WO2024006776A1 - Agents de dégradation des récepteurs alpha des oestrogènes et leur utilisation médicale - Google Patents

Agents de dégradation des récepteurs alpha des oestrogènes et leur utilisation médicale Download PDF

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WO2024006776A1
WO2024006776A1 PCT/US2023/069192 US2023069192W WO2024006776A1 WO 2024006776 A1 WO2024006776 A1 WO 2024006776A1 US 2023069192 W US2023069192 W US 2023069192W WO 2024006776 A1 WO2024006776 A1 WO 2024006776A1
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compound
pharmaceutically acceptable
acceptable salt
ring
iii
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PCT/US2023/069192
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Alexander M. Taylor
Kurt ARMBRUST
Christopher A. Lepre
Thomas H. MCLEAN
Paul R. FLEMING
Rulin Ma
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Relay Therapeutics, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • the present invention relates to compounds and methods useful for the modulation of estrogen receptor alpha (“ERD”) via ubiquitination and/or degradation by compounds according to the present invention.
  • the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
  • ER Estrogen Receptors
  • the Estrogen Receptors (ER) are members of the nuclear hormone receptor superfamily. Two classes of ER exist: estrogen receptor alpha (ER ⁇ ) and estrogen receptor beta (ER ⁇ ), encoded by the ESR1 and the ESR2 genes respectively.
  • ER ⁇ and ER ⁇ are ligand-activated transcription regulators activated by the hormone estrogen (e.g.
  • ERs The ligand of ER, estrogen, is synthesized by the enzyme aromatase.
  • aromatase The ligand of ER, estrogen, is synthesized by the enzyme aromatase.
  • ERs are largely inactive and located in the cytosol of the cell. Upon estrogen binding, ERs migrate to the nucleus, form dimers and bind to specific genomic sequences called Estrogen Response Elements (ERE). ERs further recruit co-regulators to form a multi-protein complex that regulates the transcription of multiple target genes involved in the cellular proliferation and differentiation in target tissues.
  • ER ⁇ expression is mainly restricted to reproductive tissues such as uterus, ovary, breast as well as bone and white adipose tissue.
  • ER ⁇ is also expressed in more than 70% of breast cancer and is a major contributor to the pathophysiology of this cancer. Tumors harboring high levels of ER ⁇ are classified as ER-positive breast cancer. The etiological role of estrogen and ER ⁇ in breast cancer is well established and modulation of the ER ⁇ signaling pathway through endocrine therapy is a cornerstone of ER+ breast cancer treatment.
  • Ubiquitin-Proteasome Pathway is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases.
  • E3 ubiquitin ligases The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.
  • E3 ubiquitin ligases There are over 600 E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487) titled “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling.”; Bemdsen et al. (Nat. Struct. Mol.
  • UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation.
  • the pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman’s syndrome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting.
  • the UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation.
  • Bifunctional compounds composed of a target protein binding ligand and an E3 ubiquitin ligase ligand induce 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, l7(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l):40- 46).
  • De-novo and acquired resistance to endocrine therapies can arise through distinct mechanisms such as ER ⁇ coregulators overexpression or post-translational modification of ER ⁇ and its coregulators upon activation of intercellular signaling pathways. All contribute to hypersensitivity of ER ⁇ to low circulating estrogen levels.
  • ERD estrogen receptor alpha
  • the present application relates novel bifunctional compounds, which function to recruit ERD to E3 Ubiquitin Ligase for degradation, and methods of preparation and uses thereof.
  • the present disclosure provides bifunctional compounds, which find utility as modulators of targeted ubiquitination of ERD, which is then degraded and/or otherwise inhibited by the bifunctional compounds as described herein.
  • An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation/inhibition of ERD.
  • the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as cancer, e.g., breast cancer.
  • the present application further relates to targeted degradation of ERD through the use of bifunctional molecules, including bifunctional molecules that link a cereblon-binding moiety to a ligand that binds ERD.
  • compounds of this invention, and pharmaceutically acceptable compositions thereof are effective as degraders of ERD.
  • Such compounds have the general formula I-a: I-a or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.
  • Compounds of the present invention, and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders, or conditions, associated with regulation of signaling pathways implicating ERD. Such diseases, disorders, or conditions include those described herein.
  • Compounds provided by this invention are also useful for the study of ERD enzymes in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new ERD inhibitors or ERD degraders or other regulators of ERD-mediated transcription in vitro or in vivo.
  • the present disclosure provides a pharmaceutical composition comprising a compound of formula I-a, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.
  • the present disclosure provides a method of treating an ER ⁇ - mediated disorder comprising administering to a patient in need thereof a compound of formula I- a, or composition comprising said compound.
  • the present disclosure provides a process for providing a compound of formula I-a, or synthetic intermediates thereof.
  • the present disclosure provides a process for providing pharmaceutical compositions comprising compounds of formula I-a. DETAILED DESCRIPTION 1.
  • the present disclosure provides a compound of formula I-a: I-a or a pharmaceutically acceptable salt thereof, wherein: ERBM is selected from and , wherein indicates the site of attachment of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety and indicates a single or double bond; each of X 1 and X 2 is independently –CH2–, –CH(R A1 )–, –C(R A1 )2–, –O–, –S–, –S(O)–, –S(O) 2 –, or –N(R A2 )–; each instance of R 1 , R 2 , R A1 , and R A2 is independently R A or R B , and is substituted by 0-4 instances of R C ;
  • 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” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms.
  • aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (or “carbocycle”) refers to a monocyclic C 3 –C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • 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.
  • alkyl refers to a monovalent aliphatic hydrocarbon radical having a straight chain, branched chain, monocyclic moiety, or polycyclic moiety or combinations thereof, wherein the radical is optionally substituted at one or more carbons of the straight chain, branched chain, monocyclic moiety, or polycyclic moiety or combinations thereof with one or more substituents at each carbon, wherein the one or more substituents are independently C 1 –C 10 alkyl.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.
  • the term “lower alkyl” refers to a C 1-4 straight or branched alkyl group.
  • lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • ylenyl refers to a bi-valent radical (i.e., a radical with two attachment points) of the moiety to which “ylenyl” is appended.
  • heterocyclylenyl refers to a heterocycle with two points of attachment to the rest of the molecule. One or both points of attachment could be through carbon atoms or heteroatoms.
  • phenylenyl refers to a divalent form of an optionally substituted phenyl group by itself or in part of another group
  • cycloalkylenyl refers to a divalent form of an optionally substituted cycloalkyl group by itself or part of another group.
  • C 1-8 or C 1-6 , or C 1-4 ) bivalent saturated or unsaturated, straight or branched, hydrocarbon chain
  • alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH 2 ) n –, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • heteroaryl or “heteroaromatic”, unless otherwise defined, as used herein refers to a monocyclic aromatic 5-6 membered ring containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur, or an 8-10 membered polycyclic ring system containing one or more heteroatoms, wherein at least one ring in the polycyclic ring system is aromatic, and the point of attachment of the polycyclic ring system is through a ring atom on an aromatic ring.
  • a heteroaryl ring may be linked to adjacent radicals though carbon or nitrogen.
  • heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, indole, etc.
  • 1,2,3,4-tetrahydroquinoline is a heteroaryl ring if its point of attachment is through the benzo ring, e.g.: .
  • heterocyclyl or “heterocyclic group”, unless otherwise defined, refer to a saturated or partially unsaturated 3-10 membered monocyclic or 7-14 membered polycyclic ring system, including bridged or fused rings, and whose ring system includes one to four heteroatoms, such as nitrogen, oxygen, and sulfur.
  • a heterocyclyl ring may be linked to adjacent radicals through carbon or nitrogen.
  • partially unsaturated in the context of rings, unless otherwise defined, refers to a monocyclic ring, or a component ring within a polycyclic (e.g.
  • bicyclic, tricyclic, etc.) ring system wherein the component ring contains at least one degree of unsaturation in addition to those provided by the ring itself, but is not aromatic.
  • partially unsaturated rings include, but are not limited to, 3,4-dihydro-2H-pyran, 3-pyrroline, 2-thiazoline, etc.
  • the other component rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on a partially unsaturated component ring.
  • 1,2,3,4-tetrahydroquinoline is a partially unsaturated ring if its point of attachment is through the piperidino ring, e.g.: .
  • saturated in the context of rings, unless otherwise defined, refers to a 3-10 membered monocyclic ring, or a 7-14 membered polycyclic (e.g. bicyclic, tricyclic, etc.) ring system, wherein the monocyclic ring or the component ring that is the point of attachment for the polycyclic ring system contains no additional degrees of unsaturation in addition to that provided by the ring itself.
  • monocyclic saturated rings include, but are not limited to, azetidine, oxetane, cyclohexane, etc.
  • a saturated ring is part of a polycyclic ring system
  • the other component rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on a saturated component ring.
  • 2-azaspiro[3.4]oct-6-ene is a saturated ring if its point of attachment is through the azetidino ring, e.g.: .
  • alkylene refers to a divalently bonded version of the group that the suffix modifies.
  • alkylene is a divalent alkyl group connecting the groups to which it is attached.
  • bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • 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 otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups.
  • any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • exemplary bridged bicyclics include: [0043]
  • compounds of the disclosure may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Suitable monovalent substituents on Rq are independently halogen, —(CH 2 ) 0–2 R z , –(haloR z ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR z , –(CH 2 ) 0–2 CH(OR z ) 2 ; –O(haloR z ), –CN, –N 3 , –(CH 2 ) 0–2 C(O)R z , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR z , –(CH 2 ) 0–2 SR z , –(CH 2 ) 0–2 SH, –(CH 2 ) 0–2 NH 2 , –(CH 2 ) 0
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2) 2– 3 O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, –R z , -(haloR z ), –OH, –OR z , –O(haloR z ), –CN, –C(O)OH, –C(O)OR z , –NH 2 , –NHR z , –NR z 2, or –NO 2 , wherein each R z is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ⁇ , –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O) ⁇ ⁇ ⁇ R , –C(O)CH 2 C(O)R , –S(O) 2 R , –S(O) 2 NR ⁇ 2, –C(S)NR ⁇ 2, –C(NH)NR ⁇ 2, or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, –R z , -(haloR z ), –OH, –OR z , –O(haloR z ), –CN, –C(O)OH, –C(O)OR z , –NH 2 , –NHR z , –NR z 2, or –NO 2 , wherein each R z is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “isomer” as used herein refers to a compound having the identical chemical formula but different structural or optical configurations.
  • stereoisomer refers to and includes isomeric molecules that have the same molecular formula but differ in positioning of atoms and/or functional groups in the space. All stereoisomers of the present compounds (e.g., those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this disclosure.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. It is understood that tautomers encompass valence tautomers and proton tautomers (also known as prototropic tautomers). Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • Proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Unless otherwise stated, all tautomers of the compounds of the disclosure are within the scope of the disclosure.
  • isotopic substitution refers to the substitution of an atom with its isotope.
  • isotope refers to an atom having the same atomic number as that of atoms dominant in nature but having a mass number (neutron number) different from the mass number of the atoms dominant in nature. It is understood that a compound with an isotopic substitution refers to a compound in which at least one atom contained therein is substituted with its isotope.
  • Atoms that can be substituted with its isotope include, but are not limited to, hydrogen, carbon, and oxygen.
  • Examples of the isotope of a hydrogen atom include 2 H (also represented as D) and 3 H.
  • Examples of the isotope of a carbon atom include 13 C and 14 C.
  • Examples of the isotope of an oxygen atom include 18 O.
  • all isotopic substitution of the compounds of the disclosure are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.
  • a warhead moiety, R W of a provided compound comprises one or more deuterium atoms.
  • 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. Exemplary pharmaceutically acceptable salts are found, e.g., in Berge, et al. (J. Pharm. Sci. 1977, 66(1), 1; and Gould, P.L., Int. J. Pharmaceutics 1986, 33, 201-217; (each hereby incorporated by reference in its entirety). [0054] Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 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.
  • Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound:acid is respectively 2:1.
  • Exemplary hemi-salts are those salts derived from acids comprising two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid and citric acid.
  • Other exemplary hemi-salts are those salts derived from diprotic mineral acids such as sulfuric acid.
  • Exemplary preferred hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemisuccinate.
  • an “effective amount”, “sufficient amount” or “therapeutically effective amount” as used herein is an amount of a compound that is sufficient to effect beneficial or desired results, including clinical results.
  • the effective amount may be sufficient, e.g., to reduce or ameliorate the severity and/or duration of afflictions related to ERD signaling, or one or more symptoms thereof, prevent the advancement of conditions or symptoms related to afflictions related to ERD signaling, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy.
  • An effective amount also includes the amount of the compound that avoids or substantially attenuates undesirable side effects.
  • Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminution of extent of disease or affliction, a stabilized (i.e., not worsening) state of disease or affliction, preventing spread of disease or affliction, delay or slowing of disease or affliction progression, amelioration or palliation of the disease or affliction state and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms.
  • 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.
  • the phrase “in need thereof” refers to the need for symptomatic or asymptomatic relief from conditions related to ERD singaling or that may otherwise be relieved by the compounds and/or compositions of the disclosure. 3.
  • the present disclosure provides a compound of formula I-a: or a pharmaceutically acceptable salt thereof, wherein: ERBM is selected from , indicates the site of attachment of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety and indicates a single or double bond; each of X 1 and X 2 is independently each instance of R 1 , R 2 , R A1 , and R A2 is independently R A or R B , and is substituted by 0-4 instances of R C ; each instance of R 3 is independently R A or R B , and is substituted by 0-4 instances of R C , or two R 3 groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R A is independently oxo, deuterium, halogen, –CN
  • LBM is an E3 ligase ligand.
  • E3 ligase ligands are well known to one of ordinary skill in the art and include those described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed. 2016, 55, 1966; T. Uehara et al.
  • L is a bivalent moiety that connects ERBM to LBM.
  • L moieties are well known to one of ordinary skill in the art and include those described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed. 2016, 55, 1966; T. Uehara et al.
  • the present disclosure provides a compound of formula I-b: or a pharmaceutically acceptable salt thereof, wherein: the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety and indicates a single or double bond; each of X 1 and X 2 is independently –CH 2 –, –CH(R A1 )–, –C(R A1 ) 2 –, –O–, –S–, –S(O)–, –S(O) 2 –, each instance of R 1 , R 2 , R 4 , R 5 , R A1 , and R A2 is independently R A or R B , and is substituted by 0-4 instances of R C ; each instance of R 3 is independently R A or R B , and is substituted by 0-4 instances of R C , or two R 3 groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused
  • the present disclosure provides a compound of formula I-c: or a pharmaceutically acceptable salt thereof, wherein: ERBM is selected from , indicates the site of attachment of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety and indicates a single or double bond; each of X 1 and X 2 is independently –CH 2 –, –CH(R A1 )–, –C(R A1 ) 2 –, –O–, –S–, –S(O)–, –S(O) 2 –, or –N(R A2 )–; each instance of R 1 , R 2 , R 4 , R 5 , R A1 , and R A2 is independently R A or R B , and is substituted by 0-4 instances of R C ; each instance of R 3 is independently R A or R B , and is substituted by 0-4 instances of R C ; each instance of R 3 is independently R A or R B
  • ERBM is an ERD binding moiety capable of binding to ERD ⁇
  • ERBM is selected from , wherein indicates the site of attachment of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety and indicates a single or double bond.
  • ERBM is selected from , wherein indicates the site of attachment of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety and indicates a single or double bond.
  • ERBM is
  • ERBM is some embodiments, . In some embodiments, ERBM is
  • ERBM is embodiments, . In some embodiments, ERBM is In some embodiments, . In some embodiments, ERBM is
  • ERBM is some embodiments, . In some embodiments, ERBM is some embodiments, some embodiments, ERBM is embodiments, . In some embodiments, ERBM is
  • ERBM is
  • ERBM is
  • ERBM is
  • the compound is a compound of formula I-d or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula I-e or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula I-f, I-g, I-h, I-i, I-j or I- k: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R 1 , R 2 , R 3 , X 1 , X 2 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the compound is a compound of formula I-f, I-g, I-i or I-j, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula I-f, I-g or I-i, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula I-f, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula I-g, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula I-h, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula I-i, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula I-j, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula I-k, or a pharmaceutically acceptable salt thereof.
