo evaluation was carried out in models through 3-4 week efficacy studies. 2 models (wt and mutant); 2 groups per model (vehicle or Compound B, 30 mpk IV, QW) with n=10 mice per group. STAT3 degradation leads to anti-tumor response in the STK11 mutant model, not WT; and STAT3 pathway is inhibited comparably in both genotypes (FIG. 3 and FIG. 4).

[00191] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

1. A method for treating a disease, disorder or condition in a patient, comprising administering to the patient a STAT3 degrader; wherein the patient harbors one or more mutations to serine/threonine kinase 11 (STK11) or KRAS.

2. The method of claim 1, wherein the STAT3 degrader is a compound of formulae II-r”-l, II-r”-2, II-r ”-3, II-r ”-4, Il-r ”-5, II-r ”-6, II-r ”-8, II-r ”-9, II-r ” 10, II-r”-ll, or II-r ”-12

3. Tire method of claim 1 or 2, wherein the STAT3 degrader is Compound A, or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 or 2, wherein the STAT3 degrader is Compound B, or a pharmaceutically acceptable salt thereof.

5. The method of any one of claims 1-4, comprising administering to the patient the STAT3 degrader, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and/or carrier.

6. The method of any one of claims 1-5, wherein the patient harbors one or more mutations to STK11.

7. Tire method of claim 6, wherein the patient harbors an E293* mutation to STK11.

8. The method of claim 6 or 7, wherein the patient harbors a D53Tfs* 11 mutation to STK11.

9. The method of any one of claims 1 -8, wherein the patient harbors one or more mutations to KRAS.

10. Tire method of claim 9, wherein the patient harbors a G12C mutation to KRAS.

11. The method of any one of claims 1-10. wherein the disease, disorder or condition is a STK11 or

KRAS-mediated disease, disorder or condition.

12. The method of any one of claims 1-11, wherein the disease, disorder or condition is cancer.

13. The method of claim 12, wherein the cancer is selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, skin melanomas, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), pancreatic cancer, non-small cell lung cancer (NSCLC), urothelial cancer, liver cancer, bile duct cancer, kidney cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, and hematological malignancies.

14. The method of claim 12, wherein the cancer is non-small cell lung cancer.

15. The method of any one of claims 12-14, wherein the cancer is resistant or refractory to PD1 inhibitors.