WO2021003194A1

WO2021003194A1 - Eif4e inhibitors for use as immune checkpoint modulators and related methods

Info

Publication number: WO2021003194A1
Application number: PCT/US2020/040369
Authority: WO
Inventors: Kevin R. Webster; Gary Chiang; Vikas Goel
Original assignee: Effector Therapeutics, Inc.
Priority date: 2019-07-02
Filing date: 2020-06-30
Publication date: 2021-01-07

Abstract

The present disclosure relates to the use elF4E inhibitors to inhibit immunosuppression components, such as immune checkpoint proteins PD-1, PD-L1, LAG3, TIM3, and/or IDO, in order to inhibit or release immune suppression in certain diseases, such as cancer and infectious disease. The present disclosure relates to compositions and methods for immune modulation, modulation by, for example, relieving disease-associated immune resistance mediated by induction of immune suppression molecules and reduction in molecules involved in an adaptive immune response.

Description

EIF4E INHIBITORS FOR USE AS IMMUNE CHECKPOINT MODULATORS

AND RELATED METHODS BACKGROUND

T cell mediated immune responses are initiated through antigen recognition by the T cell receptor (TCR). The ultimate amplitude and quality of the T cell response is regulated by immune checkpoints, which control the balance of co-stimulatory and co- inhibitory signals. Immune checkpoints are essential in maintaining self-tolerance and protecting tissues from damage during immune response to infection. However, dysregulated expression of immune checkpoint proteins by tumors provides an important immune resistance mechanism. Inhibitory ligands and receptors that regulate T cell effector functions in tissues are frequently overexpressed on tumor cells or on non- transformed cells in the tumor microenvironment. Two general mechanisms of expression of immune checkpoint ligands on tumor cells have emerged. In some tumors, constitutive oncogenic signaling induces inhibitor ligand expression on the tumor to provide innate immune resistance. Alternatively, an inhibitory ligand may be induced in response to inflammatory signals that are produced by an active anti-tumor immune response (adaptive immune resistance). Pre-clinical and clinical data indicates that inhibition of immune checkpoints can enhance endogenous anti-tumor immunity (see, e.g., Pardoll, Nat. Rev. Cancer 12:252, 2012).

There is a need in the art for alternative, effective modulators of immune checkpoint pathways. The present disclosure meets such needs, and further provides other related advantages. BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1A-1E. Downregulation of key checkpoint proteins in T cells by eIF4E inhibition. Expression of (A) PD-1, (B) LAG3, (C) TIM-3, and (D) PD-L1 were each assessed in activated primary T cells treated with Compound 296F by flow cytometry. Data shown are the average from 2 donors. (E) Overall T cell viability in varying concentrations of Compound 296F.

Figure 2. IFN-gamma stimulated PD-L1 expression is blocked by eIF4E inhibition. HAP-1 or HAP-1-R (eIF4Ei-resistant) cells were stimulated with IFN-g for 24 hrs. in the absence or presence of the indicated concentrations of Compound 296F. PD-L1 expression was analyzed by flow cytometry.

Figures 3A and 3B. IDO expression is inhibited by eIF4E inhibitors. (A) A375 cells were stimulated with IFN-g in the absence or presence of the indicated concentrations of Compounds 296F, 2, or 3 for 24 hrs. Whole cell lysates were immunoblotted with the indicated antibodies. (B) Growth media from A375 cells in Fig.3A was analyzed for L- kynurenine levels by LC-MS/MS. DETAILED DESCRIPTION

The present disclosure relates to compositions and methods for immune

modulation, modulation by, for example, relieving disease-associated immune resistance mediated by induction of immune suppression molecules and reduction in molecules involved in an adaptive immune response. For example, improper levels or activity of immune checkpoint proteins, such as programmed cell death protein 1 (PD-1) or its ligand (PD-L1), lymphocyte activation gene 3 (LAG3), T-cell immunoglobulin and mucin- domain containing-3(TIM-3), indoleamine 2,3-dioxygenase (IDO), or any combination thereof, may be corrected or normalized through the use of an eukaryotic translation initiation factor 4E (eIF4E) inhibitor.

By way of background, the cell-mediated immune response portion of the human adaptive immune system involves activation of lymphocytes (T cells) to mediate destruction of pathogenic or abnormal cells and related molecules. T cells can be activated by cells presenting a foreign antigen that has originated externally (e.g., invading pathogen) or internally from a cell (e.g., cancer cells). This response is highly regulated through various immune checkpoints since an aberrant response can cause damage to the host. Under normal conditions, the immune checkpoint system is an elaborate series of cellular signals and molecular interactions that prevents excessive activation or effector activity by T cells. But, this balance of positive (co-stimulatory) to negative (suppressive) signaling can be disrupted by non-normal conditions and result in an abnormal microenvironment in which the immune response or immune surveillance is suppressed. Such immune resistance can arise under certain pathogenic conditions, such as cancer or infection.

One exemplary negative regulator of T cell effector function is the PD-1 receptor found on the surface of T cells, which can transmit an inhibitory signal when bound by one of its ligands, PD-L1 (B7-H1, CD274) or PD-L2 (B7-DC, CD73), found on APCs. PD-1 limits the effector function of T cells in peripheral tissues during inflammation and helps maintain tolerance (i.e., minimize autoimmunity) (see Francisco et al., Immunol. Rev. 236:219, 2010). Further exemplary inhibitory receptors found on the surface of T cells include CD200R, LAG3, BTLA, KIR, SIRPa, TIM3 and A2aR.

Another exemplary inhibitory receptor found on the surface of activated T cells, NK cells, B cells and plasmacytoid dendritic cells is LAG3 (CD223). LAG3 has an inhibitory effect on effector T cell (TE) function and promotes regulatory T cell (Treg) mediated immune suppression. LAG3 can bind to MHC class II molecules on antigen presenting cells, which leads to the down regulation of CD4 T cell antigen specific proliferation and cytokine secretion (Anderson et al., 2016, Immunity, 44:989). LAG3 may also interact with LSECtin expressed on liver and many tumor cells, resulting in downregualtion of CD8 T cell response (Anderson et al., supra).

Another exemplary inhibitory receptor is TIM3, which is expressed on the surface of IFNg producing CD4 and CD8 T cells, Treg cells, and innate immune cells. TIM3 binds to several ligands including galectin 9, phosphatidylserine, CEACAM1, and HMGB1, and negatively regulates type 1 immunity (Anderson et al., supra).

Another negative regulator of T cell function is indoleamine-pyrrole 2,3- dioxygenase (IDO), which is an enzyme that catalyzes the first and rate-limiting step in the kynurenine pathway of tryptophan degradation. Tryptophan is an essential amino acid for cell survival and cannot be sythesized de novo. IDO is expressed by endothelial cells, mesenchymal stormal cells, fibroblasts, and various myeloid-derived antigen presenting cells (e.g., dendritic cells and macrophages), as well as tumor cells (Moon et al., 2015, J. Immunother. Cancer 3:51). Tryptophan depletion can result in suppression of tumor specific T cell response and activation of Tregs through multiple mechanisms (Moon et al., supra).

The present disclosure describes the surprising ability of eIF4E inhibitors to mediate or promote a reduction of one or more various immunosuppression components, such as PD-1, PD-L1, LAG3, TIM3, and IDO. EIF4E inhibitors can be used as a viable alternative to, or in combination with, specific inhibitors or modulators of

immunosuppression components, such as inhibitors or modulators of immune checkpoint molecules (e.g., anti-PD-1 antibody, anti-PD-L1 antibody, anti-TIM3 antibody, anti-LAG3 antibody, IDO specific small molecule; see, e.g., Pardol, Nature Rev. Cancer 12:252, 2012).

Such a reduction in one or more immunosuppression components (e.g., PD-1, PD-L1, LAG3, TIM3, IDO) by administration of a eIF4E inhibitor can be used to treat or reduce the progression of disease by, for example, increasing the activity of immune cells (e.g., T cells); reducing the down-modulation of immune cells; inducing or enhancing an immune response; prolonging an immune response; stimulating an antigen-specific T cell response; or the like. For example, a subject (e.g., a human) having a disease-associated with immune resistance (e.g., an immunosuppression component-mediated disease, such as a disease involving dysregulation of PD-1, PD-L1, TIM3, IDO, or LAG3) can be treated with a eIF4E inhibitor to induce or enhance an immune response in the subject. Exemplary diseases-associated with immune resistance include cancer and infectious disease. In addition, eIF4E inhibitors can be used in combination with (and even augment) other therapies directed against immunosuppression components, such as antibodies or small molecules specific for immune checkpoint molecules (e.g., anti-PD-1 antibody, anti-PD-L1 antibody, anti-LAG3 antibody, anti-TIM3 antibody, IDO competitive inhibitor or suicide substrate), to treat diseases in which a non-suppressed (normal, induced or enhanced) immune response would be beneficial. Prior to setting forth this disclosure in more detail, it may be helpful to an understanding thereof to provide definitions of certain terms to be used herein. Additional definitions are set forth throughout this disclosure.

In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the term "about" means ± 20% of the indicated range, value, or structure, unless otherwise indicated. It should be understood that the terms "a" and "an" as used herein refer to "one or more" of the enumerated components. The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives. As used herein, the terms "include," "have" and "comprise" are used synonymously, which terms and variants thereof are intended to be construed as non-limiting.

In addition, it should be understood that the individual compounds, or groups of compounds, derived from the various combinations of the structures and substituents described herein, are disclosed by the present application to the same extent as if each compound or group of compounds was set forth individually. Thus, selection of particular structures or particular substituents is within the scope of the present disclosure.

The term "consisting essentially of" limits the scope of a claim to the specified materials or steps, or to those that do not materially affect the basic characteristics of a claimed invention. For example, a protein domain, region, or module (e.g., a binding domain, hinge region, linker module) or a protein (which may have one or more domains, regions, or modules) "consists essentially of" a particular amino acid sequence when the amino acid sequence of a domain, region, module, or protein includes extensions, deletions, mutations, or a combination thereof (e.g., amino acids at the amino- or carboxy- terminus or between domains) that, in combination, contribute to at most 20% (e.g., at most 15%, 10%, 8%, 6%, 5%, 4%, 3%, 2% or 1%) of the length of a domain, region, module, or protein and do not substantially affect (i.e., do not reduce the activity by more than 50%, such as no more than 40%, 30%, 25%, 20%, 15%, 10%, 5%, or 1%) the activity of the domain(s), region(s), module(s), or protein (e.g., the target binding affinity of a binding protein).

"Amino" refers to the -NH2 substituent.

"Aminocarbonyl" refers to the–C(O)NH₂ substituent.

"Carboxyl" refers to the–CO2H substituent.

"Carbonyl" refers to a–C(O)- or–C(=O)- group. Both notations are used interchangeably within the specification.

"Cyano" refers to the–CºN substituent.

"Cyanoalkylene" refers to the -(alkylene)CºN subsituent.

"Acetyl" refers to the–C(O)CH₃ substituent.

"Hydroxy" or "hydroxyl" refers to the -OH substituent.

"Hydroxyalkylene" refers to the -(alkylene)OH subsituent.

"Oxo" refers to a =O substituent.

"Thio" or "thiol" refer to a–SH substituent.

"Alkyl" refers to a saturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C1-C12 alkyl), from one to eight carbon atoms (C1-C8 alkyl) or from one to six carbon atoms (C₁-C₆ alkyl), and which is attached to the rest of the molecule by a single bond. Exemplary alkyl groups include methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.

"Lower alkyl" has the same meaning as alkyl defined above but having from one to four carbon atoms (C₁-C₄ alkyl).

"Alkenyl" refers to an unsaturated alkyl group having at least one double bond and from two to twelve carbon atoms (C₂-C₁₂ alkenyl), from two to eight carbon atoms (C₂-C₈ alkenyl) or from two to six carbon atoms (C2-C6 alkenyl), and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like. "Alkynyl" refers to an unsaturated alkyl group having at least one triple bond and from two to twelve carbon atoms (C₂-C₁₂ alkynyl), from two to ten carbon atoms (C₂-C₁₀ alkynyl) from two to eight carbon atoms (C2-C8 alkynyl) or from two to six carbon atoms (C₂-C₆ alkynyl), and which is attached to the rest of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

"Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon (alkyl) chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, respectively. Alkylenes can have from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single or double bond. The points of attachment of the alkylene chain to the rest of the molecule can be through one carbon or any two carbons within the chain.“Optionally substituted alkylene” refers to alkylene or substituted alkylene.

"Alkenylene" refers to divalent alkene. Examples of alkenylene include without limitation, ethenylene (-CH=CH-) and all stereoisomeric and conformational isomeric forms thereof. "Substituted alkenylene" refers to divalent substituted alkene. "Optionally substituted alkenylene" refers to alkenylene or substituted alkenylene.

"Alkynylene" refers to divalent alkyne. Examples of alkynylene include without limitation, ethynylene, propynylene. "Substituted alkynylene" refers to divalent substituted alkyne.

"Alkoxy" refers to a radical of the formula -ORa where Ra is an alkyl having the indicated number of carbon atoms as defined above. Examples of alkoxy groups include without limitation–O-methyl (methoxy), -O-ethyl (ethoxy), -O-propyl (propoxy), -O- isopropyl (iso propoxy) and the like.

"Acyl" refers to a radical of the formula–C(O)Ra where Ra is an alkyl having the indicated number of carbon atoms.

"Alkylaminyl" refers to a radical of the formula -NHRa or -NRaRa where each Ra is, independently, an alkyl radical having the indicated number of carbon atoms as defined above. "Cycloalkylaminyl" refers to a radical of the formula -NHRa where Ra is a cycloalkyl radical as defined herein.

"Alkylcarbonylaminyl" refers to a radical of the formula–NHC(O)Ra, where Ra is an alkyl radical having the indicated number of carbon atoms as defined herein.

"Cycloalkylcarbonylaminyl" refers to a radical of the formula -NHC(O)Ra, where R_a is a cycloalkyl radical as defined herein.

"Alkylaminocarbonyl" refers to a radical of the formula -C(O)NHRa

or -C(O)NR_aR_a, where each R_a is independently, an alkyl radical having the indicated number of carbon atoms as defined herein.

"Cyclolkylaminocarbonyl" refers to a radical of the formula -C(O)NHR_a, where R_a is a cycloalkyl radical as defined herein.

"Aryl" refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. Exemplary aryls are hydrocarbon ring system radical comprising hydrogen and 6 to 9 carbon atoms and at least one aromatic ring;

hydrocarbon ring system radical comprising hydrogen and 9 to 12 carbon atoms and at least one aromatic ring; hydrocarbon ring system radical comprising hydrogen and 12 to 15 carbon atoms and at least one aromatic ring; or hydrocarbon ring system radical comprising hydrogen and 15 to 18 carbon atoms and at least one aromatic ring. For purposes of the compounds of the present disclosure, the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.“Optionally substituted aryl” refers to an aryl group or a substituted aryl group.

"Arylene" denotes divalent aryl, and "substituted arylene" refers to divalent substituted aryl. "Aralkyl" or "araalkylene" may be used interchangeably and refer to a radical of the formula -R_b-R_c where R_b is an alkylene chain as defined herein and R_c is one or more aryl radicals as defined herein, for example, benzyl, diphenylmethyl and the like.

"Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, three to nine carbon atoms, three to eight carbon atoms, three to seven carbon atoms, three to six carbon atoms, three to five carbon atoms, a ring with four carbon atoms, or a ring with three carbon atoms. The cycloalkyl ring may be saturated or unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

"Cycloalkylalkylene" or "cycloalkylalkyl" may be used interchangeably and refer to a radical of the formula -RbRe where Rb is an alkylene chain as defined herein and Re is a cycloalkyl radical as defined herein. In certain embodiments, R_b is further substituted with a cycloalkyl group, such that the cycloalkylalkylene comprises two cycloalkyl moieties. Cyclopropylalkylene and cyclobutylalkylene are exemplary cycloalkylalkylene groups, comprising at least one cyclopropyl or at least one cyclobutyl group, respectively.

"Fused" refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the present disclosure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.

"Halo" or "halogen" refers to bromo (bromine), chloro (chlorine), fluoro (fluorine), or iodo (iodine).

"Haloalkyl" refers to an alkyl radical having the indicated number of carbon atoms, as defined herein, wherein one or more hydrogen atoms of the alkyl group are substituted with a halogen (halo radicals), as defined above. The halogen atoms can be the same or different. Exemplary haloalkyls are trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

"Heterocyclyl," "heterocycle," or "heterocyclic ring" refers to a stable 3- to 18- membered saturated or unsaturated radical which consists of two to twelve carbon atoms and from one to six heteroatoms, for example, one to five heteroatoms, one to four heteroatoms, one to three heteroatoms, or one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Exemplary heterocycles include without limitation stable 3-15 membered saturated or unsaturated radicals, stable 3-12 membered saturated or unsaturated radicals, stable 3-9 membered saturated or unsaturated radicals, stable 8-membered saturated or unsaturated radicals, stable 7-membered saturated or unsaturated radicals, stable 6-membered saturated or unsaturated radicals, or stable 5- membered saturated or unsaturated radicals.

Unless stated otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. Examples of non-aromatic heterocyclyl radicals include, but are not limited to, azetidinyl, dioxolanyl,

thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, thietanyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Heterocyclyls include heteroaryls as defined herein, and examples of aromatic heterocyclyls are listed in the definition of heteroaryls below.

"Heterocyclylalkyl" or "heterocyclylalkylene" refers to a radical of the

formula -R_bR_f where R_b is an alkylene chain as defined herein and R_f is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom.

"Heteroaryl" or "heteroarylene" refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of the compounds of the present disclosure, the heteroaryl radical may be a stable 5-12 membered ring, a stable 5-10 membered ring, a stable 5-9 membered ring, a stable 5-8 membered ring, a stable 5-7 membered ring, or a stable 6 membered ring that comprises at least 1 heteroatom, at least 2 heteroatoms, at least 3 heteroatoms, at least 4 heteroatoms, at least 5 heteroatoms or at least 6 heteroatoms. Heteroaryls may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen,2 carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. The heteroatom may be a member of an aromatic or non-aromatic ring, provided at least one ring in the heteroaryl is aromatic. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,

1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl

(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl,

1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). "Heteroarylalkyl" or "heteroarylalkylene" refers to a radical of the formula -RbRg where R_b is an alkylene chain as defined above and R_g is a heteroaryl radical as defined above.

"Thioalkyl" refers to a radical of the formula -SR_a where R_a is an alkyl radical as defined above containing one to twelve carbon atoms, at least 1-10 carbon atoms, at least 1-8 carbon atoms, at least 1-6 carbon atoms, or at least 1-4 carbon atoms.

"Heterocyclylaminyl" refers to a radical of the formula–NHRf where Rf is a heterocyclyl radical as defined above.

"Thione" refers to a =S group attached to a carbon atom of a saturated or unsaturated (C₃-C₈)cyclic or a (C₁-C₈)acyclic moiety.

"Sulfoxide" refers to a–S(O)- group in which the sulfur atom is covalently attached to two carbon atoms.

"Sulfone" refers to a–S(O)2- group in which a hexavalent sulfur is attached to each of the two oxygen atoms through double bonds and is further attached to two carbon atoms through single covalent bonds.

The term "oxime" refers to a–C(R_a)=N-OR_a radical where R_a is hydrogen, lower alkyl, an alkylene or arylene group as defined above.

The compounds provided in the present disclosure can exist in various isomeric forms, as well as in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. The term "isomer" is intended to encompass all isomeric forms of a compound of the present disclosure, including tautomeric forms of the compound.

Some compounds described herein can have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. A compound provided in the present disclosure can be in the form of an optical isomer or a diastereomer. Accordingly, the invention encompasses compounds provided in the present disclosure and their uses as described herein in the form of their optical isomers, diastereoisomers and mixtures thereof, including a racemic mixture. Optical isomers of the compounds provided in the present disclosure can be obtained by known techniques such as asymmetric synthesis, chiral chromatography, or via chemical separation of stereoisomers through the

employment of optically active resolving agents.

Unless otherwise indicated, "stereoisomer" means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. Thus, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical

stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.

If there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all

stereoisomers of it. In some cases, however, where more than one chiral center exists, the structures and names may be represented as single enantiomers to help describe the relative stereochemistry. Those skilled in the art of organic synthesis will know if the compounds are prepared as single enantiomers from the methods used to prepare them.

In this description, a "pharmaceutically acceptable salt" is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound of the present disclosure. Representative pharmaceutically acceptable salts include, e.g., alkali metal salts, alkali earth salts, ammonium salts, water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate,

hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. A pharmaceutically acceptable salt can have more than one charged atom in its structure. In this instance the

pharmaceutically acceptable salt can have multiple counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterions.

As used herein, the term "derivative" refers to a modification of a compound by chemical or biological means, with or without an enzyme, which modified compound is structurally similar to a parent compound and (actually or theoretically) derivable from that parent compound. Generally, a "derivative" differs from an "analog" in that a parent compound may be the starting material to generate a "derivative," whereas the parent compound may not necessarily be used as the starting material to generate an "analog." A derivative may have different chemical, biological or physical properties from the parent compound, such as being more hydrophilic or having altered reactivity as compared to the parent compound. Derivatization (i.e., modification) may involve substitution of one or more moieties within the molecule (e.g., a change in functional group). For example, a hydrogen may be substituted with a halogen, such as fluorine or chlorine, or a hydroxyl group (-OH) may be replaced with a carboxylic acid moiety (-COOH). Other exemplary derivatizations include glycosylation, alkylation, acylation, acetylation, ubiqutination, esterification, and amidation.

