WO2025120599A1

WO2025120599A1 - METHODS OF USING eIF4E INHIBITORS FOR TREATING CANCER

Info

Publication number: WO2025120599A1
Application number: PCT/IB2024/062334
Authority: WO
Inventors: Matthew FRIEDERSDORF; Jessica Ann SORRENTINO ZIMMERMAN; Devon R. BLAKE; Charles R. HOLST
Original assignee: Ribometrix Inc
Current assignee: Ribometrix Inc
Priority date: 2023-12-08
Filing date: 2024-12-06
Publication date: 2025-06-12
Anticipated expiration: 2026-06-08

Abstract

The present disclosure provides methods of using eIF4E inhibitors for treating cancer (e.g., breast cancer).

Description

METHODS OF USING eIF4E INHIBITORS FOR TREATING CANCER

RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application Nos. 63/607,944, filed December 8, 2023, and 63/575,227, filed April 5, 2024, the contents of which are incorporated herein by reference in their entirety.

BACKGROUND

[0002] eIF4E, the main regulator and rate limiting factor of protein synthesis, is the downstream integrator of several important oncogenic signaling pathways (PI3K/AKT/mT0R, Ras/Raf/MEK, and Myc). Activation of eIF4E results in increased protein levels of key proliferation and metabolism proteins such as Cyclin DI (CCND1) and Ornithine Decarboxylase 1 (ODC1), as well as an overall increase in cellular synthesis machinery, causing cellular growth and proliferation.

[0003] Elevated levels of eukaryotic initiation factor 4E (eIF4E) are found in a broad range of cancers, including breast cancer, and have been associated with aggressive, drug resistant tumors. Furthermore, elevated eIF4E activity is sufficient to cause transformation in various cancers, while inhibition suppresses tumor growth.

[0004] As such, there is an unmet need to develop eIF4E inhibitors for treating breast cancer, including ER+ breast cancer.

SUMMARY

[0005] In certain aspects, the present disclosure provides methods of treating cancer (e.g., breast cancer) in a subject in need thereof, comprising administering to the subject an eIF4E inhibitor disclosed herein.

[0006] In certain aspects, the present disclosure provides uses of an eIF4E inhibitor disclosed herein in the manufacture of a medicament for cancer (e.g., breast cancer) in a subject in need thereof.

[0007] In certain aspects, the present disclosure provides eIF4E inhibitors disclosed herein for use in treating cancer (e.g., breast cancer) in a subject in need thereof.

[0008] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0009] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent is specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1A is a set of TR-FRET assay curves of titration of competitive cap analogs showing tight binding to 5’ mRNA cap (left), and enhanced competition for eIF4E inhibitors (right).

[0011] FIG. IB is a curve of cap-dependent dual luciferase assay showing potent and selective inhibition of cap-dependent translation.

[0012] FIG. 2A is a scheme showing that cells incorporate O-propargyl-puromycin (OPP) into actively translating peptide chains which can be fluorescently labeled by click chemistry, allowing for quantitative determination of total new protein synthesis.

[0013] FIG. 2B is a set of curves showing OPP assay in MCF-7 and HCC1806 cells incubated with OPP for 30 minutes.

[0014] FIG. 2C is a scheme showing eIF4E regulated genes.

[0015] FIG. 2D is a table showing functional category enrichment of proteins that are down- regulated upon eIF4E inhibitor treatment.

[0016] FIG. 3A is a TR-FRET assay curve showing wild type or binding pocket mutant (S92I) eIF4E binding to m7GTP.

[0017] FIG. 3B is a set of CellTiter-Glo (CTG) assay curves for Compound C and eIF4A inhibitor zotatifin.

[0018] FIG. 4A is a Western blot graph of HCC1806 cells treated with compound for 24 hours. For “washout” samples, the media containing the compound was replaced with media containing DMSO only, while other samples maintained the original treatment. Samples were collected at indicated time points to evaluate recovery of CCND1 and ODC1.

[0019] FIG. 4B is a bar graph showing densitometry quantification of Western blots in FIG.

4A [0020] FIG. 5A is a CTG assay graph for MCF-7 cells treated for 72 hr with eIF4E inhibitors Compound A, B, or C, showing that eIF4E inhibitors decreased viable cells in a concentration responsive manner.

[0021] FIG. 5B is a Western blot showing concentration dependent selective decrease of eIF4E target genes after MCF-7 cells were treated for 6 hr with Compound B.

[0022] FIG. 5C is a bar graph showing concentration dependent increase in G0/G1 population when cells are treated with two concentrations of Compound B, analyzed by DNA content flow cytometry.

[0023] FIG. 6A is a graph showing serial passaging strategy to generate MCF-7 lines with acquired resistant to palbociclib.

[0024] FIG. 6B is a DNA content flow cytometry bar graph showing palbociclib induces G1 arrest in MCF-7, which is severely reduced in palbociclib-resistant cells.

[0025] FIG. 6C is a set of Western blots of MCF-7 and palbociclib-resistant cells validating that the CDK4/6 pathway is refractory to palbociclib in palbociclib-resistant cells.

[0026] FIG. 7A is a Western blot after palbociclib-resistant cells were treated for 6hr with Compound B, showing that eIF4E pathway markers are similarly responsive in palbociclib- resistant cells as parental MCF-7 (FIG. 5B).

[0027] FIG. 7B is a set of CTG assay graphs showing sensitivities of MCF-7 and palbociclib-resistant cells to palbociclib (left) and Compound B (right).

[0028] FIG. 7C is a set of graphs representing CTG assay max inhibition values for combinations of different concentrations of Compound B and palbociclib in MCF-7 (left) and palbociclib-resistant cells (right).

[0029] FIG. 8A is a graph showing MCF-7 CDX tumor growth after daily oral treatment of eIF4E inhibitors Compound D, E, or F.

[0030] FIG. 8B is a graph showing percent change in total body weight of MCF-7 CDX model relative to day 1.

[0031] FIG. 9A is a graph showing MCF-7 xenograft tumor growth curves with daily oral treatment of i) SOC (1. palbociclib, 2. fulvestrant, or 3. palbociclib + fulvestrant), ii) Compound E, and iii) combinations of Compound E with SOC.

[0032] FIG. 9B is a bar graph showing percent change in tumor volume for individual mice in Compound E + SOC group. Dashed lines indicate cutoffs for: progressive disease >+20%, stable disease <+20% and >-30%, and partial response <-30%.

[0033] FIG. 9C is a graph showing the mean percent change in bodyweight. [0034] FIG. 9D is a table summarizing TGI, Bliss, and HSA combination index scores from day 1 to day 28 relative to vehicle change. For Bliss and HSA (highest single agent) combination index scores, >0 is synergistic, =0 is additive, and <0 is antagonistic.

DETAILED DESCRIPTION

[0035] The present disclosure also relates to methods of using an eIF4E inhibitor described herein, alone or in combination with a second therapeutic agent, in treating cancer (e.g., breast cancer) in a subject in need thereof.

Methods of Use or Use of the Present Disclosure

[0036] In certain aspects, the present disclosure provides methods of treating cancer (e.g., breast cancer) in a subject in need thereof, comprising administering to the subject an eIF4E inhibitor disclosed herein.

[0037] In certain embodiments, the eIF4E inhibitor is administered at a dose of about 1 mg/kg to about 500 mg/kg.

[0038] In certain embodiments, the eIF4E inhibitor is administered at a dose of about 1 mg/kg to about 200 mg/kg.

[0039] In certain embodiments, the eIF4E inhibitor is administered at a dose of about 10 mg/kg to about 500 mg/kg.

[0040] In certain embodiments, the eIF4E inhibitor is administered at a dose of about 20 mg to about 3000 mg.

[0041] In certain embodiments, the eIF4E inhibitor is administered at a dose of about 20 mg to about 1000 mg.

[0042] In certain embodiments, the eIF4E inhibitor is administered at a dose of about 100 mg to about 3000 mg.

[0043] In certain aspects, the present disclosure provides uses of an eIF4E inhibitor disclosed herein in the manufacture of a medicament for cancer (e.g., breast cancer) in a subject in need thereof.

[0044] In certain embodiments, the medicament is for administration at an eIF4E inhibitor dose of about 1 mg/kg to about 500 mg/kg.

[0045] In certain embodiments, the medicament is for administration at an eIF4E inhibitor dose of about 1 mg/kg to about 200 mg/kg.

[0046] In certain embodiments, the medicament is for administration at an eIF4E inhibitor dose of about 10 mg/kg to about 500 mg/kg. [0047] In certain embodiments, the medicament is for administration at an eIF4E inhibitor dose of about 20 mg to about 3000 mg.

[0048] In certain embodiments, the medicament is for administration at an eIF4E inhibitor dose of about 20 mg to about 1000 mg.

[0049] In certain embodiments, the medicament is for administration at an eIF4E inhibitor dose of about 100 mg to about 3000 mg.

[0050] In certain aspects, the present disclosure provides eIF4E inhibitors disclosed herein for use in treating cancer (e.g., breast cancer) in a subject in need thereof.

[0051] In certain embodiments, the eIF4E inhibitor is for administration at dose of about 1 mg/kg to about 500 mg/kg.

[0052] In certain embodiments, the eIF4E inhibitor is for administration at dose of about 1 mg/kg to about 200 mg/kg.

[0053] In certain embodiments, the eIF4E inhibitor is for administration at dose of about 10 mg/kg to about 500 mg/kg.

[0054] In certain embodiments, the eIF4E inhibitor is for administration at dose of about 20 mg to about 3000 mg.

[0055] In certain embodiments, the eIF4E inhibitor is for administration at dose of about 20 mg to about 1000 mg.

[0056] In certain embodiments, the eIF4E inhibitor is for administration at dose of about 100 mg to about 3000 mg.

[0057] In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 180 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 160 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 140 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 120 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 100 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 80 mg/kg.

In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 60 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 40 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 35 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 30 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 25 mg/kg.

[0058] In certain embodiments, the eIF4E inhibitor dose is about 2 mg/kg to about 180 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 2 mg/kg to about 160 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 2 mg/kg to about 140 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 2 mg/kg to about 120 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 2 mg/kg to about 100 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 2 mg/kg to about 80 mg/kg.

In certain embodiments, the eIF4E inhibitor dose is about 2 mg/kg to about 60 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 2 mg/kg to about 40 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 2 mg/kg to about 35 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 2 mg/kg to about 30 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 2 mg/kg to about 25 mg/kg.

[0059] In certain embodiments, the eIF4E inhibitor dose is about 3 mg/kg to about 180 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 3 mg/kg to about 160 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 3 mg/kg to about 140 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 3 mg/kg to about 120 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 3 mg/kg to about 100 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 3 mg/kg to about 80 mg/kg.

In certain embodiments, the eIF4E inhibitor dose is about 3 mg/kg to about 60 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 3 mg/kg to about 40 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 3 mg/kg to about 35 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 3 mg/kg to about 30 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 3 mg/kg to about 25 mg/kg.

[0060] In certain embodiments, the eIF4E inhibitor dose is about 4 mg/kg to about 180 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 4 mg/kg to about 160 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 4 mg/kg to about 140 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 4 mg/kg to about 120 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 4 mg/kg to about 100 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 4 mg/kg to about 80 mg/kg.

In certain embodiments, the eIF4E inhibitor dose is about 4 mg/kg to about 60 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 4 mg/kg to about 40 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 4 mg/kg to about 35 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 4 mg/kg to about 30 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 4 mg/kg to about 25 mg/kg.

[0061] In certain embodiments, the eIF4E inhibitor dose is about 5 mg/kg to about 180 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 5 mg/kg to about 160 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 5 mg/kg to about 140 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 5 mg/kg to about 120 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 5 mg/kg to about 100 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 5 mg/kg to about 80 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 5 mg/kg to about 60 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 5 mg/kg to about 40 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 5 mg/kg to about 35 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 5 mg/kg to about 30 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 5 mg/kg to about 25 mg/kg.

[0062] In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 180 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 160 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 140 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 120 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 100 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 80 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 60 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 40 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 35 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 30 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 25 mg/kg.

[0063] In certain embodiments, the eIF4E inhibitor dose is about 15 mg/kg to about 180 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 15 mg/kg to about 160 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 15 mg/kg to about 140 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 15 mg/kg to about 120 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 15 mg/kg to about 100 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 15 mg/kg to about 80 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 15 mg/kg to about 60 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 15 mg/kg to about 40 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 15 mg/kg to about 35 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 15 mg/kg to about 30 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 15 mg/kg to about 25 mg/kg.

[0064] In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 180 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 160 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 140 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 120 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 100 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 80 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 60 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 40 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 35 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 30 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 25 mg/kg.

[0065] In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 200 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 180 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 150 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 120 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 100 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 90 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 80 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 70 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 65 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 60 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 55 mg/kg.

[0066] In certain embodiments, the eIF4E inhibitor dose is about 75 mg/kg to about 200 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 75 mg/kg to about 160 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 75 mg/kg to about 140 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 75 mg/kg to about 130 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 75 mg/kg to about 120 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 75 mg/kg to about 110 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 75 mg/kg to about 100 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 75 mg/kg to about 95 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 75 mg/kg to about 90 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 75 mg/kg to about 85 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 75 mg/kg to about 80 mg/kg. [0067] In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 200 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 180 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 160 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 140 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 135 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 130 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 125 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 120 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 115 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 110 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 105 mg/kg.

[0068] In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 25 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 3 mg/kg to about 25 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 5 mg/kg to about 25 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 8 mg/kg to about 25 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 25 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 12 mg/kg to about 25 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 14 mg/kg to about 25 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 16 mg/kg to about 25 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 18 mg/kg to about 25 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 25 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 22 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 20 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 18 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 16 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 14 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 12 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 10 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 8 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 6 mg/kg.

[0069] In certain embodiments, the eIF4E inhibitor dose is about 1 mg/kg to about 25 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 3 mg/kg to about 23 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 5 mg/kg to about 20 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 7 mg/kg to about 18 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 8 mg/kg to about 16 mg/kg.