  • compounds of formula I-l or I-m: or a pharmaceutically acceptable salt thereof wherein each of Ring B, R 1 , R 2 , R 3 , X 1 , X 2 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the compound is a compound of formula I-l, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula I-m, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula I-n, I-o, I-q or I-r, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula I-n, I-o or I-q, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula I-n, or a pharmaceutically acceptable salt thereof.
  • each of X 1 and X 2 is independently –CH 2 –, –CH(R A1 )–, – [0096] In some embodiments, X 1 is selected from –CH 2 –, –CH(R A1 )–, –C(R A1 ) 2 –, –O–, –S–, – S(O) 2 –, and –N(R A2 )–, provided that X 1 and X 2 cannot both be heteroatoms simultaneously. [0097] In some embodiments, X 1 is selected from –CH 2 – and –O– provided that X 1 and X 2 cannot both be heteroatoms simultaneously.
  • X 1 is –CH 2 –. In some embodiments, X 1 is –CH(R A1 )–. In some embodiments, X 1 is –C(R A1 ) 2 –. In some embodiments, X 1 is –O– provided that X 2 is not a heteroatom. In some embodiments, X 1 is –S– provided that X 2 is not a heteroatom. In some embodiments, X 1 is –S(O)– provided that X 2 is not a heteroatom. In some embodiments, X 1 is – S(O) 2 – provided that X 2 is not a heteroatom.
  • X 1 is –N(R A2 )– provided that X 2 is not a heteroatom.
  • X 1 is selected from the groups depicted in the compounds in Table 1.
  • X 2 is selected from –CH(R A1 )–, –C(R A1 ) 2 –, –O–, –S–, –S(O) 2 –, and –N(R A2 )–.
  • X 2 is selected from –CH(R A1 )–, –C(R A1 ) 2 – and –O–.
  • X 2 is selected from the groups depicted in the compounds in Table 1.
  • each instance of R 1 , R 2 , R 4 , R 5 , R A1 , and R A2 is independently R A or R B , and is substituted by 0-4 instances of R C .
  • R 1 is R A substituted by 0-4 instances of R C .
  • R 1 is R B substituted by 0-4 instances of R C .
  • each R 1 is independently selected from deuterium, C 1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –SR, –OR, –NR 2 , –S(O) 2 R, – S(O) 2 NR 2 , –S(O)R, –S(O)NR 2 , –S(O)(NR)R, –C(O)OR, –C(O)NR 2 , –C(O)N(R)OR, – OC(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR 2 , –N(R)S(O) 2 NR 2 and –N(R)S(O) 2 R, wherein R is –H or a C 1-6 aliphatic chain substituted with 0-3 instances of halo.
  • each R 1 is independently selected from –Me, –Et, –F, –Cl, –SCF 3 , –OCF 3 , –CF 3 , –CN, –OH, –OMe, –NH 2 , –NHMe and –NMe 2 .
  • R 1 is selected from fluoro and methyl. In some embodiments, R 1 is fluoro. In some embodiments, R 1 is methyl.
  • R 1 is selected from the groups depicted in the compounds in Table 1.
  • R 2 is R A substituted by 0-4 instances of R C .
  • R 2 is R B substituted by 0-4 instances of R C .
  • each R 2 is independently selected from deuterium, C 1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , – S(O)R, –S(O)NR 2 , –S(O)(NR)R, –C(O)OR, –C(O)NR 2 , –C(O)N(R)OR, –OC(O)NR 2 , – N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR 2 , –N(R)S(O) 2 NR 2 and –N(R)S(O) 2 R, wherein R is – H or a C 1-6 aliphatic chain,
  • each R 2 is independently selected from –Me, –Et, –F, –Cl, –CF 3 , – CHF 2 , –CN, –OH, –OMe, –OCF 3 , –SCF 3 , –NH 2 , –NHMe and –NMe 2 .
  • each R 2 is independently selected from –Me, –Et, –F, –Cl, –CF 3 , – CN, –OH, –OMe, –NH 2 , –NHMe and –NMe 2 .
  • each R 2 is independently selected from –F, –Cl, –CF 3 , –CHF 2 , – OH, –OCF 3 , and –SCF 3 .
  • each R 2 is independently selected from –F, –Cl and –SCF 3 .
  • R 2 is methyl.
  • R 2 is trifluoromethyl.
  • R 2 is fluoro.
  • R 2 is chloro.
  • R 2 is –SCF 3 .
  • R 2 is –OH.
  • R 2 is – OCF 3 .
  • R 2 is –CHF 2 .
  • R 2 is selected from the groups depicted in the compounds in Table 1.
  • R 4 is R A substituted by 0-4 instances of R C .
  • R 4 is R B substituted by 0-4 instances of R C .
  • each R 4 is independently selected from deuterium, C 1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , – S(O)R, –S(O)NR 2 , –S(O)(NR)R, –C(O)NR 2 , –C(O)N(R)OR, –OC(O)NR 2 , –N(R)C(O)OR, – N(R)C(O)R, –N(R)C(O)NR 2 , –N(R)S(O) 2 NR 2 and –N(R)S(O) 2 R, wherein R is –H or a C 1-6 aliphatic chain.
  • each R 4 is independently selected from –Me, –Et, –F, –Cl, –CF 3 , – CN, –OH, –OMe, –NH 2 , –NHMe and –NMe 2 .
  • R 4 is fluoro.
  • R 4 is selected from the groups depicted in the compounds in Table 1.
  • R 5 is R A substituted by 0-4 instances of R C .
  • R 5 is R B substituted by 0-4 instances of R C .
  • each R 5 is independently selected from deuterium, C 1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , – S(O)R, –S(O)NR 2 , –S(O)(NR)R, –C(O)NR 2 , –C(O)N(R)OR, –OC(O)NR 2 , –N(R)C(O)OR, – N(R)C(O)R, –N(R)C(O)NR 2 , –N(R)S(O) 2 NR 2 and –N(R)S(O) 2 R, wherein R is –H or a C 1-6 aliphatic chain.
  • each R 5 is independently selected from –Me, –Et, –F, –Cl, –CF 3 , – CN, –OH, –OMe, –NH 2 , –NHMe and –NMe 2 .
  • each R 5 is independently selected from –Me and –F.
  • R 5 is selected from the groups depicted in the compounds in Table 1.
  • R A1 is R A substituted by 0-4 instances of R C .
  • R A1 is R B substituted by 0-4 instances of R C .
  • each R A1 is independently selected from deuterium, C 1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , – S(O)R, –S(O)NR 2 , –S(O)(NR)R, –C(O)NR 2 , –C(O)N(R)OR, –OC(O)NR 2 , –N(R)C(O)OR, – N(R)C(O)R, –N(R)C(O)NR 2 , –N(R)S(O) 2 NR 2 and –N(R)S(O) 2 R, wherein R is –H or a C 1-6 aliphatic chain.
  • each R A1 is independently selected from –Me, –Et, –F, –Cl, –CF 3 , –CN, –OH, –OMe, –NH 2 , –NHMe and –NMe 2 .
  • each R A1 is independently selected from –Me, –F, –OH and –OMe.
  • each R A1 is independently selected from –Me and –F.
  • each R A1 is independently –F.
  • each R A1 is independently – Me.
  • R A1 is selected from the groups depicted in the compounds in Table 1.
  • R A2 is R A substituted by 0-4 instances of R C .
  • R A2 is R B substituted by 0-4 instances of R C .
  • each R A2 is independently selected from deuterium, C 1-6 aliphatic chain substituted with 0-3 instances of halo, –S(O) 2 R, –S(O) 2 NR 2 , –S(O)R, –S(O)NR 2 , – S(O)(NR)R, –C(O)NR 2 , –C(O)OR, and –C(O)R, wherein R is –H or a C 1-6 aliphatic chain.
  • each R A2 is independently selected from –Me, –Et, –CH 2 CF 3 , – S(O) 2 Me, –S(O) 2 NMe 2 , –S(O)Me, –S(O)NMe 2 , –C(O)NMe 2 , –C(O)NR 2 , –C(O)OMe, and – C(O)Me.
  • each R A2 is independently selected from –Me, –CH 2 CF 3 , and – C(O)Me.
  • each R A2 is independently selected from –Me and –C(O)Me.
  • each R A1 is independently –C(O)Me. In some embodiments, each R A1 is independently –Me.
  • R A2 is selected from the groups depicted in the compounds in Table 1.
  • R 3 is independently R A or R B , and is substituted by 0-4 instances of R C , or two R 3 groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur which is is substituted by 0-4 instances of R C .
  • R 3 is R A substituted by 0-4 instances of R C .
  • R 3 is R B substituted by 0-4 instances of R C .
  • two R 3 groups are taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur which is is substituted by 0-4 instances of R C . [0142] In some embodiments, two R 3 groups are taken together to form . In some embodiments, two R 3 groups are taken together to form .
  • each R 3 is independently selected from deuterium, C 1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , – S(O)R, –S(O)NR 2 , –S(O)(NR)R, –C(O)OR, –C(O)NR 2 , –C(O)N(R)OR, –OC(O)NR 2 , – N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR 2 , –N(R)S(O) 2 NR 2 , –N(R)S(O) 2 R and –B(OR) 2 , wherein R is –H or a C 1-6 aliphatic chain.
  • each R 3 is independently selected from deuterium, C 1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , – S(O)R, –S(O)NR 2 , –S(O)(NR)R, –C(O)OR, –C(O)NR 2 , –C(O)N(R)OR, –OC(O)NR 2 , – N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR 2 , –N(R)S(O) 2 NR 2 and –N(R)S(O) 2 R, wherein R is – H or a C 1-6 aliphatic chain.
  • each R 3 is phenyl. In some embodiments, each R 3 is substituted or unsubstituted phenyl. . In some embodiments, each R 3 is substituted with 1-4 substituents each independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 haloalkoxy. In some embodiments, each R 3 is phenyl substituted with 1-3 halogen (e.g., fluoro). In some embodiments, R 3 is fluorophenyl. In some embodiments, R 3 is , . In some embodiments, R 3 is di-fluorophenyl. In some embodiments, embodiments, R 3 is .
  • R 3 is embodiments, each R 3 is 5-8 membered aryl fused ring. In some embodiments, each R 3 is . [0146] In some embodiments, each R 3 is a 5-6 membered monocyclic heteroaryl ring. In some embodiments, each R 3 is . In some embodiments, each R 3 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, each R 3 is , .
  • each R 3 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring optionally substituted with 1-4 substituents each independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1- 6 haloalkoxy. In some embodiments, each R 3 is . In some embodiments, each R 3 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring. In some embodiments, each R 3 is . In some embodiments, each R 3 is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, each R 3 is .
  • each R 3 is independently selected from –Me, –Et, , B(OH) 2 .
  • each R 3 is independently selected from –Me, –Et, , CO 2 H, –CN, –OH, –OMe, –NH 2 , –NHMe, –NMe 2 and –B(OH) 2 .
  • each R 3 is independently selected from –Me, –Et, –F, –Cl, –CF 3 , –CO 2 H, –CN, –OH, –OMe, –NH 2 , –NHMe and, –NMe 2 .
  • each R 3 is independently selected from –Me, –Et, , [0151] In some embodiments, R 3 is independently selected from –Me, –Et, , , and –B(OH) 2 . [0152] In some embodiments, each R 3 is independently selected from –Me, –Et, , [0153] In some embodiments, R 3 is independently selected from –Me, –Et, , , [0154] In some embodiments, R 3 is independently selected from –Me. In some embodiments, R 3 is –Et. In some embodiments, R 3 . In some embodiments, R 3 . In some embodiments, R 3 is .
  • R 3 is . In some embodiments, R 3 is . In some embodiments, R 3 is . In some embodiments, R 3 is –CF 3 . In some embodiments, R . In some embodiments, R 3 is . In some embodiments, R 3 .In some embodiments, R 3 is . In some embodiments, R 3 is . In some embodiments, R 3 is . In some embodiments, R 3 is . In some mbodiments, R 3 e is . In some embodiments, R 3 is . In some [0155] In some embodiments, R 3 is –CF 3 .
  • R 3 is selected from –F, –OH, –OMe, –B(OH) 2 and –CO 2 H. [0157] In some embodiments, R 3 is selected from –F, –OH, and –CO 2 H. [0158] In some embodiments, R 3 is selected from –OH and –CO 2 H. [0159] In some embodiments, R 3 is –OH. In some embodiments, R 3 is –CO 2 H. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is –OMe. In some embodiments, R 3 is – B(OH) 2 . In some embodiments, R 3 is –CO 2 H.
  • R 3 is selected from the groups depicted in the compounds in Table 1.
  • R hh is C 1 –C 6 alkyl substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 instances of –F, –OMe, –OEt, –OCH2CHF2, –OCH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R hh is C 1 –C 6 alkyl substituted with 0, 1, 2, 3, or 4 instances of –F, –OMe, –OEt, –OCH 2 CHF 2 , –OCH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R hh is C 1 –C 6 alkyl substituted with 0, 1, 2, 3, or 4 instances of –F, –OMe, –OEt, –OCH 2 CHF 2 , –OCH 2 CF 3 , cyclopropyl, or cyclopentyl.
  • R hh is C 1 –C 6 alkyl substituted with 0, 1, 2, 3, or 4 instances of –F, –OMe, – OCH 2 CHF 2 , or –OCH 2 CF 3 .
  • R hh is C 1 –C 6 alkyl substituted with 0, 1, 2, 3, or 4 instances of cyclopropyl or cyclopentyl.
  • R hh is C 1 –C 6 alkyl substituted with 0, 1, 2, 3, or 4 instances of –F.
  • R hh is C 1 –C 6 alkyl. In some .
  • R hh is independently selected from –Me, –Et, , [0162] In some embodiments, R hh is –Me. In some embodiments, R hh is –Et. In some embodiments, R hh is . In some embodiments, R hh is . In some embodiments, R hh is . In some embodiments, . In some embodiments, R hh is . In some embodiments, . In some embodiments, R hh is –CF 3 . In some embodiments, R hh is . In some embodiments, R hh is . In some embodiments, R hh is . In some embodiments, R hh is n some embodiments, R hh . I is .
  • R hh is . In some embodiments, R hh is . In some embodiments, R hh is . In some embodiments, R hh is . In some embodiments, R hh is . In some embodiments, R hh is . In some embodiments, R hh is . In some embodiments, R hh is . In some embodiments, R hh is . In some embodiments, R hhh is . , . In some embodiments, R hh is .
  • each instance of R A is independently oxo, deuterium, halogen, –CN, –NO 2 , –OR, –SF 5 , –SR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , –S(O) 2 F, –S(O)R, –S(O)NR 2 , – S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR 2 , –C(O)N(R)OR, – OC(O)R, –OC(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)OR, –N(R)C
  • R A is oxo, deuterium, halogen, –CN, –NO 2 , –OR, –SF 5 , –SR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , –S(O) 2 F, –S(O)R, –S(O)NR 2 , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, – C(O)R, –C(O)OR, –C(O)NR 2 , –C(O)N(R)OR, –OC(O)R, –OC(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)OR, –N(R)C(O)R,
  • R A is independently selected from deuterium, halogen, –CN, –OR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , –S(O)R, –S(O)NR 2 , –S(O)(NR)R, –C(O)OR, –C(O)NR 2 , – C(O)N(R)OR, –OC(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR 2 , –N(R)S(O) 2 NR 2 and –N(R)S(O) 2 R, wherein R is –H or a C 1-6 aliphatic chain.
  • R A is fluoro. In some embodiments, R A is –OH. In some embodiments, R A is –CO 2 H. [0167] In some embodiments, R A is selected from the groups depicted in the compounds in Table 1.
  • each instance of R B is independently a C 1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R B is a C 1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each R B is C 1-6 aliphatic chain substituted with 0-3 instances of halo.
  • R B is methyl.
  • R B together with its R C sunstituents is trifluoromethyl.
  • R B is selected from the groups depicted in the compounds in Table 1.