The term "derivative" also refers to all solvates, for example, hydrates or adducts (e.g., adducts with alcohols), active metabolites, and salts of a parent compound. The type of salt depends on the nature of the moieties within the compound. For example, acidic groups, such as carboxylic acid groups, can form alkali metal salts or alkaline earth metal salts (e.g., sodium salts, potassium salts, magnesium salts, calcium salts, and also salts with physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines such as, for example, triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine). Basic groups can form acid addition salts with, for example, inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids or sulfonic acids such as acetic acid, citric acid, lactic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Compounds that simultaneously contain a basic group and an acidic group, for example, a carboxyl group in addition to basic nitrogen atoms, can be present as zwitterions. Salts can be obtained by customary methods known to those skilled in the art, for example, by combining a compound with an inorganic or organic acid or base in a solvent or diluent, or from other salts by cation exchange or anion exchange.

The term "prodrug" refers to a precursor of a drug, a compound which upon administration to a patient, must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent. Exemplary prodrugs of compounds in accordance with, e.g., eIF4A inhibitor of Formula I, are esters, acetamides, and amides.

As used herein, the term "eIF4E," also referred to as "eukaryotic translation initiation factor-4E," refers to a translation initiation factor that, when part of an eIF4F pre- initiation complex also comprising eIF4A RNA helicase and eIF4G scaffold protein, binds to the 7-methyl-guanosine (m7GpppX) 5'-cap structure on eukaryotic mRNAs and directs ribosomes to the cap structure. The availability of eIF4E as part of the eIF4F complex is a limiting factor in controlling the rate of translation. Interactions of eIF4E and the m⁷G cap and eIF4G are tightly regulated by key mitogenic signals, such as the PI3K/mTOR and Ras/MAPK signal transduction pathways. There are four different isoforms of eIF4E: isoform 1 is the canonical sequence; isoform 2 contains an alternate in-frame exon in the 3'-coding region compared to isoform 1; isoform 3 uses an alternate 5'-terminal exon, which results in a different 5'-UTR and use of an alternate translation start codon compared to isoform 1; and isoform 4 differs in its 5'-UTR and contains an alternate exon in its 5'-coding region compared to isoform 1. In certain embodiments, eIF4E refers to eIF4E isoform 1, isoform 2, isoform 3, isoform 4, or any combination thereof. In certain embodiments, eIF4E refers to the canonical eIF4E isoform 1. In particular embodiments, eIF4E refers to human eIF4E.

As used herein, "eIF4A," also known as "eukaryotic initiation factor-4A," refers to a member of the "DEAD box" family of ATP-dependent helicases that are characterized by seven highly conserved amino acid motifs implicated in RNA remodeling. eIF4A acts as an RNA dependent ATPase and ATP-dependent RNA helicase to facilitate mRNA binding to the ribosome as part of the eIF4F (eukaryotic initiation factor 4F) complex that recognizes and initiates translation of most cellular mRNAs to synthesize specific proteins. A functional eIF4F complex consisting of eIF4A, eIF4E and eIF4G is involved in translation of mRNAs that contain highly structured 5'-UTRs or an IRES element. In particular, eIF4F recognizes the cap structure at the 5'-end of mRNA through eIF4E, unwinds the secondary structure of the 5'-UTR region through the helicase activity of eIF4A, and binds the 43S complex through interactions between eIF4G and eIF3. See,e.g., Marintchev et al., Cell, 136: 447-460, 2009, and Parsyan et al., Nat. Rev. Mol. Cell Biol. 12:235-245, 2012. eIF4A selectively regulates the translation of a subset of mRNAs. This selectivity is a result of structural elements and sequence recognition motifs found within the 5'-UTR of the mRNA. There are three eIF4A family members: eIF4AI, eIF4AII, and eIF4AIII. In particular embodiments, eIF4A refers to human eIF4A.

As used herein, the term "MNK," also known as "mitogen-activated protein kinase (MAPK)-interacting serine/threonine kinase" or "MKNK" refers to a kinase that is phosphorylated by the p42 MAP kinases ERK1 and ERK2 and the p38-MAP kinases, triggered in response to growth factors, phorbol esters, and oncogenes such as Ras and Mos, and by stress signaling molecules and cytokines. MNK also refers to a kinase that is phosphorylated by additional MAP kinase(s) affected by interleukin-1 receptor-associated kinase 2 (IRAK2) and IRAK4, which are protein kinases involved in signaling innate immune responses through toll-like receptors (e.g., TLR7) (see, e.g., Wan et al., J. Biol. Chem.284: 10367, 2009). Phosphorylation of MNK proteins stimulates their kinase activity toward eukaryotic initiation factor 4E (eIF4E), which in turn regulates

cap-dependent protein translation initiation, as well as regulate engagement of other effector elements, including hnRNPA1 and PSF (PTB (polypyrimidine tract binding protein) associated splicing factor). For example, proteins that bind the regulatory AU-rich elements (AREs) of the 3 -UTR of certain mRNAs (e.g., cytokines) are phosphorylated by MNK. Thus, MNK phosphorylation of proteins can alter the ability of these proteins to bind the 5- or 3 -UTRs of eukaryotic mRNAs. In particular, reduced MNK mediated phosphorylation of hnRNPA1 decreases its binding to cytokine-ARE (see, e.g., Buxadé et al., Immunity 23:177, 2005; Joshi and Platanias, Biomol. Concepts 3:127, 2012). MNK is encoded by two different genes, MNK1 and MNK2, which are both subject to alternative splicing. MNK1a and MNK2a represent full length transcripts, while MNK1b and MNK2b are splice variants that lack a MAPK binding domain. Therefore, MNK may refer to MNK1 or variants thereof (such as MNK1a or MNK1b), MNK2 or variants thereof (such as MNK2a or MNK2b), or combinations thereof. In particular embodiments, MNK refers to human MNK.

As used herein, the term "mTOR," also known as "mammalian target of

rapamycin," also known as "FK506-binding protein 12-rapamycin-associate protein 1" (FRAP1), refers to a serine/threonine kinase that is a member of the phosphatidylinositol 3-kinase-related kinase family that is encoded by the mTOR gene. mTOR functions as part of two structural and functionally distinct signaling complexes– mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is composed of mTOR, Raptor, GbL, and DEPTOR, and is inhibited by rapamycin. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis, including phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eIF4E). mTORC2 is composed of mTOR, Rictor, GbL, Sin1, PRR5/Protor-1, and DEPTOR. Reference to mTOR may refer to mTOR as a component of mTORC1, as a component of mTORC2, or both. In particular embodiments, mTOR refers to human mTOR.

As used herein, an "immune cell" means any cell of the immune system that originates from a hematopoietic stem cell (e.g., in the bone marrow), which gives rise to two major lineages, a myeloid progenitor cell (which give rise to myeloid cells such as myeloid-derived suppressor cells, monocytes, macrophages, dendritic cells,

meagakaryocytes and granulocytes) and a lymphoid progenitor cell (which give rise to lymphoid cells such as T cells, B cells and natural killer (NK) cells). Exemplary immune system cells include a CD4+ T cell, a CD8+ T cell, a CD4^‒ CD8^‒ double negative T cell, a gd T cell, a regulatory T cell, a mucosal associated invariant T (MAIT) cell, an antigen presenting cell (APC), a natural killer cell, and a dendritic cell. Macrophages, dendritic cells and disease cells (e.g., cancer cells) may be referred to as "antigen presenting cells" or "APCs," which are cells that can activate T cells when a MHC (HLA) receptor complexed with an antigenic peptide on the surface of the APC interacts with a TCR on the surface of a T cell. In certain embodiments, an APC is a cancer cell or tumor cell.

As used herein, the term "immune response" refers to the action of an immune cell, for example, lymphocytes, antigen presenting cells, phagocytic cells, granulocytes, and soluble macromolecules produced by the above cells or the liver (including antibodies, cytokines, and complement), that results in selective damage to, destruction of, or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancerous cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues. In certain embodiments, an immune response comprises an antigen-specific T cell response.

The phrase "inducing or enhancing an immune response" refers to causing or stimulating an immune cell (e.g., T cell) to have a sustained or amplified biological function. For example, induced or enhanced T cell responses include increased production of cytokines by CD8⁺ T cells, increased proliferation, or increased antigen responsiveness relative to the response before intervention. In certain embodiments, the level of enhanced immune cell (e.g., T cell) response after contact with an eIF4E inhibitor is as least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, as compared to immune cells not contacted with the eIF4E inhibitor. The assay for detecting cytokine levels (e.g., IL-2, IL-10, IFNg) to determine whether an immune response induced or enhanced is the multiplex assay described by Dossus et al. (J. Immunol. Methods 350:125, 2009). The assay for detecting T cell proliferation to determine whether an immune response induced or enhanced is the assay described by Liu et al. (Clin. Cancer Res.21:1639, 2015). The assay for determining increased antigen responsiveness is the assay described by Tumeh et al. (Nature 515:568, 2014).

The phrase "prolonging an immune response" refers to causing or stimulating an immune cell (e.g., T cell) to continue exhibiting a sustained or amplified biological function. In certain embodiments, a prolonged immune response is a measure of antigen specific cytotoxic T cells, of reduced tumor growth or size over time, or of reduced detectable disease after treatment is stopped. For example, tumor size may remain the same or shrink as compared to the tumor size at the start of treatment. In some

embodiments, a prolonged immune response can last at least as long as the treatment duration, or at least 1.5-fold, 2.0-fold, 2.5-fold, 3.0-fold, 3.5-fold, 4.0-fold, 4.5-fold, 5.0-fold or more than the treatment duration.

The phrase "reducing the down-modulation" of an immune cell or immune response refers to relieving or releasing an immune cell or immune system from suppression components or signals. For example, a reduced down-modulation may include increased production of cytokines (e.g., IFNg) by CD8⁺ T cells, an increase in the number of immune cells (e.g., T cells) in a tumor, an increase in the number of T cell clones in a tumor, an increase in the ratio of T_E cells to T_reg cells, or any combination thereof. In certain embodiments, the level of reduced down-modulation of an immune cell (e.g., T cell) or immune response is a reduction in detectable disease (e.g., tumor volume, infectious agents) of at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more. In other embodiments, the level of reduced down-modulation of an immune cell (e.g., T cell) or immune response is an increase in progression-free survival, which parameters will vary depending on the cancer being treated and which parameters are known to a person of ordinary skill in the art.

"Major histocompatibility complex molecules" (MHC molecules), which is used interchangeably and is understood to also refer to the human counterpart "human leukocyte antigen" (HLA molecules), refer to glycoproteins that deliver peptide antigens to a cell surface. MHC or HLA class I molecules are heterodimers consisting of a membrane spanning a chain (with three a domains) and a non-covalently associated b2 microglobulin. MHC or HLA class II molecules are composed of two transmembrane glycoproteins, a and b, both of which span the membrane. Each chain has two domains. MHC or HLA class I molecules deliver peptides originating in the cytosol to the cell surface, where a

peptide:MHC (or peptide:HLA in humans) complex is recognized by CD8⁺ T cells. A T cell peptide antigen (i.e., containing an epitope recognized by a T cell) complexed with an MHC class I molecule is referred to as an MHC class I epitope. MHC class I epitopes are recognized by T cell receptors (TCRs) and generally are found on peptide antigens having a length ranging from about 8 amino acids to about 11 amino acids. MHC class II molecules deliver peptides originating in the vesicular system to the cell surface, where they are recognized by CD4⁺ T cell receptors. A T cell peptide antigen presented by an MHC class II molecule is referred to as an MHC class II epitope. MHC class II epitopes generally are found on peptide antigens having a length ranging from about 13 to about 17 amino acids. An MHC molecule may be from various animal species, including human (HLA), mouse, rat, or other mammals.

"T cell receptor" (TCR) refers to a molecule found on the surface of T cells (or T lymphocytes) that, in association with CD3, is generally responsible for recognizing antigens bound to MHC (HLA) molecules. The TCR has a disulfide-linked heterodimer of the highly variable a and b chains (also known as TCRa and TCRb, respectively) in most T cells. In a subset of T cells, a TCR is made up of a heterodimer of variable g and d chains (also known as TCRg and TCRd, respectively). Each chain of the TCR is a member of the immunoglobulin superfamily and possesses one N-terminal immunoglobulin variable domain, one immunoglobulin constant domain, a transmembrane region, and a short cytoplasmic tail at the C-terminal end (see Janeway et al., Immunobiology: The Immune System in Health and Disease, 3^rd Ed., Current Biology Publications, p.4:33, 1997).

As used herein, the term "antigen-specific T cell response" refers to responses by a T cell having a TCR that specifically binds to a peptide antigen complexed with MHC (HLA) class I or class II. CD8⁺ effector T cells recognize HLA class I restricted antigenic peptides and are able to directly kill target cells expressing the cognate antigen. CD4⁺ helper T cells recognize HLA class II restricted antigenic peptides and produce a variety of cytokines that mediate inflammatory and effector immune responses. CD4⁺ helper T cells also facilitate the activation of CD8⁺ effector T cells and B cells. Regulatory T cells (T_reg) are CD4⁺ T cells that inhibit immune responses and produce inhibitory cytokines, such as TGFb, IL-10, IL-4, IL-1RA, and IL-35. Non-limiting examples of responses by a T cell upon antigen-specific stimulation include activation, proliferation and cytokine production (e.g., IL-2, IFNg production).

As used herein, the term "immunosuppression component" refers to one or more cells, proteins, molecules, compounds or complexes providing inhibitory signals to assist in controlling or suppressing an immune response. For example, immunosuppression components include those molecules that partially or totally block immune stimulation; decrease, prevent or delay immune activation; or increase, activate, or up regulate immune suppression. "Controlling or suppressing an immune response," as used herein, means reducing any one or more of antigen presentation, T cell activation, T cell proliferation, T cell effector function, cytokine secretion or production, and target cell lysis. Such modulation, control or suppression can promote or permit the persistence of a

hyperproliferative disease or disorder (e.g., cancer, chronic infections).

Exemplary immunosuppression components include immune checkpoint ligands (such as PD-L1, PD-L2, CD80, CD86, B7-H3, B7-H4, HVEM, adenosine, GAL9), immune checkpoint receptors (such as PD-1, CTLA-4, BTLA, KIR, LAG3, TIM3, A2aR), metabolic enzymes (such as arginase, indoleamine 2,3-dioxygenase (IDO)),

immunosuppressive cytokines (such as IL-10, IL-4, IL-1RA, IL-35), T_reg cells, or any combination thereof. In certain embodiments, an immunosuppression component is an immune checkpoint molecule, which may initiate an immune suppression signal through a ligand-receptor interaction, such as by modulating (e.g., inhibiting) an antigen-specific T cell response. For example, a T cell may express on its surface an immune checkpoint receptor (e.g., PD-1, LAG3) and an antigen presenting cell may express on its surface an immune checkpoint receptor ligand (e.g., PD-L1, MHC/HLA molecule). In further embodiments, an immunosuppression component is a metabolic enzyme (e.g., IDO) that inhibits immune responses through the local depletion of amino acids essential for lymphocyte, particularly T cell, survival and function. In still further embodiments, an immunosuppression component may be a signaling molecule, such as an

immunosuppressive cytokine (e.g., IL-10, IL-4, IL-1RA, IL-35). In still further embodiments, an immunosuppression component comprises a CD4⁺ T_reg cell that is capable of inhibiting an immune response, as well as producing or releasing immunosuppressive cytokines (e.g., IL-10, IL-4, IL-13, IL-1RA).

The term "immune resistance" refers to the process by which a cell or organism (e.g., a cancer cell, virus-infected cell, bacterial cell, fungus, parasite) resists, minimizes, evades, or avoids recognition or elimination by the immune system. Immune resistance may be due to (a) an increase in immune suppression or tolerance, (b) the ability of a cell or organism to modify activate, increase, enhance, facilitate, potentiate or up-regulate immune suppression or tolerance, or (c) the ability of a cell or organism to promote immunologic ignorance or masking of an antigen expressed by the cell or organism, or any combination thereof. In certain embodiments, immune resistance is associated with a disease or disorder, such as a cancer, a tumor or a chronic infection.

As used herein, "disease-associated immune resistance" means a disease or disorder that co-opts certain immune checkpoint pathways to suppress the immune system and, therefore, the disease or disorder presents with an immune resistance phenotype, particularly against T cells specific for, for example, tumor or infectious disease antigens. As used herein, "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, g-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a-carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.

A "conservative substitution" refers to amino acid substitutions that do not significantly affect or alter binding characteristics of a particular protein. Generally, conservative substitutions are ones in which a substituted amino acid residue is replaced with an amino acid residue having a similar side chain. Conservative substitutions include a substitution found in one of the following groups: Group 1: Alanine (Ala or A), Glycine (Gly or G), Serine (Ser or S), Threonine (Thr or T); Group 2: Aspartic acid (Asp or D), Glutamic acid (Glu or Z); Group 3: Asparagine (Asn or N), Glutamine (Gln or Q); Group 4: Arginine (Arg or R), Lysine (Lys or K), Histidine (His or H); Group 5: Isoleucine (Ile or I), Leucine (Leu or L), Methionine (Met or M), Valine (Val or V); and Group 6:

Phenylalanine (Phe or F), Tyrosine (Tyr or Y), Tryptophan (Trp or W). Additionally or alternatively, amino acids can be grouped into conservative substitution groups by similar function, chemical structure, or composition (e.g., acidic, basic, aliphatic, aromatic, or sulfur-containing). For example, an aliphatic grouping may include, for purposes of substitution, Gly, Ala, Val, Leu, and Ile. Other conservative substitutions groups include: sulfur-containing: Met and Cysteine (Cys or C); acidic: Asp, Glu, Asn, and Gln; small aliphatic, nonpolar or slightly polar residues: Ala, Ser, Thr, Pro, and Gly; polar, negatively charged residues and their amides: Asp, Asn, Glu, and Gln; polar, positively charged residues: His, Arg, and Lys; large aliphatic, nonpolar residues: Met, Leu, Ile, Val, and Cys; and large aromatic residues: Phe, Tyr, and Trp. Additional information can be found in Creighton (1984) Proteins, W.H. Freeman and Company.

As used herein, "protein" or "polypeptide" refers to a polymer of amino acid residues. Proteins apply to naturally occurring amino acid polymers, as well as to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid and non-naturally occurring amino acid polymers.

"Nucleic acid molecule" or "polynucleotide" refers to a polymeric compound including covalently linked nucleotides, which can be made up of natural subunits (e.g., purine or pyrimidine bases) or non-natural subunits (e.g., morpholine ring). Purine bases include adenine, guanine, hypoxanthine, and xanthine, and pyrimidine bases include uracil, thymine, and cytosine. Nucleic acid molecules include polyribonucleic acid (RNA), polydeoxyribonucleic acid (DNA), which includes cDNA, genomic DNA, and synthetic DNA, either of which may be single or double stranded. If single stranded, the nucleic acid molecule may be the coding strand or non-coding (anti-sense strand). A nucleic acid molecule encoding an amino acid sequence includes all nucleotide sequences that encode the same amino acid sequence. Some versions of the nucleotide sequences may also include intron(s) to the extent that the intron(s) would be removed through co- or post- transcriptional mechanisms. In other words, different nucleotide sequences may encode the same amino acid sequence as the result of the redundancy or degeneracy of the genetic code, or by splicing.

As used herein, the term "agent" refers to any molecule, either naturally occurring or synthetic, e.g., peptide, protein, oligopeptide (e.g., from about 5 to about 25 amino acids in length, preferably from about 10 to 20 or 12 to 18 amino acids in length, preferably 12, 15, or 18 amino acids in length), small organic molecule (e.g., an organic molecule having a molecular weight of less than about 2500 daltons, e.g., less than 2000, less than 1000, or less than 500 daltons), circular peptide, peptidomimetic, antibody, polysaccharide, lipid, fatty acid, inhibitory RNA (e.g., siRNA or shRNA), polynucleotide, oligonucleotide, aptamer, drug compound, or other compound.

The terms "modulate," "modulation" or the like refer to the ability of a compound to increase or decrease the function, activity or level of an immunosuppression component, such as immune checkpoint molecules or related cytokines (e.g., PD-1, PDL-1, LAG3, IL-10 or the like). "Modulation," in its various forms, is intended to encompass inhibition, antagonism, partial antagonism, activation, agonism or partial agonism of the activity associated with an immunosuppression component, such as immune checkpoint molecules or immunosuppressive cytokines. For example, a modulation that comprises a decrease or inhibition of activity may be indirectly caused by a reduction in expression of an immunosuppression component, such as an immune checkpoint molecule or

immunosuppressive cytokine. The ability of a compound to directly or indirectly modulate an immunosuppression component, such as an immune checkpoint molecule or

immunosuppressive cytokine, can be demonstrated in biochemical and cell-based assays.