[0070] In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 500 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 450 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 400 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 350 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 300 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 250 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 200 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 150 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 100 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 75 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 10 mg/kg to about 50 mg/kg.

[0071] In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 500 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 450 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 400 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 350 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 300 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 250 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 200 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 150 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 100 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 75 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg/kg to about 50 mg/kg.

[0072] In certain embodiments, the eIF4E inhibitor dose is about 30 mg/kg to about 500 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 30 mg/kg to about 450 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 30 mg/kg to about 400 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 30 mg/kg to about 350 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 30 mg/kg to about 300 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 30 mg/kg to about 250 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 30 mg/kg to about 200 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 30 mg/kg to about 150 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 30 mg/kg to about 100 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 30 mg/kg to about 75 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 30 mg/kg to about 50 mg/kg.

[0073] In certain embodiments, the eIF4E inhibitor dose is about 40 mg/kg to about 500 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg/kg to about 450 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg/kg to about 400 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg/kg to about 350 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg/kg to about 300 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg/kg to about 250 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg/kg to about 200 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg/kg to about 180 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg/kg to about 160 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg/kg to about 140 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg/kg to about 120 mg/kg.

[0074] In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 500 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 450 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 400 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 350 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 300 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 250 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 200 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 180 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 160 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 140 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg/kg to about 120 mg/kg.

[0075] In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 500 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 475 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 450 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 400 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 350 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 300 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 250 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 200 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 175 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 150 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg/kg to about 125 mg/kg.

[0076] In certain embodiments, the eIF4E inhibitor dose is about 150 mg/kg to about 500 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg/kg to about 475 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg/kg to about 450 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg/kg to about 425 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg/kg to about 400 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg/kg to about 375mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg/kg to about 350 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg/kg to about 325 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg/kg to about 300 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg/kg to about 275 mg/kg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg/kg to about 250 mg/kg.

[0077] In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 300 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 200 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 100 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 90 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 80 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 70 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 60 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 50 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 40 mg. In certain embodiments, the eIF4E inhibitor dose is about 20 mg to about 30 mg. [0078] In certain embodiments, the eIF4E inhibitor dose is about 30 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 60 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 70 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 80 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 90 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 500 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 550 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 600 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 650 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 700 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 750 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 800 mg to about 1000 mg.

[0079] In certain embodiments, the eIF4E inhibitor dose is about 30 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 60 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 70 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 80 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 90 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 500 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 550 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 600 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 650 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 700 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 750 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 800 mg to about 900 mg.

[0080] In certain embodiments, the eIF4E inhibitor dose is about 30 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 60 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 70 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 80 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 90 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 500 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 550 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 600 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 650 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 700 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 750 mg to about 800 mg.

[0081] In certain embodiments, the eIF4E inhibitor dose is about 30 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 60 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 70 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 80 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 90 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 500 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 550 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 600 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 650 mg to about 700 mg.

[0082] In certain embodiments, the eIF4E inhibitor dose is about 30 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 60 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 70 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 80 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 90 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 500 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 550 mg to about 600 mg. [0083] In certain embodiments, the eIF4E inhibitor dose is about 30 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 60 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 70 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 80 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 90 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 500 mg.

[0084] In certain embodiments, the eIF4E inhibitor dose is about 30 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 60 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 70 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 80 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 90 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 400 mg.

[0085] In certain embodiments, the eIF4E inhibitor dose is about 30 mg to about 300 mg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg to about 300 mg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg to about 300 mg. In certain embodiments, the eIF4E inhibitor dose is about 60 mg to about 300 mg. In certain embodiments, the eIF4E inhibitor dose is about 70 mg to about 300 mg. In certain embodiments, the eIF4E inhibitor dose is about 80 mg to about 300 mg. In certain embodiments, the eIF4E inhibitor dose is about 90 mg to about 300 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 300 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 300 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 300 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 300 mg.

In certain embodiments, the eIF4E inhibitor dose is about 30 mg to about 200 mg. In certain embodiments, the eIF4E inhibitor dose is about 40 mg to about 200 mg. In certain embodiments, the eIF4E inhibitor dose is about 50 mg to about 200 mg. In certain embodiments, the eIF4E inhibitor dose is about 60 mg to about 200 mg. In certain embodiments, the eIF4E inhibitor dose is about 70 mg to about 200 mg. In certain embodiments, the eIF4E inhibitor dose is about 80 mg to about 200 mg. In certain embodiments, the eIF4E inhibitor dose is about 90 mg to about 200 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 200 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 200 mg.

[0086] In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 1500 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 1250 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 1000 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 900 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 800 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 700 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 600 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 500 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 450 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 400 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 350 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 300 mg. In certain embodiments, the eIF4E inhibitor dose is about 100 mg to about 250 mg.

[0087] In certain embodiments, the eIF4E inhibitor dose is about 130 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 140 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 160 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 170 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 180 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 190 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 500 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 550 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 600 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 650 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 700 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 750 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 800 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 850 mg to about 3000 mg. In certain embodiments, the eIF4E inhibitor dose is about 900 mg to about 3000 mg.

[0088] In certain embodiments, the eIF4E inhibitor dose is about 130 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 140 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 160 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 170 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 180 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 190 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 500 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 550 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 600 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 650 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 700 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 750 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 800 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 850 mg to about 2800 mg. In certain embodiments, the eIF4E inhibitor dose is about 900 mg to about 2800 mg.

[0089] In certain embodiments, the eIF4E inhibitor dose is about 130 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 140 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 160 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 170 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 180 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 190 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 500 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 550 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 600 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 650 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 700 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 750 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 800 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 850 mg to about 2500 mg. In certain embodiments, the eIF4E inhibitor dose is about 900 mg to about 2500 mg.

[0090] In certain embodiments, the eIF4E inhibitor dose is about 130 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 140 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 160 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 170 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 180 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 190 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 500 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 550 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 600 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 650 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 700 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 750 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 800 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 850 mg to about 2400 mg. In certain embodiments, the eIF4E inhibitor dose is about 900 mg to about 2400 mg.

[0091] In certain embodiments, the eIF4E inhibitor dose is about 130 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 140 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 160 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 170 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 180 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 190 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 500 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 550 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 600 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 650 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 700 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 750 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 800 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 850 mg to about 2300 mg. In certain embodiments, the eIF4E inhibitor dose is about 900 mg to about 2300 mg.

[0092] In certain embodiments, the eIF4E inhibitor dose is about 130 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 140 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 160 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 170 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 180 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 190 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 500 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 550 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 600 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 650 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 700 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 750 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 800 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 850 mg to about 2200 mg. In certain embodiments, the eIF4E inhibitor dose is about 900 mg to about 2200 mg.

[0093] In certain embodiments, the eIF4E inhibitor dose is about 130 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 140 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 160 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 170 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 180 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 190 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 500 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 550 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 600 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 650 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 700 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 750 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 800 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 850 mg to about 2100 mg. In certain embodiments, the eIF4E inhibitor dose is about 900 mg to about 2100 mg.

[0094] In certain embodiments, the eIF4E inhibitor dose is about 130 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 140 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 150 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 160 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 170 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 180 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 190 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 200 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 250 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 300 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 350 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 400 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 450 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 500 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 550 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 600 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 650 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 700 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 750 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 800 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 850 mg to about 2000 mg. In certain embodiments, the eIF4E inhibitor dose is about 900 mg to about 2000 mg.

[0095] In certain embodiments, the eIF4E inhibitor is administered daily, once every two days, once every three days, once every four days, once every five days, once every six days, or weekly.

[0096] In certain embodiments, the eIF4E inhibitor is administered daily.

[0097] In certain embodiments, the eIF4E inhibitor is administered once daily.

[0098] In certain embodiments, the eIF4E inhibitor is administered twice daily.

[0099] In certain embodiments, the eIF4E inhibitor is administered once every three days.

[0100] In certain embodiments, the eIF4E inhibitor is administered via oral, topical

(including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, epidural, or intranasal administration.

[0101] In certain embodiments, the eIF4E inhibitor is administered intravenously.

[0102] In certain embodiments, the eIF4E inhibitor is administered orally.

Coaibinaiioii Therapy

[0103] In certain aspects, the present disclosure provides methods of treating breast cancer in a subject in need thereof, comprising administering to the subject a combination of an eIF4E inhibitor with a CDK4/6 inhibitor disclosed herein.

[0104] In certain aspects, the present disclosure provides methods of treating breast cancer in a subject in need thereof, comprising administering to the subject a combination of an eIF4E inhibitor and an estrogen receptor antagonist disclosed herein.

[0105] In certain aspects, the present disclosure provides methods of treating breast cancer in a subject in need thereof, comprising administering to the subject a combination of an eIF4E inhibitor and an aromatase inhibitor disclosed herein.

[0106] In certain aspects, the present disclosure provides methods of treating breast cancer in a subject in need thereof, comprising administering to the subject a combination of an eIF4E inhibitor, a CDK4/6 inhibitor, and an estrogen receptor antagonist disclosed herein.

[0107] In certain aspects, the present disclosure provides methods of treating breast cancer in a subject in need thereof, comprising administering to the subject a combination of an eIF4E inhibitor, a CDK4/6 inhibitor, and an aromatase inhibitor disclosed herein.

[0108] In certain aspects, the present disclosure provides uses of a combination of an eIF4E inhibitor with a CDK4/6 inhibitor disclosed herein in the manufacture of a medicament for breast cancer in a subject in need thereof. [0109] In certain aspects, the present disclosure provides uses of a combination of an eIF4E inhibitor and an estrogen receptor antagonist disclosed herein in the manufacture of a medicament for breast cancer in a subject in need thereof.

[0110] In certain aspects, the present disclosure provides uses of a combination of an eIF4E inhibitor and an aromatase inhibitor disclosed herein in the manufacture of a medicament for breast cancer in a subject in need thereof.

[oni] In certain aspects, the present disclosure provides uses of a combination of an eIF4E inhibitor, a CDK4/6 inhibitor, and an estrogen receptor antagonist disclosed herein in the manufacture of a medicament for breast cancer in a subject in need thereof.

[0112] In certain aspects, the present disclosure provides uses of a combination of an eIF4E inhibitor, a CDK4/6 inhibitor, and an aromatase inhibitor disclosed herein in the manufacture of a medicament for breast cancer in a subject in need thereof.

[0113] In certain aspects, the present disclosure provides combinations of an eIF4E inhibitor with a CDK4/6 inhibitor disclosed herein for use in treating breast cancer in a subject in need thereof.

[0114] In certain aspects, the present disclosure provides combinations of an eIF4E inhibitor and an estrogen receptor antagonist disclosed herein for use in treating breast cancer in a subject in need thereof.

[0115] In certain aspects, the present disclosure provides combinations of an eIF4E inhibitor and an aromatase inhibitor disclosed herein for use in treating breast cancer in a subject in need thereof.

[0116] In certain aspects, the present disclosure provides combinations of an eIF4E inhibitor, a CDK4/6 inhibitor, and an estrogen receptor antagonist disclosed herein for use in treating breast cancer in a subject in need thereof.

[0117] In certain aspects, the present disclosure provides combinations of an eIF4E inhibitor, a CDK4/6 inhibitor, and an aromatase inhibitor disclosed herein for use in treating breast cancer in a subject in need thereof.

[0118] In certain embodiments, the CDK4/6 inhibitor is palbociclib, ribociclib, abemaciclib, or dalpiciclib.

[0119] In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 0.5 mg/kg to about 20 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 0.5 mg/kg to about 19 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 0.5 mg/kg to about 18 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 0.5 mg/kg to about 17 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 0.5 mg/kg to about 16 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 0.5 mg/kg to about 15 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 0.5 mg/kg to about 14 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 0.5 mg/kg to about 13 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 0.5 mg/kg to about 12 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 0.5 mg/kg to about 11 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 0.5 mg/kg to about 10 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 0.5 mg/kg to about 9 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 0.5 mg/kg to about 8 mg/kg.

[0120] In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 1 mg/kg to about 20 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 1 mg/kg to about 19 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 1 mg/kg to about 18 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 1 mg/kg to about 17 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 1 mg/kg to about 16 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 1 mg/kg to about 15 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 1 mg/kg to about 14 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 1 mg/kg to about 13 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 1 mg/kg to about 12 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 1 mg/kg to about 11 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 1 mg/kg to about 10 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 1 mg/kg to about 9 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 1 mg/kg to about 8 mg/kg.

[0121] In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 2 mg/kg to about 20 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 2 mg/kg to about 19 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 2 mg/kg to about 18 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 2 mg/kg to about 17 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 2 mg/kg to about 16 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 2 mg/kg to about 15 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 2 mg/kg to about 14 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 2 mg/kg to about 13 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 2 mg/kg to about 12 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 2 mg/kg to about 11 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 2 mg/kg to about 10 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 2 mg/kg to about 9 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 2 mg/kg to about 8 mg/kg.

[0122] In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 3 mg/kg to about 20 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 3 mg/kg to about 19 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 3 mg/kg to about 18 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 3 mg/kg to about 17 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 3 mg/kg to about 16 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 3 mg/kg to about 15 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 3 mg/kg to about 14 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 3 mg/kg to about 13 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 3 mg/kg to about 13 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 3 mg/kg to about 11 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 3 mg/kg to about 10 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 3 mg/kg to about 9 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 3 mg/kg to about 8 mg/kg.

[0123] In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 20 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 19 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 18 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 17 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 16 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 15 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 14 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 13 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 14 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 11 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 10 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 9 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 8 mg/kg.

[0124] In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 15 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 14 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 13 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 14 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 11 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 10 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 9.5 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 9 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 8.5 mg/kg. In certain embodiments, the CDK4/6 inhibitor (e.g., palbociclib) dose is about 4 mg/kg to about 8 mg/kg.

[0125] In certain embodiments, the estrogen receptor antagonist is fulvestrant, elacestrant, raloxifene, or tamoxifen.

[0126] In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.1 mg/kg to about 10 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.1 mg/kg to about 9 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.1 mg/kg to about 8 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.1 mg/kg to about 7 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.1 mg/kg to about 6 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.1 mg/kg to about 4 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.1 mg/kg to about 3.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.1 mg/kg to about 3 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.1 mg/kg to about 2.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.1 mg/kg to about 2 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.1 mg/kg to about 1.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.1 mg/kg to about 1 mg/kg.