  • each instance of R C is independently oxo, deuterium, halogen, –CN, –NO 2 , –OR, –SF 5 , –SR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , –S(O) 2 F, –S(O)R, –S(O)NR 2 , –S(O)(NR)R, –C(O)R, –C(O)OR, –C(O)NR 2 , –C(O)N(R)OR, –OC(O)R, –OC(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, –N
  • R C is oxo, deuterium, halogen, –CN, –NO 2 , –OR, –SF 5 , –SR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , –S(O) 2 F, –S(O)R, –S(O)NR 2 , –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR 2 , –C(O)N(R)OR, –OC(O)R, –OC(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C
  • R C is halo. In some embodiments R C is fluoro. [0176] In some embodiments, R C is selected from the groups depicted in the compounds in Table 1. [0177] As defined generally above, each instance of R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
  • R is hydrogen, or an optionally substituted group selected from C 1- 6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.
  • R is selected from H or a C 1-6 aliphatic chain. In some embodiments R is a C 1-6 aliphatic chain. In some embodiments R is a C 1-6 aliphatic chain substituted with 0-3 instances of halo. In some embodiments R is a C 1-6 aliphatic chain substituted with 0-3 instances of fluoro. [0180] In some embodiments, R is selected from –H, –Me, –Et, –Pr, – i Pr and – t Bu. In some embodiments, R is selected from –H and –Me. In some embodiments, R is –Me. In some embodiments, R is hydrogen.
  • R is selected from the groups depicted in the compounds in Table 1.
  • Ring A and Ring B are each independently phenyl; naphthyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A and Ring B are each independently phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0186] In some embodiments, Ring A is phenyl; a 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g. ⁇ furanyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxathiazolyl).
  • Ring A is a 5-membered membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g.
  • Ring A is selected from phenyl, furanyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl and oxathiazolyl.
  • Ring A is selected from phenyl and pyrazolyl. [0191] In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyrazolyl. [0192] In some embodiments, Ring A together with its R 1 substituents is selected from wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety. [0193] In some embodiments, Ring A together with its R 1 substituents is selected from wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Ring A together with its R 1 substituents is selected from wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety. In some embodiments, Ring A together with its R 1 substituents wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety. In some embodiments, Ring A together with its R 1 substituents i , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Ring A together with its R 1 substituents wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety. In some embodiments, Ring A together with its R 1 substituents is , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety. In some embodiments, Ring A together with its R 1 substituents i wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Ring A together with its R 1 substituents wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety. In some embodiments, Ring A together with its R 1 substituents is , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety. In some embodiments, Ring A together with its R 1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Ring A together with its R 1 substituents wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety. In some embodiments, Ring A together with its R 1 substituents is , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety. In some embodiments, Ring A together with its R 1 substituents i , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Ring A together with its R 1 substituents wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Ring A together with its R 1 substituents is , [0195] In some embodiments, Ring A is selected from the groups depicted in the compounds in Table 1.
  • Ring B is phenyl; naphthyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is phenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is phenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is phenyl; benzocyclobutenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is phenyl or benzocyclobutenyl.
  • Ring B is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is phenyl; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring.
  • Ring B is phenyl; a 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g. ⁇ furanyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxathiazolyl).
  • nitrogen, oxygen, and sulfur e.g. ⁇ furanyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxathiazolyl).
  • Ring B is a an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g. ⁇ quinolinyl, isoquinolinyl, benzofuranyl, indolyl, benzimidazolyl, benzothiazolyl, benzothiophenyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl).
  • nitrogen, oxygen, and sulfur e.g. ⁇ quinolinyl, isoquinolinyl, benzofuranyl, indolyl, benzimidazolyl, benzothiazolyl, benzothiophenyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, indolinyl, isoindolinyl, tetrahydro
  • Ring B is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl).
  • monocyclic carbocyclic ring e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl.
  • Ring B is 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring (e.g., spiro [3.3] heptanyl, spiro [3,4] octanyl, adamantyl, dihydroindenyl (e.g., 2,3-dihydro-1H-indenyl), tetrahydronaphthalenyl).
  • spiro [3.3] heptanyl spiro [3,4] octanyl
  • adamantyl dihydroindenyl (e.g., 2,3-dihydro-1H-indenyl), tetrahydronaphthalenyl).
  • Ring B is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl).
  • nitrogen, oxygen, and sulfur e.g., oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl.
  • Ring B is selected from phenyl, benzocyclobutenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, spiro [3.3] heptanyl, spiro [3,4] octanyl, adamantyl, dihydroindenyl (e.g., 2,3-dihydro-1H- indenyl), tetrahydronaphthalenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl,
  • Ring B is selected from phenyl, benzocyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, adamantyl, tetrahydropyranyl, dihydroindenyl (e.g., 2,3- dihydro-1H-indenyl), dihydrobenzofuranyl, dihydroisobenzofuranyl, indolinyl, isoindolinyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyrazolyl.
  • dihydroindenyl e.g., 2,3- dihydro-1H-indenyl
  • dihydrobenzofuranyl dihydroisobenzofuranyl
  • indolinyl isoindolinyl
  • thiophenyl pyridyl
  • Ring B is selected from phenyl, benzocyclobutenyl, cyclohexyl, cyclohexenyl, adamantyl, tetrahydropyranyl, 2,3-dihydro-1H-indenyl, and pyrazolyl.
  • Ring B is phenyl.
  • Ring B is pyrazolyl.
  • Ring B is adamantyl.
  • Ring B is 2,3-dihydro-1H- indenyl.
  • Ring B is tetrahydrofuranyl.
  • Ring B is benzocyclobutenyl.
  • Ring B together with its R 2 substituents is selected from .
  • Ring B together with its R 2 substituents is selected from
  • Ring B together with its R 2 substituents is selected from . [0217] In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is .
  • Ring B together with its R 2 substituents some embodiments, Ring B together with its R 2 substituents i some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is some embodiments, Ring B together with its R 2 substituents . In some embodiments, Ring B together with its R 2 substituents i . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is .
  • Ring B together with its R 2 substituents is embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents i some embodiments, Ring B together with its R 2 substituents i . In some embodiments, Ring B together with its R 2 substituents some embodiments, Ring B together with its R 2 substituents is . e embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is .
  • Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents i some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents i some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 .
  • Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B together with its R 2 substituents is . In some embodiments, Ring B
  • Ring B together with its R 2 substituents i .
  • Ring B is selected from the groups depicted in the compounds in Table 1.
  • L is a bivalent moiety that connects ERBM to LBM.
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by —Cy–, –CH(R)–, –C(R) 2 –, –O–, –NR–, –S–, –OC(O)–, –C(O)O–, –C(O)–, –S(O)–, – S(O) 2 –, –NRS(O) 2 –, –S(O) 2 NR–, –NRC(O)–, –C(O)NR–, –OC(O)NR–, –NRC(O)O—, 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 carbo
  • L is a covalent bond.
  • L is a bivalent, saturated or unsaturated, straight or branched C 1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) 2 –, –O–, –NR–, –S–, –OC(O)–, – , 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 4-7 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 heteroatom
  • L is a bivalent, saturated or unsaturated, straight or branched C 3-5 hydrocarbon chain, wherein 0, 1, 2 or 3 methylene units of L are independently replaced by – Cy–, –CH(R)–, –C(R)2–, –O–, –NR–, –S–, –OC(O)–, –C(O)O–, –C(O)–, –S(O)–, –S(O)2–, – [0223] In some embodiments, L is a bivalent, saturated or unsaturated, straight or branched C 3-5 hydrocarbon chain, wherein 1, 2 or 3 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) 2 –, –O– or–NR– .
  • L is a bivalent, saturated or unsaturated, straight or branched C 3-5 hydrocarbon chain, wherein 1, 2 or 3 methylene units of L are independently replaced by –Cy– or–NR– .
  • each –Cy— is independently an optionally substituted bivalent ring selected from a 4-7 membered saturated or partially unsaturated monocyclic carbocyclylenyl, a 5- 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 monocyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered monocyclic saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic
  • each –Cy– is independently an optionally substituted bivalent ring selected from a 4-7 membered saturated or partially unsaturated monocyclic carbocyclylenyl, a 5- 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 monocyclic heterocyclylenyl containing 1-2 nitrogen atoms, a 5-11 membered monocyclic saturated or partially unsaturated spiro heterocyclylenyl containing 1-2 nitrogen atoms, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 nitrogen atoms, and a 6-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 nitrogen atoms.
  • the bivalent ring of each –Cy— is independently substituted with 0, 1 or 2 substituents independently selected from –C 1 –C 4 alkyl, –C 1 –C 4 haloalkyl, –C 3 –C 7 cycloalkyl, –O–C 1 –C 4 alkyl, halo, cyano, –OH, –NH 2 , –N(H)(C 1 –C 4 alkyl) and –N(C 1 –C 4 alkyl) 2 .
  • the bivalent ring of each –Cy— is independently substituted with 0, 1 or 2 substituents independently selected from –Me, –Et, –Pr, – i Pr, cyclopropyl, –CF 3 , –OMe, – F, –Cl, –CN, –NH 2 , –NHMe and –NMe 2 .
  • the bivalent ring of each –Cy— is independently substituted with 0, 1 or 2 substituents independently selected from –Me, –OMe and –F.
  • the bivalent ring of each –Cy– is independently substituted with 0, 1 or 2 instances of –Me. [0231] In some embodiments, the bivalent ring of each –Cy– is unsubstituted.
  • L is . In some embodiments, L is . , . embodiments, L is . In some embodiments, L is embodiments, L is . In some embodiments, L is embodiments, L is embodiments, . In some embodiments, L is embodiments, L is embodiments, L is . In some embodiments, L is . In some embodiments, L is [0236] In some embodiments, L is selected from the groups depicted in the compounds in Table 1. [0237] As defined generally above, LBM is a ligase binding moiety. , , , , , , , , .
  • LBM is selected from , [0241] In some embodiments, LBM is selected from , . [0242] In some embodiments, LBM is selected from , [0243] In some embodiments, LBM is selected
  • LBM is . In some embodiments, LBM is some embodiments,
  • LBM is [0249] In some embodiments, LBM is selected from the groups depicted in the compounds in Table 1. [0250] As defined generally above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2 or 3. In some embodiments, m is 0, 1 or 2. In some embodiments, m is 0 or 1. In some embodiments m is 0. In some embodiments m is 1. In some embodiments m is 2. In some embodiments m is 3. In some embodiments m is 4. [0251] In some embodiments, m is selected from the groups depicted in the compounds in Table 1. [0252] As defined generally above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2 or 3.
  • n is 0, 1 or 2. In some embodiments, n is 0 or 1. [0253] In some embodiments n is 0. In some embodiments n is 1. In some embodiments n is 2. In some embodiments n is 3. In some embodiments n is 4. [0254] In some embodiments, n is selected from the groups depicted in the compounds in Table 1. [0255] As defined generally above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0, 1, 2 or 3. In some embodiments, p is 0, 1 or 2. In some embodiments, p is 0 or 1. [0256] 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.
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • q is 1. In some embodiments q is 2. In some embodiments q is 3. In some embodiments q is 4. In some embodiments q is 5. In some embodiments q is 6. In some embodiments q is 7. In some embodiments q is 8. In some embodiments q is 9.
  • q is 10. [0261] In some embodiments, q is selected from the groups depicted in the compounds in Table 1. [0262] As defined generally above, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0, 1, 2 or 3. In some embodiments, r is 0, 1 or 2. In some embodiments, r is 0 or 1. [0263] 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. [0264] In some embodiments, r is selected from the groups depicted in the compounds in Table 1. [0265] As defined generally above, s is 0, 1, 2, 3, or 4. In some embodiments, s is 0, 1, 2 or 3.
  • s is 0, 1 or 2. In some embodiments, s is 0 or 1. [0266] In some embodiments s is 0. In some embodiments s is 1. In some embodiments s is 2. In some embodiments s is 3. In some embodiments s is 4. [0267] In some embodiments, s is selected from the groups depicted in the compounds in Table 1. [0268] As defined generally above, X 1 and X 2 cannot both be heteroatoms simultaneously. [0269] In some embodiments, X 1 and X 2 are selected from the group combinations depicted in the compounds in Table 1.
  • the present invention provides a compound of formula II-1 or II- 2 , or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R 1 , R 2 , R 3 , X 1 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, , thereby forming a compound of one of formulas II-a, II-b, II-c, II-d, II-e, or II-f, respectively: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R 1 , R 2 , R 3 , X 1 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the invention provides a compound of one of formulas II-a-1, II- b-1, II-c-1, II-d-1, II-e-1, or II-f-1:
  • each of Ring A, Ring B, R 1 , R 2 , R 3 , X 1 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a,
  • the invention provides a compound of one of formulas II-g-1, II- or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R 1 , R 2 , R 3 , X 1 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the compound is a compound of formula II-g-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-h-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-i-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-j-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-k-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-l-1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, forming a compound of one of formulas II-m, II-n, or II-o, respectively: II-o or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 1 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, forming a compound of one of formulas II-p, II-q, or II-r, respectively: II-r or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 1 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, forming a compound of one of formulas II-s, II-t, or II-u, respectively: II-u or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 1 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, forming a compound of one of formulas II-v, II-w, or II-x, respectively: II-x or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 1 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, forming a compound of one of formulas II-y, II-z, or II-aa, respectively: II-aa or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 1 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, , , thereby forming a compound of one of formulas II-bb, II-cc, II-dd, I , II-ff, or II-gg, respectively:
  • the present invention provides a compound of formula I-a, wherein , thereby forming a compound of formula II-hh: II-hh or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 1 , m, n, p, L, R hh , and LBM is as defined in embodiments and classes and subclasses herein.
  • the invention provides a compound of one of formulas II-m-1, II-
  • the compound is a compound of formula II-m-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-n-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-o-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-p-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-r-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-s-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-u-1 or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-v-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-x-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-y-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-z-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-aa-1, or a pharmaceutically acceptable salt thereof.
  • invention provides a compound one of formulas II-bb-1, II-cc-1, II-dd-1, II-ee-1, II-ff-1 or II-gg-1: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 1 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the compound is a compound of formula II-bb-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-cc-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-dd-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-ee-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula II-gg-1, or a pharmaceutically acceptable salt thereof.
  • the invention provides a of formula II-hh-1: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 1 , m, n, p, L, R hh and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, III-b, III-c, III-d, III-e, or III-f, respectively: III-a III-b or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the invention provides a compound of one of formulas III-a-1, III-b-1, III- or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the compound is a compound of formula III-b-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-c-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-d-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-e-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, , thereby forming a compound of one of formulas III-g, III-h, III-i, III-j, III-k, or III-l, respectively: or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the invention provides a compound of one of formulas III-g-1, III-h-1, III-i-1, V-f, III-k-1, or III-l-1:
  • the compound is a compound of formula III-g-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-h-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-f, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-k-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-l-1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, , thereby forming a compound of one of formulas III-m, I , or III-o, respectively: III-o or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, , thereby forming a compound of one of formulas III-p, III-q, or III-r, respectively: III-r or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, , thereby forming a compound of one of formulas III-s, I , or III-u, respectively: III-u or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, , thereby forming a compound of one of formulas III-v, III-w, or III-x, respectively: III-x or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, forming a compound of one of formulas III-y, III-z, or III-aa, respectively: III-aa or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, , , thereby forming a compound of one of formulas III-bb, III-cc, or III-dd, respectively: III-dd or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, wherein thereby forming a compound of one of formulas III-gg or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, , thereby forming a compound of formula III-hh: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, R hh and LBM is as defined in embodiments and classes and subclasses herein.
  • the invention provides a compound of one of formulas III-m-1,
  • LBM is as defined in embodiments and classes and subclasses herein.
  • the compound is a compound of formula III-m-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-n-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-o-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-p-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-q-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-r-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-s-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-u-1 or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-v-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-w-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-y-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-aa-1, or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound of one of formulas III-bb-1, III-cc-1, III-dd-1, III-ee- -gg-1: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the compound is a compound of formula III-bb-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-cc-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-dd-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-ee-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-ff-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III-gg-1, or a pharmaceutically acceptable salt thereof.