The term "inhibit" or "inhibitor" refers to an alteration, interference, reduction, down regulation, blocking, suppression, abrogation or degradation, directly or indirectly, in the expression, amount or activity of a target gene, target protein, or signaling pathway relative to (1) a control, endogenous or reference target or pathway, or (2) the absence of a target or pathway, wherein the alteration, interference, reduction, down regulation, blocking, suppression, abrogation or degradation is statistically, biologically, or clinically significant. The term "inhibit" or "inhibitor" includes gene "knock out" and gene "knock down" methods, such as by chromosomal editing.

"Treatment," "treating" or "ameliorating" refers to medical management of a disease, disorder, or condition of a subject (i.e., patient), which may be therapeutic, prophylactic/preventative, or a combination treatment thereof. A treatment may improve or decrease the severity at least one symptom of a disease, delay worsening or progression of a disease, or delay or prevent onset of additional associated diseases. "Reducing the risk of developing a disease" refers to preventing or delaying onset of a disease or reoccurrence of one or more symptoms of the disease (e.g., cancer). In certain embodiments, the immune modulation provided by the eIF4E inhibitors of this disclosure aids or augments treatment regimens or aids or augments a host organism's immune system.

As used herein, the term "immune suppression component" or "immunosuppression component" refers to one or more cells, proteins, molecules, compounds or complexes providing inhibitory signals to assist in controlling or suppressing an immune response. For example, immunosuppression components include those molecules that partially or totally block immune stimulation; decrease, prevent or delay immune activation; or increase, activate, or up regulate immune suppression. Exemplary immunosuppression component targets include immune checkpoint ligands (such as PD-L1, PD-L2, CD80, CD86, B7-H3, B7-H4, HVEM, adenosine, GAL9, VISTA, CEACAM-1, PVRL2), immune checkpoint receptors (such as PD-1, CTLA-4, BTLA, KIR, LAG3, TIM3, A2aR,

CD244/2B4, CD160, TIGIT, LAIR-1, PVRIG/CD112R), metabolic enzymes (such as arginase, indoleamine 2,3-dioxygenase (IDO)), immunosuppressive cytokines (such as IL-10, IL-4, IL-1RA, IL-35), T_reg cells, or any combination thereof. In certain

embodiments, an immunosuppression component is an immune checkpoint molecule, which may initiate an immune suppression signal through a ligand-receptor interaction, such as by modulating (e.g., inhibiting) an antigen-specific T cell response. For example, a T cell may express on its surface an immune checkpoint receptor (e.g., PD-1, LAG3) and an antigen presenting cell may express on its surface an immune checkpoint receptor ligand (e.g., PD-L1, MHC/HLA molecule). In further embodiments, an immunosuppression component is a metabolic enzyme that inhibits immune responses through the local depletion of amino acids essential for lymphocyte, particularly T cell, survival and function. In still further embodiments, an immunosuppression component may be a signaling molecule, such as an immunosuppressive cytokine (e.g., IL-10, IL-4, IL-1RA, IL-35). In still further embodiments, an immunosuppression component comprises a CD4⁺ T_reg cell that is capable of inhibiting an immune response, as well as producing or releasing immunosuppressive cytokines (e.g., IL-10, IL-4, IL-13, IL-1RA).

With regard to an eIF4E inhibitor, "does not significantly reduce or inhibit T cell activation" means the reduction or inhibition of T cell activation is less than about 25%, 20%, 15%, 10%, 5%, 2%, 1%, 0.5%, 0.25%, 0.1% or less as compared to the same T cells not exposed or contacted with the eIF4E inhibitor. In certain embodiments, T cell activation is determined by measuring expression of CD69, an early activation marker.

Also with regard to a eIF4E-specific inhibitor, "does not significantly reduce or inhibit T cells viability," "does not significantly reduce or inhibit T cell proliferation," means that the reduction or inhibition of T cell viability is less than about 25%, 20%, 15%, 10%, 5%, 2%, 1%, 0.5%, 0.25%, 0.1% or less as compared to the same corresponding cells not exposed or contacted with the eIF4E inhibitor.

Also, with regard to an eIF4E inhibitor, "significantly reduce or inhibit expression of one or more immunosuppression components" means the reduction or inhibition of expression of one or more immunosuppression components in T cells, APCs (e.g., disease associted cell), or both is at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75% as compared to the same T cells, APCs, or both not exposed or contacted with the eIF4E inhibitor. In certain embodiments, an APC is a cancer cell or a tumor cell. Further, optionally, eIF4E inhibitors in any of the disclosed embodiments can also significantly reduce or inhibit expression of one or more immunosuppression components (e.g., immune checkpoint molecules, immunosuppressive cytokines) in T cells, APCs or both. In certain embodiments, an eIF4E inhibitor reduces or inhibits expression of PD-1, PD-L1, LAG3, TIM3, or any combination thereof in a T cell. In certain embodiments, an eIF4E inhibitor reduces or inhibits expression of PD-L1, IDO, or both in an antigen presenting cell or disease-associated cell.

A "patient" or "subject" includes an animal, such as a human, cow, horse, sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig. The animal can be a mammal, such as a non-primate and a primate (e.g., monkey and human). In one embodiment, a patient is a human, such as a human infant, child, adolescent or adult.

"Effective amount" or "therapeutically effective amount" refers to that amount of a composition described herein which, when administered to a mammal (e.g., human), is sufficient to aid in treating a disease. The amount of a composition that constitutes a "therapeutically effective amount" will vary depending on the cell preparations, the condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure. When referring to an individual active ingredient or composition, administered alone, a therapeutically effective dose refers to that ingredient or composition alone. When referring to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients, compositions or both that result in the therapeutic effect, whether administered serially, concurrently or simultaneously.

As used herein, "hyperproliferative disorder" or "hyperproliferative disease" refers to excessive growth or proliferation as compared to a normal cell or an undiseased cell. Exemplary hyperproliferative disorders include dysplasia, neoplasia, non-contact inhibited or oncogenically transformed cells, tumors, cancers, carcinoma, sarcoma, malignant cells, pre-malignant cells, as well as non-neoplastic or non-malignant hyperproliferative disorders (e.g., adenoma, fibroma, lipoma, leiomyoma, hemangioma, fibrosis, restenosis, or the like). In certain embodiments, a cancer being treated by the compositions and methods of this disclosure includes carcinoma (epithelial), sarcoma (connective tissue), lymphoma or leukemia (hematopoietic cells), germ cell tumor (pluripotent cells), blastoma (immature "precursor" cells or embryonic tissue), or any combination thereof. These various forms of hyperproliferative disease are known in the art and have established criteria for diagnosis and classification (e.g., Hanahan and Weinberg, Cell 144:646, 2011; Hanahan and

Weinberg Cell 100:57, 2000; Cavallo et al., Canc. Immunol. Immunother.60:319, 2011; Kyrigideis et al., J. Carcinog.9:3, 2010). A. Altering Immunomodulatory Activity

Innate immunity is the first line of defense against invading pathogens and is made up of resident immune effector cells, including macrophages, monocytes, eiosinophils, basophils, and natural killer cells (Medzhitov and Janeway, N. Engl. J. Med.343:338, 2000; Vivier et al., Science 331:44, 2011). However, adaptive immunity is what provides specificity to the immune response in higher eukaryotes. Antigens are presented to T cells through Major Histocompatability Complex (MHC) Class I (MHC-I) or Class II (MHC-II) molecules (Braciale et al., Immunol. Rev.98:95, 1987). MHC class II genes encode cell surface glycoproteins involved in the binding and presentation of peptides to CD4⁺ T cells. These genes encode the polymorphic HLA-DR, -DQ, and -DP molecules, which are expressed on the cell surface as a- and b-chain heterodimers. MHC class II molecules are central to the initiation of cellular and humoral immune responses. But, to ensure immune system remains in check once an antigen is cleared, regulatory T cells (Tregs, which are CD25⁺CD4⁺Foxp3⁺) are induced to actively engage in the maintenance of immunological self-tolerance and immune homeostasis. A tumor microenvironment can be unique in that increased expression of immune suppression molecules (e.g., PD-1, PD-L1, LAG3, TIM3, and IDO) may allow cells in that environment to escape immune surveillance. Moreover, recent evidence indicates that suppression of MHC class I and class II expression on multiple tumor types may also play a role in tumor immunoevasion (Garrido et al., Cancer Immunol. Immunother.59:13, 2010).

Certain eIF4E inhibitor compounds of this disclosure are potent and selective inhibitors of eIF4E (e.g., compounds of Formula I, II, III, IV, and V). The eukaryotic translation initiation factor 4F (eIF4F) complex, of which eIF4E is the capbinding subunit component, binds to the cap structure of mRNA and initiates translation. The activity of eIF4E is regulated in part by signaling pathways, such as PI3K/AKT/mTOR and

RAS/MAPK/MNK. Hyperactivation of these pathways results in increased eIF4E activity, and eIF4E is activated or overexpressed in a large number of tumors.

The present disclosure provides methods of reducing the level or activity of PD-1, PD-L1, LAG3, TIM3, IDO, any combination thereof, by the use of eIF4E inhibitors, which unexpectedly reduce or down-regulate the expression of various immunosuppression components, such as immune checkpoint proteins, including PD-1, PD-L1, LAG3, TIM3, and IDO. In further embodiments, a eIF4E inhibitor reduces the level of PD-1, PD-L1, LAG3, TIM3, or any combination thereof in a cell, and blocks or reduces the ability of eIF4E to initiate cap dependent protein translation. In still further embodiments, a eIF4E inhibitor reduces the level of PD-L1, IDO, or both in a cell, and blocks or reduces the ability of eIF4E to initiate cap dependent protein translation.

EIF4E inhibitors of this disclosure can be used in combination with other therapies, including for example, a vaccine, an inhibitor of an immunosuppression component, a radiation therapy, surgery, a chemotherapeutic agent, an immunotherapeutic agent targeting a disease antigen, or any combination thereof.

An eIF4E inhibitor can be administered to a subject in need of immune modulation (e.g., a subject having a cancer or an infection). Exemplary methods of immune modulation comprise increasing in the activity of an immune cell; reducing the down- modulation of an immune cell; inducing or enhancing an immune response; prolonging an immune response; stimulating an antigen-specific T cell response; inhibiting an

immunosuppressive signaling pathway; promoting endogenous immunity (e.g., pre-existing or de novo, such as anti-cancer); enhancing a vaccine-induced immune response; or inhibiting disease-associated immune resistance (e.g., cancer, infection), as described herein. eIF4E Inhibitors

An "eIF4E inhibitor" for use in the methods provided herein refers to an agent or compound that directly interacts with eIF4E and may block, inactivate, reduce or minimize eIF4E activity (e.g., initiation of cap-dependent translation or translational effects), or reduce activity by promoting degradation of eIF4E, by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more as compared to untreated eIF4E. An eIF4E inhibitor may be a compound, antisense molecule, ribozyme, RNAi molecule, or low molecular weight organic molecule (e.g., peptide).

In certain embodiments, an eIF4E inhibitor inhibits eIF4E activity by blocking eIF4E interaction with eIF4G, thus inhibiting formation of the eIF4F complex. Examples of eIF4E-eIF4G interaction inhibitors include thiazol hydrazones (Chen et al., Bioorganic Medicinal Chem. Lett.14:5401-5405, 2004, which compounds are incorporated herein by reference in their entirety); compound EGI-1 (U.S. Patent No.8,257,931, which compound is incorporated herein by reference in its entirety); eIF4G1 peptide fragments (e.g., eIF4G_569-580) (U.S. Patent No.7,141,541, which peptides are incorporated herein by reference in their entirety); eIF4G1 peptides that have been modified to stabilize the c-helix (PCT Publication No. WO 2011/136744, which peptides are incorporated herein by reference in their entirety); and cross-linked eIF4G1 peptides (PCT Publication No.

WO 2014/149001, which peptides are incorporated herein by reference in their entirety).

In some embodiments, an eIF4E inhibitor blocks binding of eIF4E to a mRNA cap. Examples of cap binding inhibitors are briciclib (Jasani et al., Cancer Res., 75(15

Suppl):Abstract No.1649, 2015) and Ribivirin (Kentsis et al., Proc. Nat'l. Acad. Sci.

U.S.A.101:18105-10, 2004).

Further examples of eIF4E inhibitors that block binding to the mRNA cap include compounds disclosed in U.S. Application No.16/916,820 (claiming priority to U.S.

Provisional Application No.62/869,662), which compounds and synthetic methods disclosed therein are incorporated herein by reference in their entirety.

In some embodiments, an eIF4E inhibitor includes compounds according to Formula I

or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:

X¹ is CR², -C-L¹-Y or N;

X², X⁵ and X⁶ are independently CR² or N,

wherein X⁵ and X⁶ together with 3 or 4 carbon or nitrogen atoms combine to form a 5- or 6-membered cycloalkyl or heterocyclyl, or when X² is CR², R¹ and R² together with the atoms they attached to form a 6-membered aryl or heteroaryl;

X³ is C, or X³ is C or N when X⁴ is a bond;

X⁴ is a bond, CR² or N,

wherein X⁴ and X⁵ together with 3 or 4 carbon or nitrogen atoms combine to form a 5- or 6-membered heteroaryl;

Q is H or–L¹-Y;

L¹ is–(CH2)–,–(CH2)2–,–(CH2)3–,–CH((C1-C8)alkyl)(CH2)–,–CH((C1- C8)alkyl)(CH2)2–,–(CH2)2-O–,–CH2CH=CH–,–CH2CºC– or–CH2(cyclopropyl)–;

Y is

Ring B is a six-membered aryl, heteroaryl or heterocyclyl;

R¹ is H, OH, halo, CN, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C6)cycloalkyl or NR⁵R⁵; R² is independently H, halo, CN, NO, NO₂, CºH, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, CH₂SR⁵, OR⁵, NHR⁵, NR⁵R⁵, [(C₁-C₈)alkylene]heterocyclyl, [(C₁-C₈)alkylene]heteroaryl, [(C1-C8)alkylene]NHR⁵, [(C1-C8)alkylene]NR⁵R⁵, [(C1-C8)alkylyne]NR⁵R⁵, C(O)R⁵, C(O)OR⁵, C(O)NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO2R⁵, SO2NHR⁵, SO2NR⁵R⁵,

NH(CO)R⁶, NR⁵(CO)R⁶, aryl, heteroaryl, cycloalkyl or heterocyclyl;

R³ is independently OH, halo, CN, NO2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)alkoxy, CºH, NHR⁷, NR⁷R⁷, CO2H, CO2R⁷, [(C1-C3)alkylene] (C1-C3)alkoxy, [(C1- C₃)alkylene]CO₂H, (C₃-C₅)cycloalkyl, =O. =S, SR⁷, SO₂R⁷, NH(CO)R⁷ or NR⁷(CO)R⁷; R⁴ is H, OH, halo, CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, SR⁷ or Z, wherein Z is

Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl;

L² is -C(R⁶)(R⁶)-, -C(R⁶)(R⁶)C(R⁶)(R⁶)-, -C(R⁶)=C(R⁶)-, -N(R⁵)C(R⁶)(R⁶)-, -OC(R⁶)(R⁶)-, -C(=O)-, -C(=O)N(R⁵)C(R⁶)(R⁶)- or a bond;

R⁵ is independently H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C5)cycloalkyl, CO2H, [(C1-C3)alkylene]heteroaryl, [(C1-C3)alkylene]aryl, [(C1-C3)alkylene]CO2H, heterocyclyl, aryl or heteroaryl,

or wherein two R⁵ substituents together with a nitrogen atom form a 4-, 5-, 6- or 7- membered heterocyclyl;

R⁶ is independently H, OH, halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁- C₃)alkoxy, NHR⁷, NR⁷R⁷, CO₂H, [(C₁-C₃)alkylene]CO₂H, (C₃-C₅)cycloalkyl, SR⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁷ is independently H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

R⁸ is H, OH, CO2H, CO2R⁷, CF2C(R⁶)2OH, C(R⁶)2OH, C(CF3)2OH, SO2H, SO3H, CF2SO2C(R⁶)3, CF2SO2N(H)R⁵, SO2N(H)R⁵, SO2N(H)C(O)R⁶, C(O)N(H)SO2R⁵,

C(O)haloalkyl, C(O)N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, C(O)NR⁵C(O)N(R⁵)₂, P(O)(OR⁵)OH, P(O)(O)N(H)R⁵, P(O)(C(R⁶)3)C(R⁶)3, B(OH)2, heterocyclyl or heteroaryl; n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2 or 3 groups selected from OH, CN, SH, SCH3, SO2CH3, SO2NH2, SO2NH(C1-C4)alkyl, halogen, NH2, NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, NH(aryl), C(O)NH2, C(O)NH(alkyl), CH2C(O)NH(alkyl), COOH, COOMe, acetyl, (C1-C8)alkyl, (C1- C₈)haloalkyl, O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH2, alkylene-C(O)-NH(Me), NHC(O)alkyl, CH2-C(O)-(C1-C8)alkyl, C(O)-(C1-C8)alkyl and alkylcarbonylaminyl, or a cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with OH, halogen, (C₁-C₈)alkyl, (C₁- C₈)haloalkyl, O(C₁-C₈)alkyl or O(C₁-C₈)haloalkyl,

wherein when X⁴ is a bond ring A forms a 5-membered heteroaryl wherein X¹, X⁵ and X⁶ can in addition to the above defined substituents be NR², and X¹ can in addition be -N-L¹-Y; and

wherein either Q is–L¹-Y, or X¹ is -C-L¹-Y or -N-L¹-Y.

In certain embodiments, the eIF4E inhibitor includes compounds according to Formula II

X² and X⁵ are independently CR² or N,

or when X² is CR², R¹ and R² together with the atoms they attached to form a 6-membered aryl or heteroaryl;

L¹ is–(CH₂)–,–(CH₂)₂–,–(CH₂)₃–,–CH((C₁-C₈)alkyl)(CH₂)–,–CH((C₁- C8)alkyl)(CH2)2–,–(CH2)2-O–,–CH2CH=CH–,–CH2CºC– or–CH2(cyclopropyl)–;

L² is -C(R⁶)(R⁶)-, -C(R⁶)(R⁶)C(R⁶)(R⁶)-, -C(R⁶)=C(R⁶)-, -N(R⁵)C(R⁶)(R⁶)-, -OC(R⁶)(R⁶)-, -C(=O)-, -C(=O)N(R⁵)C(R⁶)(R⁶)- or a bond; Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl;

R¹ is H, OH, halo, CN, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C6)cycloalkyl or NR⁵R⁵; R² is independently H, halo, CN, NO, NO₂, CºH, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, CH2SR⁵, OR⁵, NHR⁵, NR⁵R⁵, [(C1-C8)alkylene]heterocyclyl, [(C1-C8)alkylene]heteroaryl, [(C1-C8)alkylene]NHR⁵, [(C1-C8)alkylene]NR⁵R⁵, [(C1-C8)alkylyne]NR⁵R⁵, C(O)R⁵, C(O)OR⁵, C(O)NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO₂R⁵, SO₂NHR⁵, SO₂NR⁵R⁵,

NH(CO)R⁶, NR⁵(CO)R⁶, aryl, heteroaryl, cycloalkyl or heterocyclyl;

R³ is independently OH, halo, CN, NO2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)alkoxy, CºH, NHR⁷, NR⁷R⁷, CO2H, CO2R⁷, [(C1-C3)alkylene] (C1-C3)alkoxy, [(C1- C₃)alkylene]CO₂H, (C₃-C₅)cycloalkyl, =O. =S, SR⁷, SO₂R⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

or wherein two R⁵ substituents together with a nitrogen atom form a 4-, 5-, 6-, or 7- membered heterocyclyl;

R⁷ is independently H, (C1-C8)alkyl, (C1-C8)haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

C(O)haloalkyl, C(O)N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, C(O)NR⁵C(O)N(R⁵)₂, P(O)(OR⁵)OH, P(O)(O)N(H)R⁵, P(O)(C(R⁶)3)C(R⁶)3, B(OH)2, heterocyclyl or heteroaryl; m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3; wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2 or 3 groups selected from OH, CN, SH, SCH3, SO2CH3, SO₂NH₂, SO₂NH(C₁-C₄)alkyl, halogen, NH₂, NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, NH(aryl), C(O)NH2, C(O)NH(alkyl), CH2C(O)NH(alkyl), COOH, COOMe, acetyl, (C1-C8)alkyl, (C1- C8)haloalkyl, O(C1-C8)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH₂, alkylene-C(O)-NH(Me), NHC(O)alkyl, CH₂-C(O)-(C₁-C₈)alkyl, C(O)-(C₁-C₈)alkyl and alkylcarbonylaminyl, or a cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with OH, halogen, (C1-C8)alkyl, (C1- C8)haloalkyl, O(C1-C8)alkyl or O(C1-C8)haloalkyl. In certain embodiments, the eIF4E inhibitor includes compounds according to Formula III

Ring C is a heteroaryl;

R¹ is H, OH, halo, CN, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C6)cycloalkyl or NR⁵R⁵; R² is independently H, halo, CN, NO, NO2, CºH, (C1-C8)alkyl, (C1-C8)haloalkyl, CH2SR⁵, OR⁵, NHR⁵, NR⁵R⁵, [(C1-C8)alkylene]heterocyclyl, [(C1-C8)alkylene]heteroaryl, [(C₁-C₈)alkylene]NHR⁵, [(C₁-C₈)alkylene]NR⁵R⁵, [(C₁-C₈)alkylyne]NR⁵R⁵, C(O)R⁵, C(O)OR⁵, C(O)NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO2R⁵, SO2NHR⁵, SO2NR⁵R⁵,