[0127] In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.3 mg/kg to about 10 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.3 mg/kg to about 9 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.3 mg/kg to about 8 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.3 mg/kg to about 7 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.3 mg/kg to about 6 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.3 mg/kg to about 4 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.3 mg/kg to about 3.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.3 mg/kg to about 3 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.3 mg/kg to about 2.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.3 mg/kg to about 2 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.3 mg/kg to about 1.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.3 mg/kg to about 1 mg/kg.

[0128] In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.5 mg/kg to about 10 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.5 mg/kg to about 9 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.5 mg/kg to about 8 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.5 mg/kg to about 7 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.5 mg/kg to about 6 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.5 mg/kg to about 4 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.5 mg/kg to about 3.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.5 mg/kg to about 3 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.5 mg/kg to about 2.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.5 mg/kg to about 2 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.5 mg/kg to about 1.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.5 mg/kg to about 1 mg/kg.

[0129] In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.7 mg/kg to about 10 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.7 mg/kg to about 9 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.7 mg/kg to about 8 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.7 mg/kg to about 7 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.7 mg/kg to about 6 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.7 mg/kg to about 4 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.7 mg/kg to about 3.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.7 mg/kg to about 3 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.7 mg/kg to about 2.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.7 mg/kg to about 2 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.7 mg/kg to about 1.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 0.7 mg/kg to about 1 mg/kg.

[0130] In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1 mg/kg to about 10 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1 mg/kg to about 9 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1 mg/kg to about 8 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1 mg/kg to about 7 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1 mg/kg to about 6 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1 mg/kg to about 4 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1 mg/kg to about 3.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1 mg/kg to about 3 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1 mg/kg to about 2.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1 mg/kg to about 2 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1 mg/kg to about 1.5 mg/kg. [0131] In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.2 mg/kg to about 10 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.2 mg/kg to about 9 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.2 mg/kg to about 8 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.2 mg/kg to about 7 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.2 mg/kg to about 6 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.2 mg/kg to about 4 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.2 mg/kg to about 3.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.2 mg/kg to about 3 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.2 mg/kg to about 2.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.2 mg/kg to about 2 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.2 mg/kg to about 1.5 mg/kg.

[0132] In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.5 mg/kg to about 10 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.5 mg/kg to about 9 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.5 mg/kg to about 8 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.5 mg/kg to about 7 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.5 mg/kg to about 6 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.5 mg/kg to about 4 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.5 mg/kg to about 3.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.5 mg/kg to about 3 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.5 mg/kg to about 2.5 mg/kg. In certain embodiments, the estrogen receptor antagonist (e.g., fulvestrant) dose is about 1.5 mg/kg to about 2 mg/kg.

[0133] In certain embodiments, the aromatase inhibitor is exemestane, letrozole, or anastrozole.

Breast Cancer

[0134] The term “breast cancer”, as used herein, includes all types of breast cancer including, but not limited to, invasive or non-invasive breast cancers. Invasive breast cancer includes, but not limited to, triple-negative breast cancer, ER+ breast cancer, PR+ breast cancer, HER2+ breast cancer, inflammatory breast cancer, metastatic breast cancer, recurrent breast cancer, male breast cancer, or Paget disease. Non-invasive breast cancer includes, but not limited to, ductal carcinoma in situ and lobular carcinoma in situ.

[0135] In certain embodiments, the breast cancer is a resistant breast cancer.

[0136] In certain embodiments, the breast cancer is resistant to CDK4/6 inhibitors.

[0137] In certain embodiments, the CDK4/6 inhibitor is palbociclib, ribociclib, or abemaciclib. eIF4E Inhibitors

[0138] In certain embodiments, the eIF4E Inhibitor is of Formula I:

or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, wherein: each -L- is independently -O-, -NR^L-, -CR^L1R^L2-, -CR^L1=CR^L2-, or -C=C-; each R^L is independently hydrogen or optionally substituted Ci-6 alkyl; each R^L1 and each R^L2 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, Ci-6 alkoxy, or Ci-6 alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted; q is an integer selected from 1 to 5;

Ring C and Ring D are independently Ce-io aryl or 5- to 10-membered heteroaryl;

R^C1, each R^C2 and each R^D are independently halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted; r and s are independently an integer selected from 0 to 6, as valency permits;

R² is hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, Ce-io aryl, 5- to 10-membered heteroaryl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -C(=0)NR^cS(=0)2R^a, -C(=O)NR^cR^d, -(CH2)C(=0)0R^b, or - C(=O)OR^b, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted, R¹ is -NR^laR^lb or -OR^1C;

R¹ is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted; or

R¹ and R¹ , together with the carbon atom to which they are bonded, from C3-12 carbocyclyl or 3- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted;

R^la and R^lb are each independently hydrogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, - (Ci-6 alkylene)-(C6-io aryl), -(Ci-6 alkylene)-(5- to 10-membered heteroaryl), -(Ci-6 alkylene)-(C3-i2 carbocyclyl), -(Ci-6 alkylene)-(3- to 12-membered heterocyclyl), - S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or

R^la and R^lb, together with the nitrogen atom to which they are attached, form 3- to 12- membered heterocycle, wherein the heterocycle is optionally substituted with one or more R^ab; each R^ab is independently oxo, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, Ce-io aryl, 5- to 10-membered heteroaryl, or -S(=O)R^a, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or two vicinal R^ab, together with the atoms to which they are bonded, form Ce aryl or 5- to 6- membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted;

R^lc is hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;

X is -O- or -C(R^X)₂-; each R^x is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted; two R^x, together with the carbon atom to which they are bonded, form an oxo; or two R^x, together with the carbon atom to which they are bonded, form C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted; m and m’ are independently an integer selected from 0 to 2; each R^A is independently oxo, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted; n is an integer selected from 0 to 10, as valency permits;

R^B is hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted; wherein: each R^a is independently Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl; each R^b is independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl; and each R^c and each R^d is independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl; or

R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 12- membered heterocyclyl; wherein each occurrence of R^a, R^b, R^c, and R^d is independently and optionally substituted.

[0139] In certain embodiments, the eIF4E Inhibitor is of Formula I-l-i, I-l-ii, I-l-iii, or 1-1- iv:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0140] In certain embodiments, the eIF4E Inhibitor is of Formula I-l-i-1, 1-l-i-2, I-l-i-3, 1-1- iii-1, 1-l-iii-2, or I-l-iii-3:

iii-3), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. [0141] Embodiments of the variables in any of the Formulae described herein, e.g., Formula I-Formula I-l-iii-3, as applicable, are described below. Any of the variables can be any moiety as described in the embodiments below. Also, any moieties described for any of the variables can be combined, as applicable, with any moieties described for any of the remaining variables.

[0142] In certain embodiments, R¹ is -NR^laR^lb or -OR^1C. In certain embodiments, R¹ is - NR^laR^lb. In certain embodiments, R¹ is -OR^1C.

[0143] In certain embodiments, R¹ is -NR^laR^lb.

[0144] In certain embodiments, R^la and R^lb are each independently hydrogen, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), //-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), t- butyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce)), C2-e alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1- butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), Ce-io aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- I //-in deny! (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), -(Ci-6 alkylene)-(Ce-io aryl), -(Ci-6 alkylene)-(5- to 10-membered heteroaryl), -(Ci-6 alkylene)-(C3-i2 carbocyclyl), -(Ci-6 alkylene)-(3- to 12-membered heterocyclyl), -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, the Ci-6 alkene is selected from is selected from methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). In certain embodiments, R^la and R^lb are each optionally independently substituted with one or more R^u.

[0145] In certain embodiments, R^la and R^lb are each independently hydrogen, Ci-6 alkyl, Ce-io aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -(Ci-6 alkylene)-(Ce-io aryl), -(Ci-6 alkylene)-(5- to 10-membered heteroaryl), -(Ci-6 alkylene)-(C3-i2 carbocyclyl), -(Ci-6 alkylene)-(3- to 12-membered heterocyclyl), -S(=O)R^a, -S(=0)2R^a, - S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R^la and R^lb are each optionally independently substituted with one or more R^u.

[0146] In certain embodiments, R^la and R^lb are each independently hydrogen, Ci-6 alkyl, Ce-io aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -(Ci-6 alkylene)-(5- to 10-membered heteroaryl), -(Ci-6 alkylene)-(Ce-io aryl), -(Ci-6 alkylene)-(C3-i2 carbocyclyl), -(Ci-6 alkylene)-(3- to 12-membered heterocyclyl), -S(=O)2R^a, or -C(=O)R^a, wherein the alkyl, alkylene, carbocyclyl, heterocyclyl, or heteroaryl is optionally substituted. In certain embodiments, R^la and R^lb are each optionally independently substituted with one or more R^u.

[0147] In certain embodiments, R^la and R^lb are each independently hydrogen, -CN, Ci-6 alkyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -(Ci-6 alkylene)-(Ce-io aryl), -(Ci-6 alkylene)-(5- to 10-membered heteroaryl), -(Ci-6 alkylene)-(C3-i2 carbocyclyl), or -(Ci-6 alkylene)-(3- to 12-membered heterocyclyl), wherein the alkyl, alkylene, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0148] In certain embodiments, R^la and R^lb are each independently hydrogen, optionally substituted Ci-₆ alkyl, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d.

[0149] In certain embodiments, at least one of R^la and R^lb is hydrogen, at least one of R^la and R^lb is not hydrogen. In certain embodiments, at least one of R^la and R^lb is optionally substituted Ci-6 alkyl. In certain embodiments, at least one of R^la and R^lb is optionally substituted Ce-io aryl. In certain embodiments, at least one of R^la and R^lb is optionally substituted 5- to 10-membered heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted C3-12 carbocyclyl. In certain embodiments, at least one of R^la and R^lb is optionally substituted 3- to 12-membered heterocyclyl comprising one or two 3- to 8- membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is -(Ci-6 alkylene)-(Ce-io aryl), wherein the alkylene or aryl is optionally substituted. In certain embodiments, at least one of R^la and R^lb is -(Ci-6 alkylene)- (5- to 10-membered heteroaryl), wherein the heteroaryl comprises one or two 5- or 6- membered rings and 1-5 heteroatoms selected from N, O, and S, wherein the alkylene or heteroaryl is optionally substituted. In certain embodiments, at least one of R^la and R^lb is - (Ci-6 alkylene)-(C3-i2 carbocyclyl), wherein the alkylene or carbocyclyl is optionally substituted. In certain embodiments, at least one of R^la and R^lb is -(Ci-6 alkylene)-(3- to 12- membered heterocyclyl), wherein the heterocyclyl comprises one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S, wherein the alkylene or heterocyclyl is optionally substituted. In certain embodiments, at least one of R^la and R^lb is -S(=O)2R^a. In certain embodiments, at least one of R^la and R^lb is -C(=O)R^a. In certain embodiments, R^la and R^lb is optionally substituted with one or more R^u.

[0150] In certain embodiments, at least one of R^la and R^lb is optionally substituted Ce-io aryl. In certain embodiments, the aryl is optionally substituted with one or more R^u.

[0151] In certain embodiments, at least one of R^la and R^lb is optionally substituted 5- to 10- membered heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heteroaryl comprising one 5-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heteroaryl comprising one 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heteroaryl comprising two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heteroaryl comprising two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heteroaryl comprising two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heteroaryl comprising one 5- membered ring and one 6- membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the heteroaryl is optionally substituted with one or more R^u.

[0152] In certain embodiments, at least one of R^la and R^lb is optionally substituted C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1/7- indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)). In certain embodiments, the carbocyclyl is optionally substituted with one or more R^u.

[0153] In certain embodiments, at least one of R^la and R^lb is optionally substituted 3- to 12- membered heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heterocyclyl comprising one 3- to 8-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heterocyclyl comprising one 3-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heterocyclyl comprising one 4-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heterocyclyl comprising one 5-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heterocyclyl comprising one 6-membered ring and 1-4 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heterocyclyl comprising one 7-membered ring and 1-4 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heterocyclyl comprising one 8-membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heterocyclyl comprising two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heterocyclyl comprising two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heterocyclyl comprising two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, at least one of R^la and R^lb is optionally substituted heterocyclyl comprising one 5- membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the heterocyclyl is optionally substituted with one or more R^u. [0154] In certain embodiments, at least one of R^la and R^lb is -(Ci-6 alkylene)-(Ce-io aryl), wherein the alkylene or aryl is optionally substituted. In certain embodiments, the aryl is optionally substituted with one or more R^u.

[0155] In certain embodiments, at least one of R^la and R^lb is -(Ci-6 alkylene)-(5- to 10- membered heteroaryl), wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S, wherein the alkylene or heteroaryl is optionally substituted. In certain embodiments, the optionally substituted heteroaryl comprises one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heteroaryl comprises one 5-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heteroaryl comprises one 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heteroaryl comprises two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heteroaryl comprises two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heteroaryl comprises two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heteroaryl comprises one 5- membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the heteroaryl is optionally substituted with one or more R^u.

[0156] In certain embodiments, at least one of R^la and R^lb is -(Ci-6 alkylene)-(C3-i2 carbocyclyl), wherein the C3-12 carbocyclyl is selected from cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- I //-in deny! (C9), decahydronaphthalenyl (C10), and spiro[4.5]decanyl (C10), wherein the alkylene or carbocyclyl is optionally substituted. In certain embodiments, the carbocyclyl is optionally substituted with one or more R^u.

[0157] In certain embodiments, at least one of R^la and R^lb is -(Ci-6 alkylene)-(3- to 12- membered heterocyclyl), wherein the heterocyclyl comprises one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S, wherein the alkylene or heterocyclyl is optionally substituted. In certain embodiments, the optionally substituted heterocyclyl comprises one 3- to 8-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 3-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 4-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 5- membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 6-membered ring and 1-4 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 7-membered ring and 1-4 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 8-membered ring and 1- 5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises two 5- membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 5- membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the heterocyclyl is optionally substituted with one or more R^u.