  • invention provides a compound of formula III-hh-1: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, R hh and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, wherein ,
  • the invention provides a compound of one of formulas IV-a-1, or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the invention provides a compound of one of formulas IV-a-1, or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the compound is a compound of formula IV-a-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-b-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-c-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-d-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-e-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-f-1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, , thereby forming a compound of one of formulas IV-g, IV-h, IV-i, IV-j, IV-k, or IV-l, respectively: or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the invention provides a compound of one of formulas IV-g-1, IV-h-1, IV-i-1, IV-j-1, V-e, or IV-l-1:
  • the compound is a compound of formula IV-g-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-h-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-i-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-j-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-e, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-l-1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, forming a compound of one of formulas IV-m, IV-n, or IV-o, respectively: IV-o or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, forming a compound of one of formulas IV-s, IV-t, or IV-u, respectively: IV-u or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, , thereby forming a compound of one of formulas IV-v, IV-w, or IV-x, respectively: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, forming a compound of one of formulas IV-y, IV-z, or IV-aa, respectively: IV-aa or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, wherein , , thereby forming a compound of one of formulas IV-bb, IV-cc or IV-dd, respectively: IV-dd or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, thereby forming a compound of one of formulas IV- ee, IV-ff, or IV-gg, respectively: IV-gg or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, wherein , thereby forming a compound of formula IV-hh: or a pharmaceutically acceptable salt thereof, wherein wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, R hh and LBM is as defined in embodiments and classes and subclasses herein.
  • the invention provides a compound of one of formulas IV-m-1, IV-n-1, IV-o-1, IV-p-1, IV-q-1, IV-r-1, IV-s-1, IV-t-1, IV-u-1, IV-v-1, IV-w-1, IV-x-1, IV-y- 1, IV-z-1, or IV-aa-1:
  • the compound is a compound of formula IV-m-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-n-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-o-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-p-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-q-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-r-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-s-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-t-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-u-1 or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-v-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-w-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-y-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-z-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-aa-1, or a pharmaceutically acceptable salt thereof.
  • the the invention provides a compound of one of formulas IV-bb- 1, IV-cc-1, IV-dd-1, IV-ee-1, IV-ff-1 or IV-gg-1: -gg-1 or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the compound is a compound of formula IV-bb-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-cc-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-dd-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-ee-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-ff-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula IV-gg-1, or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound of formula IV-hh-1: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , m, n, p, L, R hh and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, wherein
  • the compound is a compound of formula V-a, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-b, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-c, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-d, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, thereby forming a compound of one of formulas V-g, V-h, V-i, V-j, V-k, V-l, or V-m respectively:
  • the compound is a compound of formula V-g, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-h, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-i, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-j, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-k, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-m, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, wherein ERBM is , ,
  • the compound is a compound of formula V-n, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-o, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-p, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-q, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-r, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, formulas V-s, V-t, V-u, V-v, V-w, V-x or V-y, respectively:
  • the compound is a compound of formula V-s, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-t, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-u, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-v, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-w, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-x, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-y, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, , thereby forming a compound of one of formulas V-z, V-aa, V-bb, V-cc, V-dd, V-ee, V-ff, V-gg or V-hh:
  • the compound is a compound of formula V-z, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-aa, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-bb or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-cc, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-dd, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-ee, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-ff or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-gg, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-hh, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, , ompound of one of formulas V-ii, V-jj, V-kk, V-ll, V-mm, V-nn, V-oo, V-pp, V-qq, V-rr, V-ss, V-tt, V-uu, or V-
  • the compound is a compound of formula V-ii, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-jj, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-kk or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-ll, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-mm, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-nn, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-oo or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-pp, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-qq, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-rr, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-ss, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-tt or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-uu, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-vv, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, wherein
  • V-ww V-xx, V-yy, V-zz, V-aa-1, V-bb-1, V-cc-1, V-dd-1, V-ee-1, V-ff-1, V-gg-1, V-hh-1, V-ii-1, V-jj-1, V-kk-1, or V-ll-1:
  • the compound is a compound of formula V-ww, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-xx, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-yy or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-zz, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-aa-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-bb-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-cc-1 or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-dd-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-ee-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-ff-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-gg-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-hh-1 or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-jj-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-kk-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula V-ll-1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, wherein ,
  • the invention provides a compound of one of formulas VI-a-1, VI-b-1, VI-c-1, VI-d-1, VI-e-1, or VI-f-1: pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R 1 , R 2 , R 3 , X 2 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the compound is a compound of formula VI-a-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-b-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-c-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-d-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-e-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-f-1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, , thereby forming a compound of one of formulas VI-g, VI-h, VI-i, VI-j, VI-k, or VI-l, respectively:
  • each of Ring B, R 1 , R 2 , R 3 , X 2 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the invention provides a compound of one of formulas VI-g-1,
  • the compound is a compound of formula VI-g-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-h-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-i-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-j-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-k-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-l-1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, forming a compound of one of formulas VI-m, VI-n, or VI-o, respectively: VI-o or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 2 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, VI-r or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 2 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, forming a compound of one of formulas VI-s, VI-t, or VI-u, respectively: VI-u or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 2 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, forming a compound of one of formulas VI-v, VI-w, or VI-x, respectively: VI-x or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 2 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the present invention provides a compound of formula I-a, for VI-aa or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 2 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the invention provides a compound of one of formulas VI-m-1, VI- n-1, VI-o-1, VI-p-1, VI-q-1, VI-r-1, VI-s-1, VI-t-1, VI-u-1, VI-v-1, VI-w-1, VI-x-1, VI-y-1, VI- z-1, or VI-aa-1: pharmaceutically acceptable salt thereof, wherein each of Ring A, R 1 , R 2 , R 3 , X 2 , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein.
  • the compound is a compound of formula VI-m-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-n-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-o-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-p-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-q-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-r-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-s-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-t-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-u-1 or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-v-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-w-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-x-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-y-1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VI-aa-1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I-a, forming a compound of one of formulas VII-a, VII-b, VII-c, VII-d, VII-e, VII-f, VII-g,or VII- h, respectively:
  • the compound is a compound of formula VII-a, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VII-b, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VII-c, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VII-d, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VII-e, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VII-f, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VII-g, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula VII-h, or a pharmaceutically acceptable salt thereof.
  • Examples of compounds of the present disclosure include those listed in the Tables and exemplification herein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.
  • the present disclosure provides a compound selected from those depicted in Table 1, below, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the present disclosure provides a compound set forth in Table 1, below, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound set forth in Table 1, below.
  • the present disclosure comprises a compound of formula I-a selected from those depicted in Table 1, above, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.
  • the present disclosure provides a compound of formula I-a selected from those depicted in Table 1, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-a selected from those depicted in Table 1, above. [0525]
  • the compounds in Table 1 were made in accordance with chemical procedures described in the Examples section, or similar procedures that would be readily understood by a person of skill in the art on the basis of the instant disclosure and knowledge present in the art.
  • the compounds marked with (*) in Table 1 are prophetic examples and can be made by methods similar to those included in the Examples section. 4.
  • the disclosure provides a composition comprising a compound of this disclosure, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the disclosure provides a pharmaceutical composition comprising a compound of this disclosure, and a pharmaceutically acceptable carrier.
  • the amount of compound in compositions of this disclosure is such that is effective to measurably degrade ERD, or a mutant thereof, in a biological sample or in a patient.
  • the amount of compound in compositions of this disclosure is such that it is effective to measurably degrade ERD, or a mutant thereof, in a biological sample or in a patient.
  • a composition of this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this disclosure is formulated for oral administration to a patient.
  • the terms “subject” and “patient,” as used herein, means an animal (i.e., a member of the animal kingdom), preferably a mammal, and most preferably a human. In some embodiments, the subject is a human, mouse, rat, cat, monkey, dog, horse, or pig. In some embodiments, the subject is a human. In some embodiments, the subject is a mouse, rat, cat, monkey, dog, horse, or pig.
  • compositions of this disclosure refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxyprop
  • a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily active metabolite or residue thereof.
  • the term “degratorily active metabolite or residue thereof” means that a metabolite or residue thereof is also a degrader of ERD, or a mutant thereof.
  • Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • compositions of this disclosure may be administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di- glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this disclosure may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal or vaginal temperature and therefore will melt in the rectum or vagina to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
  • Pharmaceutically acceptable compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • compositions of this disclosure may be formulated in an ointment such as petrolatum.
  • Pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • pharmaceutically acceptable compositions of this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food.
  • compositions of this disclosure are administered with food.
  • the amount of compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the patient treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • suitable dose ranges for oral administration of the compounds of the disclosure are generally about 1 mg/day to about 1000 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 800 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 500 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 250 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 100 mg/day.
  • the oral dose is about 5 mg/day to about 50 mg/day. In some embodiments, the oral dose is about 5 mg/day. In some embodiments, the oral dose is about 10 mg/day. In some embodiments, the oral dose is about 20 mg/day. In some embodiments, the oral dose is about 30 mg/day. In some embodiments, the oral dose is about 40 mg/day. In some embodiments, the oral dose is about 50 mg/day. In some embodiments, the oral dose is about 60 mg/day. In some embodiments, the oral dose is about 70 mg/day. In some embodiments, the oral dose is about 100 mg/day.
  • compositions contain a provided compound and/or a pharmaceutically acceptable salt thereof at a concentration ranging from about 0.01 to about 90 wt%, about 0.01 to about 80 wt%, about 0.01 to about 70 wt%, about 0.01 to about 60 wt%, about 0.01 to about 50 wt%, about 0.01 to about 40 wt%, about 0.01 to about 30 wt%, about 0.01 to about 20 wt%, about 0.01 to about 2.0 wt%, about 0.01 to about 1 wt%, about 0.05 to about 0.5 wt%, about 1 to about 30 wt%, or about 1 to about 20 wt%.
  • the composition can be formulated as a solution, suspension, ointment, or a capsule, and the like.
  • the pharmaceutical composition can be prepared as an aqueous solution and can contain additional components, such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity- modifying ingredients and the like.
  • Pharmaceutically acceptable carriers are well-known to those skilled in the art, and include, e.g., adjuvants, diluents, excipients, fillers, lubricants and vehicles.
  • the carrier is a diluent, adjuvant, excipient, or vehicle.
  • the carrier is a diluent, adjuvant, or excipient.
  • the carrier is a diluent or adjuvant. In some embodiments, the carrier is an excipient.
  • pharmaceutically acceptable carriers may include, e.g., water or saline solution, polymers such as polyethylene glycol, carbohydrates and derivatives thereof, oils, fatty acids, or alcohols.
  • oils as pharmaceutical carriers include oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical carriers may also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
  • auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.
  • suitable pharmaceutical carriers are described in e.g., Remington’s: The Science and Practice of Pharmacy, 22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5 th Ed. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7 th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)) (each of which hereby incorporated by reference in its entirety).
  • the pharmaceutically acceptable carriers employed herein may be selected from various organic or inorganic materials that are used as materials for pharmaceutical formulations and which are incorporated as analgesic agents, buffers, binders, disintegrants, diluents, emulsifiers, excipients, extenders, glidants, solubilizers, stabilizers, suspending agents, tonicity agents, vehicles and viscosity-increasing agents.
  • Pharmaceutical additives such as antioxidants, aromatics, colorants, flavor-improving agents, preservatives, and sweeteners, may also be added.
  • acceptable pharmaceutical carriers include carboxymethyl cellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powders, saline, sodium alginate, sucrose, starch, talc and water, among others.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • Surfactants such as, e.g., detergents, are also suitable for use in the formulations.
  • surfactants include polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates and others, anionic surfactants, such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sufate and sodium cetyl sulfate; sodium dodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fatty acids, in particular those derived from coconut oil, cationic surfactants, such as water-soluble quaternary ammonium salts of formula N +
  • Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, and the like.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, and the like.
  • the present compositions may also contain wetting or emulsifying agents, or pH buffering agents.
  • Tablets and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which are known in the art.
  • adjuvants such as lactose or sucrose, dibasic calcium phosphate anhydrous, corn starch, mannitol, xylitol, cellulose or derivatives thereof, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffering agents, disintegrants, and colorants.
  • compositions may contain one or more optional agents such as, e.g., sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preservative agents, to provide a pharmaceutically palatable preparation.
  • optional agents such as, e.g., sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preservative agents, to provide a pharmaceutically palatable preparation.
  • sweetening agents such as fructose, aspartame or saccharin
  • flavoring agents such as peppermint, oil of wintergreen, or cherry
  • coloring agents such as peppermint, oil of wintergreen, or cherry
  • preservative agents to provide a pharmaceutically palatable preparation.
  • ERD degraders of the present disclosure are useful for the treatment of cellular proliferative diseases generally.
  • the activity of a compound utilized in this disclosure as an degrader of ERD, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of either the signaling activity and/or the subsequent functional consequences, of an activated ERD, or a mutant thereof.
  • Alternative in vitro assays quantitate the ability of the degrader to degrade ERD.
  • Representative in vitro and in vivo assays useful in assaying an ERD degrader include those described and disclosed in the patent and scientific publications described herein.
  • the present disclosure provides a method of treating an ERD-mediated disorder in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing, to a subject in need thereof.
  • the present disclosure provides a method of treating an ERD-mediated disorder in a subject comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof.
  • the subject has a mutant ERD.
  • the subject has ERD containing a D538G, Y537S, or L536R mutation.
  • the term “ERD-mediated” disorders, diseases, and/or conditions means any disease or other deleterious condition in which ERD or a mutant thereof is known to play a role.
  • ERD-mediated disorders include, but are not limited to, cellular proliferative disorders (e.g. cancer).
  • the ERD-mediated disorder is a disorder mediated by a mutant ERD.
  • the ERD-mediated disorder is a disorder mediated by an ERD containing a D538G, Y537S, or L536R mutation.
  • the present disclosure provides a method for treating a cellular proliferative disease, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing.
  • the present disclosure provides a method for treating a cellular proliferative disease, said method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.
  • the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said provided compound in a therapeutically effective amount to treat, suppress and/or prevent the disease state or condition in a subject in need of such treatment.
  • the subject has a mutant ERD.
  • the subject has ERD containing a D538G, Y537S, or L536R mutation.
  • the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said composition in a therapeutically effective amount to treat, suppress and/or prevent the disease state or condition in a subject in need of such treatment.
  • the subject has a mutant ERD.
  • the subject has ERD containing a D538G, Y537S, or L536R mutation.
  • Another aspect of the disclosure provides a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for use in the treatment of a disorder described herein.
  • Another aspect of the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for the treatment of a disorder described herein.
  • the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disorder described herein.
  • the disorder is a cellular proliferative disease.
  • the cellular proliferative disease is cancer. In some embodiments, the cancer is a tumor. In some embodiments, the cancer is a hematopoietic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cellular proliferative disease is a tumor and/or cancerous cell growth. In some embodiments, the cellular proliferative disease is a tumor. In some embodiments, the cellular proliferative disease is a solid tumor. In some embodiments, the cellular proliferative disease is a cancerous cell growth.
  • the cancer is selected from sarcoma; lung; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden disease); pancreas; gastrointestinal; colon; rectum; carcinoma; colon carcinoma; adenoma; colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); multiple myeloma; esophagus; a leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; a carcinoma of the brain; oral cavity and pharynx; larynx; small
  • the cancer is selected from lung; bronchus; prostate; breast (including sporadic breast cancers and Cowden disease); pancreas; gastrointestinal; colon; rectum; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; endometrial; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); esophagus; a leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; neck; and head.
  • the cancer is selected from sarcoma; carcinoma; colon carcinoma; adenoma; colorectal adenoma; glioma; glioblastoma; melanoma; multiple myeloma; a carcinoma of the brain; non-Hodgkin lymphoma; villous colon adenoma; a neoplasia; a neoplasia of epithelial character; lymphoma; a mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom macroglobulinemia.
  • the cancer is selected from lung; bronchus; prostate; breast (including sporadic breast cancers and Cowden disease); pancreas; gastrointestinal; colon; rectum; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; endometrial; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); esophagus; brain; oral cavity and pharynx; larynx; small intestine; neck; and head.
  • the cancer is a leukemia.
  • the cancer is acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; or myeloid leukemia.
  • the cancer is breast cancer (including sporadic breast cancers and Cowden disease).
  • the cancer is breast cancer.
  • the cancer is ER+ breast cancer.
  • the cancer is ER+/HER2- breast cancer.