NH(CO)R⁶, NR⁵(CO)R⁶, aryl, heteroaryl, cycloalkyl or heterocyclyl;

R³ is independently OH, halo, CN, NO₂, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁- C₆)alkoxy, CºH, NHR⁷, NR⁷R⁷, CO₂H, CO₂R⁷, [(C₁-C₃)alkylene] (C₁-C₃)alkoxy, [(C₁- C3)alkylene]CO2H, (C3-C5)cycloalkyl, =O. =S, SR⁷, SO2R⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁵ is independently H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C5)cycloalkyl or heterocyclyl;

R⁶ is independently H, OH, halo, CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1- C3)alkoxy, NHR⁷, NR⁷R⁷, CO2H, [(C1-C3)alkylene]CO2H, (C3-C5)cycloalkyl, SR⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁸ is H, OH, CO₂H, CO₂R⁷, CF₂C(R⁶)₂OH, C(R⁶)₂OH, C(CF₃)₂OH, SO₂H, SO₃H, CF₂SO₂C(R⁶)₃, CF₂SO₂N(H)R⁵, SO₂N(H)R⁵, SO₂N(H)C(O)R⁶, C(O)N(H)SO₂R⁵,

C(O)haloalkyl, C(O)N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, C(O)NR⁵C(O)N(R⁵)2, P(O)(OR⁵)OH, P(O)(O)N(H)R⁵, P(O)(C(R⁶)3)C(R⁶)3, B(OH)2, heterocyclyl or heteroaryl;

R⁹ is H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl or heterocyclyl;

m is 0, 1, or 2;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2 or 3 groups selected from OH, CN, SH, SCH3, SO2CH3, SO₂NH₂, SO₂NH(C₁-C₄)alkyl, halogen, NH₂, NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, NH(aryl), C(O)NH₂, C(O)NH(alkyl), CH₂C(O)NH(alkyl), COOH, COOMe, acetyl, (C₁-C₈)alkyl, (C₁- C8)haloalkyl, O(C1-C8)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH2, alkylene-C(O)-NH(Me), NHC(O)alkyl, CH₂-C(O)-(C₁-C₈)alkyl, C(O)-(C₁-C₈)alkyl and alkylcarbonylaminyl. In certain embodiments, the eIF4E inhibitor includes compounds according to Formula IV

X² and X⁵ are independently CR² or N,

X³ is C, or X³ is C or N when X⁴ is a bond;

X⁴ is a bond, CR² or N,

L¹ is–(CH2)–,–(CH2)2–,–(CH2)3–,–CH((C1-C8)alkyl)(CH2)–,–CH((C1- C₈)alkyl)(CH₂)₂–,–(CH₂)₂-O–,–CH₂CH=CH–,–CH₂CºC– or–CH₂(cyclopropyl)–;

L² is -C(R⁶)(R⁶)-, -C(R⁶)(R⁶)C(R⁶)(R⁶)-, -C(R⁶)=C(R⁶)-, -N(R⁵)C(R⁶)(R⁶)-, -OC(R⁶)(R⁶)-, -C(=O)-, -C(=O)N(R⁵)C(R⁶)(R⁶)-;

Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl;

NH(CO)R⁶, NR⁵(CO)R⁶, aryl, heteroaryl, cycloalkyl or heterocyclyl;

R⁵ is independently H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C5)cycloalkyl, CO2H, [(C₁-C₃)alkylene]heteroaryl, [(C₁-C₃)alkylene]aryl, [(C₁-C₃)alkylene]CO₂H, heterocyclyl, aryl or heteroaryl,

R⁸ is H, OH, CO2H, CO2R⁷, CF2C(R⁶)2OH, C(R⁶)2OH, C(CF3)2OH, SO2H, SO3H, CF₂SO₂C(R⁶)₃, CF₂SO₂N(H)R⁵, SO₂N(H)R⁵, SO₂N(H)C(O)R⁶, C(O)N(H)SO₂R⁵,

C(O)haloalkyl, C(O)N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, C(O)NR⁵C(O)N(R⁵)2, P(O)(OR⁵)OH, P(O)(O)N(H)R⁵, P(O)(C(R⁶)3)C(R⁶)3, B(OH)2, heterocyclyl or heteroaryl; n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2 or 3 groups selected from OH, CN, SH, SCH₃, SO₂CH_3, SO₂NH₂, SO₂NH(C₁-C₄)alkyl, halogen, NH₂, NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, NH(aryl), C(O)NH2, C(O)NH(alkyl), CH2C(O)NH(alkyl), COOH, COOMe, acetyl, (C1-C8)alkyl, (C1- C8)haloalkyl, O(C1-C8)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH2, alkylene-C(O)-NH(Me), NHC(O)alkyl, CH₂-C(O)-(C₁-C₈)alkyl, C(O)-(C₁-C₈)alkyl and alkylcarbonylaminyl, or a cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with OH, halogen, (C1-C8)alkyl, (C1- C8)haloalkyl, O(C1-C8)alkyl or O(C1-C8)haloalkyl,

wherein when X⁴ is a bond, ring A forms a 5-membered heteroaryl wherein X¹and X⁵ can in addition to C be N. In certain embodiments, the eIF4E inhibitor includes compounds according to Formula V

Q is–L¹-Y;

L¹ is–(CH₂)–,–(CH₂)₂–,–(CH₂)₃–,–CH((C₁-C₈)alkyl)(CH₂)–,–CH((C₁- C₈)alkyl)(CH₂)₂–,–(CH₂)₂-O–,–CH₂CH=CH–,–CH₂CºC– or–CH₂(cyclopropyl)–;

Y is

Ring B is a six-membered aryl, heteroaryl or heterocyclyl;

R¹ is H, OH, halo, CN, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₆)cycloalkyl or NR⁵R⁵; R² is independently H, halo, CN, NO, NO2, CºH, (C1-C8)alkyl, (C1-C8)haloalkyl, CH2SR⁵, OR⁵, NHR⁵, NR⁵R⁵, [(C1-C8)alkylene]heterocyclyl, [(C1-C8)alkylene]heteroaryl, [(C₁-C₈)alkylene]NHR⁵, [(C₁-C₈)alkylene]NR⁵R⁵, [(C₁-C₈)alkylyne]NR⁵R⁵, C(O)R⁵, C(O)OR⁵, C(O)NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO2R⁵, SO2NHR⁵, SO2NR⁵R⁵,

NH(CO)R⁶, NR⁵(CO)R⁶, aryl, heteroaryl, cycloalkyl or heterocyclyl;

R⁴ is H, OH, halo, CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, SR⁷ or Z, wherein Z is

Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl;

R⁵ is independently H, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₃-C₅)cycloalkyl, CO₂H, [(C₁-C₃)alkylene]heteroaryl, [(C₁-C₃)alkylene]aryl, [(C₁-C₃)alkylene]CO₂H, heterocyclyl, aryl or heteroaryl,

or wherein two R⁵ substituents together with a nitrogen atom form a 4-, 5-, or 6- membered heterocyclyl;

R⁷ is independently H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R⁸ is H, OH, CO2H, CO2R⁷, CF2C(R⁶)2OH, C(R⁶)2OH, C(CF3)2OH, SO2H, SO3H, CF2SO2C(R⁶)3, CF2SO2N(H)R⁵, SO2N(H)R⁵, SO2N(H)C(O)R⁶, C(O)N(H)SO2R⁵,

C(O)haloalkyl, C(O)N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, P(O)(OR⁵)OH,

P(O)(O)N(H)R⁵, P(O)(C(R⁶)3)C(R⁶)3, B(OH)2, heterocyclyl or heteroaryl;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

q is 0, 1, 2, 3 or 4;

wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2 or 3 groups selected from OH, CN, SH, SCH3, SO2CH3, SO₂NH₂, SO₂NH(C₁-C₄)alkyl, halogen, NH₂, NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, NH(aryl), C(O)NH2, C(O)NH(alkyl), CH2C(O)NH(alkyl), COOH, COOMe, acetyl, (C1-C8)alkyl, (C1- C8)haloalkyl, O(C1-C8)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH₂, alkylene-C(O)-NH(Me), NHC(O)alkyl, CH2-C(O)-(C1-C8)alkyl, C(O)-(C1-C8)alkyl and alkylcarbonylaminyl, or a cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with OH, halogen, (C1-C8)alkyl, (C1- C₈)haloalkyl, O(C₁-C₈)alkyl or O(C₁-C₈)haloalkyl. In certain embodiments, the eIF4E inhibitor includes compounds according to Formula VI

Q is–L¹-Y;

Y is

, wherein

Ring B is a six-membered aryl, heteroaryl or heterocyclyl;

NH(CO)R⁶, NR⁵(CO)R⁶, aryl, heteroaryl, cycloalkyl or heterocyclyl;

Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl;

R⁵ is independently H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C5)cycloalkyl, CO2H, [(C1-C3)alkylene]heteroaryl, [(C1-C3)alkylene]aryl, [(C1-C3)alkylene]CO2H, heterocyclyl, aryl or heteroaryl, or wherein two R⁵ substituents together with a nitrogen atom form a 4-, 5-, or 6- membered heterocyclyl;

R⁶ is independently H, OH, halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁- C3)alkoxy, NHR⁷, NR⁷R⁷, CO2H, [(C1-C3)alkylene]CO2H, (C3-C5)cycloalkyl, SR⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

p is 0, 1, 2 or 3;

q is 0, 1, 2, 3 or 4;

wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2 or 3 groups selected from OH, CN, SH, SCH₃, SO₂CH_3, SO₂NH₂, SO₂NH(C₁-C₄)alkyl, halogen, NH₂, NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, NH(aryl), C(O)NH2, C(O)NH(alkyl), CH2C(O)NH(alkyl), COOH, COOMe, acetyl, (C1-C8)alkyl, (C1- C8)haloalkyl, O(C1-C8)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH₂, alkylene-C(O)-NH(Me), NHC(O)alkyl, CH2-C(O)-(C1-C8)alkyl, C(O)-(C1-C8)alkyl and alkylcarbonylaminyl, or a cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with OH, halogen, (C1-C8)alkyl, (C1- C₈)haloalkyl, O(C₁-C₈)alkyl or O(C₁-C₈)haloalkyl.

In one embodiment X² of Formulae I, II, and IV is N.

In one embodiment X³ of Formulae I and IV is C.

In one embodiment X⁴ of Formulae I and IV is CR² or N.

In one embodiment X⁵ of Formulae I and IV is CR². In one embodiment L¹ of Formulae I, II, III, IV, V and VI is–(CH2)2-O–, –CH2CH=CH– or–CH2CºC–. In another embodiment L¹ is–(CH2)2-O–.

In one embodiment L² of Formulae I, II, III, IV, V and VI is a bond.

In one embodiment Ring B of Formulae I, V and VI is aryl.

In one embodiment Ring C of Formulae I, II, III, IV, V and VI is heteroaryl.

In one embodiment Ring C of Formulae I, II, III, IV, V and VI is

.

In one embodiment Ring C of Formula III is

.

In one embodiment R¹ of Formulae I, II, III, IV, V and VI is H, (C₁-C₈)alkyl or (C₁- C8)haloalkyl.

In one embodiment R¹ of Formula IV is NHR⁵ or N[(C1-C3)alkyl](R⁵).

In one embodiment R² of Formulae I, II, III, IV, V and VI is halo, CN, (C₁- C₈)alkyl, (C₁-C₈)haloalkyl or OR⁵. In another embodiment R² is halo, CN or (C₁- C8)haloalkyl.

In one embodiment R³ of Formulae I, II, III, IV, V and VI is halo, CN, (C1-C3)alkyl or (C₁-C₃)haloalkyl.

In one embodiment R⁴ of Formulae I, V and VI is Z, wherein Z is

In one embodiment R⁵ of Formulae I, II, III, V and VI is H, (C₁-C₃)alkyl or (C₁- C₃)haloalkyl. In another embodiment R⁵ of Formula IV is aryl.

In one embodiment R⁶ of Formulae I, II, III, IV, V and VI is H, OH, halo, CN, (C1- C3)alkyl, (C1-C3)haloalkyl or (C1-C3)alkoxy.

In one embodiment R⁷ of Formulae I, II, III, IV, V and VI is H, (C₁-C₈)alkyl or (C₁- C8)haloalkyl.

In one embodiment R⁸ of Formulae I, II, III, IV, V and VI is CO2H or

C(O)N(H)SO₂R⁵.

In one embodiment R⁹ of Formula III is (C1-C8)alkyl or (C1-C8)haloalkyl.

In one embodiment R⁹ of Formula III is cycloalkyl or heterocyclyl.

In one embodiment“m” of Formulae I and II = 2 or 3. In another embodiment“n” of Formulae I, II, IV, V and VI = 1 or 2. In yet another embodiment“p” of Formulae I, II, III, IV, V and VI = 0 or 1.

In one embodiment the optional substituents of alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl are OH, CN, halogen, (C₁-C₈)alkyl, O(C₁-C₈)alkyl, haloalkyl, alkylene- C(O)NH2 or alkylene-C(O)-NH(Me).

In one embodiment the optional substituents of alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl are cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with OH, halogen, (C1-C8)alkyl, (C1-C8)haloalkyl, O(C1-C8)alkyl or O(C1-C8)haloalkyl. In certain embodiments, an eIF4E inhibitor is compound X according to:

. In certain embodiments, an eIF4E inhibitor is compound Y according to:

.

In yet further embodiments, an eIF4E inhibitor is selected from

7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)- yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-6-(4,4-difluorocyclohexyl)-2-methyl-4-oxopyrido[3,4- d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-6-((dimethylamino)methyl)-2-methyl-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3-2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)- yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid,

5'-chloro-2'-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)-[1,1'-biphenyl]-3-carboxylic acid, 7-(5-chloro-2-(2-(2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3- carboxylic acid, 7-(5-chloro-2-(2-(5-cyano-6-(difluoromethoxy)-7-((dimethylamino)methyl)-2-methyl-4- oxoquinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid, 7-(5-chloro-2-(2-(5-cyano-6-(5-fluoro-2-methylpyridin-3-yl)-2-methyl-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-2-methyl-6-((4-methylpiperazin-1-yl)methyl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-Chloro-2-(2-(5-cyano-6-((dimethylamino)methyl)-2-methyl-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-6-(2-(dimethylamino)ethyl)-2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-Chloro-2-(2-(5-cyano-6-(2-(dimethylamino)ethyl)-2-methyl-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(2-(2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)pyrido[3,2-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2- b]pyridine-3-carboxylic acid,

3-(2-(4-chloro-2-(thieno[3,2-b]pyridin-7-yl)phenoxy)ethyl)-2-methyl-6-(4- methylpiperazin-1-yl)-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile, 7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxopyrido[3,4- d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(1-methylcyclopropyl)-4-oxopyrido[3,4- d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid, 7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

3-(2-(4-chloro-2-(5-methylthieno[3,2-b]pyridin-7-yl)phenoxy)ethyl)-2-methyl-6-(4- methylpiperazin-1-yl)-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile, 7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-6-(1-(trifluoromethyl)cyclopropyl)pyrido[3,4- d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid 7-(5-chloro-2-(3-(5-cyano-2-methyl-4-oxo-6-(4-(2,2,2-trifluoroethyl)piperazin-1- yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-6-(4,4-difluorocyclohex-1-en-1-yl)-2-methyl-4-oxopyrido[3,4- d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-6-(3-(2,2-difluoroethoxy)azetidin-1-yl)-2-methyl-4- oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-6-ethyl-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)ethoxy)phenyl)-5-ethylthieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-Chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-ethylthieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-Chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-2-methylthieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((trans-4-(3,3-difluoroazetidin-1- yl)cyclohexyl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn- 1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-2-methyl-6-(methyl(1-(2,2,3,3-tetrafluoropropyl)piperidin-4- yl)amino)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid, 7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluoroethyl)piperidin-4-yl)(methyl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluoro-3-hydroxy-3-methylbutyl)piperidin-4- yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1- yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((1-((1r,3r)-3-(difluoromethoxy)cyclobutyl)piperidin-4- yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1- yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-(2-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-(2-(2,2-difluoropropyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-Chloro-2-(2-(5-cyano-6-(2-(dimethylamino)ethyl)-2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy)phenyl)-5-methyl-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide, 7-(5-chloro-2-(2-(5-cyano-6-((1-(2,2-difluoropropyl)piperidin-4-yl)(methyl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-2-methyl-6-(methyl(1-(2,2,2-trifluoroethyl)piperidin-4- yl)amino)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluoropropyl)piperidin-4-yl)(methyl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((1-(2-fluoro-2-methylpropyl)piperidin-4-yl)(methyl)amino)- 2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid, 7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluoropropyl)piperidin-4-yl)(methyl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)-N-(pyridin-4- ylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide,

7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluoropropyl)piperidin-4-yl)(methyl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)-N-(pyridin-3- ylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide,

7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxopyrido[3,4- d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid 7-(5-chloro-2-(2-(5-cyano-2,8-dimethyl-4-oxo-6-(2-(trifluoromethyl)phenyl)pyrido[3,4- d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-6-(3-hydroxypyrrolidin-1-yl)-2,8-dimethyl-4-oxopyrido[3,4- d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid 7-(5-Chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-7-(methylsulfonyl)-4- oxoquinazolin-3(4H)-yl)ethoxy)phenyl)-2,5-dimethylthieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-N-(methylsulfonyl)thieno[3,2- b]pyridine-3-carboxamide,

7-(5-chloro-2-(2-(5-cyano-6-((1s,3s)-3-methoxycyclobutyl)-2-methyl-4-oxopyrido[3,4- d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylic acid, 7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-6-(2,2,2-trifluoroethoxy)-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

5'-Chloro-2'-(3-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)prop-1-yn-1-yl)-[1,1'-biphenyl]-3-carboxylic acid, 7-(5-chloro-2-(2-(2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)pyrido[3,2-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-N- (methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide, 7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)-6-(4-(3,3,3- trifluoropropyl)piperazin-1-yl)quinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(methyl(1-(2,2,2-trifluoroethyl)piperidin-4- yl)amino)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-N- (methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide,

7-(5-chloro-2-(2-(5-cyano-6-(6-cyclopropyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-methyl-4- oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-Chloro-2-(2-(5-cyano-6-(4-cyclopropylpiperazin-1-yl)-2-methyl-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-2-methyl-4-oxo-6-(4-(3,3,3-trifluoropropyl)piperazin-1- yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-2-methyl-4-oxo-6-(4-(2-(trifluoromethoxy)ethyl)piperazin-1- yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-(4-cyclopropylpiperazin-1-yl)-2-methyl-4-oxopyrido[3,4- d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid, 7-(5-chloro-2-(3-(5-cyano-6-(4-(3,3-difluorocyclobutyl)piperazin-1-yl)-2-methyl-4- oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-Chloro-2-(2-(5-cyano-6-(4-(2,3-difluoro-2-methylpropyl)piperazin-1-yl)-2-methyl-4- oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(methyl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid, 7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluorocyclobutyl)piperidin-4-yl)(methyl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-(4-((1-fluorocyclopropyl)methyl)piperazin-1-yl)-2-methyl-4- oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-Chloro-2-(2-(5-cyano-6-((1-(2,2-difluorobutyl)piperidin-4-yl)(methyl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((1-((1-fluorocyclopropyl)methyl)piperidin-4- yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1- yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-2-methyl-6-(methyl(1-(2-(trifluoromethoxy)ethyl)piperidin-4- yl)amino)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-Chloro-2-(3-(5-cyano-6-((1-cyclopropylpiperidin-4-yl)(methyl)amino)-2-methyl-4- oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((1-(3-(difluoromethoxy)cyclobutyl)piperidin-4- yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1- yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-2-methyl-6-(methyl(1-((1s,3s)-3- (trifluoromethoxy)cyclobutyl)piperidin-4-yl)amino)-4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((1-((1-fluorocyclobutyl)methyl)piperidin-4- yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1- yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-Chloro-2-(3-(5-cyano-2-methyl-6-(methyl(1-((1R,2R)-2- (trifluoromethyl)cyclopropyl)piperidin-4-yl)amino)-4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid, 7-(5-Chloro-2-(3-(5-cyano-6-(ethyl(1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)-2-methyl- 4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-Chloro-2-(3-(5-cyano-6-((1-(2,2-difluoropropyl)piperidin-4-yl)(ethyl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-(6-cyclopropyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-methyl-4- oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine- 3-carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-6-(4-cyclopropylpiperazin-1-yl)-2-methyl-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-N-(methylsulfonyl)thieno[3,2- b]pyridine-3-carboxamide,

7-(5-Chloro-2-(3-(5-cyano-6-(4,4-difluoro-[1,4'-bipiperidin]-1'-yl)-2-methyl-4- oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((1-((1r,3r)-3-fluorocyclobutyl)piperidin-4-yl)(methyl)amino)- 2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-Chloro-2-(3-(5-cyano-6-((1-(3-(difluoromethyl)oxetan-3-yl)piperidin-4- yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1- yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluoropropyl)piperidin-4-yl)(methyl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)-N-(oxetan-3- ylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide,