[0158] In certain embodiments, at least one of R^la and R^lb is -S(=O)R^a, -S(=O)2R^a, - S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d In certain embodiments, at least one of R^la and R^lb is -S(=O)₂R^a. In certain embodiments, at least one of R^la and R^lb is -C(=O)R^a

[0159] In certain embodiments, R^la and R^lb, together with the nitrogen atom to which they are attached, form optionally substituted 3- to 12-membered heterocycle (e.g., heterocycle comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S). In certain embodiments, R^la and R^lb, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocycle optionally substituted with one or more R^u. In certain embodiments, R^la and R^lb, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocycle optionally substituted with one or more R^ab. In certain embodiments, the optionally substituted heterocyclyl comprises one 3- to 8-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 3-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 4- membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 5-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 6-membered ring and 1-4 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 7-membered ring and 1- 4 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 8-membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises two 3- to 8- membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the optionally substituted heterocyclyl comprises one 5- membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S.

[0160] In certain embodiments, each R^ab is independently oxo, halogen (e.g., -F, -Cl, -Br, or - I), -CN, -NO2, -OH, -NH2, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Z-butyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce)), C2-e alkynyl e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), Ci-6 alkoxy e.g., methoxy, ethoxy, propoxy, z-propoxy, //-butoxy, z-butoxy, .s- butoxy, /-butoxy, pentoxy, or hexoxy), Ci-6 alkylamino e.g., dimethylamino, diethylamino, di-w-propylamino, di-z-propylamino, di-w-butylamino, di-z-butylamino, di-s-butylamino, di-Z- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-Z-butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z- propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl -z-butyl amino, ethyl-Z- butylamino, ethylpentylamino, ethylhexylamino, propyl-w-butylamino, propyl-z-butylamino, propyl-s-butylamino, propyl -Z-butyl amino, propylpentylylamino, propylhexylamino, n- butylpentylamino, z-butylpentylamino, s-butylpentylamino, Z-butylpentylamino, n- butylhexyl amino, z-butylhexylamino, s-butylhexylamino, Z-butylhexylamino, or pentylhexylamino), C3-6 carbocyclyl e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), or cyclohexadienyl (Ce)), 3- to 6-membered heterocyclyl e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), Ce-io aryl (i.e., phenyl or naphathalenyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two rings and 1-5 heteroatoms selected from N. O, and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R¹ is optionally substituted with one or more R^u.

[0161] In certain embodiments, each R^ab is independently oxo, halogen, -OH, Ci-6 alkyl, Ci-6 alkoxy, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, Ce aryl, or 5- to 6-membered heteroaryl, or -S(=O)R^a, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0162] In certain embodiments, each R^ab is independently oxo, halogen, -OH, Ci-6 alkyl, Ci-6 alkoxy, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, or -S(=O)R^a, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.

[0163] In certain embodiments, two vicinal R^ab, together with the atoms to which they are bonded, form Ce aryl (i.e., phenyl) or 5- to 6-membered heteroaryl (e.g., heteroaryl comprising one 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the aryl or heteroaryl is optionally substituted. In certain embodiments, two vicinal R^ab, together with the atoms to which they are bonded, form Ce aryl or 5- to 6-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R^u. [0164] In certain embodiments, R¹ is -OR^1C.

[0165] In certain embodiments, R^lc is hydrogen, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), n- propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), /-butyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), Ce-io aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- I //-in deny! (C9), decahydronaphthal enyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), -C(=O)R^a, - C(=O)OR^b, or -C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R^lc is optionally substituted with one or more R^u.

[0166] In certain embodiments, R^lc is hydrogen, Ci-6 alkyl, Ce-io aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -C(=O)R^a, -C(=O)OR^b, or - C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R^lc is optionally substituted with one or more R^u.

[0167] In certain embodiments, R^lc is Ci-6 alkyl, Ce-io aryl, 5- to 10-membered heteroaryl, C3- 12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R^lc is optionally substituted with one or more R^u.

[0168] In certain embodiments, R^lc is Ci-6 alkyl or 3- to 12-membered heterocyclyl, the alkyl or heterocyclyl is optionally substituted. In certain embodiments, R^lc is optionally substituted Ci-6 alkyl. In certain embodiments, R^lc is optionally substituted 3- to 12-membered heterocyclyl. In certain embodiments, R^lc is optionally substituted with one or more R^u.

[0169] In certain embodiments, R^lc is optionally substituted Ce-io aryl. In certain embodiments, the aryl is optionally substituted with one or more R^u.

[0170] In certain embodiments, R^lc is optionally substituted 5- to 10-membered heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heteroaryl comprising one 5- or 6- membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heteroaryl comprising one 5-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heteroaryl comprising one 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heteroaryl comprising two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heteroaryl comprising two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heteroaryl comprising two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heteroaryl comprising one 5- membered ring and one 6- membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the heteroaryl is optionally substituted with one or more R^u.

[0171] In certain embodiments, R^lc is optionally substituted C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- I //-in deny! (C9), decahydronaphthalenyl (Cio), or spiro[4.5]decanyl (Cio)). In certain embodiments, the carbocyclyl is optionally substituted with one or more R^u.

[0172] In certain embodiments, R^lc is optionally substituted 3- to 12-membered heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heterocyclyl comprising one 3- to 8- membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heterocyclyl comprising one 3-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heterocyclyl comprising one 4-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heterocyclyl comprising one 5-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heterocyclyl comprising one 6-membered ring and 1-4 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heterocyclyl comprising one 7-membered ring and 1-4 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heterocyclyl comprising one 8-membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heterocyclyl comprising two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heterocyclyl comprising two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heterocyclyl comprising two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, R^lc is optionally substituted heterocyclyl comprising one 5- membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, the heterocyclyl is optionally substituted with one or more R^u.

[0173] In certain embodiments, R¹ is hydrogen, deuterium, halogen (c.g, -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Cbutyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce)), C2-e alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), Ci-6 alkoxy (e.g., methoxy, ethoxy, propoxy, z-propoxy, //-butoxy, z-butoxy, .s- butoxy, /-butoxy, pentoxy, or hexoxy), Ci-6 alkylamino (e.g., dimethylamino, diethylamino, di-zz-propylamino, di-z-propylamino, di-w-butylamino, di-z-butylamino, di-s-butylamino, di-Z- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-Z-butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z- propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl-z -butyl amino, ethyl -/- butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z-butylamino, propyl-s-butylamino, propyl -/-butyl amino, propylpentylylamino, propylhexylamino, n- butylpentylamino, z-butylpentylamino, s-butylpentylamino, Z-butylpentylamino, n- butylhexyl amino, z-butylhexylamino, s-butylhexylamino, Z-butylhexylamino, or pentylhexylamino), C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), or cyclohexadienyl (Ce)), or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted. In certain embodiments, R¹ is optionally substituted with one or more R^u.

[0174] In certain embodiments, R¹ is hydrogen, deuterium, or Ci-6 alkyl.

[0175] In certain embodiments, R¹ and R¹ , together with the carbon atom to which they are bonded, from C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- I //-in deny! (C9), decahydronaphthal enyl (C10), or spiro[4.5]decanyl (C10)) or 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein carbocyclyl or heterocyclyl is optionally substituted with one or more R^u. In certain embodiments, R¹ and R¹ , together with the carbon atom to which they are bonded, from C3-12 carbocyclyl or 3- to 12-membered heterocyclyl, wherein carbocyclyl or heterocyclyl is optionally substituted with one or more R^u.

[0176] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2.

[0177] In certain embodiments, m’ is 0. In certain embodiments, m’ is 1. In certain embodiments, m’ is 2.

[0178] In certain embodiments, m is 0 and m’ is 0. In certain embodiments, m is 0 and m’ is 1. In certain embodiments, m is 0 and m’ is 2. In certain embodiments, m is 1 and m’ is 0. In certain embodiments, m is 1 and m’ is 1. In certain embodiments, m is 1 and m’ is 2. In certain embodiments, m is 2 and m’ is 0. In certain embodiments, m is 2 and m’ is 1. In certain embodiments, m is 2 and m’ is 2.

[0179] In certain embodiments, each R^A is independently oxo, halogen (e.g., -F, -Cl, -Br, or - I), -CN, -NO2, -OH, -NH2, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Z-butyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce)), C2-e alkynyl e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), Ci-6 alkoxy e.g., methoxy, ethoxy, propoxy, z-propoxy, zz-butoxy, z-butoxy, .s- butoxy, /-butoxy, pentoxy, or hexoxy), Ci-6 alkylamino e.g., dimethylamino, diethylamino, di-zz-propylamino, di-z-propylamino, di-zz-butylamino, di-z-butylamino, di-s-butylamino, di-Z- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-Z-butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z- propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl -z-butyl amino, ethyl-Z- butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z-butylamino, propyl-s-butylamino, propyl -Z-butyl amino, propylpentylylamino, propylhexylamino, n- butylpentylamino, z-butylpentylamino, s-butylpentylamino, Z-butylpentylamino, n- butylhexyl amino, z-butylhexylamino, s-butylhexylamino, Z-butylhexylamino, or pentylhexylamino), C3-6 carbocyclyl e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), or cyclohexadienyl (Ce)), or 3- to 6-membered heterocyclyl e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted. In certain embodiments, each R^A is independently optionally substituted with one or more R^u.

[0180] In certain embodiments, each R^A is independently oxo, halogen, -CN, -NO2, -OH, - NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, or Ci-6 alkylamino, wherein the alkyl, alkenyl, alkynyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, each R^A is independently optionally substituted with one or more R^u.

[0181] In certain embodiments, each R^A is independently halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, Ci-6 alkoxy, or Ci-6 alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, each R^A is independently optionally substituted with one or more R^u.

[0182] In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8. In certain embodiments, n is 9. In certain embodiments, n is 10.

[0183] In certain embodiments, R^B is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2,

-OH, -NH2, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), ft-butyl (C4), z-butyl (C4), 5-butyl (C4), Z-butyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce)), C2-e alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), Ci-6 alkoxy (e.g. , methoxy, ethoxy, propoxy, z-propoxy, //-butoxy, z-butoxy, .s-butoxy, /-butoxy, pentoxy, or hexoxy), Ci-6 alkylamino (e.g., dimethylamino, di ethylamino, di-zz-propylamino, di-z-propylamino, di-w-butylamino, di -z-butyl amino, di-s-butylamino, di-Z-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z- propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-Z- butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z- propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl -z-butyl amino, ethyl-Z- butylamino, ethylpentylamino, ethylhexylamino, propyl-w-butylamino, propyl-z-butylamino, propyl-s-butylamino, propyl -Z-butyl amino, propylpentylylamino, propylhexylamino, n- butylpentylamino, z-butylpentylamino, s-butylpentylamino, Z-butylpentylamino, n- butylhexyl amino, z-butylhexylamino, s-butylhexylamino, Z-butylhexylamino, or pentylhexylamino), C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), or cyclohexadienyl (Ce)), or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted. In certain embodiments, each R^B is independently optionally substituted with one or more R^u.

[0184] In certain embodiments, R^B is hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, or Ci-6 alkylamino, wherein the alkyl, alkenyl, alkynyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R^B is independently optionally substituted with one or more R^u. [0185] In certain embodiments, R^B is hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, Ci-6 alkoxy, or Ci-6 alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R^B is independently optionally substituted with one or more R^u.

[0186] In certain embodiments, R^B is hydrogen or optionally substituted Ci-6 alkyl. In certain embodiments, R^B is hydrogen. In certain embodiments, R^B is optionally substituted Ci-6 alkyl. In certain embodiments, R^B is optionally substituted with one or more R^u.

[0187] In certain embodiments, Ring C is Ce-io aryl or 5- to 10-membered heteroaryl. [0188] In certain embodiments, Ring C is Ce-io aryl (e.g., phenyl or naphthyl).

[0189] In certain embodiments, Ring C is 5- to 10-membered heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is 5- to 10-membered heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is 5- to 10-membered heteroaryl comprising one 5-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is 5- to 10-membered heteroaryl comprising one 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is 5- to 10-membered heteroaryl comprising two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is 5- to 10- membered heteroaryl comprising two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is 5- to 10-membered heteroaryl comprising two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring C is 5- to 10-membered heteroaryl comprising one 5- membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S.

[0190] In certain embodiments, Ring C is phenyl or pyridinyl.

[0191] In certain embodiments, R^C1 is halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, - NH2, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), ft-butyl (C4), z-butyl (C4), 5-butyl (C4), Z-butyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), Ci-6 alkoxy (e.g., methoxy, ethoxy, propoxy, z-propoxy, //-butoxy, z-butoxy, .s-butoxy, /-butoxy, pentoxy, or hexoxy), Ci-6 alkylamino (e.g., dimethylamino, di ethylamino, di-w-propylamino, di-z- propylamino, di-w-butylamino, di-z-butylamino, di-s-butylamino, di-/-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z- propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-/- butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z- propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl -z-butyl amino, ethyl-/- butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z-butylamino, propyl-s-butylamino, propyl -/-butyl amino, propylpentylylamino, propylhexylamino, zz- butylpentylamino, z-butylpentylamino, s-butylpentylamino, /-butylpentylamino, n- butylhexyl amino, z-butylhexylamino, s-butylhexylamino, /-butylhexylamino, or pentylhexylamino), C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), or cyclohexadienyl (Ce)), or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted. In certain embodiments, R^C1 is optionally substituted with one or more R^u.

[0192] In certain embodiments, R^C1 is halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, Ci-6 alkoxy, or Ci-6 alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R^C1 is optionally substituted with one or more R^u.

[0193] In certain embodiments, R^C1 is halogen or -OH. In certain embodiments, R^C1 is halogen (e.g., -F, -Cl, -Br, or -I). In certain embodiments, R^C1 is -Cl. In certain embodiments, R^C1 is -OH. In certain embodiments, R^C1 is optionally substituted Ci-6 alkyl (e.g, methyl, ethyl, propyl, z-propyl, zz-butyl, z-butyl, .s-butyl, /-butyl, pentyl, or hexyl). In certain embodiments, R^C1 is optionally substituted with one or more R^u.