  • the cancer is ER+/HER2- breast cancer, and the subject is intolerant to, or ineligible for, treatment with alpelisib.
  • the cancer is sporadic breast cancer.
  • the cancer is Cowden disease.
  • the cancer is ER+ advanced/metastatic breast cancer. In some embodiments, the cancer is ER+/HER2- advanced/metastatic breast cancer. In some embodiments, the breast cancer has mutant ERD. In some embodiments, the breast cancer has ERD containing a D538G, Y537S, or L536R mutation. [0566] In some embodiments, the cancer is uterine cancer. In some embodiments, the uterine cancer has mutant ERD. In some embodiments, the uterine cancer has ERD containing a D538G, Y537S, or L536R mutation. [0567] In some embodiments, the ERD-mediated disorder is endometriosis.
  • the endometriosis has mutant ERD. In some embodiments, the endometriosis has ERD containing a D538G, Y537S, or L536R mutation.
  • the cellular proliferative disease displays overexpression or amplification of ERD, or somatic mutation of ERD.
  • Routes of Administration and Dosage Forms may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder (e.g. a proliferative disorder).
  • unit dosage form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.
  • compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like.
  • the compounds of the disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzy
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure.
  • the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • Dosage Amounts and Regimens [0580]
  • the compounds of the disclosure are administered to the subject in a therapeutically effective amount, e.g., to reduce or ameliorate symptoms of the disorder in the subject. This amount is readily determined by the skilled artisan, based upon known procedures, including analysis of titration curves established in vivo and methods and assays disclosed herein.
  • the methods comprise administration of a therapeutically effective dosage of the compounds of the disclosure.
  • the therapeutically effective dosage is at least about 0.0001 mg/kg body weight, at least about 0.001 mg/kg body weight, at least about 0.01 mg/kg body weight, at least about 0.05 mg/kg body weight, at least about 0.1 mg/kg body weight, at least about 0.25 mg/kg body weight, at least about 0.3 mg/kg body weight, at least about 0.5 mg/kg body weight, at least about 0.75 mg/kg body weight, at least about 1 mg/kg body weight, at least about 2 mg/kg body weight, at least about 3 mg/kg body weight, at least about 4 mg/kg body weight, at least about 5 mg/kg body weight, at least about 6 mg/kg body weight, at least about 7 mg/kg body weight, at least about 8 mg/kg body weight, at least about 9 mg/kg body weight, at least about 10 mg/kg body weight, at least about 15 mg/kg body weight, at least about 20 mg/kg body weight, at least about 25 mg/kg body weight, at least about 30 mg/kg body weight, at least about
  • the therapeutically effective dosage is in the range of about 0.1 mg to about 10 mg/kg body weight, about 0.1 mg to about 6 mg/kg body weight, about 0.1 mg to about 4 mg /kg body weight, or about 0.1 mg to about 2 mg/kg body weight.
  • the therapeutically effective dosage is in the range of about 1 to 500 mg, about 2 to 150 mg, about 2 to 120 mg, about 2 to 80 mg, about 2 to 40 mg, about 5 to 150 mg, about 5 to 120 mg, about 5 to 80 mg, about 10 to 150 mg, about 10 to 120 mg, about 10 to 80 mg, about 10 to 40 mg, about 20 to 150 mg, about 20 to 120 mg, about 20 to 80 mg, about 20 to 40 mg, about 40 to 150 mg, about 40 to 120 mg or about 40 to 80 mg.
  • the methods comprise a single dosage or administration (e.g., as a single injection or deposition).
  • the methods comprise administration once daily, twice daily, three times daily or four times daily to a subject in need thereof for a period of from about 2 to about 28 days, or from about 7 to about 10 days, or from about 7 to about 15 days, or longer.
  • the methods comprise chronic administration.
  • the methods comprise administration over the course of several weeks, months, years or decades.
  • the methods comprise administration over the course of several weeks.
  • the methods comprise administration over the course of several months.
  • the methods comprise administration over the course of several years.
  • the methods comprise administration over the course of several decades.
  • the dosage administered can vary depending upon known factors such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; time of administration of active ingredient; age, sex, health and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment and the effect desired; and rate of excretion. These are all readily determined and may be used by the skilled artisan to adjust or titrate dosages and/or dosing regimens.
  • Degradation of ERD [0586] According to one embodiment, the disclosure relates to a method of degrading ERD in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound.
  • the disclosure relates to a method of degrading ERD, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound.
  • the disclosure relates to a method of degrading ERD, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound.
  • the ERD is a mutant ERD.
  • ERD contains a D538G, Y537S, or L536R mutation.
  • PROTACs proteolysis targeting chimeras
  • a PROTAC is a bifunctional molecule, with one portion capable of engaging an E3 ubiquitin ligase, and the other portion having the ability to bind to a target protein meant for degradation by the cellular protein quality control machinery. Recruitment of the target protein to the specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used.
  • the portion of the PROTAC that engages the E3 ligase is connected to the portion of the PROTAC that engages the target protein via a linker which consists of a variable chain of atoms. Recruitment of ERD to the E3 ligase will thus result in the destruction of the ERD protein.
  • the variable chain of atoms can include, for example, rings, heteroatoms, and/or repeating polymeric units. It can be rigid or flexible. It can be attached to the two portions described above using standard techniques in the art of organic synthesis. [0588] In some embodiments, the disclosure provides a method of selectively inhibiting a mutant ERD over a wild-type ERD.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • ERD for example, ERD, or a mutant thereof
  • Inhibition of activity of a ERD (for example, ERD, or a mutant thereof) in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
  • Another embodiment of the present disclosure relates to a method of inhibiting ERD- mediated transcription regulation in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound.
  • the disclosure relates to a method of inhibiting activity of a ERD, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound.
  • the disclosure relates to a method of inhibiting activity of ERD, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound.
  • the ERD is a mutant ERD.
  • the ERD contains a D538G, Y537S, or L536R mutation.
  • the present disclosure provides a method for treating a disorder mediated by a ERD, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof.
  • the present disclosure provides a method for treating a disorder mediated by ERD, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof.
  • the ERD is a mutant ERD.
  • the ERD contains a D538G, Y537S, or L536R mutation.
  • the present disclosure provides a method of inhibiting ERD-mediated transcription regulation, or a mutant thereof, in a subject, comprising administering a therapeutically effective amount of a compound according to the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof.
  • the present disclosure provides a method of inhibiting ERD-mediated transcription regulation in a subject, comprising administering a therapeutically effective amount of a compound according to the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof.
  • the ERD is a mutant ERD.
  • the ERD contains a D538G, Y537S, or L536R mutation. In some embodiments, the subject has a D538G, Y537S, or L536R mutant ERD. In some embodiments, the subject has ERD containing D538G, Y537S, or L536R mutation.
  • Combination Therapies [0595] Depending upon the particular disorder, condition, or disease, to be treated, additional therapeutic agents, that are normally administered to treat that condition, may be administered in combination with compounds and compositions of this disclosure.
  • the method of treatment comprises administering the compound or composition of the disclosure in combination with one or more additional therapeutic agents.
  • the methods of treatment comprise administering the compound or composition of the disclosure as the only therapeutic agent.
  • a compound of the current disclosure may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation.
  • a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • a compound of the current disclosure can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the disclosure and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.
  • a compound of the current disclosure can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these.
  • Those additional agents may be administered separately from an inventive compound- containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure.
  • a compound of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present disclosure provides a single unit dosage form comprising a compound of the current disclosure, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of both an inventive compound and additional therapeutic agent in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • compositions of this disclosure should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered.
  • that additional therapeutic agent and the compound of this disclosure may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 – 1,000 Pg/kg body weight/day of the additional therapeutic agent can be administered.
  • the amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • Any of the compounds and/or compositions of the disclosure may be provided in a kit comprising the compounds and/or compositions.
  • the compound and/or composition of the disclosure is provided in a kit.
  • Selected Embodiments Embodiment 1. A compound of formula I-c: or a pharmaceutically acceptable salt thereof, wherein:
  • each of X 1 and X 2 is independently –CH2–, –CH(R A1 )–, –C(R A1 )2–, –O–, –S–, –S(O)–, –S(O)2–, or –N(R A2 )–; each instance of R 1 , R 2 , R 4 , R 5 , R A1 , and R A2 is independently R A or R B , and is substituted by 0-4 instances of R C ; each instance of R 3 is independently R A or R B , and is substituted by 0-4 instances of R C , or two R 3 groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R A is independently
  • Embodiment 2 The compound of embodiment 1, wherein the compound is a compound of formula I-d or I-e Embodiment 3. The compound of embodiment 1, wherein the compound is a compound of formula I-d or a pharmaceutically acceptable salt thereof. Embodiment 4. The compound of embodiment 1, wherein the compound is a compound of formula I-e or a pharmaceutically acceptable salt thereof. Embodiment 5. The compound of embodiment 1, wherein the compound is a compound of formula I-f, I-g, I-h, I-i, I-j or I-k: Embodiment 6. The compound of embodiment 5, wherein the compound is a compound of formula I-f, I-g, I-i or I-j, or a pharmaceutically acceptable salt thereof. Embodiment 7.
  • Embodiment 5 The compound of embodiment 5, wherein the compound is a compound of formula I-f, I-g or I-i, or a pharmaceutically acceptable salt thereof.
  • Embodiment 8. The compound of embodiment 1, wherein the compound is a compound of formula I-f, or a pharmaceutically acceptable salt thereof.
  • Embodiment 9. The compound of embodiment 1, wherein the compound is a compound of formula I-g, or a pharmaceutically acceptable salt thereof.
  • Embodiment 10. The compound of embodiment 1, wherein the compound is a compound of formula I-h, or a pharmaceutically acceptable salt thereof.
  • Embodiment 11 The compound of embodiment 1, wherein the compound is a compound of formula I-i, or a pharmaceutically acceptable salt thereof.
  • Embodiment 17 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 18 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents i , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 19 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 20 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 21 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 22 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 23 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents i , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 24 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 25 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents i wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 26 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 27 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents i wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 28 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 29 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 30 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents i wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 31 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents is , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 32 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 33 The compound of any one of embodiments 1-13, wherein Ring A together with its R 1 substituents i , wherein the top attachment point connects to L and the bottom attachment point connects to the seven-member ring of the ERBM moiety.
  • Embodiment 34 The compound of any one of embodiments 1-33, wherein Ring B together Embodiment 35.
  • Embodiment 71 The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i .
  • Embodiment 72 The compound of any one of embodiments 1-33, wherein Ring B together .
  • Embodiment 73 The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i .
  • Embodiment 74 The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i .
  • Embodiment 75 The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i
  • Embodiment 75 The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i
  • Embodiment 76 The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents .
  • Embodiment 77 The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents Embodiment 78. The compound of any one of embodiments 1-33, wherein Ring B together . Embodiment 79. The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i Embodiment 80. The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i Embodiment 81. The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i . Embodiment 82. The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i .
  • Embodiment 83 The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i .
  • Embodiment 84 The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i .
  • Embodiment 85 The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i .
  • Embodiment 86 The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i .
  • Embodiment 87 The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i .
  • Embodiment 88 The compound of any one of embodiments 1-33, wherein Ring B together with its R 2 substituents i .
  • Embodiment 90 The compound of embodiment 1, wherein the compound is a compound of formula I-l or I-m Embodiment 91. The compound of embodiment 90, wherein the compound is a compound of formula I-l, or a pharmaceutically acceptable salt thereof. Embodiment 92. The compound of embodiment 90, wherein the compound is a compound of formula I-m, or a pharmaceutically acceptable salt thereof. Embodiment 93. The compound of embodiment 1, wherein the compound is a compound of formula I-n, I-o, I-p, I-q, I-r or I-s:
  • Embodiment 94 The compound of embodiment 93, wherein the compound is a compound of formula I-n, I-o, I-q or I-r, or a pharmaceutically acceptable salt thereof.
  • Embodiment 95 The compound of embodiment 93, wherein the compound is a compound of formula I-n, I-o or I-q, or a pharmaceutically acceptable salt thereof.
  • Embodiment 96 The compound of embodiment 93, wherein the compound is a compound of formula I-n, or a pharmaceutically acceptable salt thereof.
  • Embodiment 97 The compound of embodiment 93, wherein the compound is a compound of formula I-o, or a pharmaceutically acceptable salt thereof.
  • Embodiment 98 The compound of embodiment 93, wherein the compound is a compound of formula I-o, or a pharmaceutically acceptable salt thereof.
  • Embodiment 93 wherein the compound is a compound of formula I-p, or a pharmaceutically acceptable salt thereof.
  • Embodiment 99 The compound of embodiment 93, wherein the compound is a compound of formula I-q, or a pharmaceutically acceptable salt thereof.
  • Embodiment 100 The compound of embodiment 93, wherein the compound is a compound of formula I-r, or a pharmaceutically acceptable salt thereof.
  • Embodiment 101 The compound of embodiment 93, wherein the compound is a compound of formula I-s, or a pharmaceutically acceptable salt thereof.
  • Embodiment 102 The compound of any one of embodiments 1-101, wherein X 2 is selected from –CH 2 – and –O–.
  • Embodiment 103 The compound of any one of embodiments 1-101, wherein X 2 is selected from –CH 2 – and –O–.
  • Embodiment 104 The compound of embodiment 103, wherein the compound is a compound of formula II-1 or II-2 pharmaceutically acceptable salt thereof.
  • Embodiment 105 The compound of embodiment 1, wherein the compound is a compound of one of formulas II-a, II-b, II-c, II-d, II-e, or II-f: or a pharmaceutically acceptable salt thereof.
  • Embodiment 106 The compound of embodiment 1, wherein the compound is a compound of or a pharmaceutically acceptable salt thereof.
  • Embodiment 107 The compound of embodiment 106, wherein the compound is a compound of formula II-a-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 108 The compound of embodiment 106, wherein the compound is a compound of formula II-b-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 109 The compound of embodiment 106, wherein the compound is a compound of formula II-c-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 110 The compound of embodiment 106, wherein the compound is a compound of formula I , or a pharmaceutically acceptable salt thereof.
  • Embodiment 111 The compound of embodiment 106, wherein the compound is a compound of formula II-e-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 112. The compound of embodiment 106, wherein the compound is a compound of formula I , or a pharmaceutically acceptable salt thereof.
  • Embodiment 113 The compound of embodiment 106, wherein the compound is a compound of formula I , or a pharmaceutically acceptable salt thereof.
  • Embodiment 114 The compound of embodiment 1, wherein the compound is a compound of one of formulas II-g, II-h, II-i, II-j, II-k, or II-l: , or a pharmaceutically acceptable salt thereof.
  • Embodiment 114 The compound of embodiment 1, wherein the compound is a compound of one of formulas II-g-1, II-h-1, II-i-1, II-j-1, II-k-1, or II-l-1: Embodiment 115. The compound of embodiment 114, wherein the compound is a compound of formula II-g-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 116 The compound of embodiment 114, wherein the compound is a compound of formula II-h-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 117 The compound of embodiment 114, wherein the compound is a compound of formula II-i-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 118 The compound of embodiment 114, wherein the compound is a compound of formula II-j-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 119 The compound of embodiment 114, wherein the compound is a compound of formula II-k-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 120 The compound of embodiment 114, wherein the compound is a compound of formula II-l-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 121 The compound of embodiment 114, wherein the compound is a compound of formula II-l-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 126. The compound of embodiment 1, wherein the compound is a compound of one of formulas II-bb, II-cc, II-dd, II-ee, II-ff, or II-gg: II-ee II-ff II-gg or a pharmaceutically acceptable salt thereof.
  • Embodiment 129 The compound of embodiment 128, wherein the compound is a compound of formula II-m-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 130 The compound of embodiment 128, wherein the compound is a compound of formula I , or a pharmaceutically acceptable salt thereof.
  • Embodiment 131 The compound of embodiment 128, wherein the compound is a compound of formula II-o-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 132. The compound of embodiment 128, wherein the compound is a compound of formula II-p-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 133 The compound of embodiment 128, wherein the compound is a compound of formula II-q-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 134 The compound of embodiment 128, wherein the compound is a compound of formula II-r-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 135. The compound of embodiment 128, wherein the compound is a compound of formula II-s-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 136. The compound of embodiment 128, wherein the compound is a compound of formula II-t-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 137 The compound of embodiment 128, wherein the compound is a compound of formula II-u-1 or a pharmaceutically acceptable salt thereof.