7-(5-chloro-2-(3-(5-cyano-6-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(ethyl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((1-((3-fluorooxetan-3-yl)methyl)piperidin-4- yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1- yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid, 7-(5-Chloro-2-(3-(5-cyano-6-(ethyl(1-(oxetan-3-yl)piperidin-4-yl)amino)-2-methyl-4- oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-(4-(3-(difluoromethoxy)azetidin-1-yl)piperidin-1-yl)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(methyl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)-N- (methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide,

7-(5-Chloro-2-(3-(5-cyano-6-((1-((3-(difluoromethoxy)cyclobutyl)methyl)piperidin-4- yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1- yl)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(3-(5-cyano-6-((1-(3,3-difluorobutyl)piperidin-4-yl)(methyl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-Chloro-2-(3-(5-cyano-6-(ethyl(1-(2,2,3,3-tetrafluoropropyl)piperidin-4-yl)amino)-2- methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-Chloro-2-(3-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-Chloro-2-(3-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)prop-1-yn-1-yl)phenyl)-5-methylthieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-methyl-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic 7-(5-chloro-2-(2-(5-cyano-6-((1-(2-cyclopropyl-2,2-difluoroethyl)piperidin-4- yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)- yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid, 7-(5-chloro-2-(3-(5-cyano-2-methyl-6-(methyl(1-(3-methyloxetan-3-yl)piperidin-4- yl)amino)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylic acid,

Methyl 7-(5-chloro-2-(3-(5-cyano-2-methyl-4-oxo-6-(4-(2- (trifluoromethoxy)ethyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1- yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate,

Methyl 7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluoroethyl)piperidin-4-yl)(methyl)amino)- 2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylate,

Methyl 7-(5-chloro-2-(3-(5-cyano-2-methyl-6-(methyl(1-(2,2,2-trifluoroethyl)piperidin-4- yl)amino)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2- b]pyridine-3-carboxylate,

Methyl 7-(5-chloro-2-(2-(5-cyano-6-(4-cyclopropylpiperazin-1-yl)-2-methyl-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate, 7-(5-chloro-2-(2-(5-cyano-2,8-dimethyl-4-oxo-6-(4-(2,2,2-trifluoroethyl)piperazin-1- yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid 7-(5-chloro-2-(2-(5-cyano-6-(4-(2-fluoroethyl)piperazin-1-yl)-2-methyl-4-oxopyrido[3,4- d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-methyl-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-6-(4-(2-fluoroethyl)piperazin-1-yl)-2-methyl-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-ethyl-2-methylthieno[3,2- b]pyridine-3-carboxylic acid, 7-(5-chloro-2-(2-(5-cyano-6-(4-(2-methoxyethyl)piperazin-1-yl)-2-methyl-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-(fluoromethyl)-2-methylthieno[3,2- b]pyridine-3-carboxylic acid,

7-(5-Chloro-2-(2-(5-cyano-2-methyl-6-(4-(oxetan-3-yl)piperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylic acid,

7-(5-Chloro-2-(2-(5-cyano-2-methyl-6-(4-(oxetan-3-yl)piperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3- carboxylic acid,

7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7- (trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-(methoxymethyl)-2- methylthieno[3,2-b]pyridine-3-carboxylic acid, and

7-(5-chloro-2-(3-(5-cyano-6-((trans-4-(3,3-difluoroazetidin-1- yl)cyclohexyl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn- 1-yl)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide, or

any combination of two to four of the compounds.

In further embodiments, an eIF4E inhibitor is an antisense oligonucleotide.

Examples of eIF4E specific antisense oligonucleotides are described in PCT Publication No. WO 2005/028628, the inhibitors of which are incorporated herein by reference in their entirety.

Methods of measuring inhibition of eIF4E binding eIF4G include an m⁷GTP pull- down assay (Moerke et al., Cell 128:257-267, 2007, which assay is incorporated herein by reference in its entirety); fluorescence polarization competition assay (Moerke et al., 2007; PCT Publication No. WO 2014/149001; each assay of which is incorporated herein by reference in its entirety), and a cell based assay comprising Gaussia luciferase reporter gene with a 5'-UTR of c-myc (PCT Publication No. WO 2011/136744, the assay of which is incorporated herein by reference in its entirety). Methods of measuring imhibition of eIF4E binding to the mRNA cap include fluorescence polarization competition assay (U.S. Application No.16/916,820 (claiming priority to U.S. Provisional Application No.

62/869,662), which assays are incorporated herein by reference in their entirety) and competition binding assay involving cross-linking of recombinant eIF4E to cap-labeled oxidized mRNA (Sonenberg et al., Proc. Nat'l. Acad. Sci. U.S.A.74:4288-4292, 1977; Sonenberg et al., Proc. Nat'l. Acad. Sci. U.S.A.75:4843-4847, 1978, the assays of which are incorporated herein by reference in their entirety).

In certain embodiments, a eIF4E inhibitor is a compound of any one of Formulae I, II, III, IV, V or VI, which is formulated as a pharmaceutical composition in an amount effective to treat a particular disease or condition of interest (e.g., cancer, chronic infection) upon administration of the pharmaceutical composition to a mammal (e.g., human). In particular embodiments, a pharmaceutical composition comprises a eIF4E inhibitor as described herein and a pharmaceutically acceptable carrier, diluent or excipient.

In this regard, a "pharmaceutically acceptable carrier, diluent or excipient" includes any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

Further, a "mammal" includes primates, such as humans, monkeys and apes, and non-primates such as domestic animals, including laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals, such as wildlife or the like.

A pharmaceutical composition of this disclosure can be prepared by combining or formulating an eIF4E inhibitor as described herein with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Exemplary routes of administering such pharmaceutical compositions include oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. The term parenteral, as used herein, includes subcutaneous injections, intravenous,

intramuscular, intrasternal injection or infusion techniques. Pharmaceutical compositions of this disclosure are formulated to allow the active ingredients contained therein to be bioavailable upon administration to a patient. Compositions that will be administered to a subject or patient take the form of one or more dosage units, where, for example, a tablet may be a single dosage unit, and a container of an eIF4E inhibitor as described herein in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). A composition to be administered will, in any event, contain a therapeutically effective amount of na eIF4E inhibitor of this disclosure, or a pharmaceutically acceptable salt thereof, for modulating an immune response to aid in treatment of a disease or condition of interest in accordance with the teachings herein.

A pharmaceutical composition of an eIF4E inhibitor as described herein may be in the form of a solid or liquid. In one aspect, the carrier(s) are particulate so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with a composition being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration. When intended for oral administration, a pharmaceutical composition of an eIF4E inhibitor of this disclosure is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.

As a solid composition for oral administration, a pharmaceutical composition of an eIF4E inhibitor as described herein may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

A pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred compositions contain, in addition to an eIF4E inhibitor, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of eIF4E inhibitors, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably

physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile. A liquid pharmaceutical composition of an eIF4E inhibitor intended for either parenteral or oral administration should contain an amount of an eIF4E inhibitor of this disclosure such that a suitable dosage will be obtained.

A pharmaceutical composition of an eIF4E inhibitor may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, a composition of an eIF4E inhibitor of this disclosure may be included with a transdermal patch or iontophoresis device.

The pharmaceutical composition of an eIF4E inhibitor may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug. A composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, for example, lanolin, cocoa butter or polyethylene glycol.

The pharmaceutical composition of an eIF4E inhibitor may include various materials that modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule.

The pharmaceutical composition of this disclosure in solid or liquid form may include an agent that binds to an eIF4E inhibitor described herein and thereby assist in the delivery of the compound. Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.

A pharmaceutical composition of an eIF4E inhibitor may consist of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of eIF4E inhibitors may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation, may determine preferred aerosol formulations and delivery modes.

A pharmaceutical composition of this disclosure may be prepared by methodology well-known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining an eIF4E inhibitor as described herein with a sterile solvent so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with a compound of this disclosure so as to facilitate dissolution or homogeneous suspension of the compound in an aqueous delivery system.

In certain embodiments, a "combination" refers to a combination comprising an eIF4E inhibitor and an inhibitor of an immunosuppression component, each of which may be administered serially (sequentially), concurrently or simultaneously, as described herein. For example, any one of the eIF4E inhibitors of Formula I, II, III, IV, V, or VI can be combined with (a) an antibody specific for PD-1, such as pidilizumab, nivolumab, or pembrolizumab; (b) an antibody specific for PD-L1, such as avelumab, atezolizumab, durvalumab, or MDX-1105 (BMS-936559); (c) an antibody specific for TIM3, such TSR- 022 or MBG453; (d) an antibody specific for LAG3, such as BMS-986016; (e) an inhibitor of IDO, such as indoximod, epacadostat, navoximod, GDC-0919, BMS-986205, NLG802, HTI-1090, PF-06840003, OM2983, or RG-70099; (f) anti-CD137 (4-1BB) antibody, such as urelumab; (g) an anti-CD134 (OX-40) antibody, such as MDI6469 (an OX-40 agonist); (h) lenalidomide or pomalidomide; or (i) any combination thereof.

In certain embodiments, a combination of an eIF4E inhibitor with an inhibitor of an immunosuppression component further comprises a chemotherapeutic agent, each of which may be administered serially (sequentially), concurrently or simultaneously, as described herein. For example, any one of the eIF4E inhibitors of Formula I, II, III, IV, V or VI can be combined with (a) an antibody specific for PD-1, such as pidilizumab, nivolumab, or pembrolizumab; (b) an antibody specific for PD-L1, such as avelumab, atezolizumab, durvalumab, or MDX-1105 (BMS-936559); (c) an antibody specific for TIM3, such TSR- 022 or MBG453; (d) an antibody specific for LAG3, such as BMS-986016; (e) an inhibitor of IDO, such as indoximod, epacadostat, navoximod, GDC-0919, BMS-986205, NLG802, HTI-1090, PF-06840003, OM2983, or RG-70099; (f) lenalidomide or pomalidomide; and a chemotherapeutic agent, such as a MNK inhibitor, an eIF4A inhibitor, a mTOR inhibitor, a MEK inhibitor, a VEGF inhibitor, a VEGFR inhibitor, a tyrosine kinase inhibitor, an anti- mitotic agent, vemurafenib, dabrafenib, trametinib, cobimetinib, sunitinib, erlotinib, paclitaxel, or docetaxel. B. Combination Therapy

In other aspects, methods for immune modulation of the present disclosure comprise administering to a subject an eIF4E inhibitor and an additional therapeutic agent. For example, a combination therapy may comprise administering an eIF4E inhibitor in combination with an inhibitor of an immunosuppression component, radiation therapy, surgery, a chemotherapeutic agent (e.g., a RAF inhibitor, MEK inhibitor, mTOR inhibitor, MNK specific inhibitor, eIF4A inhibitor, or any combination thereof), an

immunotherapeutic agent targeting a disease antigen (e.g., antibody or adoptive

immunotherapeutic agent targeting a cancer antigen expressed by a tumor cell), a cytokine, an RNA interference agent, or any combination thereof, which components may be administered simultaneously, concurrently, or sequentially.

As used herein, a“chemotherapeutic agent” includes to traditional cytotoxic agents that inhibits cell growth, inhibits cell proliferation, leads to cell death or the like in rapidly dividing cells, as well as targeted, cytostatic agents that inhibit a target molecule involved in carcinogenesis and tumor growth.

A chemotherapeutic agent includes, for example, an inhibitor of chromatin function, a topoisomerase inhibitor, a microtubule inhibiting drug, a DNA damaging agent, an antimetabolite (such as folate antagonists, pyrimidine analogs, purine analogs, and sugar-modified analogs), a DNA synthesis inhibitor, a DNA interactive agent (such as an intercalating agent), or a DNA repair inhibitor. Chemotherapeutic agents include, for example, the following groups: anti-metabolites/anti-cancer agents, such as pyrimidine analogs (5-fluorouracil, floxuridine, capecitabine, gemcitabine and cytarabine) and purine analogs, folate antagonists and related inhibitors (methotrexate, pemetrexed,

mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine));

antiproliferative/antimitotic agents including natural products such as vinca alkaloids (vinblastine, vincristine, and vinorelbine), microtubule disruptors such as taxane

(paclitaxel, docetaxel), vincristin, vinblastin, vindesine, vinorelbine, nocodazole, epothilones, eribulin and navelbine; epidipodophyllotoxins (etoposide, teniposide); DNA damaging agents (actinomycin, amsacrine, anthracyclines, bleomycin, busulfan, camptothecin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin, procarbazine, taxol, taxotere, temozolamide, teniposide,

triethylenethiophosphoramide and etoposide (VP 16)); DNA methyltransferase inhibitors (azacytidine); antibiotics such as dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin

(mithramycin) and mitomycin; enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents; antiproliferative/antimitotic alkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine and thiotepa), alkylsulfonates (busulfan), nitrosoureas (carmustine (BCNU) and analogs, streptozocin), triazenes (dacarbazine (DTIC)); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory agents; antisecretory agents (breveldin); immunosuppressives (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); anti-angiogenic compounds (TNP470, genistein, pomalidomide) and growth factor inhibitors (vascular endothelial growth factor (VEGF)) inhibitors, such as ziv-aflibercept; fibroblast growth factor (FGF) inhibitors); inhibitors of apoptosis protein (IAP) antagonists (birinapant); histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, chidamide, panobinostat, mocetinostat, abexinostat, belinostat, entinostat, resminostat, givinostat, quisinostat, SB939); proteasome inhibitors (ixazomib); angiotensin receptor blocker; nitric oxide donors; anti-sense oligonucleotides; antibodies (trastuzumab, panitumumab, pertuzumab, cetuximab, adalimumab, golimumab, infliximab, rituximab, ocrelizumab, ofatumumab, obinutuzumab, alemtuzumab, abciximab, atlizumab, daclizumab, denosumab, efalizumab, elotuzumab, rovelizumab, ruplizumab, ustekinumab, visilizumab, gemtuzumab

ozogamicin, brentuximb vedotin); chimeric antigen receptors; cell cycle inhibitors

(flavopiridol, roscovitine, bryostatin-1) and differentiation inducers (tretinoin); mTOR inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), amsacrine, camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan (CPT- 11) and mitoxantrone, topotecan, irinotecan), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, and prenisolone); PARP inhibitors (niraparib, olaparib); focal adhesion kinase (FAK) inhibitors (defactinib (VS-6063), VS- 4718, VS-6062, GSK2256098); growth factor signal transduction kinase inhibitors (cediranib, galunisertib, rociletinib, vandetanib, afatinib, EGF816, AZD4547); c-Met inhibitors (capmatinib, INC280); tyrosine kinase inhibitors; serine/threonine kinase inhibitors; ALK inhibitors (ceritinib, crizotinib); mitochondrial dysfunction inducers, toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin, and caspase activators; and chromatin disruptors. As used herein, the term "vascular endothelial growth factor inhibitor" or "VEGF inhibitor" refers to any agent that reduces or inhibits the activity of VEGF. VEGF is a pro- angiogenic factor that promotes vasculogenesis, angiogenesis, and increases vascular permeability. VEGF may refer to VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, or any combination thereof. Non-limiting examples of VEGF inhibitors include

bevacizumab, ranibizumab, AZD2171, cannbidiol, THC, or any combination thereof.

As used herein, the term "vascular endothelial growth factor receptor inhibitor" or "VEGFR inhibitor" refers to any agent that inhibits the activity of VEGF-specific tyrosine kinase receptors VEGFR1, VEGFR2, VEGFR3, or any combination thereof. Non-limiting examples of VEGFR inhibitors include axitinib, sunitinib, vatalanib, sorafenib, GW- 786034, CP-547632, AG-013736, lenvatinib, motesanib, pazopanib, regorafenib, ramucirumab, CDP-791, or any combination thereof.

As used herein, the term "tyrosine kinase inhibitor" refers to any agent that inhibits a tyrosine kinase. Tyrosine kinase inhibitors include inhibitors that provide competitive ATP inhibition at the catalytic binding site of tyrosine kinase and allosteric inhibitors. Non-limiting examples of tyrosine kinase inhibitors include axitinib, imatinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, pazopanib, vandetanib, and dasatinib.

In certain embodiments, the subject is administered an eIF4E inhibitor in combination with a chemotherapeutic agent comprising a RAF inhibitor, MEK inhibitor, mTOR inhibitor, MNK specific inhibitor, eIF4A inhibitor, or any combination thereof. (i) MNK-Specific Inhibitors

A "MNK inhibitor," as used herein, may directly block, inactivate, reduce or minimize MNK activity (e.g., kinase activity or translational effects), or reduce activity by promoting degradation of MNK, by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more as compared to untreated MNK. In certain embodiments, a MNK inhibitor blocks, inactivates, reduces or minimizes the ability of MNK to phosphorylate eIF4E, hnRNPA1, PSF or combinations thereof. In further embodiments, a MNK inhibitor enhances or promotes expansion of CD4+ central memory T cells, CD8+ central memory T cells, or both. In yet further embodiments, a MNK inhibitor induces or enhances a T cell response. Non-limiting examples of inhibitors include small molecules, antisense molecules, ribozymes, inhibitory nucleic acid molecules, endonucleases, or the like.

As used herein, a "MNK-specific inhibitor" refers to an agent that (a) inhibits MNK enzyme (kinase) activity (i.e., MNK1 and MNK2), (b) has at least about 25-fold less activity against the rest of a host cell kinome as set forth in Table A (i.e., other than MNK enzymes), and (c) does not significantly reduce or inhibit IL-2 production by T cells. As used herein, "a host cell kinome" refers to the 412 protein and lipid kinases listed in Table A (not including the MNK1 and MNK2 enzymes), which may be from a particular organism or cell of interest (e.g., human). The activity of a host cell kinome in the presence and absence of a candidate MNK-specific inhibitor or a known MNK-specific inhibitor (see, e.g., Compound 107 of Table B) is measured using the FRET-based method of Rodems et al. (Assay. Drug Dev. Technol.1:9, 2002, which assay is incorporated herein by reference in its entirety).

In certain embodiments, the host cell kinome of Table A is from a human cell. In further embodiments, a MNK-specific inhibitor compound is a small molecule and has at least 50-fold less activity against a serine/threonine kinome of an organism or cell as listed in Table A, and does not significantly reduce or inhibit IL-2 production by T cells. In particular embodiments, the serine/threonine kinome of Table A is from a human cell. In still further embodiments, a MNK-specific inhibitor compound has at least about 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, 70-fold, 75-fold, 80- fold, 85-fold, 90-fold, 95-fold, 100-fold less, 200-fold less, 250-fold less, 300-fold less, 400-fold less, 500-fold less, 750-fold less, 1000-fold less, or even less activity against kinome enzymes of Table A other than the serine/threonine kinome enzymes of Table A, and does not significantly reduce or inhibit IL-2 production by T cells. Table A. Protein and Lipid Kinases of "Host Cell Kinome" (excluding MNK)

In any of the aforementioned embodiments, a MNK-specific inhibitor compound can block, inactivate, reduce or minimize the ability of MNK1a, MNK1b, MNK2a, MNK2b, or any combination thereof to phosphorylate eIF4E, hnRNPA1, PSF or any combination thereof. In particular embodiments, a MNK-specific inhibitor compound can block, inactivate, reduce or minimize the ability of MNK1a, MNK1b, MNK2a, and MNK2b to phosphorylate eIF4E. MNK-specific inhibitors in any of the aforementioned embodiments may optionally not significantly reduce or inhibit (i) T cell viability, (ii) T cell proliferation, (iii) expression of MHC or HLA molecules in APCs, or (iv) production by T cells of IL-2, CD25, IFNg or any combination thereof. Further, optionally,

MNK-specific inhibitors in any of the aforementioned embodiments can also significantly reduce or inhibit expression of one or more immunosuppression components (e.g., immune checkpoint molecules, immunosuppressive cytokines) in T cells, APCs or both. The assay for measuring T cell viability is the assay described by Mosmann (J. Immunol. Meth.

65:55, 1983).

With regard to a MNK-specific inhibitor compound, "does not significantly reduce or inhibit IL-2 production by T cells" means the reduction or inhibition of IL-2 production by T cells is less than about 25%, 20%, 15%, 10%, 5%, 2%, 1%, 0.5%, 0.25%, 0.1% or less as compared to the same T cells not exposed or contacted with the MNK-specific inhibitor compound.

Also with regard to a MNK-specific inhibitor compound, "does not significantly reduce or inhibit T cells viability," "does not significantly reduce or inhibit T cell proliferation," "does not significantly reduce or inhibit MHC or HLA molecule expression in T cells, APCs or both," and "does not significantly reduce or inhibit production of IL-2, CD25, IFNg or any combination thereof by T cells," refers to the reduction or inhibition of T cell viability; T cell proliferation; expression of MHC or HLA molecules in T cells, APCs or both; or production of IL-2, CD25, IFNg or any combination thereof by T cells; respectively, is less than about 25%, 20%, 15%, 10%, 5%, 2%, 1%, 0.5%, 0.25%, 0.1% or less as compared to the same corresponding cells not exposed or contacted with the MNK-specific inhibitor.