[0194] In certain embodiments, each R^C2 is independently halogen (e.g, -F, -Cl, -Br, or -I), - CN, -NO2, -OH, -NH2, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), n- butyl (C4), z-butyl (C4), s-butyl (C4), /-butyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), Ci-6 alkoxy (e.g., methoxy, ethoxy, propoxy, z-propoxy, zz-butoxy, z-butoxy, .s- butoxy, /-butoxy, pentoxy, or hexoxy), Ci-6 alkylamino (e.g., dimethylamino, diethylamino, di-zz-propylamino, di-z-propylamino, di-zz-butylamino, di-z-butylamino, di-s-butylamino, di-Z- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-/-butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z- propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl-z -butyl amino, ethyl -/- butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z-butylamino, propyl-s-butylamino, propyl -/-butyl amino, propylpentylylamino, propylhexylamino, zz- butylpentylamino, z-butylpentylamino, s-butylpentylamino, Z-butylpentylamino, n- butylhexyl amino, z-butylhexylamino, s-butylhexylamino, Z-butylhexylamino, or pentylhexylamino), C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), or cyclohexadienyl (Ce)), or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted. In certain embodiments, each R^C2 is independently optionally substituted with one or more R^u.

[0195] In certain embodiments, each R^C2 is independently halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, Ci-6 alkoxy, or Ci-6 alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, each R^C2 is independently optionally substituted with one or more R^u.

[0196] In certain embodiments, r is 0. In certain embodiments, r is 1. In certain embodiments, r is 2. In certain embodiments, r is 3. In certain embodiments, r is 4. In certain embodiments, r is 5. In certain embodiments, r is 6.

[0197] In certain embodiments, Ring D is Ce-io aryl or 5- to 10-membered heteroaryl. [0198] In certain embodiments, Ring D is Ce-io aryl (e.g., phenyl or naphthyl).

[0199] In certain embodiments, Ring D is 5- to 10-membered heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring D is 5- to 10-membered heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, Ring D is 5- to 10-membered heteroaryl comprising one 5-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, Ring D is 5- to 10-membered heteroaryl comprising one 6-membered ring and 1-3 heteroatoms selected from N, O, and S. In certain embodiments, Ring D is 5- to 10-membered heteroaryl comprising two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring D is 5- to 10-membered heteroaryl comprising two 5-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring D is 5- to 10-membered heteroaryl comprising two 6-membered rings and 1-5 heteroatoms selected from N, O, and S. In certain embodiments, Ring D is 5- to 10-membered heteroaryl comprising one 5- membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S.

[0200] In certain embodiments, Ring D is phenyl, pyridinyl, pyrrolopyridazinyl, or thienopyridinyl.

[0201] In certain embodiments, R² is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), ft-butyl (C4), z-butyl (C4), 5-butyl (C4), Z-butyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce)), C2-e alkynyl e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), Ci-6 alkoxy (e.g. , methoxy, ethoxy, propoxy, z-propoxy, //-butoxy, z-butoxy, .s-butoxy, /-butoxy, pentoxy, or hexoxy), Ci-6 alkylamino e.g., dimethylamino, di ethylamino, di-w-propylamino, di-z-propylamino, di-w-butylamino, di -z-butyl amino, di-s-butylamino, di-Z-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z- propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-Z- butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z- propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl -z-butyl amino, ethyl-Z- butylamino, ethylpentylamino, ethylhexylamino, propyl-w-butylamino, propyl-z-butylamino, propyl-s-butylamino, propyl -Z-butyl amino, propylpentylylamino, propylhexylamino, n- butylpentylamino, z-butylpentylamino, s-butylpentylamino, Z-butylpentylamino, n- butylhexyl amino, z-butylhexylamino, s-butylhexylamino, Z-butylhexylamino, or pentylhexylamino), Ce-io aryl e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), C3-6 carbocyclyl e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), or cyclohexadienyl (Ce)), 3- to 6-membered heterocyclyl e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), -C(=O)NR^cS(=O)2R^a, -C(=O)NR^cR^d, -(CH2)C(=O)OR^b, or C(=O)OR^b, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R² is optionally substituted with one or more R^u.

[0202] In certain embodiments, R² is hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, Ce-io aryl, 5- to 10-membered heteroaryl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -C(=O)NR^cS(=O)2R^a, - C(=O)NR^cR^d, -(CH2)C(=O)OR^b, or C(=O)OR^b, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R² is optionally substituted with one or more R^u.

[0203] In certain embodiments, R² is hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, -C(=O)NR^cS(=O)2R^a, -C(=O)NR^cR^d, - (CH2)C(=O)OR^b, or C(=O)OR^b, wherein the alkyl, alkenyl, alkynyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R² is optionally substituted with one or more R^u.

[0204] In certain embodiments, R² is hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, Ci-6 alkoxy, Ci-₆ alkylamino, -C(=O)NR^cS(=O)₂R^a, -C(=O)NR^cR^d, -(CH₂)C(=O)OR^b, or C(=O)OR^b, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R² is optionally substituted with one or more R^u.

[0205] In certain embodiments, R² is hydrogen, halogen, Ci-6 alkyl, Ce-io aryl, 5- to 10- membered heteroaryl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -NR^cS(=O)2R^a, - N(S(=O)₂R^a)₂, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)OR^b, -C(=O)NR^cS(=O)₂R^a, or C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R² is optionally substituted with one or more R^u.

[0206] In certain embodiments, R² is hydrogen, -C(=O)NR^cS(=O)R^a, -C(=O)NR^cR^d, - (CH2)C(=O)OR^b, or -C(=O)OR^b. In certain embodiments, R² is -C(=O)NHS(=O)2CH3 or - COOH.

[0207] In certain embodiments, R² is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), ft-butyl (C4), z-butyl (C4), 5-butyl (C4), Z-butyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce)), C2-6 alkynyl e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), Ci-6 alkoxy (e.g. , methoxy, ethoxy, propoxy, z-propoxy, //-butoxy, z-butoxy, .s-butoxy, /-butoxy, pentoxy, or hexoxy), Ci-6 alkylamino e.g., dimethylamino, di ethylamino, di-w-propylamino, di-z-propylamino, di-w-butylamino, di -z-butyl amino, di-s-butylamino, di-Z-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z- propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-Z- butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z- propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl -z-butyl amino, ethyl-Z- butylamino, ethylpentylamino, ethylhexylamino, propyl-w-butylamino, propyl-z-butylamino, propyl-s-butylamino, propyl -Z-butyl amino, propylpentylylamino, propylhexylamino, n- butylpentylamino, z-butylpentylamino, s-butylpentylamino, Z-butylpentylamino, n- butylhexyl amino, z-butylhexylamino, s-butylhexylamino, Z-butylhexylamino, or pentylhexylamino), Ce-io aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), or cyclohexadienyl (Ce)), 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), -C(=0)NR^cS(=0)2R^a, or C(=O)OR^b, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R² is optionally substituted with one or more R^u.

[0208] In certain embodiments, R² is halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, Ce-io aryl, 5- to 10-membered heteroaryl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -C(=O)NR^cS(=O)2R^a, or C(=O)OR^b, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R² is optionally substituted with one or more R^u.

[0209] In certain embodiments, R² is halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, -C(=O)NR^cS(=O)2R^a, or C(=O)OR^b, wherein the alkyl, alkenyl, alkynyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R² is optionally substituted with one or more R^u.

[0210] In certain embodiments, R² is halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, -C(=O)NR^cS(=O)2R^a, or C(=O)OR^b, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, R² is optionally substituted with one or more R^u.

[0211] In certain embodiments, R² is halogen, Ci-6 alkyl, Ce-io aryl, 5- to 10-membered heteroaryl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -NR^cS(=O)2R^a, -N(S(=O)2R^a)2, - S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -C(=O)OR^b, -C(=O)NR^cS(=O)₂R^a, or C(=O)NR^cR^d, wherein the alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted. In certain embodiments, R² is optionally substituted with one or more R^u.

[0212] In certain embodiments, R² is -C(=O)NR^cS(=O)R^a or -C(=O)OR^b. In certain embodiments, R² is -C(=O)NHS(=O)2CH3 or -COOH.

[0213] In certain embodiments, each R^D is independently halogen (e.g., -F, -Cl, -Br, or -I), - CN, -NO2, -OH, -NH2, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), //-propyl (C3), z-propyl (C3), n- butyl (C4), z-butyl (C4), s-butyl (C4), Z-butyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce)), C2-e alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), Ci-6 alkoxy (e.g., methoxy, ethoxy, propoxy, z-propoxy, //-butoxy, z-butoxy, .s- butoxy, /-butoxy, pentoxy, or hexoxy), Ci-6 alkylamino (e.g., dimethylamino, diethylamino, di-w-propylamino, di-z-propylamino, di-w-butylamino, di-z-butylamino, di-s-butylamino, di-Z- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-w-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-Z-butylamino, methylpentylamino, methylhexylamino, ethyl-w-propylamino, ethyl-z- propylamino, ethyl-w-butylamino, ethyl-s-butylamino, ethyl -z-butyl amino, ethyl-Z- butylamino, ethylpentylamino, ethylhexylamino, propyl-w-butylamino, propyl-z-butylamino, propyl-s-butylamino, propyl -Z-butyl amino, propylpentylylamino, propylhexylamino, n- butylpentylamino, z-butylpentylamino, s-butylpentylamino, Z-butylpentylamino, n- butylhexyl amino, z-butylhexylamino, s-butylhexylamino, Z-butylhexylamino, or pentylhexylamino), C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), or cyclohexadienyl (Ce)), or 3- to 6-membered heterocyclyl e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted. In certain embodiments, each R^D is independently optionally substituted with one or more R^u.

[0214] In certain embodiments, each R^D is independently halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, Ci-6 alkoxy, or Ci-6 alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, each R^D is independently optionally substituted with one or more R^u.

[0215] In certain embodiments, each R^D is independently halogen or optionally substituted Ci-6 alkyl. In certain embodiments, at least one R^D is halogen. In certain embodiments, each R^D is independently halogen. In certain embodiments, at least one R^D is optionally substituted Ci-6 alkyl. In certain embodiments, each R^D is independently optionally substituted Ci-6 alkyl. In certain embodiments, each R^D is independently optionally substituted with one or more R^u. [0216] In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6. [0217] In certain embodiments, each -L- is independently -O-, -NR^L-, -CR^L1R^L2-, - CR^L1=CR^L2-, or -C=C-. In certain embodiments, each -L- is independently -O-, -CR^L1R^L2-, or -C=C-.

[0218] In certain embodiments, [L]_q is

wherein:

* denotes attachment to Ring B, and ** denotes attachment to Ring C; p is an integer selected from 0 to 3; and Y is -O-, -CR^L1R^L2-, or -C=C-.

[0219] In certain embodiments, L is Y.

[0220] In certain embodiments, each R^L1 and each R^L2 is independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), n- propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Cbutyl (C4), pentyl (C5), or hexyl (Ce)), Ci-6 alkoxy (e.g., methoxy, ethoxy, propoxy, z-propoxy, zz-butoxy, z-butoxy, .s- butoxy, /-butoxy, pentoxy, or hexoxy), or Ci-6 alkylamino e.g., dimethylamino, diethylamino, di-zz-propylamino, di-z-propylamino, di-zz-butylamino, di-z-butylamino, di-.s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, m ethyl -zz- propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, m ethyl -s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl -zz- propylamino, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl-z- butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, zz-butylpentylamino, z-butylpentylamino, s-butylpentylamino, /- butylpentylamino, zz-butylhexylamino, z-butylhexylamino, s-butylhexylamino, t- butylhexylamino, or pentylhexylamino), wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, each R^L1 and each R^L2 is independently optionally substituted with one or more R^u.

[0221] In certain embodiments, each R^L1 and each R^L2 is hydrogen.

[0222] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. [0223] In certain embodiments, Y is -O-. In certain embodiments, Y is -NR^L-. In certain embodiments, Y is -CR^L1R^L2-. In certain embodiments, Y is -C=C-.In certain embodiments, Y is -O- or -C=C-.

[0224] In certain embodiments, Y is -O- and p is 0, or Y is -C=C- and p is 0. [0225] In certain embodiments, X is -O-. In certain embodiments, X is -C(R^X)2-.

[0226] In certain embodiments, each R^x is independently hydrogen, halogen (e.g., -F, -Cl, - Br, or -I), -CN, -NO2, -OH, -NH2, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), i- propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), Cbutyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), Ci-6 alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), //-butoxy (C4), z-butoxy (C4), .s-butoxy (C4), ^-butoxy (C4), pentoxy (C5), or hexoxy (Ce)), Ci-6 alkylamino (e.g., dimethylamino, di ethylamino, di-zz-propylamino, di -z-propyl amino, di-zz- butylamino, di-z-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl -s- butylamino, ethyl-z-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, zz-butylpentylamino, z-butylpentylamino, s- butylpentylamino, t-butylpentylamino, zz-butylhexylamino, z-butylhexylamino, s- butylhexyl amino, t-butylhexylamino, or pentylhexylamino), C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), or cyclohexadienyl (Ce)), or 3- to 6- membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted. In certain embodiments, each R^x is independently optionally substituted with one or more R^u.

[0227] In certain embodiments, each R^x is independently hydrogen, halogen, -CN, -NO2, - OH, -NH2, Ci-6 alkyl, Ci-6 alkoxy, or Ci-6 alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted. In certain embodiments, each R^x is independently optionally substituted with one or more R^u.

[0228] In certain embodiments, each R^x is independently hydrogen or Ci-6 alkyl. [0229] In certain embodiments, each R^x is independently Ci-6 alkyl.

[0230] In certain embodiments, each R^x is hydrogen.