  • Embodiment 138. The compound of embodiment 128, wherein the compound is a compound of formula II-v-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 140 The compound of embodiment 128, wherein the compound is a compound of formula II-x-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 141 The compound of embodiment 128, wherein the compound is a compound of formula II-y-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 142 The compound of embodiment 128, wherein the compound is a compound of formula II-z-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 143 The compound of embodiment 128, wherein the compound is a compound of formula II-aa-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 144 The compound of embodiment 128, wherein the compound is a compound of formula II-aa-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 145 The compound of embodiment 144, wherein the compound is a compound of formula II-bb-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 146 The compound of embodiment 144, wherein the compound is a compound of formula II-cc-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 147 The compound of embodiment 144, wherein the compound is a compound of formula II-dd-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 148 The compound of embodiment 144, wherein the compound is a compound of formula II-dd-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 144 wherein the compound is a compound of formula II-ee-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 149 The compound of embodiment 144, wherein the compound is a compound of formula II-ff-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 150 The compound of embodiment 144, wherein the compound is a compound of formula II-gg-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 154 The compound of embodiment 153, wherein the compound is a compound of formula III-a-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 155 The compound of embodiment 153, wherein the compound is a compound of formula III-b-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 156 The compound of embodiment 153, wherein the compound is a compound of formula III-c-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 157 The compound of embodiment 153, wherein the compound is a compound of formula III-c-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 153, wherein the compound is a compound of formula III-d-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 158. The compound of embodiment 153, wherein the compound is a compound of formula III-e-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 159. The compound of embodiment 153, wherein the compound is a compound of formula III-f-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 160 The compound of embodiment 1, wherein the compound is a compound of one of formulas : or a pharmaceutically acceptable salt thereof.
  • Embodiment 161. The compound of embodiment 1, wherein the compound is a compound of one of formulas III-g-1, III-h-1, III-i-1, V-f, III-k-1, or III-l-1:
  • Embodiment 162 The compound of embodiment 161, wherein the compound is a compound of formula III-g-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 163. The compound of embodiment 161, wherein the compound is a compound of formula III-h-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 164. The compound of embodiment 161, wherein the compound is a compound of formula III-i-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 165 The compound of embodiment 161, wherein the compound is a compound of formula V-f, or a pharmaceutically acceptable salt thereof.
  • Embodiment 166. The compound of embodiment 161, wherein the compound is a compound of formula III-k-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 161 wherein the compound is a compound of formula III-l-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 168 The compound of embodiment 1, wherein the compound is a compound of one of formulas III-m, III-n, III-o, III-p, III-q, III-r, III-s, III-t, III-u, III-v, III-w, III-x, III- y, III-z, or III-aa: III-u III-v or a pharmaceutically acceptable salt thereof.
  • Embodiment 169 The compound of embodiment 1, wherein the compound is a compound of one of formulas III-bb, III-cc, III-dd, III-ee, III-ff, or III-gg:
  • Embodiment 170 The compound of embodiment 1, wherein the compound is a compound of formula or a pharmaceutically acceptable salt thereof, wherein R hh is –C 1 –C 6 alkyl substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 instances of –F, –OMe, –OEt, –OCH 2 CHF 2 , –OCH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Embodiment 172. The compound of embodiment 171, wherein the compound is a compound of formula I , or a pharmaceutically acceptable salt thereof.
  • Embodiment 173. The compound of embodiment 171, wherein the compound is a compound of formula III-n-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 171, wherein the compound is a compound of formula III-o-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 171 The compound of embodiment 171, wherein the compound is a compound of formula III-p-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 176 The compound of embodiment 171, wherein the compound is a compound of formula III-q-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 177 The compound of embodiment 171, wherein the compound is a compound of formula III-r-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 178 The compound of embodiment 171, wherein the compound is a compound of formula III-s-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 179 The compound of embodiment 171, wherein the compound is a compound of formula III-t-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 180 The compound of embodiment 171, wherein the compound is a compound of formula III-t-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 171, wherein the compound is a compound of formula III-u-1 or a pharmaceutically acceptable salt thereof.
  • Embodiment 181. The compound of embodiment 171, wherein the compound is a compound of formula III-v-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 182. The compound of embodiment 171, wherein the compound is a compound of formula III-w-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 171, wherein the compound is a compound of formula III-x-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 184. The compound of embodiment 171, wherein the compound is a compound of formula III-y-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 171 wherein the compound is a compound of formula III-z-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 186 The compound of embodiment 171, wherein the compound is a compound of formula III-aa-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 187 The compound of embodiment 1, wherein the compound is a compound of one of formulas III-bb-1, III-cc-1, III-dd-1, III-ee-1, III-ff-1 or III-gg-1: or a pharmaceutically acceptable salt thereof.
  • Embodiment 188 The compound of embodiment 187, wherein the compound is a compound of formula III-bb-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 189 The compound of embodiment 187, wherein the compound is a compound of formula III-bb-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 187, wherein the compound is a compound of formula III-cc-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 190. The compound of embodiment 187, wherein the compound is a compound of formula III-dd-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 191. The compound of embodiment 187, wherein the compound is a compound of formula III-ee-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 187, wherein the compound is a compound of formula , or a pharmaceutically acceptable salt thereof.
  • Embodiment 193. The compound of embodiment 187, wherein the compound is a compound of formula III-gg-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 196 The compound of of embodiment 1, wherein the compound is a compound of one of formulas IV-a-1, IV-b-1, IV-c-1, IV-d-1, IV-e-1, or IV-f-1: or a pharmaceutically acceptable salt thereof.
  • Embodiment 197 The compound of embodiment 196, wherein the compound is a compound of formula IV-a-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 198 The compound of embodiment 196, wherein the compound is a compound of formula IV-b-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 199 The compound of embodiment 196, wherein the compound is a compound of formula IV-c-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 200 The compound of embodiment 196, wherein the compound is a compound of formula IV-d-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 201 The compound of embodiment 196, wherein the compound is a compound of formula IV-e-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 202 The compound of embodiment 196, wherein the compound is a compound of formula IV-f-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 203 The compound of of embodiment 1, wherein the compound is a compound of one of formulas IV-g, IV-h, IV-i, IV-j, IV-k, or IV-l: or a pharmaceutically acceptable salt thereof.
  • Embodiment 204 The compound of embodiment 1, wherein the compound is a compound of one of formulas IV-g, IV-h, IV-i, IV-j, IV-k, or IV-l: or a pharmaceutically acceptable salt thereof.
  • Embodiment 205 The compound of embodiment 204, wherein the compound is a compound of formula IV-g-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 206 The compound of embodiment 204, wherein the compound is a compound of formula IV-h-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 207 The compound of embodiment 204, wherein the compound is a compound of formula IV-i-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 208 The compound of embodiment 204, wherein the compound is a compound of formula IV-i-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 209 The compound of embodiment 204, wherein the compound is a compound of formula V-k, or a pharmaceutically acceptable salt thereof.
  • Embodiment 210 The compound of embodiment 204, wherein the compound is a compound of formula IV-l-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 212 The compound of embodiment 1, wherein the compound is a compound of one of formulas IV-bb, IV-cc, IV-dd, IV-ee, IV-ff, or IV-gg:
  • Embodiment 213. The compound of embodiment 1, wherein the compound is a compound of formula IV-hh: or a pharmaceutically acceptable salt thereof, wherein wherein h is –C 1 –C 6 alkyl substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 instances of –F, –OMe, –OEt, –OCH2CHF2, –OCH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Embodiment 214. The compound of embodiment 1, wherein the compound is a compound of one of formulas I 1, IV-w-1, IV-x-1, IV-y-1, IV-z-1, or IV-aa-1:
  • Embodiment 215. The compound of embodiment 214, wherein the compound is a compound of formula IV-m-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 216. The compound of embodiment 214, wherein the compound is a compound of formula IV-n-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 217. The compound of embodiment 214, wherein the compound is a compound of formula IV-o-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 218. The compound of embodiment 214, wherein the compound is a compound of formula IV-p-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 214, wherein the compound is a compound of formula IV-q-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 220. The compound of embodiment 214, wherein the compound is a compound of formula IV-r-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 221. The compound of embodiment 214, wherein the compound is a compound of formula IV-s-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 214, wherein the compound is a compound of formula IV-t-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 223. The compound of embodiment 214, wherein the compound is a compound of formula IV-u-1 or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 214, wherein the compound is a compound of formula IV-v-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 225 The compound of embodiment 214, wherein the compound is a compound of formula IV-w-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 226 The compound of embodiment 214, wherein the compound is a compound of formula IV-x-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 214, wherein the compound is a compound of formula IV-y-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 228 The compound of embodiment 214, wherein the compound is a compound of formula IV-z-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 230 The compound of embodiment 1, wherein the compound is a compound of one of formulas IV-bb-1, IV-cc-1, IV-dd-1, IV-ee-1, IV-ff-1 or IV-gg-1: or a pharmaceutically acceptable salt thereof.
  • Embodiment 231. The compound of embodiment 230, wherein the compound is a compound of formula IV-bb-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 232. The compound of embodiment 230, wherein the compound is a compound of formula IV-cc-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 233 The compound of embodiment 230, wherein the compound is a compound of formula IV-cc-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 230, wherein the compound is a compound of formula IV-dd-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 234. The compound of embodiment 230, wherein the compound is a compound of formula IV-ee-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 235. The compound of embodiment 230, wherein the compound is a compound of formula IV-ff-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 236 The compound of embodiment 230, wherein the compound is a compound of formula IV-gg-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 239. The compound of embodiment 238, wherein the compound is a compound of formula V-a, or a pharmaceutically acceptable salt thereof.
  • Embodiment 240. The compound of embodiment 238, wherein the compound is a compound of formula V-b, or a pharmaceutically acceptable salt thereof.
  • Embodiment 241. The compound of embodiment 238, wherein the compound is a compound of formula V-c, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 238, wherein the compound is a compound of formula V-d, or a pharmaceutically acceptable salt thereof.
  • Embodiment 243. The compound of embodiment 1, wherein the compound is a compound of one of formulas V-g, V-h, V-i, V-j, V-k, V-1, or V-m:
  • Embodiment 244 The compound of embodiment 243, wherein the compound is a compound of formula V-g, or a pharmaceutically acceptable salt thereof.
  • Embodiment 245. The compound of embodiment 243, wherein the compound is a compound of formula V-h, or a pharmaceutically acceptable salt thereof.
  • Embodiment 246 The compound of embodiment 243, wherein the compound is a compound of formula V-i, or a pharmaceutically acceptable salt thereof.
  • Embodiment 247 The compound of embodiment 243, wherein the compound is a compound of formula V-j, or a pharmaceutically acceptable salt thereof.
  • Embodiment 248. The compound of embodiment 243, wherein the compound is a compound of formula V-k, or a pharmaceutically acceptable salt thereof.
  • Embodiment 249. The compound of embodiment 243, wherein the compound is a compound of formula V-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 250. The compound of embodiment 243, wherein the compound is a compound of formula V-m, or a pharmaceutically acceptable salt thereof.
  • Embodiment 251. The compound of embodiment 1, wherein the compound is a compound of one of formulas V-n, V-o, V-p, V-q or V-r: or a pharmaceutically acceptable salt thereof, wherein R hh is –C 1 –C 6 alkyl substituted with 0, 1, 2, or 3 instances of –F.
  • Embodiment 252. The compound of embodiment 251, wherein the compound is a compound of formula V-n, or a pharmaceutically acceptable salt thereof.
  • Embodiment 253 The compound of embodiment 251, wherein the compound is a compound of formula V-o, or a pharmaceutically acceptable salt thereof.
  • Embodiment 254. The compound of embodiment 251, wherein the compound is a compound of formula V-p, or a pharmaceutically acceptable salt thereof.
  • Embodiment 255. The compound of embodiment 251, wherein the compound is a compound of formula V-q, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 251, wherein the compound is a compound of formula V-r, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 257, wherein the compound is a compound of formula V-v, or a pharmaceutically acceptable salt thereof.
  • Embodiment 262. The compound of embodiment 257, wherein the compound is a compound of formula V-w, or a pharmaceutically acceptable salt thereof.
  • Embodiment 263. The compound of embodiment 257, wherein the compound is a compound of formula V-x, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 257, wherein the compound is a compound of formula V-y, or a pharmaceutically acceptable salt thereof.
  • Embodiment 265. The compound of embodiment 1, wherein the compound is a compound of one of formulas V-z, V-aa, V-bb, V-cc, V-dd, V-ee, V-ff, V-gg or V-hh:
  • Embodiment 266 The compound of embodiment 265, wherein the compound is a compound of formula V-z, or a pharmaceutically acceptable salt thereof.
  • Embodiment 267 The compound of embodiment 265, wherein the compound is a compound of formula V-aa, or a pharmaceutically acceptable salt thereof.
  • Embodiment 268 The compound of embodiment 265, wherein the compound is a compound of formula V-bb or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 265, wherein the compound is a compound of formula V-cc, or a pharmaceutically acceptable salt thereof.
  • Embodiment 270 The compound of embodiment 265, wherein the compound is a compound of formula V-dd, or a pharmaceutically acceptable salt thereof.
  • Embodiment 271 The compound of embodiment 265, wherein the compound is a compound of formula V-ee, or a pharmaceutically acceptable salt thereof.
  • Embodiment 272. The compound of embodiment 265, wherein the compound is a compound of formula V-ff or a pharmaceutically acceptable salt thereof.
  • Embodiment 273. The compound of embodiment 265, wherein the compound is a compound of formula V-gg, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 265, wherein the compound is a compound of formula V-hh, or a pharmaceutically acceptable salt thereof.
  • Embodiment 276 The compound of embodiment 275, wherein the compound is a compound of formula V-ii, or a pharmaceutically acceptable salt thereof.
  • Embodiment 277 The compound of embodiment 275, wherein the compound is a compound of formula V-jj, or a pharmaceutically acceptable salt thereof.
  • Embodiment 278 The compound of embodiment 275, wherein the compound is a compound of formula V-kk or a pharmaceutically acceptable salt thereof.
  • Embodiment 279. The compound of embodiment 275, wherein the compound is a compound of formula V-ll, or a pharmaceutically acceptable salt thereof.
  • Embodiment 280 The compound of embodiment 275, wherein the compound is a compound of formula V-mm, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 275, wherein the compound is a compound of formula V-nn, or a pharmaceutically acceptable salt thereof.
  • Embodiment 282. The compound of embodiment 275, wherein the compound is a compound of formula V-oo or a pharmaceutically acceptable salt thereof.
  • Embodiment 283. The compound of embodiment 275, wherein the compound is a compound of formula V-pp, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 275, wherein the compound is a compound of formula V-qq, or a pharmaceutically acceptable salt thereof.
  • Embodiment 285. The compound of embodiment 275, wherein the compound is a compound of formula V-rr, or a pharmaceutically acceptable salt thereof.
  • Embodiment 287 The compound of embodiment 275, wherein the compound is a compound of formula V-tt or a pharmaceutically acceptable salt thereof.
  • Embodiment 288 The compound of embodiment 275, wherein the compound is a compound of formula V-uu, or a pharmaceutically acceptable salt thereof.
  • Embodiment 289. The compound of embodiment 275, wherein the compound is a compound of formula V-vv, or a pharmaceutically acceptable salt thereof.
  • Embodiment 290 The compound of embodiment 275, wherein the compound is a compound of formula V-vv, or a pharmaceutically acceptable salt thereof.
  • Embodiment 292. The compound of embodiment 290, wherein the compound is a compound of formula V-ww, or a pharmaceutically acceptable salt thereof.
  • Embodiment 293. The compound of embodiment 290, wherein the compound is a compound of formula V-xx, or a pharmaceutically acceptable salt thereof.
  • Embodiment 294. The compound of embodiment 290, wherein the compound is a compound of formula V-zz or a pharmaceutically acceptable salt thereof.