Also, with regard to a MNK-specific inhibitor compound, "significantly reduce or inhibit expression of one or more immunosuppression components" means the reduction or inhibition of expression of one or more immunosuppression components in T cells, APCs or both is at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75% as compared to the same T cells or APCs not exposed or contacted with the

MNK specific inhibitor. In certain embodiments, an APC is a cancer cell or a tumor cell.

Other assays for detecting kinase activity in the presence or absence of inhibitors are well known in the art, which can be used as a back-up to the FRET-based host cell kinome assay to show a particular MNK inhibitor compound is a MNK-specific inhibitor compound, such as the assay taught by Karaman et al. (Nat. Biotechnol.26:127, 2007). Assays for detecting the cytokine levels (e.g., IL-2, IL-10, IFNg) are known in the art, such as the DuoSet® ELISA assay from R&D Systems (using the manufacturer's instructions). Assays for detecting T cell viability, T cell proliferation, MHC or HLA molecule expression, and expression of immunosuppression components like immune checkpoint molecules PD-1, PD-L1, LAG3 or the like are those described in PCT Publication No. WO 2016/172010.

In certain aspects, MNK-specific inhibitor compounds that are potent and selective inhibitors of MNK1 and MNK2 may be used in the pharmaceutical compositions and methods of use described herein. MNK-specific inhibitor compounds include compounds of Formula I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa or VIIb, including

Compound 107 (see, e.g., PCT Publication WO 2016/172010, which compounds and synthetic methods are incorporated herein in their entirety). By way of background, MNK1 and MNK2 integrate signals from several oncogenic and immune signaling pathways by phosphorylating eukaryotic initiation factor 4E (eIF4E) and other mRNA binding proteins, which regulate the stability and translation of select mRNAs important for tumor growth and survival.

Administration of a MNK-specific inhibitor to a subject in combination with the modified T cells disclosed herein may further enhance expansion of central memory T cells, enhance cytotoxic T cell activity, or both.

Exemplary MNK-specific inhibitor compounds inhibit both MNK1 and MNK2 kinase activity. In certain embodiments, a MNK-specific inhibitor selectively inhibits MNK1 kinase activity over MNK2 kinase activity, or selectively inhibits MNK2 kinase activity over MNK1 kinase activity. In other embodiments, a MNK-specific inhibitor selectively inhibits kinase activity of full length isoforms MNK1a and MNK2a over the kinase activity of MNK1b and MNK2b. In further embodiments, a MNK-specific inhibitor selectively inhibits either MNK1 kinase activity or MNK2 kinase activity. In still further embodiments, a MNK-specific inhibitor selectively inhibits kinase activity of any one of full length isoforms MNK1a, MNK1b, MNK2a, or MNK2b, or inhibits the kinase activity of all the MNK isoforms.

In certain embodiments, a MNK-specific inhibitor compound is a compound having the following structure (I):

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof wherein: W¹ and W² are independently O, S or N-OR’, where R’ is lower alkyl;

Y is–N(R⁵)–, -O-, -S-, -C(O)-, -S=O, -S(O)₂-, or–CHR⁹–;

R¹ is hydrogen, lower alkyl, cycloalkyl or heterocyclyl wherein any lower alkyl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups; n is 1, 2 or 3;

R² and R³ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, araalkylene, heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene, wherein any alkyl, aryl, araalkylene, heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene, is optionally substituted with 1, 2 or 3 J groups;

or R² and R³ taken together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, wherein any cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups;

R^4a and R^4b are each independently hydrogen, halogen, hydroxyl, thiol,

hydroxyalkylene, cyano, alkyl, alkoxy, acyl, thioalkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclyl;

R⁵ is hydrogen, cyano, or lower alkyl;

or R⁵ and R⁸ taken together with the atoms to which they are attached form a fused heterocyclyl optionally substituted with 1, 2 or 3 J groups;

R⁶, R⁷ and R⁸ are each independently hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl, and wherein any amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl is optionally substituted with 1, 2 or 3 J groups;

or R⁷ and R⁸ taken together with the atoms to which they are attached form a fused heterocyclyl or heteroaryl optionally substituted with 1, 2 or 3 J groups;

J is–SH, -SR⁹, -S(O)R⁹, -S(O)2R⁹, -S(O)NH2, -S(O)NR⁹R⁹, -NH2, -NR⁹R⁹, -COOH, -C(O)OR⁹, -C(O)R⁹, -C(O)-NH₂, -C(O)-NR⁹R⁹, hydroxy, cyano, halogen, acetyl, alkyl, lower alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl, cyanoalkylene, alkylaminyl, NH₂-C(O)-alkylene , NR⁹R⁹-C(O)-alkylene, -CHR⁹-C(O)-lower alkyl, -C(O)- lower alkyl, alkylcarbonylaminyl, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl, cycloalkylaminyl, -CHR⁹-C(O)-cycloalkyl, -C(O)-cycloalkyl, -CHR⁹-C(O)-aryl, -CHR⁹-aryl, -C(O)-aryl, -CHR⁹-C(O)-heterocycloalkyl,

-C(O)-heterocycloalkyl, heterocyclylaminyl, or heterocyclyl; or any two J groups bound to the same carbon or hetero atom may be taken together to form oxo; and

R⁹ is hydrogen, lower alkyl or -OH.

In certain embodiments of structure (I), the present disclosure provides a compound having the following structure (Ia), as well as stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

.

For Formula Ia compounds, substituent R¹ is hydrogen or lower alkyl and subscript n is 1, 2 or 3. Substituents R² and R³ in Formula Ia are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl or heterocyclylalkyl, and any such alkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl or heterocyclylalkyl can optionally be substituted with 1, 2 or 3 J groups.

Substitutents R² and R³ in Formula Ia when taken together with the carbon atom to which they are attached can form a cycloalkyl or heterocyclyl, wherein any such cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups. In Formula Ia, R^4a is hydrogen, halogen, hydroxy, alkyl, alkoxy, thioalkyl, alkenyl or cycloalkyl and substituent R⁵ is hydrogen or lower alkyl.

Alternatively, substituent groups R⁵ and R⁸ taken together with the atoms to which they are attached form a fused heterocyclyl that is optionally substituted with 1, 2 or 3 J groups.

In certain embodiments, substituents R⁶, R⁷ and R⁸ are independently and at each occurrence hydrogen, halogen, alkyl, alkenyl, cycloalkly, cycloalkylalkyl, cycloalkylalkenyl, amino, alkylaminyl, alklycarbonylaminyl, cycloalkylcarbonylaminyl, alkylaminyl or cycloalkylaminyl, and any such alkyl, alkenyl, cycloalkly, cycloalkylalkyl, cycloalkylalkenyl, amino, alkylaminyl, alklycarbonylaminyl, cycloalkylcarbonylaminyl, alkylaminyl or cycloalkylaminyl is optionally substituted with 1, 2 or 3 J groups. For some compounds in accordance with Formula Ia, R⁷ and R⁸ taken together with the atoms to which they are attached form a fused heterocyclyl unsubstituted or substituted with 1, 2 or 3 J groups.

Variable J in Formula Ia is -SH, -SR⁹, -S(O) R⁹, -S(O)₂ R⁹, -S(O)NH₂,

-S(O)NR⁹R⁹, -NH2, -NR⁹R⁹, -COOH, -C(O)OR⁹, -C(O)R⁹, -C(O)- NH2, -C(O)-NR⁹R⁹, hydroxy, cyano, halogen, acetyl, alkyl, lower alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl, cyanoalkylene, alkylaminyl, NH2-C(O)-alkylene , NR⁹R⁹-C(O)-alkylene, -CHR⁹- C(O)-lower alkyl, -C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl, cycloalkylaminyl, -CHR⁹-C(O)- cycloalkyl, -C(O)-cycloalkyl, -CHR⁹-C(O)-aryl, -CHR⁹-aryl, -C(O)-aryl, -CHR⁹-C(O)- heterocycloalkyl, -C(O)-heterocycloalkyl, heterocyclylaminyl, or heterocyclyl. For some compounds according to Formula Ia, any two J groups bound to the same carbon or hetero atom may be taken together to form an oxo group.

In some embodiments, variable J in Formula Ia is halogen, amino, alkyl, haloalkyl, alkylaminyl, cycloalkyl or heterocyclyl. Alternatively, for certain Formula Ia compounds, any two J groups when bound to the same carbon or hetero atom may be taken together to form oxo group.

Further MNK-specific inhibitor compounds are compounds according to Formula IIa, illustrated below, where variable Y is–N(R⁵)– and subscript "n" is 1.

According to one embodiment, variable Y in Formula I is -O-, -S-, -C(O)-, sulfoxide, sulfone,–CHR⁹– or–CH₂–, subscript "n" is 1 and the compounds conform to Formula IIb. When "Y" is–CHR⁹- in Formula IIb, substituent R⁹ is hydrogen, lower alkyl or hydroxy.

In more MNK-specific inhibitor compound embodiments, variable "Y" in Formula I is–N(R⁵)–, subscript "n" is 2 or 3 and the compounds conform to Formula IIIa or Formula IVa, respectively:

Alternatively, in certain embodiments, variable "Y" in Formula I is -O-, -S-, -C(O)-, sulfoxide, sulfone,–CHR⁹- or–CH2-, "n" is 2 or 3 and the compounds conform to Formula IIIb and Formula IVb, respectively: When "Y" is–CHR⁹- in Formula IIIb or Formula IVb, substituent R⁹ is either hydrogen, lower alkyl or hydroxy.

For MNK-specific inhibitor compounds according to Formulae IIa, IIb, IIIa, IIIb, IVa and IVb, variables W¹ and W² are both oxo. In certain embodiments for compounds according to Formulae IIa, IIb, IIIa, IIIb, IVa and IVb, W¹ is oxo and W² is thione group. According to one embodiment, Formulae IIa, IIb, IIIa, IIIb, IVa and IVb compounds comprise an oxo at W¹ and a =N-OR' group at W². Also encompassed within the scope of the present MNK-specific inhibitor compounds are Formulae IIa, IIb, IIIa, IIIb, IVa and IVb compounds having a thione group at W¹ and an oxo group at W².

For Formulae IIa, IIb, IIIa, IIIb, IVa and IVb compounds, each of substituents R² and R³ can be the same in which case the carbon atom which R² and R³ are attached is not a chiral carbon. In certain embodiments, however, substituents R² and R³ are different. Thus, the carbon atom to which R² and R³ are attached is chiral and the resulting compound will have stereoisomers.

In certain MNK-specific inhibitor compound embodiments, each R² and R³ in Formulae IIa, IIb, IIIa, IIIb, IVa and IVb is hydrogen. Alternatively, one of R² or R³ groups in Formulae IIa, IIb, IIIa, IIIb, IVa and IVb is hydrogen and the other group is alkyl optionally substituted with 1, 2 or 3 J groups. For certain compounds according to

Formulae IIa, IIb, IIIa, IIIb, IVa and IVb, R² and R³ are both alkyl groups that are optionally substituted with 1, 2 or 3 J groups.

For some compounds in accordance with Formula IIa or Formula IIb, R² is alkyl and R³ is alkyl substituted with 1, 2 or 3 J groups. Exemplary of this category of Formula IIa and Formula IIb compounds are the following: compounds with substituent R² as alkyl and R³ is haloalkyl; compounds with substituent compounds with substituent R² as alkyl and R³ is cycloalkyl optionally substituted with 1, 2 or 3 J groups; compounds with substituent R² as alkyl and R³ is cyclopentyl optionally substituted with 1, 2 or 3 J groups; compounds with substituent R² as alkyl and R³ is aryl optionally substituted with 1, 2 or 3 J groups; compounds with substituent R² as alkyl and R³ is phenyl optionally substituted with 1, 2 or 3 J groups; compounds with substituent R² as alkyl and R³ is

cycloalkylalkylene optionally substituted with 1, 2 or 3 J groups; compounds with substituent R² as alkyl and R³ is aralkylene optionally substituted with 1, 2 or 3 J groups; compounds with substituent R² as alkyl and R³ is benzyl optionally substituted with 1, 2 or 3 J groups; compounds with substituent R² as alkyl and R³ is heterocyclyl optionally substituted with 1, 2 or 3 J groups; compounds with substituent R² as alkyl and R³ is heteroaryl optionally substituted with 1, 2 or 3 J groups; compounds with substituent R² as alkyl and R³ is thiophenyl, thiazolyl or pyridinyl; compounds with substituent R² as alkyl and R³ is heterocyclylalkylene substituted or substituted with 1, 2 or 3 J groups; or compounds with substituent R² as alkyl and R³ is heteroarylalkylene optionally substituted with 1, 2 or 3 J groups.

In some embodiments, for compounds according to Formulae IIa, IIb, IIIa, IIIb, IVa and IVb, each R² and R³ are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl or heterocyclylalkylene, and any such alkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl or heterocyclylalkylene can optionally be substituted with 1, 2 or 3 J groups, idependently selected from the group consisting of halogen, amino, alkylaminyl and alkyl.

For certain Formulae IIIa, IIIb, IVa and IVb compounds, R² and R³ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring.

Also contemplated are Formula I compounds where Y is–N(R⁵)-, subscript "n" is 1 and R² and R³ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring "A." Such compounds conform to Formula Va and the cycloalkyl or heterocyclyl ring "A" may optionally be substituted with 1, 2 or 3 J groups.

Alternatively, in some embodiments Y in Formula I is -O-, -S-, -C(O)-, sulfoxide, sulfone,–CHR⁹- or–CH2-, "n" is 1 and R² and R³ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring A. Such compounds conform to Formula Vb and the cycloalkyl or heterocyclyl ring "A" may optionally be substituted with 1, 2 or 3 J groups. When "Y" is–CHR⁹- in Formula Vb, substituent R⁹ is either hydrogen, lower alkyl or hydroxy.

For Formula Va and Formula Vb compounds, W¹ and W² are both oxo and ring A is a cycloalkyl optionally substituted with 1, 2 or 3 J groups. Also contemplated are Formula Va and Formula Vb compounds for which ring A is a fused cycloalkyl optionally substituted with 1, 2 or 3 J groups; ring A is a cycloalkyl optionally substituted with 1, 2 or 3 J groups; ring A is a cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with 1, 2 or 3 J groups, for example, J groups selected from the group consisting of halogen, amino, alkylaminyl and alkyl.

For some embodiments, ring A of a Formula Va or a Formula Vb is a heterocyclyl optionally substituted with 1, 2 or 3 J groups. Exemplary of such heterocyclyl groups are pyrrolidinyl, piperidinyl, tetrahydropyranyl, thietanyl or azetidinyl. In one embodiment, each of the above exemplified heterocyclyl may optionally be substituted with 1, 2 or 3 J groups. For certain Formula Va or a Formula Vb compounds ring A is a cycloalkyl substituted with at least 2J groups attached to the same carbon atom of the cycloalkyl, and the two J groups attached to the same carbon taken together form oxo group. In another embodiment, ring A of a Formula Va or a Formula Vb is a heterocyclyl substituted with at least 2J groups that are attached to the same hetero atom and wherein such 2 J groups taken together to form oxo. For some Formula Va or a Formula Vb compounds the cycloalkyl or heterocyclyl ring A is substituted with J groups selected from from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, N-methyl amino, methyl, difluoroethylene, and methylenenitrile. The present disclosure also provides compounds in accordance with Formula VI or its stereoisomers, tautomers or pharmaceutically acceptable salts. Formula VI is a sub- genus of Formula I in which Y is–N(R⁵)- and substituent groups R⁵ and R⁸ together with the atoms to which they are attached form a heterocycle ring B which may optionally be substituted with 1, 2 or 3 J groups.

Also encompassed within the scope of the present MNK-specific inhibitor compounds are Formula I compounds in which variable "Y" is–N(R⁵)-, and substituent groups R⁷ and R⁸ together with the atoms to which they are attached form a fused ring C. Such compounds or the stereoisomer, tautomer or pharmaceutically acceptable salt conform to Formula VIIa. For Formula VIIa compounds, ring C may optionally be substituted with 1, 2 or 3 J groups.

According to one embodiment, variable "Y" in Formula I is -O-, -S-, -C(O)-, sulfoxide, sulfone,–CHR⁹- or–CH2-, and substituent groups R⁷ and R⁸ together with the atoms to which they are attached form a fused ring C. Such compounds and their stereoisomers, tautomers or pharmaceutically acceptable salts conform to Formula VIIb. For Formula VIIb compounds where "Y" is–CHR⁹-, substituent R⁹ can be hydrogen, lower alkyl or hydroxy.

For Formula VIIb compounds, fused ring C may optionally be substituted with 1, 2 or 3 J groups. In one MNK-specific inhibitor embodiment, W¹ and W² are both oxo for Formula VI, Formula VIIa and Formula VIIb compounds.

MNK-specific inhibitor compounds of this disclosure are further directed to Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa and VIIb compounds where R¹ is hydrogen or a lower alkyl group selected from methyl, ethyl, propyl, butyl, iso- propyl, sec-butyl, or tert-butyl, for example, compounds with R¹ as methyl.

For certain Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa and VIIb compounds, R^4a is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, thioalkyl, alkenyl, and cycloalkyl while substituent R^4b is hydrogen or halogen. R⁵ in Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa and VIIb is hydrogen or lower alkyl, while substituents R⁶, R⁷ and R⁸ are hydrogen.

In certain embodiments of this disclosure, R⁶ and R⁷ in Formula VI are both hydrogen, while for certain Formula VIIa and Formula VIIb compounds R⁶ is hydrogen.

MNK-specific inhibitor compounds of this disclosure are further directed to Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb compounds where substituent groups R⁶ and R⁸ are both hydrogen, and R7 is selected from the group consisting of hydroxy, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl, alkylcarbonylaminyl,

cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl, heteroaryl, and heterocyclyl. For these compounds, any alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl is optionally substituted with 1, 2 or 3 J groups. In certain embodiments, R7 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylene,

cycloalkylalkenylene, amino, alkylaminyl, alklycarbonylaminyl,

cycloalkylcarbonylaminyl, heterocyclylaminyl, heteroaryl, heterocyclyl and

cycloalkylaminyl. For such compounds any alkyl, alkenyl, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl, alklycarbonylaminyl,

cycloalkylcarbonylaminyl, heterocyclylaminyl, heteroaryl, heterocyclyl or

cycloalkylaminyl may optionally be substituted with 1, 2 or 3 J groups. Thus, certain embodiments provide Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb compounds where substituent groups R⁶ and R⁸ are both hydrogen, and R₇ is amino; substituent groups R⁶ and R⁸ are both hydrogen, and R7 is alkylaminyl; substituent groups R⁶ and R⁸ are both hydrogen, and R₇ is–NHCH₃; substituent groups R⁶ and R⁸ are both hydrogen, and R₇ is cycloalkyl, for example cyclopropyl; substituent groups R⁶ and R⁸ are both hydrogen, and R₇ is cycloalkylaminyl substituted with 1 to 3 J groups, for instance halogens.

In one embodiment, for compounds in accordance with Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb, substituent groups R⁶ and R⁸ are both hydrogen, and R₇ is selected from the group consisting of–NHCH(CF3)cyclopropyl,

cycloalkylcarbonylaminyl,–NHC(O)cyclopropyl, cycloalkylalkenylene,

and -CH=CHcyclopropyl.

For any compound in accordance with Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa, and VIIb, J is–SH, -SR⁹, -S(O)R⁹, -S(O)2 R⁹, -S(O)NH2, - S(O)NR⁹R⁹, -NH₂, -NR⁹R⁹, -COOH, -C(O)OR⁹, -C(O)R⁹, -C(O)-NH₂, -C(O)-NR⁹R⁹, hydroxy, cyano, halogen, acetyl, alkyl, lower alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl, cyanoalkylene, alkylaminyl, NH₂-C(O)-alkylene, NR⁹R⁹-C(O)-alkylene, -CHR⁹- C(O)-lower alkyl, -C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl, cycloalkylaminyl, -CHR⁹-C(O)- cycloalkyl, -C(O)-cycloalkyl, -CHR⁹-C(O)-aryl, -CHR⁹-aryl, -C(O)-aryl, -CHR⁹-C(O)- heterocycloalkyl, -C(O)-heterocycloalkyl, heterocyclylaminyl, or heterocyclyl and R⁹ is hydrogen, lower alkyl or -OH. Additionally, when two J groups bound to the same carbon or hetero atom they may be taken together to form oxo.

For certain compounds according to Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa, and VIIb, J is halogen, hydroxy, alkyl, alkenyl, alkynyl or cyanoalkylene. Illustrative alkyl or alkylene chains are those having C1-C10 carbon atoms, C1-C8 carbon atoms, C₁-C₆ carbon atoms, C₁-C₄ carbon atoms, C₁-C₃ carbon atoms as well as ethyl and methyl groups. Alternatively, when J is alkenyl, or alkynyl, the carbon chain has at least one double or triple bond respectively and C₂-C₁₀ carbon atoms, C₂-C₈ carbon atoms, C₂-C₆ carbon atoms, C2-C4 carbon atoms, or C2-C3 carbon atoms.