[0231] In certain embodiments, each R^x is independently halogen or optionally substituted Ci-6 alkyl. In certain embodiments, at least one R^x is halogen. In certain embodiments, each R^x is independently halogen. In certain embodiments, at least one R^x is optionally substituted Ci-6 alkyl. In certain embodiments, each R^x is independently optionally substituted Ci-6 alkyl. In certain embodiments, each R^x is independently optionally substituted with one or more R^u. [0232] In certain embodiments, two R^x, together with the carbon atom to which they are bonded, form an oxo.

[0233] In certain embodiments, two R^x, together with the carbon atom to which they are bonded, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), or cyclohexadienyl (Ce)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocyclyl or heterocyclyl is optionally substituted. In certain embodiments, two R^x, together with the carbon atom to which they are bonded, form C3-6 carbocyclyl or 3- to 6- membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substitutedwith one or more R^u.

[0234] In certain embodiments, two R^x, together with the carbon atom to which they are bonded, form C3-4 carbocyclyl or 3- to 4-membered heterocyclyl.

[0235] In certain embodiments, each occurrence of R^a, R^b, R^c, and R^d is independently and optionally substituted. In certain embodiments, each occurrence of R^a, R^b, R^c, and R^d is independently optionally substituted with one or more R^u.

[0236] In certain embodiments, each R^a is independently Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), //-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), ^-butyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce), C2-e alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2- butynyl (C4), pentynyl (C5), or hexynyl (Ce)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- l/Z-indenyl (C9), decahydronaphthalenyl (Cio), or spiro[4.5]decanyl (Cio)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u. [0237] In certain embodiments, each R^a is independently Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the alkyl, alkenyl, or alkyny, is optionally substituted with one or more R^u. [0238] In certain embodiments, each R^b is independently hydrogen, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), /-butyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (Cio), cyclodecenyl (Cio), octahydro- I //-in deny! (C9), decahydronaphthalenyl (Cio), or spiro[4.5]decanyl (Cio)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

[0239] In certain embodiments, each R^b is independently Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the alkyl, alkenyl, or alkyny, is optionally substituted with one or more R^u. [0240] In certain embodiments, each R^c and each R^d is independently hydrogen, Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), /-butyl (C4), pentyl (C5), or hexyl (Ce)), C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1- butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- I //-in deny! (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

[0241] In certain embodiments, each R^c and each R^d is independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R^u.

[0242] In certain embodiments, R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is optionally substituted with one or more R^u.

[0243] In certain embodiments, each R^u is independently deuterium, oxo, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, Ci-6 alkyl e.g., methyl (Ci), ethyl (C2), //-propyl (C3), z-propyl (C3), //-butyl (C4), z-butyl (C4), s-butyl (C4), /-butyl (C4), pentyl (C5), or hexyl (Ce)), Ci-6 alkoxy e.g., methoxy, ethoxy, propoxy, z-propoxy, //-butoxy, z-butoxy, .s-butoxy, t- butoxy, pentoxy, or hexoxy), Ci-6 alkylamino e.g., dimethylamino, diethylamino, di-zz- propylamino, di-z-propylamino, di-w-butylamino, di-z-butylamino, di-s-butylamino, di-Z- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-w-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-/-butylamino, methylpentylamino, methylhexylamino, ethyl-w-propylamino, ethyl-z- propylamino, ethyl-w-butylamino, ethyl-s-butylamino, ethyl -z-butyl amino, ethyl -Z- butylamino, ethylpentylamino, ethylhexylamino, propyl-w-butylamino, propyl-z-butylamino, propyl-s-butylamino, propyl -Z-butyl amino, propylpentylylamino, propylhexylamino, n- butylpentylamino, z-butylpentylamino, s-butylpentylamino, Z-butylpentylamino, n- butylhexyl amino, z-butylhexylamino, s-butylhexylamino, Z-butylhexylamino, or pentylhexylamino), C2-6 alkenyl e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (Ce)), C2-6 alkynyl e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2- butynyl (C4), pentynyl (C5), or hexynyl (Ce)), Ce-io aryl e.g., phenyl or naphthyl), 5- to 10- membered heteroaryl e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), C3-12 carbocyclyl e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- I //-in deny! (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR^b, -S(=O)R^a, -S(=O)₂R^a, -S(=O)₂OR^b, -S(=O)₂NR^cR^d, -NR^cS(=O)₂R^a, -NR^cS(=O)R^a, - NR^cS(=O)₂OR^b, -NR^cS(=O)₂NR^cR^d, -NR^bC(=O)NR^cR^d, -NR^bC(=O)R^a, -NR^bC(=O)OR^b, - OS(=O)₂R^a, -OS(=O)₂OR^b, -OS(=O)₂NR^cR^d, -OC(=O)R^a, -OC(=O)OR^b, -OC(=O)NR^cR^d, - C(=O)R^a, -C(=O)OR^b, or -C(=O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO₂, -OH, -NH₂, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, C₂-6 alkenyl, C₂-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

[0244] In certain embodiments, each R^u is independently deuterium, oxo, halogen, -CN, - NO₂, -OH, -NH₂, CI-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, C₂-6 alkenyl, C₂-6 alkynyl, Ce-io aryl,

5- to 10-membered heteroaryl, C3-U carbocyclyl, 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, - NO₂, -OH, -NH₂, CI-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, C₂-6 alkenyl, C₂-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

[0245] In certain embodiments, each R^u is independently deuterium, oxo, halogen, -CN, - NO₂, -OH, -NH₂, CI-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, C₂-6 alkenyl, C₂-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO₂, -OH, -NH₂, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, C₂-6 alkenyl, C₂-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

[0246] In certain embodiments, each R^u is independently deuterium, oxo, halogen, -CN, - NO₂, -OH, -NH₂, CI-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO₂, -OH, -NH₂, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, C₂-6 alkenyl, C₂-6 alkynyl, C3-6 carbocyclyl, and 3- to

6-membered heterocyclyl.

[0247] In certain embodiments, the eIF4E inhibitor is Compound A

[0248] In certain embodiments, the eIF4E inhibitor is Compound B

[0249] In certain embodiments, the eIF4E inhibitor is Compound C

[0250] In certain embodiments, the eIF4E inhibitor is Compound D

[0251] In certain embodiments, the eIF4E inhibitor is Compound E

[0252] In certain embodiments, the eIF4E inhibitor is Compound F

[0253] The compounds of the present disclosure possess advantageous characteristics, as compared to known compounds, such as known eIF4E inhibitors. For example, the compounds of the present disclosure display more potent eIF4E inhibition activity, more favorable pharmacokinetic properties (e.g., as measured by Cmax, T_max, and/or AUC), and/or less interaction with other cellular targets (e.g., hepatic cellular transporter such as 0ATP1B1) and accordingly improved safety e.g., drug-drug interaction). These beneficial properties of the compounds of the present disclosure can be measured according to methods commonly available in the art, such as methods exemplified herein.

[0254] Due to the existence of double bonds, the compounds of the present disclosure may be in cis or trans, or Z or E, configuration. It is understood that although one configuration may be depicted in the structure of the compounds or formulae of the present disclosure, the present disclosure also encompasses the other configuration. For example, the compounds or formulae of the present disclosure may be depicted in cis or trans, or Z or E, configuration.

[0255] In one embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a pharmaceutically acceptable salt. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a solvate. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a hydrate.

Pharmaceutically acceptable salts

[0256] In certain embodiments, the compounds disclosed herein exist as their pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0257] In certain embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In certain embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0258] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenyl acetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

[0259] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l -carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0260] In certain embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N⁺(CI-4 alkyl)4, and the like.

[0261] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogen-containing groups they contain. In certain embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.

Solvates

[0262] “ Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the disclosure may be prepared e.g., in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0263] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates are within the scope of the disclosure. [0264] It will also be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms or the pharmaceutically acceptable solvates thereof are contemplated and are within the scope of the present disclosure.

[0265] In certain embodiments, the compounds described herein exist as solvates. The present disclosure provides for methods of treating diseases by administering such solvates. The present disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0266] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Isomers (stereoisomers, geometric isomer, tautomer, etc.)

[0267] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”

[0268] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R - and S - sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)- isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is termed a “racemic mixture”.

[0269] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0270] As used herein and unless otherwise indicated, the term “enantiomerically pure (IQ- compound” refers to at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, at least about 99% by weight (R)-compound and at most about 1% by weight (S)-compound, or at least about 99.9 % by weight (R)-compound and at most about 0.1% by weight (S)-compound. In certain embodiments, the weights are based upon total weight of compound.

[0271] As used herein and unless otherwise indicated, the term “enantiomerically pure (S)- compound” refers to at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, at least about 99% by weight (S)-compound and at most about 1% by weight (R)-compound or at least about 99.9% by weight (S)-compound and at most about 0.1% by weight (R)-compound. In certain embodiments, the weights are based upon total weight of compound.

[0272] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure (R)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such compositions can, for example, comprise, at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure (S)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0273] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0274] In certain embodiments, the compounds described herein exist as geometric isomers. In certain embodiments, the compounds described herein possess one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. All geometric forms of the compounds disclosed herein are contemplated and are within the scope of the disclosure. [0275] In certain embodiments, the compounds disclosed herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the disclosure. [0276] In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In certain embodiments, dissociable complexes are preferred. In certain embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In certain embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In certain embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.

Tautomers

[0277] In certain embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein.

[0278] Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and an adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of the disclosure. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.

Pharmaceutical Compositions

[0279] In certain embodiments, the compound described herein is administered as a pure chemical. In certain embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21^st Ed. Mack Pub. Co., Easton, PA (2005)).

[0280] Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0281] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, less than about 1%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0282] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0283] In certain embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration.

Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous injection. In certain embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In certain embodiments, the pharmaceutical composition is formulated as a tablet.

Preparation and Characterization of the Compounds

[0284] The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. The compounds of the present disclosure (z.e., a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein)) can be synthesized by following the general synthetic scheme below as well as the steps outlined in the examples, schemes, procedures, and/or synthesis described herein e.g., Examples).

General Synthetic Scheme

[0285] Those skilled in the art will recognize if a stereocenter exists in the compounds of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[0286] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka) (Pittsburgh, PA).

[0287] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-lnterscience, New York, 1992; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[0288] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Analytical Methods, Materials, and Instrumentation [0289] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 400 MHz. Spectra are given in ppm (5) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC/MS) were collected using a SHIMADZU LCMS- 2020EV or Agilent 1260-6125B LCMS. Purity and low resolution mass spectral data were measured using Agilent 1260-6125B LCMS system (with Diode Array Detector, and Agilent G6125BA Mass spectrometer) or using Waters Acquity UPLC system (with Diode Array Detector, and Waters 3100 Mass Detector). The purity was characterized by UV wavelength 214 nm, 220 nm, 254 nm and ESI. Column: poroshell 120 EC-C18 2.7 pm 4.6 X 100 mm; Flow rate 0.8 mL/min; Solvent A (100/0.1 water/formic acid), Solvent B (100 acetonitrile); gradient: hold 5% B to 0.3 min, 5-95% B from 0.3 to 2 min, hold 95% B to 4.8 min, 95-5% B from 4.8 to 5.4 min, then hold 5% B to 6.5 min. Or, column: Acquity UPLC BEH C18 1.7 pm 2.1 X 50 mm; Flow rate 0.5 mL/min; Solvent A (0.1%formic acid water), Solvent B (acetonitrile); gradient: hold 5%B for 0.2 min, 5-95% B from 0.2 to 2.0 min, hold 95% B to 3.1 min, then 5% B at 3.5 min.

Definitions

[0290] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

Chemical Definitions

[0291] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modem Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987.

[0292] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.F. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).

[0293] The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [0294] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1.6, Ci-5, C1.4, C1.3, C1.2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C₄-6, C4-5, and C_5.6 alkyl.

[0295] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure.

When describing the disclosure, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[0296] “Alkyl” as used herein, refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1.20 alkyl”). In certain embodiments, an alkyl group has 1 to 12 carbon atoms (“C1.12 alkyl”). In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci-io alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1.9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1.7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”, which is also referred to herein as “lower alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1.5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1.4 alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1.3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1.2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of Ci-6 alkyl groups include methyl (Ci), ethyl (C2), zz-propyl (C3), isopropyl (C3), zz-butyl (C4), tert-butyl (C4), ec-butyl (C4), isobutyl (C4), zz-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3- methyl-2-butanyl (C5), tertiary amyl (C5), and zz-hexyl (Ce). Additional examples of alkyl groups include zz-heptyl (C7), zz-octyl (Cs) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted Ci-io alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted Ci-io alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), z-Pr (-CH(CH₃)₂), zz-Pr (-CH2CH2CH3), zz-Bu (-CH2CH2CH2CH3), or z-Bu (-CH₂CH(CH₃)2).

[0297] “Alkylene” as used herein, refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (- CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted divalent alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,-CH₂CH(CH₃)-, -C(CH₃)2CH2-,-CH₂C(CH3)2-), substituted propylene (-CH(CH₃)CH₂CH2-, -CH₂CH(CH₃)CH2-, -CH₂CH₂CH(CH3)-, -C(CH₃)2CH₂CH2-, -CH₂C(CH3)₂CH₂-, -CH₂CH₂C(CH3)2-), and the like.

[0298] “Alkenyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carboncarbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carboncarbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-10 alkenyl.

[0299] “Alkenylene” as used herein, refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkenylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkenylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (- CH=CH-) and propenylene (e.g., -CEUCHCH2-, -CH2-CEUCH-). Exemplary substituted divalent alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene e.g., -C(CH₃)=CHCH₂-, -CH=C(CH₃)CH₂-, -CH=CHCH(CH₃)-, - CH=CHC(CH₃)₂-, -CH(CH₃)-CH=CH-,-C(CH₃)2-CH=CH-, -CH₂-C(CH₃)=CH-, -CH₂- CH=C(CH₃)-), and the like.

[0300] “Alkynyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carboncarbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1- propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl.