  • Embodiment 295. The compound of embodiment 290, wherein the compound is a compound of formula V-aa-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 290, wherein the compound is a compound of formula V-bb-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 290, wherein the compound is a compound of formula V-cc-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 290, wherein the compound is a compound of formula V-dd-1 or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 290, wherein the compound is a compound of formula V-ee-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 290, wherein the compound is a compound of formula V-ff-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 290, wherein the compound is a compound of formula V-gg-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 302. The compound of embodiment 290, wherein the compound is a compound of formula V-hh-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 303. The compound of embodiment 290, wherein the compound is a compound of formula V-ii-1 or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 290, wherein the compound is a compound of formula V-jj-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 305. The compound of embodiment 290, wherein the compound is a compound of formula V-kk-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 307 The compound of embodiment 1, wherein the compound is a compound of one of formulas VI-a, VI -b, VI -c, VI -d, VI -e, or VI -f:
  • Embodiment 308 The compound of embodiment 1, wherein the compound is a compound of one of formulas VI-a-1, VI-b-1, VI-c-1, VI-d-1, VI-e-1, or VI-f-1: or a pharmaceutically acceptable salt thereof.
  • Embodiment 309 The compound of embodiment 307, wherein the compound is a compound of formula VI-a-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 310 The compound of embodiment 307, wherein the compound is a compound of formula VI-b-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 311 The compound of embodiment 307, wherein the compound is a compound of formula VI-c-1, or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 307, wherein the compound is a compound of formula VI-d-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 313. The compound of embodiment 307, wherein the compound is a compound of formula VI-e-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 314. The compound of embodiment 307, wherein the compound is a compound of formula VI-f-1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 315 The compound of any one of embodiments 1-313, wherein X 2 is selected from Embodiment 316.
  • the compound of any one of embodiments 1-313, wherein X 2 is selected from Embodiment 317.
  • Embodiment 320 The compound of embodiment 318, wherein the compound is a compound of formula VII-a, or a pharmaceutically acceptable salt thereof.
  • Embodiment 321. The compound of embodiment 318, wherein the compound is a compound of formula VII-b, or a pharmaceutically acceptable salt thereof.
  • Embodiment 322. The compound of embodiment 318, wherein the compound is a compound of formula VII-c or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 318, wherein the compound is a compound of formula VII-d, or a pharmaceutically acceptable salt thereof.
  • Embodiment 324. The compound of embodiment 318, wherein the compound is a compound of formula VII-e, or a pharmaceutically acceptable salt thereof.
  • Embodiment 325 The compound of embodiment 318, wherein the compound is a compound of formula VII-f or a pharmaceutically acceptable salt thereof.
  • Embodiment 326 The compound of embodiment 318, wherein the compound is a compound of formula VII-g, or a pharmaceutically acceptable salt thereof.
  • Embodiment 327 The compound of embodiment 318, wherein the compound is a compound of formula VII-h, or a pharmaceutically acceptable salt thereof.
  • Embodiment 331 The compound of any one of embodiments 1-326, wherein L is a bivalent, saturated or unsaturated, straight or branched C 3-5 hydrocarbon chain, wherein 1, 2 or 3 methylene units of L are independently replaced by –Cy– or–NR– .
  • Embodiment 332 The compound of any one of embodiments 1-326, wherein L is a bivalent, saturated or unsaturated, straight or branched C 3-5 hydrocarbon chain, wherein 1, 2 or 3 methylene units of L are independently replaced by –Cy– or–NR– .
  • each –Cy— is independently an optionally substituted bivalent ring selected from a 4-7 membered saturated or partially unsaturated monocyclic carbocyclylenyl, a 5-11 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 monocyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered monocyclic 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 and a 6-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylenyl having 118
  • Embodiment 333 The compound of any one of embodiments 1-330, wherein each –Cy— is independently an optionally substituted bivalent ring selected from a 4-7 membered saturated or partially unsaturated monocyclic carbocyclylenyl, a 5-11 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 monocyclic heterocyclylenyl containing 1-2 nitrogen atoms, a 5-11 membered monocyclic saturated or partially unsaturated spiro heterocyclylenyl containing 1-2 nitrogen atoms, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 nitrogen atoms, and a 6-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 nitrogen atoms.
  • Embodiment 334 The compound of any one of embodiments 1-330, wherein the bivalent ring of each –Cy— is independently substituted with 0, 1 or 2 substituents independently selected from –C 1 –C 4 alkyl, –C 1 –C 4 haloalkyl, –C 3 –C 7 cycloalkyl, –O–C 1 –C 4 alkyl, halo, cyano, –OH, –NH 2 , – N(H)(C 1 –C 4 alkyl) and –N(C 1 –C 4 alkyl) 2 .
  • Embodiment 335 Embodiment 335.
  • Embodiment 345 The compound of any one of embodiments 1-337, wherein L is .
  • Embodiment 346 The compound of any one of embodiments 1-337, wherein L is . he compound of any one of embodiments 1-337, wherein L is . he compound of any one of embodiments 1-337, wherein L is .
  • Embodiment 349 The compound of any one of embodiments 1-337, wherein L is . he compound of any one of embodiments 1-337, wherein L is . he compound of any one of embodiments 1-337, wherein L is .
  • Embodiment 352. The compound of any one of embodiments 1-337, wherein L is .
  • Embodiment 354 The compound of any one of embodiments 1-337, wherein L is .
  • Embodiment 356 The compound of any one of embodiments 1-337, wherein L is .
  • Embodiment 357 The compound of any one of embodiments 1-337, wherein L is .
  • the compound of any one of embodiments 1-337, wherein L is .
  • Embodiment 359. The compound of any one of embodiments 1-337, wherein L is .
  • Embodiment 360 The compound of any one of embodiments 1-337, wherein L is . he compound of any one of embodiments 1-337, wherein L is .
  • Embodiment 363. The compound of any one of embodiments 1-337, wherein L is . he compound of any one of embodiments 1-337, wherein L is .
  • Embodiment 366 The compound of any one of embodiments 1-337, wherein L is .
  • Embodiment 367 The compound of any one of embodiments 1-337, wherein L is . he compound of any one of embodiments 1-337, wherein L is . he compound of any one of embodiments 1-337, wherein L is .
  • Embodiment 370. The compound of any one of embodiments 1-368, wherein LBM is .
  • Embodiment 371 The compound of any one of embodiments 1-368, wherein LBM is .
  • Embodiment 372. The compound of any one of embodiments 1-370, wherein each R 4 is independently selected from deuterium, C 1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , –S(O)R, –S(O)NR 2 , –S(O)(NR)R, – C(O)NR 2 , –C(O)N(R)OR, –OC(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR 2 , – N(R)S(O) 2 NR 2 and –N(R)S(O) 2 R, wherein R is –H or a C
  • Embodiment 373 The compound of any one of embodiments 1-370, wherein each R 4 is independently selected from –Me, –Et, –F, –Cl, –CF 3 , –CN, –OH, –OMe, –NH 2 , –NHMe and – NMe 2 .
  • Embodiment 374 The compound of any one of embodiments 1-370, wherein each R 4 is independently selected from –Me, –Et, –F, –Cl, –CF 3 , –CN, –OH, –OMe, –NH 2 , –NHMe and – NMe 2 .
  • each R 5 is independently selected from deuterium, C 1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , –S(O)R, –S(O)NR 2 , –S(O)(NR)R, – C(O)NR 2 , –C(O)N(R)OR, –OC(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR 2 , – N(R)S(O) 2 NR 2 and –N(R)S(O) 2 R, wherein R is –H or a C 1-6 aliphatic chain.
  • Embodiment 375 The compound of any one of embodiments 1-372, wherein each R 5 is independently selected from –Me, –Et, –F, –Cl, –CF 3 , –CN, –OH, –OMe, –NH 2 , –NHMe and – NMe 2 .
  • Embodiment 376 The compound of any one of embodiments 1-372, wherein each R 5 is independently selected from –Me and –F.
  • Embodiment 377 The compound of any one of embodiments 1-375, wherein r is 0, 1 or 2.
  • Embodiment 378 The compound of any one of embodiments 1-375, wherein r is 0. Embodiment 379.
  • Embodiment 380 The compound of any one of embodiments 1-375, wherein r is 1.
  • Embodiment 380 The compound of any one of embodiments 1-375, wherein r is 2.
  • Embodiment 381. The compound of any one of embodiments 1-379, wherein s is 0, 1 or 2.
  • Embodiment 382. The compound of any one of embodiments 1-379, wherein s is 0.
  • Embodiment 383. The compound of any one of embodiments 1-379, wherein s is 1.
  • Embodiment 384 The compound of any one of embodiments 1-379, wherein s is 2.
  • Embodiment 385 The compound of any one of embodiments 1-383, wherein LBM is .
  • each R 1 is independently selected from deuterium, C 1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –SR, –OR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , –S(O)R, –S(O)NR 2 , –S(O)(NR)R, –C(O)OR, –C(O)NR 2 , –C(O)N(R)OR, –OC(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR 2 , –N(R)S(O) 2 NR 2 and –N(R)S(O) 2 R, wherein R is –H or a C 1-6 aliphatic chain substituted with 0-3 instances of halo.
  • Embodiment 402. The compound of any one of embodiments 1-399, wherein each R 1 is independently selected from –Me, –Et, –F, –Cl, –SCF 3 , –OCF 3 , –CF 3 , –CN, –OH, –OMe, –NH 2 , –NHMe and –NMe 2 .
  • Embodiment 403. The compound of any one of embodiments 1-399, wherein R 1 is –F.
  • each R 2 is independently selected from deuterium, C 1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , –S(O)R, –S(O)NR 2 , –S(O)(NR)R, – C(O)OR, –C(O)NR 2 , –C(O)N(R)OR, –OC(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR 2 , –N(R)S(O) 2 NR 2 and –N(R)S(O) 2 R, wherein R is –H or a C 1-6 aliphatic chain.
  • Embodiment 405. The compound of any one of embodiments 1-402, wherein each R 2 is independently selected from –Me, –Et, –F, –Cl, –CF 3 , –CHF 2 , –CN, –OH, –OMe, –OCF 3 , –NH 2 , –NHMe and –NMe 2 .
  • Embodiment 406. The compound of any one of embodiments 1-402, wherein each R 2 is independently selected from –Me, –Et, –F, –Cl, –CF 3 , –CN, –OH, –OMe, –NH 2 , –NHMe and – NMe 2 .
  • each R 2 is independently selected from –F, –Cl, –CF 3 , –CHF 2 , –OH, –OCF 3 and –SCF 3 .
  • Embodiment 408 The compound of any one of embodiments 1-402, wherein each R 2 is independently selected from –F, –Cl and –SCF 3 .
  • Embodiment 409 The compound of any one of embodiments 1-407, wherein m is 0, 1 or 2.
  • Embodiment 410. The compound of any one of embodiments 1-407, wherein m is 0.
  • Embodiment 411 The compound of any one of embodiments 1-407, wherein m is 1. Embodiment 412.
  • Embodiment 413 The compound of any one of embodiments 1-411, wherein n is 0, 1 or 2.
  • Embodiment 414. The compound of any one of embodiments 1-411, wherein n is 0.
  • Embodiment 415. The compound of any one of embodiments 1-411, wherein n is 1.
  • Embodiment 416. The compound of any one of embodiments 1-411, wherein n is 2.
  • Embodiment 417 Embodiment 417.
  • each R 3 is independently selected from deuterium, C 1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR 2 , –S(O) 2 R, –S(O) 2 NR 2 , –S(O)R, –S(O)NR 2 , –S(O)(NR)R, – C(O)OR, –C(O)NR 2 , –C(O)N(R)OR, –OC(O)NR 2 , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR 2 , –N(R)S(O) 2 NR 2 , –N(R)S(O) 2 R and –B(OR) 2 , wherein R is –H or a C 1-6 aliphatic chain.
  • Embodiment 418 The compound of any one of embodiments 1-415, wherein each R 3 is independently selected from –Me, –Et, , , , , , –OMe, and –B(OH) 2 .
  • Embodiment 419 The compound of any one of embodiments 1-415, wherein each R 3 is independently selected from –Me, NMe2 and –B(OH)2.
  • each R 3 is independently selected from –Me, –Et, –F, –Cl, –CF 3 ,-CO 2 H, –CN, –OH, –OMe, –NH 2 , –NHMe and –NMe2.
  • Embodiment 421 The compound of any one of embodiments 1-415, wherein each R 3 is independently selected from –Me, –Et, , , , , –F, –CF 3 , Embodiment 422.
  • Embodiment 423 The compound of any one of embodiments 1-415, wherein R 3 is selected from –F, –OH, and –CO 2 H.
  • Embodiment 429 The compound of any one of embodiments 1-426, wherein each R hh is independently selected from –Me, –Et, , , , , Embodiment 430.
  • Embodiment 431 A pharmaceutical composition comprising a compound of any one of embodiments 1-429, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.
  • Embodiment 432 A pharmaceutical composition comprising a compound of any one of embodiments 1-429, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.
  • a method of inhibiting ERD signaling in a sample e.g., in vivo or in vitro, by contacting ERD with a compound of any one of embodiments 1-428, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 429.
  • Embodiment 433. The method of embodiment 431, wherein the inhibiting of ERD signaling comprises reducing the signaling activity of ERD by at least 1%, 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, e.g., relative to a reference standard.
  • Embodiment 434 Embodiment 434.
  • Embodiment 435 A method of treating an ERD-mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of embodiments 1-428, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 429.
  • Embodiment 436 The method of embodiment 434, wherein the ERD-mediated disorder is associated with estrogen receptor accumulation and aggregation.
  • Embodiment 437 A method of treating an ERD-mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of embodiments 1-428, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 429.
  • Embodiment 438 The method of embodiment 436, wherein the ERD-mediated disorder is a disorder mediated by a ERD containing a D538G, Y537S, or L536R mutation.
  • Embodiment 439 The method of any one of embodiments 431-437, wherein the ERD- mediated disorder is a disorder described herein.
  • Embodiment 440 The method of any one of embodiments 431-437, wherein the ERD- mediated disorder is a disorder described herein.
  • the method of any one of embodiments 431-437 wherein the method comprises the steps of: (i) identifying a subject in need of such treatment; (ii) providing a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said provided compound in a therapeutically effective amount to treat, suppress and/or prevent the disease state or condition in a subject in need of such treatment.
  • Embodiment 441. The method of any one of embodiments 431-437, wherein the ERD- mediated disorder is breast cancer or uterine cancer.
  • Embodiment 443 The method of any one of embodiments 431-437, wherein the ERD- mediated disorder is endometriosis.
  • Embodiment 444 A compound or pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, according to any one of embodiments 1-429 or a pharmaceutical composition of embodiment 430, for use as a medicament.
  • Embodiment 445 A compound or pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, according to any one of embodiments 1-429 or a pharmaceutical composition of embodiment 430, for use in the treatment of an ERD-mediated disorder.
  • the parameters for the LCMS (acidic) measurement in the synthesis procedures below are one of the following: (1) Mobile Phase: 1.5ML/4LTFA in water (solvent A) and 0.75ML/4LTFA in acetonitrile (solvent B), using the elution gradient 5%-95% (solvent B) over0.7 minutes and holding at 95%; for 0.4 minutes at a flow rate of 1.5 ml/min; Column: MerckChromolith®FlashRP-183*25mm,3um; Wavelength:UV 220nm,254nm; Column temperature: 50°C; MS ionization: ESI.
  • the black suspension was carbonylated in a hydrogenated bottle at 80° C under 50 psi of CO for 48 hours. 300 mL H 2 O was added, and the mixture was extracted with ethyl acetate (2 ⁇ 80 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness in vacuo to give a black solution (17 g, crude). The black solution was subjected to column chromatography over silica gel (gradient elution: 0 – 12% EtOAc in petroleum ether). The desired fractions were collected, and concentrated to dryness in vacuo to give 1.4 as a yellow solution (9.34 g, 100% purity).
  • the reaction vessel was removed from the ice bath and allowed to gradually warm to 20 ° C over the course of 5 min, after which time stirring was continued for 16 h. Then ice (100 g) was added and the slurry partitioned between water and DCM. The organic phase was concentrated to dryness in vacuo to give a yellow oil. The yellow oil was subjected to column chromatography over silica gel (gradient elution: 0 – 18% EtOAc in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 1.5 as a brown oil (14.83 g, 98.3% purity).