A MNK-specific inhibitor compound of Formula (I), as well as Formulae Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa and VIIb, may be isotopically-labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of structure (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. These radiolabelled compounds may be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action. Certain isotopically-labelled compounds of Formula (I), for example, those incorporating a radioactive isotope, are useful in drug or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., ³H, and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of Formula (I), as well as Formulae Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa and VIIb, can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Preparations and Examples as set out in U.S. Patent Application No. 14/748,990 filed June 24, 2015 and entitled "MNK Inhibitors and Methods Related

Thereto," which compounds and synthetic methods are incorporated herein in their entirety, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Embodiments of this disclosure are also meant to encompass the in vivo metabolic products of the MNK-specific inhibitor compounds of Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa and VIIb. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the instant disclosure includes compounds produced by a process comprising administering a MNK-specific inhibitor compound of this disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabelled MNK-specific inhibitor as described herein in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating conversion products from the urine, blood or other biological samples.

In some embodiments, a MNK-specific inhibitor compound of any one of compounds according to Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa and VIIb are in the form of a pharmaceutically acceptable salt, which includes both acid and base addition salts.

To this end, a "pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, or the like.

Similarly, a "pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine,

N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. Often crystallizations produce a solvate of a MNK-specific inhibitor compound of this disclosure. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the present disclosure with one or more molecules of solvent. A solvent may be water, in which case the solvate may be a hydrate. Alternatively, a solvent may be an organic solvent. Thus, the MNK-specific inhibitor compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate or the like, as well as the corresponding solvated forms. The MNK-specific inhibitor compounds of this disclosure may be true solvates, while in other cases, the compounds may merely retain adventitious water or be a mixture of water plus some adventitious solvent.

A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not

interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposeable mirror images of one another.

MNK-specific inhibitor compounds of this disclosure, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

The term "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. For example, when W¹ is oxo and R¹ is H, the present disclosure provides tautomers of a Formula I compound as illustrated below:

Similar tautomers exists for Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa and VIIb compounds. The compounds are synthesized using conventional synthetic methods, and more specifically using the general methods and specific synthetic protocols of the Examples found in U.S. Patent Application Serial No.14/748,990 filed June 24, 2015 and entitled "MNK Inhibitors and Methods Related Thereto," which compounds and synthetic methods are incorporated herein in their entirety.

Representative MNK-specific inhibitor compounds of this disclosure are set forth in Table B and in U.S. Patent Application Publication No. US 2015/0376181, which compounds are incorporated herein by reference in their entirety. Similarly, incorporated herein by reference in their entirety are compounds and methods of making the same from U.S. Patent No.10,112,955 (claiming priority to U.S. Provisional Patent Application No. 62/247,953 (entitled "Isoindoline, Azaisoindoline, Dihydroindenone and

Dihydroazaindenone Inhibitors of MNK1 and MNK2")) and U.S. Application No.

15/337,237 (claiming priority to U.S. Provisional Patent Application No.62/247,966 (entitled "Pyrrolo-, Pyrazolo-, Imidazo-Pyrimidine and Pyridine Compounds that Inhibit MNK1 and MNK2")). Such compounds are provided for purpose of illustration and not limitation. Table B. Exemplary MNK-Specific Inhibitors

(ii) eIF4A Inhibitors

An "eIF4A inhibitor," as used herein, refers to an agent or compound that directly interacts with eIF4A, either alone or in a complex (e.g., a ternary complex of an eIF4A inhibitor, an eIF4A and a mRNA) and may block, inactivate, reduce or minimize eIF4A activity (e.g., helicase activity or translational effects), or reduce activity by promoting degradation of eIF4A, by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more as compared to untreated eIF4A. In certain embodiments, an eIF4A inhibitor is a catalytic inhibitor that directly inhibits eIF4A helicase activity. An example of an eIF4A catalytic inhibitor is BPSL1549, a bacterial toxin from Burkholderia pseudomallei that deamidates Gln339 of eIF4A and converts it into a dominant-negative mutant (Cruz-Migoni et al., Science 334:821-824, 2011, which inhibitor is incorporated herein by reference in its entirety).

In some embodiments, an eIF4A inhibitor is an allosteric inhibitor. An allosteric eIF4A inhibitor binds to eIF4A at a site other than the active site, wherein its binding induces a conformational change in eIF4A so that a substrate can no longer bind eIF4A or eIF4A activity is reduced. In certain embodiments, an allosteric eIF4A inhibitor includes hippuristanol (Bordeleau et al., Nat Chem. Biol.2: 213-220, 2006, which compound is incorporated herein by reference in its entirety) and derivatives or analogs thereof.

Hippuristanol, which binds the C-terminal domain of both free eIF4A (eIF4A_f) and eIF4A bound in an eIF4F complex (eIF4Ac), inhibits eIF4A helicase and ATPase activities.

In further embodiments, an eIF4A inhibitor is a chemical inducer of dimerization. An eIF4A chemical inducer of dimerization causes a non-sequence specific interaction between eIF4Af and RNA and stimulates the ATP hydrolysis activity of eIF4A, resulting in sequestering of eIF4A_f and depletion of eIF4A_c. Examples of eIF4A inhibitors that are chemical inducers of dimerization include pateamine A, and analogs, derivatives, or precursors thereof. Examples of pateamine A derivatives have been described in U.S. Patent No.7,230,021; PCT Publication WO 2016/161168 (a-amino derivatives that lack the C5-methyl group); and U.S. Patent No.7,737,134 (desmethyl, desamino-pateamine A derivatives), each derivative of which is incorporated by reference in its entirety.

In still further embodiments, an eIF4A inhibitor is a site-directed eIF4A inhibitor. A "site-directed eIF4A inhibitor," as used herein, refers to an agent or compound that interacts with a specific nucleotide sequence of a mRNA molecule, such as a non-coding nucleotide sequence (e.g., located in the 5'-UTR of a target mRNA), and is capable of forming a stable ternary complex comprised of the site-directed eIF4A inhibitor, an eIF4A and a target mRNA. Exemplary site-directed eIF4A inhibitors include silverstrol, rocaglamide compounds, as well as analogs, derivatives, or precursors thereof.

Representative silverstrol derivatives and analogs include CR-1-31-B, hydroxamate derivative of silvestrol (Rodrigo et al., J. Med. Chem.55:558-562, 2012; which compounds are incorporated herein by reference in their entirety); episilvestrol (Hwang et al., J. Org. Chem.69:3350-3358, 2004; which compound is incorporated herein by reference in its entirety); Compounds 74 and 76 (Liu et al., J. Med. Chem.55:8859-8878, 2012, which compounds are incorporated herein by reference in their entirety), silvestrol dioxane, episilvesterol dioxane, Flavagline 61, (-)-4-desmethoxyepisilvestrol, and 1-O- formylaglafoline. Examples of rocaglates and precursors include aglapervirisin A and aglapervirisins B-J (An et al., Scientific Reports, Article No.20045, 2016). Further examples of naturally silvestrol and rocaglamide derivatives and analogs are described in Pan et al., Nat. Prod. Rep.31:924-939, 2014; Kim et al., Anticancer Agents Med. Chem. 6:319-45, 2006; and U.S. Patent Publication US 2014/0255432, compounds from which are incorporated herein by reference in their entirety.

Further examples of site-directed eIF4A inhibitors include compounds as disclosed in PCT Application No. PCT/US2016/063353, which compounds and synthetic methods disclosed therein are incorporated herein by reference in their entirety. In certain embodiments, site-directed eIF4A inhibitors include compounds according to Formula I,

,

or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

X is CR⁶R⁷, O, S, NH, N(C₁-C₈)alkyl, C(O), C=CR⁶R⁷, N(CO)R⁸, S(O) or S(O)₂; Y is a 5-membered heteroaryl or a 6-membered aryl or heteroaryl;

R¹ and R² independently are aryl, heterocyclyl, heteroaryl or cycloalkyl;

R^3a, R^3b, R^4a and R^4b independently are H, halogen, CN, C1-C8(alkyl), (C1- C₈)haloalkyl, C₂-C₈(alkenyl), (C₂-C₈)alkynyl, OR⁹, NHR⁹, NR⁹R⁹, [(C₁-C₈)alkylene]OR⁹, [(C1-C8)alkylene]NHR⁹, [(C1-C8)alkylene]NR⁹R⁹, C(O)R⁸, C(O)NHR⁹, C(O)NR⁹R⁹, C(O)[(C₁-C₈)alkylene]NHR⁹, C(O)[(C₁-C₈)alkylene]NR⁹R⁹, CO₂R⁹, C(S)NHR⁹,

C(S)NR⁹R⁹, SR⁹, S(O)R⁹, SO2R⁹, SO2NHR⁹, SO2NR⁹R⁹, NH(CO)R⁸, NR⁹(CO)R⁸, NH(CO)NHR⁹, NH(CO)NR⁹R⁹, NR⁹(CO)NHR⁹, NR⁹(CO)NR⁹R⁹, P(O)(OH)(OR⁹), P(O)(OR⁹) (OR⁹), aryl, heteroaryl, cycloalkyl or heterocyclyl;

R^3a and R^3b, and R^4a and R^4b independently combine to form oxo or alkenyl, or a cycloalkyl or heterocyclyl ring; or

R^3a and R^4a, R^3b and R^4b or R^4a and R⁵ together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring; or

R² and R^3a together with the carbon atom to which they are attached form a bicyclic ring system;

R⁵ is H, halogen, OH, CN, N₃, SR⁹, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, O(C₁-C₈)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkynyl, NHC(O)(C1-C8)alkyl or heteroaryl;

R⁶ and R⁷ independently are H, CN, halogen, OR⁹, SR⁹, (C₁-C₈)alkyl, NH(R⁹) or NR⁹R⁹; R⁸ is H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, cycloalkyl, O(cycloalkyl), heterocyclyl, O(heterocyclyl), aryl, O(aryl), heteroaryl or O(heteroaryl);

R⁹ is H, (C1-C8)alkyl, (C1-C8)haloalkyl, cycloalkyl, heterocyclyl, [(C1-C8)alkylene] heterocyclyl, aryl, [(C₁-C₈)alkylene] aryl or heteroaryl;

wherein the two R⁹’s together with the nitrogen atom to which they are attached of NR⁹R⁹, [(C₁-C₈)alkylene]NR⁹R⁹, C(O)NR⁹R⁹, C(O)[(C₁-C₈)alkylene]NR⁹R⁹, C(S)NR⁹R⁹, SO2NR⁹R⁹, NH(CO)NR⁹R⁹ or NR⁹(CO)NR⁹R⁹, optionally form a heterocyclyl ring;

wherein any alkyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, or 3 groups selected from OH, CN, SH , SO2NH2, SO2(C1-C4)alkyl, SO₂NH(C₁-C₄)alkyl, halogen, NH₂, NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, C(O)NH₂, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1-C8)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2- C₈)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, NH₂-C(O)-alkylene , NH(Me)-C(O)-alkylene, CH2-C(O)-lower alkyl, C(O)-lower alkyl, alkylcarbonylaminyl, CH₂-[CH(OH)]_m-(CH₂)_p-OH, CH₂-[CH(OH)]_m-(CH₂)_p-NH₂ or CH₂-aryl-alkoxy; or

wherein any alkyl, cycloalkyl or heterocyclyl is optionally substituted with oxo; "m" and "p" are 1, 2, 3, 4, 5 or 6; and

wherein when Y is a 6-membered aryl then X is not O.

In some embodiments, the 6-membered aryl or heteroaryl is

wherein

A¹ is N or CR¹⁰;

A² is N or CR¹¹;

A³ is N or CR¹²;

A⁴ is N or CR¹³; and R¹⁰, R¹¹, R¹² and R¹³ independently are H, halogen, C₁-C₈(alkyl), (C₁-C₈)haloalkyl, C(O)O(C1-C8)alkyl, C(O)(C1-C8)alkyl, SO2(C1-C8)alkyl, C2-C8(alkenyl), (C2-C8)alkynyl, OR⁹, NHR⁹, NR⁹R⁹, CN, [(C₁-C₈)alkylene]OR⁹, [(C₁-C₈)alkylene]NHR⁹, [(C₁- C8)alkylene]NR⁹R⁹, C(O)R⁸, C(O)NHR⁹, C(O)NR⁹R⁹, C(O)[(C1-C8)alkylene]NHR⁹, C(O)[(C₁-C₈)alkylene]NR⁹R⁹, CO₂R⁹, C(S)NHR⁹, C(S)NR⁹R⁹, SR⁹, S(O)R⁹, SO₂R⁹, SO2NHR⁹, SO2NR⁹R⁹, NH(CO)R⁸, NR⁹(CO)R⁸, NH(CO)NHR⁹, NH(CO)NR⁹R⁹,

NR⁹(CO)NHR⁹, NR⁹(CO)NR⁹R⁹, P(O)(OH)(OR⁹), P(O)(OR⁹) (OR⁹), aryl, heteroaryl, cycloalkyl or heterocyclyl.

In certain embodiments, the 5-membered heteroaryl is

wherein any two of B¹, B² and B³ are CR¹⁴ and N and the remaining B ring atom is N(R¹⁵) or S, wherein R¹⁴ is H, CN, halogen, OR⁹, SR⁹, (C₁-C₈)alkyl, C(O)O(C₁-C₈)alkyl, C(O)(C1-C8)alkyl, SO2(C1-C8)alkyl, SO2NR⁹R⁹, C(O)NR⁹R⁹, NR⁹R⁹ or NR⁹C(O)R⁸, and R¹⁵ is H or (C₁-C₈)alkyl.

In a particular embodiments, eIF4A inhibitor compounds of Formula I are selected from:

Rac-(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-3-methoxy-5a-(4-methoxyphenyl)-N,N- dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7- carboxamide (Cpd. No.1F),

(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6- phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.2F),

(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6- phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.3F), (5aR,6S,7R,8R,8aS)-3-cyano-8,8a-dihydroxy-5a-(4-methoxyphenyl)-N,N-dimethyl- 6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.4F),

(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-5a-(4-methoxyphenyl)-N,N-dimethyl- 6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.5F),

(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-3-methoxy-N,N-dimethyl- 6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.6F),

(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(p-tolyl)- 5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.7F), (5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(4- (trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7- carboxamide (Cpd. No.8F),

(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6-phenyl- 5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.9F), (5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-fluorophenyl)-8,8a-dihydroxy-N,N-dimethyl-6- phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.10F),

(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-8,8a-dihydroxy-N,N-dimethyl-6- phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.11F),

(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-5a-(4- (methylsulfonyl)phenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- b]pyridine-7-carboxamide (Cpd. No.12F),

Rac-(1R,2R,3S,3aR,8bS)-6-cyano-3a-(4-cyanophenyl)-1,8b-dihydroxy-N,N- dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]thiophene-2- carboxamide (Cpd. No.13F), Rac-(5aR,6S,7R,8R,8aS)-3-cyano-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N- dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7- carboxamide (Cpd. No.14F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-cyanophenyl)-4b,5-dihydroxy-2-methoxy-N,N- dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-b]pyridine-6- carboxamide (Cpd. No.15F),

(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-8,8a-dihydroxy-N,N- dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7- carboxamide (Cpd. No.16F),

(5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6-phenyl-5a-(4- (trifluoromethoxy)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7- carboxamide (Cpd. No.17F),

(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-6-phenyl- 5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No. 18F),

Rac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-N,N- dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7- carboxamide (Cpd. No.19F),

(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N-methyl-6- phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.20F),

Rac-methyl (4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-methyl-5- phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxylate (Cpd. No.21F),

Rac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N- dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7- sulfonamide ( Cpd. No.22F),

(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2-trimethyl-5-phenyl- 2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide (Cpd. No.23F), Rac-methyl (5aR,6R,6aS,7aS,7bR)-3-chloro-5a-(4-cyanophenyl)-7b-hydroxy-6- phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4',5']cyclopenta[1',2':4,5]furo[3,2-b]pyridine- 6a(6H)-carboxylate (Cpd. No.24F),

Rac-methyl (5aR,6R,6aS,7aS,7bR)-3-chloro-5a-(4-cyanophenyl)-7b-hydroxy-6- phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4',5']cyclopenta[1',2':4,5]furo[3,2-b]pyridine- 6a(6H)-carboxylate (Cpd. No.25F),

Rac-4-((5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-7-(oxazol-2-yl)-6-phenyl- 6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No. 26F),

Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl- 5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbothioamide (Cpd. No. 27F),

Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-6-phenyl- 5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carbothioamide (Cpd. No. 28F),

Rac-(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-3,8,8a-trihydroxy-N,N-dimethyl-6- phenyl-2-(trifluoromethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7- carboxamide (Cpd. No.29F),

Rac-4-((5aR,6S,7S,8R,8aS)-7-(aminomethyl)-3-chloro-8,8a-dihydroxy-6-phenyl- 6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No. 30F),

Rac-(5aR,6R,6aS,7aS,7bR)-3-chloro-5a-(4-cyanophenyl)-7b-hydroxy-N,N- dimethyl-6-phenyl-5a,7,7a,7b-tetrahydrocyclopropa[4',5']cyclopenta[1',2':4,5]furo[3,2- b]pyridine-6a(6H)-carboxamide (Cpd. No.31F),

Rac-(5aR,6S,7R,8aR)-3-chloro-5a-(4-cyanophenyl)-8a-hydroxy-N,N-dimethyl-8- oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.32F),

Rac-(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N,8- trimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7- carboxamide (Cpd. No.33Fa) and Rac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)- 8,8a-dihydroxy-N,N,8-trimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H- cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.33Fb),

Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8-methylene-6-phenyl-5a,6,7,8- tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol (Cpd. No.34F),

Rac-(5aR,6R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8-methoxy-N,N- dimethyl-6-phenyl-5a,8a-dihydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.35F),

Rac-(4aR,5S,6R,7R,7aS)-3-chloro-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2- trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6- carboxamide (Cpd. No.36F),

Rac-(4aR,5S,6R,7R,7aS)-4a-(4-bromophenyl)-3-chloro-7,7a-dihydroxy-N,N,2- trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6- carboxamide (Cpd. No.37F),

Rac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-6,7- dihydrospiro[cyclopenta[4,5]furo[3,2-b]pyridine-8,2'-oxetan]-8a(5aH)-ol (Cpd. No.38F), Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-7-((methylamino)methyl)-6- phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No.39F),

Rac-4-((5aR,6S,7R,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-6- phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No.40Fa), rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a- dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a- yl)benzonitrile (Cpd. No.40Fb), and rac-4-((5aR,6S,7S,8S,8aS)-3-chloro-7- ((dimethylamino)methyl)-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro-5aH- cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No.40Fc)

Rac-4-((5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1- ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No.41Fa), rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7- (pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a- yl)benzonitrile (Cpd. No.41Fb), and rac-4-((5aR,6S,7S,8S,8aS)-3-chloro-8,8a-dihydroxy- 6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2- b]pyridin-5a-yl)benzonitrile (Cpd. No.41Fc),

Rac-(1R,2R,3S,3aR,8bS)-8b-azido-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)- N,N-dimethyl-3-phenyl-2,3-dihydro-1H-cyclopenta[b]benzofuran-2-carboxamide (Cpd. No.42F),

Rac-methyl (5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8a-fluoro-8- hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7- carboxylate (Cpd. No.43F),

Rac-(1R,2R,3S,3aR,8bS)-8b-amino-1-hydroxy-6-methoxy-3a-(4-methoxyphenyl)- N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-carboxamide (Cpd. No.44F),

Rac-(1R,2R,3S,3aR,8bS)-8b-acetamido-1-hydroxy-6-methoxy-3a-(4- methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3,3a,8b-tetrahydro-1H- cyclopenta[b]benzofuran-2-carboxamide (Cpd. No.45F),

Rac-dimethyl 2-[[(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-8- oxo-6-phenyl-6,7-dihydrocyclopenta[4,5]furo[1,2-b]pyridin-7-yl]methyl]propanedioate (Cpd. No.46F),

Rac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,7,8,8a- tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8-carbonitrile (Cpd. No.47F),

Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8-ethynyl-6-phenyl-5a,6,7,8- tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol (Cpd. No.48F),

Rac-methyl (5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-cyano-8a- hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7- carboxylate (Cpd. No.49F),

Rac-methyl (5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy- 6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate (Cpd. No.50F), Rac-(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-N,N- dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7- carboxamide (Cpd. No.51F),

Rac-(5aR,6S,7R,8R,8aR)-3-chloro-8-cyano-5a-(4-cyanophenyl)-8a-hydroxy-6- phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.52F),

Rac-(3aR,3bS,8aR,9R,9aR)-8a-(4-bromophenyl)-6-chloro-3b-hydroxy-9-phenyl- 1,3a,3b,8a,9,9a-hexahydro-2H-oxazolo[4'',5'':4',5']cyclopenta[1',2':4,5]furo[3,2-b]pyridin- 2-one (Cpd. No.53F),

Rac-4-((3aR,3bS,8aR,9R,9aR)-6-chloro-3b-hydroxy-2-oxo-9-phenyl-1,2,3a,3b,9,9a- hexahydro-8aH-oxazolo[4'',5'':4',5']cyclopenta[1',2':4,5]furo[3,2-b]pyridin-8a- yl)benzonitrile (Cpd. No.54F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-6- phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No. 55F),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-7-(hydroxymethyl)-6-phenyl- 6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No. 56F),

Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-methyl-6-phenyl-5a,6,7,8- tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No.57F),

Rac-methyl (5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7-fluoro-8,8a- dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7- carboxylate (Cpd. No.58F),