[0301] “Alkynylene” as used herein, refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkynylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0302] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“Ci-io heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“C1.9 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“Ci-s heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“C1.7 heteroalkyl”). In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“Ci-6 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“C1.5 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and/or 2 heteroatoms (“C1.4 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“C1.3 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“C1.2 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“Ci heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“C2-6 heteroalkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted Ci-io heteroalkyl. In certain embodiments, the heteroalkyl group is a substituted Ci-io heteroalkyl.

[0303] The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“C2-10 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“C2-9 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“C2-8 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“C2-7 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“C2-6 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“C2-5 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“C2-4 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“C2-3 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“C2-6 heteroalkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted C2-10 heteroalkenyl. In certain embodiments, the heteroalkenyl group is a substituted C2-10 heteroalkenyl.

[0304] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“C2-10 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“C2-9 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“C2-8 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“C2-7 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“C2-6 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“C2-5 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“C2-4 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“C2-3 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“C2-6 heteroalkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted C2-10 heteroalkynyl. In certain embodiments, the heteroalkynyl group is a substituted C2-10 heteroalkynyl.

[0305] Analogous to “alkylene,” “alkenylene,” and “alkynylene” as defined above, “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” as used herein, refer to a divalent radical of heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular “heteroalkylene,” “heteroalkenyl ene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear divalent chain. “Heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.

[0306] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 TI electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1 -naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted Ce-i4 aryl. In certain embodiments, the aryl group is substituted Ce- 14 aryl.

[0307] “Heteroaryl” refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 TI electrons shared in a cyclic array) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 14-membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.

[0308] “Heteroaryl” also includes ring systems wherein the heteroaryl group, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the heteroaryl or the one or more aryl groups, and in such instances, the number of ring members designates the total number of ring members in the fused (aryl/heteroaryl) ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heteroaryl or the one or more aryl groups. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2- indolyl) or the ring that does not contain a heteroatom (e.g., 5 -indolyl).

[0309] In certain embodiments, a heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In certain embodiments, a heteroaryl is a

5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In certain embodiments, the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to

6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5- to 14- membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5- to 14- membered heteroaryl. [0310] 5 -membered heteroaryl containing one heteroatom includes, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadi azolyl. Exemplary 5-membered heteroaryl containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6- membered heteroaryl containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl include, without limitation, indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadi azolyl, benzthiazolyl, benzisothi azolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0311] “Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3- 10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Exemplary C3-6 carbocyclyl include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- I //-in deny! (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.

[0312] In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Examples of C5-6 carbocyclyl include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 carbocyclyl include the aforementioned C5-6 carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 carbocyclyl include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C3-12 carbocyclyl.

[0313] In certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (“polycyclic carbocyclyl”) that contains a fused, bridged or spiro ring system and can be saturated or can be partially unsaturated. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-12 carbocyclyl.

[0314] “Fused carbocyclyl” or “fused carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, is fused with, i.e., share one common bond with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons designates the total number of carbons in the fused carbocyclyl ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings.

[0315] “Spiro carbocyclyl” or “spiro carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the carbocyclyl rings in which the spiro structure is embedded.

[0316] “Bridged carbocyclyl” or “bridged carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form bridged structure with, i.e., share more than one atoms (as such, share more than one bonds) with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of carbons designates the total number of carbons of the bridged rings. When substitution is indicated, unless otherwise specified, substitution can occur on any of the carbocyclyl rings in which the bridged structure is embedded.

[0317] “Heterocyclyl” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Exemplary 3- membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5- membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0318] In certain embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 10- membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In certain embodiments, the 5- to 6- membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0319] In certain embodiments, a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (“polycyclic heterocyclyl”) that contains a fused, bridged or spiro ring system, and can be saturated or can be partially unsaturated. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl group, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members designates the total number of ring members in the entire ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3- to 12-membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3- to 12- membered heterocyclyl.

[0320] “Fused heterocyclyl” or “fused heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, is fused with, i.e., share one common bond with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons designates the total number of ring members in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings.

[0321] “Spiro heterocyclyl” or “spiro heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded.

[0322] “Bridged heterocyclyl” or “bridged heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form bridged structure with, i.e., share more than one atoms (as such, share more than one bonds) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the bridged rings.

[0323] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, sulfur, boron, phosphorus, or silicon heteroatom, as valency permits. Hetero may be applied to any of the hydrocarbyl groups described above having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0324] “Alkoxy” as used herein, refers to the group -OR, wherein R is alkyl, carbocyclyl, or heterocyclyl as defined herein. Ci-6 alkoxy refers to the group -OR, wherein each R is Ci-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, as defined herein. Exemplary Ci-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl is set forth above.

[0325] “Alkylamino” as used herein, refers to the group -NHR or -NR2, wherein each R is independently alkyl, carbocyclyl, or heterocyclyl, as defined herein. Ci-6 alkylamino refers to the group -NHR or -NR2, wherein each R is independently Ci-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl as defined herein. Exemplary Ci-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl is set forth above.

[0326] “ Oxo” refers to =0. When a group other than aryl and heteroaryl or an atom is substituted with an oxo, it is meant to indicate that two geminal radicals on that group or atom form a double bond with an oxygen radical. When a heteroaryl is substituted with an oxo, it is meant to indicate that a resonance structure/tautomer involving a heteroatom provides a carbon atom that is able to form two geminal radicals, which form a double bond with an oxygen radical.

[0327] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

[0328] “Protecting group” as used herein i art-recognized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups that need to be protected include but not limited to hydroxyl, amino, thiol, and carboxylic acid. Accordingly, the protecting groups are termed hydroxyl-protecting groups, arnino-protecting groups, thiol-protecting groups, and carboxylic acid-protecting groups, respectively.

[0329] Common types of hydroxyl-protecting groups include but not limited to ethers (e.g., methoxymethyl (MOM), P-Methoxy ethoxymethyl (MEM), tetrahydropyranyl (THP), p- methoxyphenyl (PMP), /-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)), silyl ethers (e.g, t-butyldiphenylsilyl (TBDPS), trimethyl silyl (TMS), triisopropyl silyl (TIPS), tri- /xo-propylsilyloxymethyl (TOM), and /-butyldimethylsilyl (TBDMS)), and esters (e.g, pivalic acid ester (Piv) and benzoic acid ester (benzoate; Bz)). [0330] C ommon types of a ino-protecting groups include but not limited to carbamates (e. ., /-butyl oxy carbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), -methoxybenzyl carbonyl (Moz or MeOZ), 2,2,2-trichloroehtoxycarbonyl (Troc), and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac); benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g, benzyl (Bn), -methoxybenzyl (PMB), -methoxyphenyl (PMP), and triphenylmethyl (trityl)), and sulfonamides (e.g., tosyl (Ts), Aralkyl nitrobenzenesulfonamides (Nosyl), and 2- nitrophenylsulfenyl (Nps)).

[0331] C ommon types of thiol-protecting groups include but not limited to sulfide (e.g, p- methylbenzyl (Meb), /-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)).

[0332] C ommon types of carboxylic acid-protecting groups include but not Limited to esters (e.g., methyl ester, triphenylmethyl (Trityl), /-butyl ester, benzyl ester (Bn), S-Abutyl ester, silyl esters, and orthoesters) and oxazoline.

[0333] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The disclosure is not intended to be limited in any manner by the above exemplary listing of substituents.

Other Definitions

[0334] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0335] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2]-oct-2-ene-l -carboxylic acid, glucoheptonic acid , 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid , gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion , an alkaline earth ion , or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0336] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or an adult subject (e.g., young adult, middle aged adult or senior adult) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0337] An “effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to affect such treatment or prevention. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. A “therapeutically effective amount” refers to the effective amount for therapeutic treatment. A “prophylactically effective amount” refers to the effective amount for prophylactic treatment.

[0338] “Preventing”, “prevention” or “prophylactic treatment” refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject not yet exposed to a disease-causing agent, or in a subject who is predisposed to the disease in advance of disease onset).

[0339] The term “prophylaxis” is related to “prevention,” and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization, and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high. [0340] “Treating” or “treatment” or “therapeutic treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment, “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

[0341] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability or within statistical experimental error, and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, or 5% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, or 3% of the stated number or numerical range.

[0342] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features. [0343] The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” may refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. [0344] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0345] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) may refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0346] While the present teachings have been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. [0347] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

[0348] The claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and detail may be made by one of ordinary skill in the art without departing from the spirit and scope of the appended claims. All embodiments that come within the spirit and scope of the following claims and equivalents thereto are claimed.

EXAMPLES

[0349] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Assay Protocols

Generation of palbociclib resistant MCF -7 cells.

[0350] MCF-7 cells were plated at 4xl0⁶ cells per T75 flask and eight dishes were maintained in EMEM growth media supplemented with 1 uM palbociclib. After one week, cells were washed with PBS and treated with 2 mL of Trypsin then returned to the incubator for 5 minutes. 13 mL of complete EMEM growth media was added to cells and then were transferred to 15 mL tube and centrifuged at 500 xg for 5 minutes. Media was aspirated and cells were resuspended in 15 mL of complete EMEM growth media with 1 uM palbociclib and transferred to a single T75 flask. Cells were maintained in EMEM growth media with 1 uM palbociclib for 10 weeks, changing out fresh media with palbociclib twice a week. When cells reached -90% confluency they were split and replated at 4xl0⁶ cells in a single T75 flash.

Cell cycle analysis

[0351] Cells were plated into each well of a 6-well plate at a density of 100,000/well with 2mL of standard media. Cells were treated with Compound B for 48 hours at IX and 10X IC50 values. EdU was then added to each well to a final concentration of lOuM an hour before cells were harvested for analysis. Cells were collected by scraping and placed into conical tubes. Cells were pelleted and washed with 2mL of 1%BSA in PBS. Click-It fixative solution was used to fix cells for 15 minutes at room temperature. After fixation, cells were washed with 2mL of 1% BSA in PBS and were pelleted. Click-IT Plus reaction cocktail was prepared according to manufacturer’s instruction. 0.5 mL of reaction cocktail was added to fixed cells, and the mixture was incubated for 30 minutes at room temperature. Then, cells were washed again with 2mL of 1%BSA in PBS and were pelleted. Supernatant was removed and cells were resuspended in ImL of PBX with luL of FxCycle Violet reagent. Cellular DNA content was processed through a flow cytometer and was analyzed by Flow Jo.

Western blot

[0352] Protein lysates were prepared using mPER lysis buffer supplemented with protease and phosphatase inhibitor cocktail (HALT). Lysates were clarified by centrifugation at maximum speed for 10 minutes at 4 °C. Protein concentrations were determined using BCA kit according to manufacturer’s instruction. Protein lysates were diluted to the lowest concentration using mPER lysis buffer. Finally, 4X Laemmli sample buffer supplemented with BME was added to the protein lysates and boiled for 5 minutes at 95 °C. 30 ug of protein were loaded into Biorad precast Criterion 4-15% gradient gels and resolved at 200V for 30min. Proteins were transferred onto PVDF membrane using transblot turbo instrument. Membranes were blocked with 5% non-fat milk in lx TBS-T buffer for one hour at room temperature. Primary antibodies were diluted in 5% BSA in lx TBS-T buffer and membranes were incubated in primary antibody overnight at 4 °C. Anti-cyclin DI (ab 16663) at 1 :200 dilution, anti-ODCl (ab270300) at 1 : 1000 dilution, anti-pERKl/2 (CST # 4370) at 1 : 1000 dilution, anti-ERKl/2 (CST #9102) at 1 : 1000 dilution, anti-pMEKl/2 (ab278723) at 1 : 1000 dilution, anti-MEKl/2 (CST #9122) at 1 : 1000 dilution, anti-pEIF4E (abl83301) at 1 : 1000 dilution, anti-EIF4E (ab33768) at 1 : 1000 dilution, anti-cyclin D3 (abl83338) at 1 :200 dilution, anti-vinculin (Sigma #v9131) at 1 :5000 dilution were used. Blots were washed 3 times for 10 min each with lx TBS-T and were incubated with corresponding secondary antibody (1 :5000 dilution in 5% milk) for 1 hour at room temperature. HRP-conjugated affinipure goat anti -rabbit (Jackson Immunoresearch 111-035-003) and HRP-conjugated affinipure goat anti-mouse (Jackson immunoresearch 115-035-003) were used. Blots were developed using Clarity (Biorad #1705061) or Clarity Max (BioRad #1705062) chemiluminescence reagent. Images were capture using Azure C600 Imager.

CTG assay

[0353] Compound assay plates were prepared by in house compound management. For each compound, 150 nL of 3-fold titration, starting at 10 mM in an 11-point dilution series were added to 384-well standard tissue culture plates using the Mosquito instrument. Compounds were diluted in DMSO. Column 6 of each plate contains only 150 nL of DMSO to serve as controls. Plates were kept at room temperature, protected from light for up to 4 weeks until ready to use.

[0354] Cells were cultured and maintained in conditions recommended by ATCC. Cells were harvested and diluted to 0.035 x 106 cells/mL. Multidrop Combi instrument was used to dispense 30 uL of cell solution into each well of the compound assay plates prepared previously. Plates were centrifuged briefly for 30 seconds at 500 rpm. Assay plates were placed in a humidity chamber and in cell incubator for 144 hours.

[0355] Cell Titer gio reagent was used to quantify the viability of cells. Briefly, reagent and assay plates were allowed to equilibrate to room temperature for approximately 30 minutes. Multidrop Combi instrument was used to dispense 30 uL of Cell Titer Gio reagent into each well. Plates were centrifuged briefly for 30 seconds at 500 rpm and then were shaken at 500 rpm for 10 minutes to ensure complete cell lysis. Luminescence signals were read using Clariostar. Percent inhibition was calculated as 100 - (100 * (X/XDMSO). Data were fitted using Prism with a 4-parameter logistic fit equation.