  • the 100 mL round-bottomed flask was equipped with a reflux condenser, and tee-junction with a N 2 balloon.
  • the suspension was degassed in vacuo and purged with N 2 several times.
  • the reaction mixture was heated at 85 °C for 16 hour. Then the reaction was cooled to room temperature.
  • 150 mL H 2 O was added, and the mixture was extracted with ethyl acetate (2 ⁇ 50 mL).
  • the combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness in vacuo to give a black oil.
  • the suspension was degassed in vacuo and purged with N 2 several times.
  • the reaction mixture was heated at 100 °C for 16 hours. Then the reaction was cooled to room temperature. 15 mL H 2 O was added, and the mixture was extracted with ethyl acetate (2 ⁇ 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness in vacuo to give a black solid.
  • the black solid was subjected to column chromatography over silica gel (gradient elution: 0 – 20% EtOAc in petroleum ether).
  • the yellow oil was purified by prep-HPLC (column: Xtimate C18100*30mm*3um; mobile phase: [water (FA)-ACN]; B%: 7%-47%, 12min). The pure fractions were collected and concentrated in vacuo to remove organic solvent.
  • Methyl 8-(2,4-dichlorophenyl)-9-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)- 6,7-dihydro-5H-benzo[7]annulene-3-carboxylate 3.1 200 mg, 89.925% purity, 53.1% yeild was obtained was obtained as a white solid.
  • the reaction was concentrated to dryness in vacuo to give a yellow oil.
  • the yellow oil was purified by prep-HPLC (Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)- ACN];B%: 30%-60%,7min). The pure fractions were collected and concentrated in vacuo to remove organic solvent.
  • reaction mixture was quenched by added to addition of saturation solution of NH 4 Cl (50 mL) under 0 °C, extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was quenched by addition of water (50 mL), extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 1 A mixture of 4-bromo-1H-indazole (50 g, 253.77 mmol, 1 eq) and selectfluor (98.89 g, 279.14 mmol, 1.1 eq) was added in DMF (300 mL), and then the mixture was stirred at 70 °C for 12 hr. The residue was diluted with ethyl acetate (1 L) and extracted with solvent ethyl acetate (300 mL * 3). The combined organic layers were washed with brine (300 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 8 A mixture of (1-fluoro-3-tetrahydropyran-2-yl-9,10-dihydro-8H- cyclohepta[e]indazol-6-yl) trifluoromethanesulfonate (1.1 g, 2.53 mmol, 1 eq), 4- (dimethoxymethyl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (914.84 mg, 2.53 mmol, 1 eq), Na 2 CO 3 (805.16 mg, 7.60 mmol, 3 eq), Pd-118 (165.04 mg, 253.22 umol, 0.1 eq) in dioxane (20 mL) and H 2 O (5 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred
  • Step 3 To a mixture of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (10.6 g, 1 Eq, 48.6 mmol)Cesium carbonate (47.5 g, 11.7 mL, 3 Eq, 146 mmol) and ETHYL-4- BROMOTBUTYRATE (14.2 g, 10.4 mL, 1.5 Eq, 72.8 mmol) in HCN (50 mL) . The mixture was stirred at 25 °C for 4h. LCMS ⁇ TLC ⁇ showed the reaction was completed. The mixture was concentrated in reduced pressure at 25°C. The aqueous phase was extracted with ethyl acetate (100 mL*2).
  • Step 2 To a solution of ethyl 2-(2,2,2-trifluoroethyl)pent-4-enoate (7.7 g, 36.63 mmol) in THF (40 mL) was added 9-BBN (0.5 M, 80.59 mL) under N 2 atmosphere and stirred at 60 °C for 3 h.
  • 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (2.15 g, 6.02 mmol) in THF (5 mL) was added dropwise at -70 °C and stirred at 25 °C for 16 h.
  • the reaction mixture was quenched by addition sat.aq. NH 4 Cl (30 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was quenched by water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the aqueous phase was lyophilized to dryness to give 6-(4-chlorophenyl)-5-[4-[4-[[4-[2-[(3S)-2,6-dioxo-3-piperidyl]-1-oxo-isoindolin-5- yl]piperazin-1-yl]methyl]-1-piperidyl]phenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (52.9 mg, 66.26 umol, 21.47% yield) as a yellow solid.
  • Step 8 To a solution of methyl 8-(2,4-dichlorophenyl)-9-(2,6-difluoro-4- hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (430 mg, 1 Eq, 905 ⁇ mol) and TEA (915 mg, 1.26 mL, 10 Eq, 9.05 mmol) in DCM (30 mL) was added Phenyl triflimide (970 mg, 3 Eq, 2.71 mmol) in DCM (30 mL) at 0 °C under N 2 .
  • the aqueous phase was extracted with ethyl acetate (200 mL*2).
  • the combined organic phase was washed with brine (50 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
  • Step 4 To a mixture of 9-(4-(benzyloxy)-2,6-difluorophenyl)-8-bromo-3-methoxy-6,7- dihydro -5H-benzo[7]annulene (500 mg, 1 Eq, 1.06 mmol) and phenylboronic acid (155 mg, 1.2 Eq, 1.27 mmol),PdCl2(dppf) (77.6 mg, 0.1 Eq, 106 ⁇ mol),K2CO3 (440 mg, 3 Eq, 3.18 mmol) in Dioxane (30 mL)and h2o (0.2 mL)was added reagent in one portion at 25°C and degressed 3 times under N2 . The mixture was stirred at 25 °C for 5 min, then heated to 85°C and stirred for 8 hours.
  • the aqueous phase was extracted with ethyl acetate (50 mL*2).
  • the combined organic phase was washed with brine (20mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
  • Step 9 To a mixture of 1-(3,5-difluoro-4-(3-methoxy-8-phenyl-6,7-dihydro-5H-benzo[7] annulen-9-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 211 ⁇ mol), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (83.2 mg, 1.2 Eq, 253 ⁇ mol) in DCM (20 mL),Adjust the PH to about 6 with 4-methylmorfolin (64.1 mg, 70 ⁇ L, 3 Eq, 633 ⁇ mol). The mixture was stirred at 25°C for 10 min, then add Sodium triacetoxyborohydride (134 mg, 93.9 ⁇ L, 3 Eq, 633 ⁇ mol) and stirred for 3 hours.
  • Sodium triacetoxyborohydride 134 mg, 93.9 ⁇ L, 3
  • Step 2 To a mixture of compound 3 (1.89 g, 3.91 mmol, 1.0 eq.) in DCM (10 mL) was added tribromoborane (1.47 g, 565 ⁇ L, 5.86 mmol, 1.5 eq.) in one portion at 0 °C. The mixture was stirred at 0 °C for 1 hours. LCMS showed the reaction was completed. The mixture was poured into MeOH and DCM (200 mL, 1:1) and stirred for 30 min. The aqueous phase was extracted with ethyl acetate (100 mL x 2).
  • Step 3 A mixture of ethyl 5-(3-methoxyphenyl)-3-methylpenta-2,4-dienoate (50 mg, 1 Eq, 0.15 mmol), Pd/C (50 mg, 10% Wt, 0.31 Eq, 47 ⁇ mol), H 2 (0.31 mg, 1 Eq, 0.15 mmol) in MeOH (2 mL). The suspension was degassed and purged with H 2 for 3 times. The mixture was stirred under H 2 (15 psi) at 25 °C for 16 hour. Then the reaction was cooled to room temperature.
  • Step 4 A 100 mL thread vial equipped with magnetic stirrer, sodium hydroxide (451 mg, 5.63 mL, 2 molar, 5 Eq, 11.3 mmol) was added to the solution of ethyl 5-(3-methoxyphenyl)-3- methylpentanoate (600 mg, 1 Eq, 2.25 mmol) in MeOH (10 mL).
  • Trifluoroaceticanhydride (5.2 g, 3.5 mL, 5 Eq, 25 mmol) was added to the solution of 5-(3-methoxyphenyl)-3- methylpentanoic acid (1.1 g, 1 Eq, 4.9 mmol) in DCM (12 mL). The mixture was stirred at 0 °C for 16 hour. The reaction was treated with H 2 O (50 mL), extracted with DCM (50 mL). The combined extracts was dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness in vacuo to give a yellow oil.
  • the mixture was stirred at 25 °C for 16 hr.
  • the reaction mixture was diluted with 30 mL H 2 O and extracted with ethyl acetate (20 mL * 2).
  • the combined organic layers were washed with brine (10 mL * 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 2 To a solution of 7-(cyclopenten-1-yl)-6-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]-3-tetrahydropyran-2-yl-9,10-dihydro-8H-cyclohepta[e]indazole (120 mg, 211.36 ⁇ mol, 1 eq) in EtOAc (4 mL) and EtOH (4 mL) was added Pd/C (10%, 0.11 g) under N 2 atmosphere. The suspension was degassed and purged with H 2 for 3 times. The mixture was stirred under H 2 (15 psi) at 25 °C for 16 hr.
  • HPLC 100%, purity at 220 nm.
  • SFC Rt: 4.022 min; Area, 96.374%; method: ID_MeOH_DEA_MeCN_50_1ML_10MIN_5CM.
  • Step 4 To a solution of compound 5 (30 mg, 66.14 ⁇ mol, 1 eq) and (3S)-3-(1-oxo-5- piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (21.72 mg, 66.14 ⁇ mol, 1 eq) in DCM (3 mL) and MeOH (3 mL) , after stirred 30 min was added NaBH(OAc) 3 (42.05 mg, 198.41 ⁇ mol, 3 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to yield a residue.
  • reaction mixture was quenched by addition of water (150 mL), extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (petroleum ether/ethyl acetate from 100/0 to 90/10) to yield a product.
  • Example 25 Synthesis of (S)-3-(5-(4-((1-(4-(7-(2-chlorophenyl)-1-fluoro-3,8,9,10- tetrahydrocyclohepta[e]indazol-6-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione, I-56 [0881] Step 1. A 8 mL thread vial was equipped with magnetic stirrer.
  • Pd(dppf)Cl 2 (13.643 mg, 0.1 Eq, 16.707 ⁇ mol) was added to a mixture suspension of 7-bromo-6-(4-(4-(dimethoxymethyl) piperidin-1-yl) phenyl)-1-fluoro-3-(tetrahydro-2H-pyran-2-yl)-3, 8, 9, 10- tetrahydrocyclohepta[e]indazole (100 mg, 1 Eq, 167 ⁇ mol) and sodium carbonate (53.1 mg, 3 Eq, 501.2 ⁇ mol) and (2-chlorophenyl)boronic acid (31.3 mg, 1.2 Eq, 200.5 ⁇ mol) in 1,4-dioxane (3 mL) and H 2 O (0.6 mL).
  • reaction mixture was quenched by addition H 2 O (15 mL) at 25 °C, and then diluted with DCM (5 mL) and extracted with DCM (15 mL * 2). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Xtimate C18150*40mm*10um; mobile phase:[water(FA)-ACN]; B%: 27%-57%,7min).
  • the reaction mixture was quenched by addition 100 mL H 2 O at 25 °C, and then diluted with 50 mL ethyl acetate and extracted with ethyl acetate(100 mL * 3). The combined organic layers were washed with brine 100 mL, dried over drying Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 20% Ethyl acetate/Petroleum ether gradient @ 40 mL/min).
  • reaction mixture was quenched by addition H 2 O 20 mL at 25 °C, and then diluted with 20 mL ethyl acetate and extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with 20 mL brine, dried over drying Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Xtimate C18150*40mm*5um; mobile phase: [water(FA)-ACN];gradient:20%- 60% B over 9 min).
  • reaction mixture was quenched by saturated NaHCO 3 aqueous solution addition 10 mL at 25 °C, and then diluted with 10 mL H 2 O and extracted with 30 mL ethyl acetate (15 mL * 2). The combined organic layers were washed with brine 20 mL (10 mL * 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 3 To a solution of 1-[4-[7-(2,4-dichlorophenyl)-1-fluoro-3-tetrahydropyran-2-yl- 9,10-dihydro-8H-cyclohepta[e]indazol-6-yl]phenyl]piperidine-4-carbaldehyde (60 mg, 97.0 ⁇ mol, 1 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (72.8 mg, 145.5 ⁇ mol, 1.5 eq, PhSO 3 H salt) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (15.91 mg, 194.0 ⁇ mol, 2 eq) . The mixture was stirred at 25 °C for 0.5 h.
  • Step 3 To a solution of Pd/C (1.5 g, 10% purity) in MeOH (10 mL) was added ethyl (E)- 5-(3-methoxyphenyl)-2-(2,2,2-trifluoroethyl)pent-4-enoate (1.5 g, 4.60 mmol) under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (50 psi) at 50 °C for 2 h.
  • Step 2 To a solution of compound 2 (350 mg, 676 ⁇ mol, 1.0 eq.) in DCM (10 mL) was added BBr 3 (846 mg, 3.38 mmol, 5.0 eq.). The mixture was stirred at 20 °C for 1 hour and then water (1 mL) in DCM (10 mL) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The mixture was concentrated and then water (20 mL) was added. The mixture was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated.
  • Step 2 To a solution of compound 3(300 mg, 1 eq., 670 ⁇ mol) in MeOH (10 mL) was added Pd/C (143 mg, 10% Wt, 134 ⁇ mol, 0.2 eq.). The suspension was degassed under vacuum and purged with H 2 several times. The mixture was heated to 25 °C (15 psi) and stirred for 3 hours. LCMS showed that the desired compound was detected. The crude product was filtered and the filter was concentrated to give the crude as a grey solid.
  • Step 3 To a mixture of compound 4 (110 mg, 245 ⁇ mol, 1.0 eq.) in DCM (15 mL)was added tribromoborane (613 mg, 2.45 mmol, 10.0 eq.) in one portion . The mixture was stirred at 25 °C for 2 hours. LCMS showed the reaction was completed. The mixture was concentrated afford the crude compound 5 (60 mg, 0.15 mmol, 63 % yield). [0934] LC-MS (ESI + ) m/z: 390.4 (M+H) + . [0935] Step 4.
  • reaction mixture was quenched by addition EA 30 mL at 20 C, and then diluted with water 30 mL and extracted with EA 90 mL (30 mL x 3). The combined organic layers were washed with EA 30 mL (10 mL * 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 2 To a solution of compound 2 (200 mg, 385 ⁇ mol, 1.0 eq.) in DCM (10 mL) was added BBr 3 (483 mg, 1.93 mmol, 5.0 eq.). The mixture was stirred at 20 °C for 2 hour and then water (2 mL) in DCM (10 mL) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 30 min. LCMS showed the reaction was completed. The mixture was concentrated and then water (20 mL) was added. The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated.
  • the reaction was clean according to TLC (Iodine reagent color).
  • the reaction mixture was concentrated under reduced pressure to remove solvent.
  • the residue was diluted with NH 4 Cl 200 ml and extracted with ethly acetate 200 ml (20 ml x 2).
  • the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue to offer ethyl 2-(tert-butyl)pent-4-enoate (13.55 g, 59 mmol, 85 % yield, 80% Purity).
  • reaction solution was slowly dripped with n-Butyllithium, 2.5 Minhexane (468 mg, 3.65 mL, 2.0 molar, 1.5 eq, 7.31 mmol) and kept at a temperature of -68 °C. After half an hour, the reaction liquid becomes milky white and raw material6-(tert-butyl)-2- methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.20 g, 1 eq, 4.87 mmol) is added to the reaction droplet. After an hour, test the reaction fluid LC-MS showed Reactant 7 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent.

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Abstract

L'invention concerne des composés bifonctionnels qui agissent comme agents de dégradation du récepteur alpha des oestrogènes (ERα) et qui sont utiles pour traiter des troubles associés à la régulation de la transcription médiée par ERα, tels que l'endométriose et le cancer. Ces composés sont des molécules bifonctionnelles comprenant une fraction de liaison au céréblon, LBM, liée à un ligand ERBM qui se lie à ERα et comprend un cycle à 7 chaînons benzocondensé.
PCT/US2023/069192 2022-06-27 2023-06-27 Agents de dégradation des récepteurs alpha des oestrogènes et leur utilisation médicale WO2024006776A1 (fr)

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