TR-FRET

[0356] Assay plates containing tested compounds were stored in freezer and were allowed to equilibrate to room temperature for 30 minutes. Control column 6 of each plate contains only DMSO. hEIF4E (8 nM) and Europium anti-HIS antibody (Perkin Elmer AD00400, 401,402) (5 nM) were diluted into assay buffer (50 mM HEPES, pH 7.5, 100 mM KC1, 0.02% Tween- 20, 0.1 mg/ml BSA and ImM TCEP, prepared fresh before use). Multidrop Combi was used to dispense 5uL of hEIF4E and europium anti-HIS antibody into each well of the assay plate. The mixture was incubated for 15 minutes at room temperature. 5 uL of 10 nM solution of EDA-m7GDP-ATTO-647N (Jena Bioscience NU-827-647N) in assay buffer was then dispensed into each well using Multidrop Combi instrument. Assay plates were incubated at room temperature for 15 minutes and read on a plate reader equipped with TR-FRET capability at excitation of 340 nm and emission of 620 nm and 665 nm.

Ribo-Seq

[0357] Ribo-seq data generation was performed by EIRNA. Briefly, COLO205 cells were treated for 1 hour with IX and 10X IC50 RBX compound and both total RNA and ribosome- associated RNA were isolated and quantified. Adapter sequences were removed using cutadapt. Reads below 20 nucleotides in length after adapter removal were discarded. Reads were aligned to rRNA and tRNA sequences using bowtie. Reads that map to rRNA or tRNA were discarded while remaining reads were aligned to the transcriptome. UMI's were removed where applicable. For RNA-seq data, the number of reads that map to the entire mRNA transcript were output as counts and for Ribo-seq data, only reads that mapped to the coding regions (CDS) were used. Differential expression analyses were performed in-house using the R package edgeR as part of a modified approach of deltaTE. This entails analyzing differential changes in mRNA counts, RPFs (mRNA protected fragments) and TE (the ratio of the RPFs over mRNA counts) for each gene. Genes with a false discovery rate (FDR) <= 0.05 were considered significant. Functional enrichment analyses were performed using g:Profiler and the R package fGSEA [vl.26.0]. Tumor xenografts

[0358] MCF-7.1 cells were cultured and maintained as a monolayer. Cells were grown in an exponential growth phase before tumor inoculation. CR female NCr nu/nu mice aged 8-12 weeks were injected with IxlO⁷ MCF-7.1 cells in 0% Matrigel s.c. in the flank. Mice were provided drinking water with 10 ug/mL 17-beta estradiol supplementation 3 days prior to cell implantation and for the duration of the study. Once tumors reached an average size of 100- 150 mm³ mice were pair matched and compound treatment began. The major endpoint is to see if the tumor growth can be delayed or mice can be cured. Survival is a secondary endpoint of this study. Tumor sizes were measured three times weekly in two dimensions using a caliper, and the volume will be expressed in mm³ using the formula: V = 0.5 a x b² where a and b are the long and short diameters of the tumor, respectively. The tumor sizes are then used for the calculations of both T/C and TGI values. The T/C value (in percent) is an indication of antitumor effectiveness, T and C are the mean volume of the treated and control groups, respectively, on a given day. TGI is calculated for each group using the formula: TGI (%) = [l-(Ti-TO)/ (Vi-V0)] * 100; Ti is the average tumor volume of a treatment group on a given day, TO is the average tumor volume of the treatment group on the first day of treatment, Vi is the average tumor volume of the vehicle control group on the same day with Ti, and V0 is the average tumor volume of the vehicle group on the first day of treatment.

Example 1. eIF4E inhibitors (eIF4Ei) potently and selectively inhibited cap-dependent translation.

[0359] Multiple novel eIF4E inhibitors were developed and biochemically validated by i) TR-FRET assay using recombinant HIS-tagged human eIF4E and Europium-conjugated antibody incubated with fluorescently labeled 5’ mRNA cap analog. HEK293-Flpln cells were transfected with bicistronic dual luciferase reporter were treated with eIF4E inhibitors for 24 hours. Cap-dependent dual luciferase assay was performed. As shown in FIGs. 1A-1B, eIF4E inhibitors potently and selectively inhibited cap-dependent translation.

Example 2. eIF4E inhibitors repressed translation of a subset of mRNAs enriched for growth associated genes.

[0360] OPP assay was performed to assess the protein synthesis. Cycloheximide (CHX) control and eIF4A inhibitor inhibit all nascent translation while eIF4E inhibitors represses translation of -75% of total protein (FIG. 2B).

[0361] To demonstrate regulation of cell cycle progression through preferential repression of growth associated genes, COLO 205 cells were treated for 1 hour with Compound B. Both total RNA and ribosome associated RNA (Ribo-seq) were isolated and quantified by RNA- seq. In addition, Western blot analysis of Cyclin DI in cells treated with Compound A and DNA content analysis were performed. The results are summarized in FIGs. 2A-2D. Example 3. eIF4E inhibitors inhibited cell growth through selective binding to eIF4E. [0362] eIF4E mutants that disrupt binding of eIF4E inhibitors but maintain binding to m7GTP were generated. TR-FRET assay with Compound C was performed, and CellTiter- Glo (CTG) assay with Compound eIF4A was performed as a control. The results show that protein expression recovered after removal of the eIF4E inhibitors, as summarized in FIGs. 3 A and 3B.

Example 4. Inhibition with eIF4E inhibitors is reversible.

[0363] HCC1806 cancer cell line was treated with eIF4E inhibitor Compound B for 24 hours. Results show that protein expression recovered after removal of eIF4E inhibitor, as summarized in FIGs. 4A and 4B.

Example 5. eIF4E inhibitors led to cell cycle arrest in ER+ breast cancer.

[0364] MCF-7 cells were treated with eIF4E inhibitors for 72 hours. Cell viability assay, Western plot, and DNA content cell cycle analysis were performed. The results are summarized in FIGs. 5A-5C. The results demonstrate that eIF4E inhibitors decreased viable cells in a concentration responsive manner (FIG. 5A); there is a concentration-dependent selective decrease of eIF4E target genes (FIG. 5B); and there is a concentration-dependent increase in G0/G1 population (FIG. 5C). .

Example 6. CDK4/6 inhibitor (palbociclib)-resistant breast cancer cell lines are sensitive to eIF4E inhibition.

[0365] A series of studies were performed to evaluate the inhibitory effects of Compound B on that breast cancer cell lines that are resistant to typical CDK4/6 inhibitors such as palbociclib. Results are summarized in FIGs. 6A-6C and FIGs. 7A-7C. The results demonstrate that palbociclib induces G1 arrest in MCF-7 but is severely reduced in palbociclib resistant cells (FIG. 6B); the CDK4/6 pathway is refractory to palbociclib in PalboR cells (FIG. 6C); eIF4E pathway markers are similarly responsive in PalboR cells as parental MCF-7 (FIG. 7A); and palbociclib-resistant cells have reduced sensitivity to eIF4E inhibition, but are many times more responsive to eIF4E inhibition than to palbociclib (FIG. 7B)

Example 7. eIF4E inhibition with eIF4E inhibitors shows anti-tumor efficacy in ER+ breast cancer model.

[0366] An in vivo mouse study was performed that evaluates tumor growth and percentage change of body weight by eIF4E inhibitors Compound D, E, or F. Results are summarized in FIGs. 8A and 8B Example 8. eIF4E inhibitors synergize with CDK4/6 inhibitors and SERDs to cause tumor regression in an ER+ breast cancer model.

[0367] An in vivo mouse (ER+ breast cancer model) study with daily oral treatment of i) SOC (1. palbociclib, 2. fulvestrant, or 3. palbociclib + fulvestrant), ii) Compound E, and iii) combinations of Compound E with SOC was performed to evaluates tumor growth, percentage change of body weight, and synergistic effects. Results are summarized in FIGs.

9A-9D

EQUIVALENTS

[0368] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth.

[0369] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method of treating breast cancer, comprising administering to a subject in need thereof an eIF4E inhibitor, wherein the eIF4E inhibitor is of Formula I:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: each -L- is independently -O-, -NR^L-, -CR^L1R^L2-, -CR^L1=CR^L2-, or -C=C-; each R^L is independently hydrogen or optionally substituted Ci-6 alkyl; each R^L1 and each R^L2 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, Ci-6 alkoxy, or Ci-6 alkylamino, wherein the alkyl, alkoxy, or alkylamino is optionally substituted; q is an integer selected from 1 to 5;

Ring C and Ring D are independently Ce-io aryl or 5- to 10-membered heteroaryl;

R² is hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, Ce-io aryl, 5- to 10-membered heteroaryl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -C(=0)NR^cS(=0)2R^a, -C(=O)NR^cR^d, -(CH2)C(=0)0R^b, or - C(=O)OR^b, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted,

R¹ is -NR^laR^lb or -OR^1C;

R¹ is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted; or R¹ and R¹ , together with the carbon atom to which they are bonded, from C3-12 carbocyclyl or 3- to 12-membered heterocyclyl, wherein carbocyclyl or heterocyclyl is optionally substituted;

R^la and R^lb, together with the nitrogen atom to which they are bonded, form 3- to 12- membered heterocycle, wherein the heterocycle is optionally substituted with one or more R^ab; each R^ab is independently oxo, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, or -S(=O)R^a, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or two vicinal R^ab, together with the atoms to which they are bonded, form Ce aryl or 5- to 6- membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted;

2. Use of an eIF4E inhibitor in the manufacture of a medicament for treating breast cancer in a subject in need thereof, wherein the eIF4E inhibitor is of Formula I:

Ring C and Ring D are independently Ce-io aryl or 5- to 10-membered heteroaryl;

R² is hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 alkylamino, Ce-io aryl, 5- to 10-membered heteroaryl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -C(=O)NR^cS(=O)2R^a, -C(=O)NR^cR^d, -(CH2)C(=O)OR^b, or - C(=O)OR^b, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted,

R¹ is -NR^laR^lb or -OR^1C;

R¹ and R¹ , together with the carbon atom to which they are bonded, from C3-12 carbocyclyl or 3- to 12-membered heterocyclyl, wherein carbocyclyl or heterocyclyl is optionally substituted;

3. An eIF4E inhibitor for use in treating breast cancer in a subj ect in need thereof, wherein the eIF4E inhibitor is of Formula I:

Ring C and Ring D are independently Ce-io aryl or 5- to 10-membered heteroaryl;

R¹ is -NR^laR^lb or -OR^1C;

4. The method, use, or compound for use of any one of claims 1-3, wherein the eIF4E inhibitor is for administration at a dose of about 1 mg/kg to about 500 mg/kg, or about 20 mg to about 3000 mg.

5. The method, use, or compound for use of any one of claims 1-3, wherein the method further comprises administering a CDK4/6 inhibitor or an estrogen receptor antagonist; the medicament further comprises a CDK4/6 inhibitor or an estrogen receptor antagonist; or the eIF4E inhibitor is used in combination with a CDK4/6 inhibitor or an estrogen receptor antagonist.

6. The method, use, or compound for use of any one of claims 1-3, wherein the method further comprises administering a CDK4/6 inhibitor and an estrogen receptor antagonist; the medicament further comprises a CDK4/6 inhibitor and an estrogen receptor antagonist; or the eIF4E inhibitor is used in combination with a CDK4/6 inhibitor and an estrogen receptor antagonist.

7. The method, use, or compound for use of claim 5 or 6, wherein the CDK4/6 inhibitor is palbociclib, ribociclib, abemaciclib, or dalpiciclib.

8. The method, use, or compound for use of claim 5 or 6, wherein the estrogen receptor antagonist is fulvestrant, elacestrant, raloxifene, or tamoxifen.

9. The method, use, or compound for use of any one of claims 1-8, wherein the breast cancer is ER+ breast cancer.

10. The method, use, or compound for use of any one of claims 1-9, wherein the breast cancer is CDK4/6 inhibitor-resistant breast cancer.

11. The method, use, or compound for use of claim 10, wherein the breast cancer is palbociclib-resistant breast cancer.

12. The method, use, or compound for use of any one of claim 1-11, wherein Ring C is phenyl.

13. The method, use, or compound for use of claim 12, wherein the eIF4E inhibitor is of

Formula I-l-i:

14. The method, use, or compound for use of any one of claim 1-13, wherein Ring D is thienopyridinyl.

15. The method, use, or compound for use of any one of claim 1-14, wherein R² is - COOH.

16. The method, use, or compound for use of claim 15, wherein the eIF4E inhibitor is of

Formula I-l-i-1:

17. The method, use, or compound for use of any one of claims 1-16, wherein R^C1 is halogen; R^D is Ci-6 alkyl; r is 0; and s is 0.

18. The method, use, or compound for use of any one of claims 1-17, wherein [L]_q is

wherein:

* denotes attachment to Ring B, and ** denotes attachment to Ring C; p is an integer selected from 0 to 3; and Y is -O-, -NR^L-, -CR^L1R^L2-, or -C=C-.

19. The method, use, or compound for use of claim 18, wherein Y is -O-, and p is 1, and each R^L1 and each R^L2 is hydrogen.

20. The method, use, or compound for use of any one of claims 1-19, wherein each of m and m’ is 1; and n is 0.

21. The method, use, or compound for use of any one of claims 1-20, wherein R^B is Ci-6 alkyl.

22. The method, use, or compound for use of any one of claims 1-21, wherein X is - C(R^X)₂-, and each R^x is independently hydrogen or Ci-6 alkyl; or two R^x, together with the carbon atom to which they are bonded, form C3-4 carbocyclyl or 3- to 4-membered heterocyclyl.

23. The method, use, or compound for use of any one of claims 1-22, wherein R¹ is - NR^laR^lb, and R¹ is hydrogen.

24. The method, use, or compound for use of claim 23, wherein i) at least one of R^la and R^lb is not hydrogen; and R^la and R^lb are each independently hydrogen, Ci-6 alkyl, or -(Ci-6 alkylene)-(C3-i2 carbocyclyl), wherein the alkyl, alkylene, carbocyclyl, or heterocyclyl is optionally substituted; or ii) R^la and R^lb, together with the nitrogen atom to which they are attached, form 3- to 12- membered heterocycle, wherein the heterocycle is optionally substituted one or more R^ab.

25. The method, use, or compound for use of any one of claim 1-24, wherein the eIF4E inhibitor is