Rac-methyl (5aR,6S,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-7-fluoro-8,8a-dihydroxy- 6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxylate

No.59F),

Rac-(2aS,3S,3aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-3-phenyl-2a,3,3a,8c- tetrahydrooxeto[3'',2'':4',5']cyclopenta[1',2':4,5]furo[3,2-b]pyridin-8b(2H)-ol (Cpd. No. 60F), Rac-(2aS,3S,3aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-3-phenyl-2a,3,3a,8c- tetrahydrooxeto[3'',2'':4',5']cyclopenta[1',2':4,5]furo[3,2-b]pyridin-8b(2H)-ol (Cpd. No. 61F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(methoxymethyl)-6- phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No. 62F),

Rac-(1aS,3S,3aR,8bS)-3a-(4-bromophenyl)-6-chloro-3-phenyl-1a,2,3,3a-tetrahydro- oxireno[2'',3'':1',5']cyclopenta[1',2':4,5]furo[3,2-b]pyridine (Cpd. No.63F),

(4bS,5R,6R,7S,7aR)-7a-(4-Cyanophenyl)-4b,5-dihydroxy-4-methoxy-N,N-dimethyl- 7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide (Cpd. No.64F),

Rac-4-((4bS,5R,6S,7S,7aR)-6-(aminomethyl)-4b,5-dihydroxy-4-methoxy-7-phenyl- 5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No. 65F),

4-((4bS,5R,6S,7S,7aR)-6-((Dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.66F),

4-((4bS,5R,6S,7S,7aR)-4b,5-Dihydroxy-4-methoxy-7-phenyl-6-(piperazin-1- ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.67F),

Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((4-methylpiperazin-1- yl)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.68F),

Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methylamino)methyl)- 7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.69F),

Rac-4-((4bS,5R,6S,7S,7aR)-6-((ethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)cyclohexa-1,3- diene-1-carbonitrile (Cpd. No.70F), Rac-4-((4bS,5R,6S,7S,7aR)-6-(azetidin-1-ylmethyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.71F),

Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(pyrrolidin-1- ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.72F),

4-((4bS,5R,6S,7S,7aR)-6-((Diethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.73F),

Rac-4-((4bS,5R,6S,7S,7aR)-6-((ethyl(methyl)amino)methyl)-4b,5-dihydroxy-4- methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.74F),

Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2- hydroxyethyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH- cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.75F),

Rac-4-((4bS,5R,6S,7S,7aR)-6-((benzyl(methyl)amino)methyl)-4b,5-dihydroxy-4- methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.76F),

Rac-4-((4bS,5R,6S,7S,7aR)-6-((benzylamino)methyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.77F),

Rac-4-((5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(((pyridin-3- ylmethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.78F),

Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxyethyl)amino)methyl)-4- methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.79F), Rac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-isopropyl-N,N- dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6- carboxamide (Cpd. No.80F),

4-((3aR,4R,4aR,9bS,9cR)-9b-Hydroxy-9-methoxy-2-oxo-4-phenyl-2,3,3a,4,9b,9c- hexahydro-4aH-oxazolo[4'',5'':4',5']cyclopenta[1',2':4,5]furo[2,3-c]pyridin-4a- yl)benzonitrile (Cpd. No.81F),

Rac-(4aR,5S,6R,7R,7aS)-3-cyano-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N,2- trimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6- carboxamide (Cpd. No.82F),

4-((5aR,6S,7R,8S,8aS)-3-Chloro-8,8a-dihydroxy-6-phenyl-7-(pyrrolidin-1- ylsulfonyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No.83F),

Rac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7-(methylsulfonyl)-6- phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No. 84F),

Rac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-7-(methylsulfonyl)-6-phenyl- 6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No. 85F),

(5aR,6S,7R,8S,8aS)-5a-(4-Cyanophenyl)-8,8a-dihydroxy-7-(methylsulfonyl)-6- phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrile (Cpd. No.86F),

Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6- yl)(morpholino)methanone (Cpd. No.87F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N- methyl-7-phenyl-N-(2,2,2-trifluoroethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3- c]pyridine-6-carboxamide (Cpd. No.88F), Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-cyclopropyl-4b,5-dihydroxy-4- methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6- carboxamide (Cpd. No.89F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl- N-(2,2,2-trifluoroethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6- carboxamide (Cpd. No.90F),

Rac-(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-7,7-difluoro-6-phenyl-5a,6,7,8- tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No.91F),

Rac-(5aR,6R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6- dihydrospiro[cyclopenta[4,5]furo[3,2-b]pyridine-7,1'-cyclopropane]-8,8a(8H)-diol (Cpd. No.92F),

Rac-(5aR,6S,7R,8S,8aS)-7-(benzylsulfonyl)-5a-(4-bromophenyl)-3-chloro-6- phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No. 93F),

Rac-4-((5aR,6S,7R,8S,8aS)-7-(benzylsulfonyl)-3-chloro-8,8a-dihydroxy-6-phenyl- 6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No. 94F),

(4bS,5R,6R,7S,7aR)-7a-(4-Cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7-phenyl- 4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide (Cpd. No. 95F),

Rac-(4bS,5R,6R,7S,7aR)-4-cyano-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,N- dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6- carboxamide (Cpd. No.96F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4-chloro-4b,5-dihydroxy-N,N- dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6- carboxamide (Cpd. No.97F),

(4bS,5R,6R,7S,7aR)-4-Chloro-7a-(4-cyanophenyl)-4b,5-dihydroxy-N,N-dimethyl-7- phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide (Cpd. No.98F), Rac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-2-(4-methoxybenzyl)- N,N-dimethyl-5-phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6- carboxamide (Cpd. No.99F),

Rac-(4aR,5S,6R,7R,7aS)-4a-(4-cyanophenyl)-7,7a-dihydroxy-N,N-dimethyl-5- phenyl-2,4a,5,6,7,7a-hexahydrocyclopenta[4,5]furo[3,2-c]pyrazole-6-carboxamide (Cpd. No.100F),

Rac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-6-(methylsulfonyl)-7- phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No. 101F),

4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(methylsulfonyl)-7-phenyl- 4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No. 102F),

4-((4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.103F),

(5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,N-dimethyl-6- phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-carboxamide (Cpd. No.104F),

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8,8a- dihydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3- carbonitrile (Cpd. No.105F),

(4bS, 5R, 6S, 7S, 7aR)-7a-(4-(difluoromethyl)phenyl)-6-((dimethylamino)methyl)- 4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No.106F),

(4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(4- (trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5- diol (Cpd. No.107F), (5aR,6S,7R,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7- ((dimethylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2- b]pyridine-8,8a-diol (Cpd. No.108F),

(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-6-phenyl-5a-(4- (trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a- diol (Cpd. No.109F),

4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(morpholinomethyl)-7-phenyl- 4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No. 110F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2,2-difluoroethyl)-4b,5- dihydroxy-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H- cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide (Cpd. No.111F),

4-((4bS,5R,6S,7S,7aR)-6-(((2,2-difluoroethyl)(methyl)amino)methyl)-4b,5- dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.112F),

4-((4bS,5R,6S,7S,7aR)-6-((4,4-difluoropiperidin-1-yl)methyl)-4b,5-dihydroxy-4- methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.113F),

Rac-((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R,7S,7aR)-7a-(4- bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H- cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone (Cpd. No.114F),

4-((4bS,5R,6S,7S,7aR)-6-(((2,2-difluoroethyl)amino)methyl)-4b,5-dihydroxy-4- methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.115F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2,2-difluoroethyl)-4b,5- dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3- c]pyridine-6-carboxamide (Cpd. No.116F), Rac-(4bS,5S,6R,7S,7aR)-7a-(4-bromophenyl)-4-methoxy-7-phenyl-6-((2,2,2- trifluoroethyl)sulfonyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5- diol (Cpd. No.117F),

Rac-4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6- (phenylsulfonyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.118F),

Rac-4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(pyridin-2- ylsulfonyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.119F),

4-((4bR,5R,7S,7aR)-4b-hydroxy-5-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7- tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.120F), Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(3,3- difluoroazetidin-1-yl)methanone (Cpd. No.121F),

4-((4bS,5R,6S,7S,7aR)-6-((3,3-difluoroazetidin-1-yl)methyl)-4b,5-dihydroxy-4- methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl) benzonitrile (Cpd. No.122F),

Rac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N-methyl-6- phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide (Cpd. No.123F),

Rac-(5aR,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N-methyl-6- phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide (Cpd. No.124F),

Rac-(5aR,6S,7R,8S,8aS)-3-chloro-5a-(4-cyanophenyl)-8,8a-dihydroxy-N-methyl-6- phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7-sulfonamide (Cpd No.125F),

4-((4bS,5S,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(morpholinosulfonyl)-7- phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.126F), Rac-(5aR,6S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro- 8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No.127F),

Rac-4-((5aR,6S,8R,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro- 5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No.128F),

Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl-5a,6,7,8a- tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-one (Cpd. No.129F),

Rac-(5aR,6S,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6,7,8-tetrahydro- 8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No.130F),

Rac-4-((5aR,6S,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-6,7,8,8a-tetrahydro- 5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No.131F),

Rac-N'-((5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8a-hydroxy-6-phenyl- 5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-b]pyridin-8-ylidene)-4- methylbenzenesulfonohydrazide (Cpd. No.132F),

Rac-(5aR,6S,8aR)-5a-(4-bromophenyl)-3-chloro-6-phenyl-5a,6-dihydro-8aH- cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol (Cpd. No.133F),

Rac-methyl (4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate (Cpd. No.134F),

Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(4,4- difluoropiperidin-1-yl)methanone (Cpd. No.135F),

Rac-methyl (5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1- methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7- carboxylate (Cpd. No.136F),

Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy- N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7- carboxamide (Cpd. No.137F), Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)- 1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No.138F),

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8,8a- dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.139F),

4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-1- methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a- yl)benzonitrile (Cpd. No.140F),

Rac-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy- 6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No.141F),

Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)- 1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No.142F),

Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7- ((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH- cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No.143F),

Rac-(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl- 5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2- c]pyridine-8,8a-diol (Cpd. No.144F),

(5aR,6S,7S,8R,8aS)-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-8,8a- dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.145F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7- ((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H- cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No.146F), (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6- phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.147F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7- ((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH- cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No.148F),

Rac-(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4- (trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a- diol (Cpd. No.149F),

Rac-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy- 3-(methylamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a- yl)benzonitrile (Cpd. No.150F),

(5aR,6S,7S,8R,8aS)-5a-(4-Cyanophenyl)-8,8a-dihydroxy-1-methoxy-7- (morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine- 3-carbonitrile (Cpd. No.151F),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7- (morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin- 5a-yl)benzonitrile (Cpd. No.152F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropyrrolidin-1- yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H- cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No.153F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropiperidin-1- yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H- cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No.154F),

Rac-(5aR,6S,7S,8R,8aS)-7-((tert-butylamino)methyl)-5a-(4-cyanophenyl)-8,8a- dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.155F), Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((4-fluoropiperidin-1-yl)methyl)- 8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.156aF),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4-fluoropiperidin-1-yl)methyl)-8,8a- dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2- c]pyridin-5a-yl)benzonitrile (Cpd. No.156bF),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4-fluoropiperidin-1-yl)methyl)- 8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.156cF),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((4,4-difluoropiperidin-1- yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H- cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No.157aF),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a- dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2- c]pyridin-5a-yl)benzonitrile (Cpd. No.157bF),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4,4-difluoropiperidin-1- yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H- cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No.157cF),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl- 7-(pyrrolidin-1-ylmethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3- carbonitrile (Cpd. No.158aF),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-7- (pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a- yl)benzonitrile (Cpd. No.158bF),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl- 7-(pyrrolidin-1-ylmethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3- carbonitrile (Cpd. No.158cF), Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((diethylamino)methyl)-8,8a- dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.159aF),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((diethylamino)methyl)-8,8a-dihydroxy-1- methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a- yl)benzonitrile (Cpd. No.159bF),

R,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((diethylamino)methyl)-8,8a- dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.159cF),

R,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2- ylthio)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No. 160aF),

Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2- ylthio)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No. 160bF),

Rac-methyl (1aS,2R,3S,3aR,8bS)-3a-(4-bromophenyl)-6-chloro-3-phenyl-1a,2,3,3a- tetrahydro-oxireno[2'',3'':1',5']cyclopenta[1',2':4,5]furo[3,2-b]pyridine-2-carboxylate (Cpd. No.161F),

Rac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-(hydroxymethyl)-6-phenyl- 5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol (Cpd. No.162F),

R,6S,7R,8S,8aS)-5a-(4-bromophenyl)-3-chloro-6-phenyl-7-(pyridin-2- ylsulfonyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridine-8,8a-diol (Cpd. No.163F),

Rac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyridin-2- ylsulfonyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No.164F),

Rac-(5aR,6S,8S,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl- 5a,6,7,8-tetra-hydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol (Cpd. No.165), Rac-(5aR,6S,8S,8aR)-5a-(4-bromophenyl)-3-chloro-8-(hydroxymethyl)-6-phenyl- 5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol (Cpd. No.166F),

Rac-4-((5aR,6S,8R,8aR)-3-chloro-8a-hydroxy-8-(hydroxymethyl)-6-phenyl- 6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No. 167F),

Rac-4-((5aR,6S,8S,8aR)-3-chloro-8a-hydroxy-8-(hydroxymethyl)-6-phenyl- 6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No. 168F),

Rac-(2aR,3S,3aR,8bS,8cR)-3a-(4-bromophenyl)-6-chloro-8b-hydroxy-3-phenyl- 3,3a,8b,8c-tetrahydrooxeto[3'',2'':4',5']cyclopenta[1',2':4,5]furo[3,2-b]pyridin-2(2aH)-one (Cpd. No.169F),

Rac-(4bR,5R,6R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-6- (hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3- c]pyridin-4b-ol (Cpd. No.170F),

Rac-4-((4bR,5R,6R,7S,7aR)-5-(aminomethyl)-4b-hydroxy-6-(hydroxymethyl)-4- methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.171F),

Rac-(4bR,5R,7S,7aR)-5-(aminomethyl)-7a-(4-bromophenyl)-4-methoxy-7-phenyl- 5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol (Cpd. No.172F),

Rac-4-((4bR,5R,7S,7aR)-5-(aminomethyl)-4b-hydroxy-4-methoxy-7-phenyl- 4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No. 173F),

Rac-(5aR,6S,8R,8aR)-8-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-6-phenyl- 5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol (Cpd. No.174F),

Rac-4-((5aR,6S,8R,8aR)-8-(aminomethyl)-3-chloro-8a-hydroxy-6-phenyl-6,7,8,8a- tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No.175F), Rac-(5aR,6S,8R,8aR)-8-(aminomethyl)-5a-(4-cyanophenyl)-8a-hydroxy-6-phenyl- 5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-3-carbonitrile (Cpd. No. 176F), Rac-(5aR,6S,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-(morpholinomethyl)-6- phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-b]pyridin-8a-ol (Cpd. No.177F), Rac-4-((5aR,6S,8R,8aR)-3-chloro-8a-hydroxy-8-(morpholinomethyl)-6-phenyl- 6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No. 178F),

Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5- (morpho-linomethyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin- 4b-ol (Cpd. No.179F),

Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5- (morpholino-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin- 7a-yl)benzonitrile (Cpd. No.180F),

Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-(((2,2- difluoroethyl)amino)methyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro- 4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol (Cpd. No.181F),

Rac-4-((4bR,5R,6R,7S,7aR)-5-(((2,2-difluoroethyl)amino)methyl)-4b-hydroxy-6- (hydroxyl-methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.182F),

Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5-((4- methylpiperazin-1-yl)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3- c]pyridin-4b-ol (Cpd. No.183F),

Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((4- methyl-piperazin-1-yl)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.184F),

Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5- ((oxetan-3-ylamino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3- c]pyridin-4b-ol (Cpd. No.185F),

Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((oxetan- 3-ylamino)-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin- 7a-yl)-benzonitrile (Cpd. No.186F), Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-7- phenyl-5-(((pyridin-4-ylmethyl)amino)methyl)-5,6,7,7a-tetrahydro-4bH- cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol (Cpd. No.187F),

Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl- 5-(((pyridin-4-ylmethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.188F),

Rac-4-((5aR,6S,7R,8S,8aS)-3-chloro-8,8a-dihydroxy-6-phenyl-7-(pyridin-2-ylthio)- 6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-b]pyridin-5a-yl)benzonitrile (Cpd. No. 189F),

Rac-(5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8-ethynyl-8,8a-dihydroxy-N,N- dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7- carboxamide (Cpd. No.190F),

Rac-(5aR,6S,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-N,N-dimethyl-6- phenyl-8-(prop-1-yn-1-yl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-7- carboxamide (Cpd. No.191F),

Rac-(4bR,7S,7aR)-7a-(4-bromophenyl)-4b-hydroxy-4-methoxy-N,N-dimethyl-5- oxo-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide (Cpd. No.192F),

Rac-methyl (4bS,5R,6R,7aR)-4b,5-dihydroxy-7a-(4-iodophenyl)-4-methoxy-7- phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxylate (Cpd. No.193F),

Rac-4-((4bS,5R,6S,7S,7aR)-6-((4-acetylpiperazin-1-yl)methyl)-4b,5-dihydroxy-4- methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.194F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-(((2,2- difluoroethyl)amino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH- cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No.195F), Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-8,8a- dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2- c]pyridin-5a-yl)benzonitrile (Cpd. No.196F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2-difluoroethyl)amino)methyl)- 8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.197F),

4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-((4-methylpiperazin- 1-yl)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a- yl)benzonitrile (Cpd. No.198aF),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-((4- methylpiperazin-1-yl)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.198bF),

Rac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-7-(hydroxymethyl)-1- methoxy-8-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH- cyclopenta[4,5]furo[3,2-c]pyridin-8a-ol (Cpd. No.199F),

Rac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8a-hydroxy-7-(hydroxymethyl)-1- methoxy-8-(morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H- cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No.200F),

Rac-(4bR,5R,6R,7S,7aR)-5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-7a-(4- bromophenyl)-6-(hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH- cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol (Cpd. No.201F),

Rac- 4-((4bR,5R,6R,7S,7aR)-5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-4b- hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH- cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.202F),

Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-6-(hydroxymethyl)-4-methoxy-5- ((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-5,6,7,7a-tetrahydro-4bH- cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol (Cpd. No.203F), Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-((((1- methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH- cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.204F),

Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-((dimethylamino)methyl)-6- (hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3- c]pyridin-4b-ol (Cpd. No.205F),

Rac-4-((4bR,5R,6R,7S,7aR)-5-((dimethylamino)methyl)-4b-hydroxy-6- (hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.206F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)- 8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.207aF),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a- dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2- c]pyridin-5a-yl)benzonitrile (Cpd. No.207bF),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2- difluoroethyl)(methyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a- tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No.208aF),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)(methyl)amino)methyl)- 8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2- c]pyridin-5a-yl)benzonitrile (Cpd. No.208bF),

Rac-(5aR,6S,7R,8R,8aR)-5a-(4-bromophenyl)-3-chloro-8-((dimethylamino)methyl)- 7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2- c]pyridin-8a-ol (Cpd. No.209F),

Rac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8-((dimethylamino)methyl)-8a- hydroxy-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H- cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No.210F), Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3-fluoroazetidin-1-yl)methyl)- 8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.211aF),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3-fluoroazetidin-1-yl)methyl)-8,8a- dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2- c]pyridin-5a-yl)benzonitrile (Cpd. No.211bF),

(5aR,6S,7S,8R,8aS)-7-(Azetidin-1-ylmethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1- methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3- carbonitrile (Cpd. No.212F),

Rac-(5aR,6S,7R,8R,8aR)-5a-(4-cyanophenyl)-8-((4,4-difluoropiperidin-1- yl)methyl)-8a-hydroxy-7-(hydroxymethyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H- cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No.213F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((3,3- dimethylmorpholino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2- b]pyridine-8,8a-diol (Cpd. No.214F),

Rac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1- methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3- (difluoromethyl)azetidin-1-yl)methanone (Cpd. No.215F),

Rac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1- methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(3- (difluoromethyl)azetidin-1-yl)methanone (Cpd. No.216F),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3-(difluoromethyl)azetidin-1-yl)methyl)- 8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2- c]pyridin-5a-yl)benzonitrile (Cpd. No.217F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3-(difluoromethyl)azetidin-1- yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H- cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No.218F), Rac-((5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1- methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)(1,1- difluoro-4-azaspiro[2.3]hexan-4-yl)methanone (Cpd. No.219F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-7-((1,1-difluoro-4- azaspiro[2.3]hexan-4-yl)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH- cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No.220F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((1,1-difluoro-4-azaspiro[2.3]hexan- 4-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H- cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No.221F),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((1,1-difluoro-4-azaspiro[2.3]hexan-4- yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH- cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No.222F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-3-chloro-1-methoxy-7- ((methylamino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2- c]pyridine-8,8a-diol (Cpd. No.223F),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7- ((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2- c]pyridin-5a-yl)benzonitrile (Cpd. No.224F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-7- ((methylamino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.225F),

Rac-(4bR,5R,6R,7S,7aR)-7a-(4-bromophenyl)-5-((tert-butylamino)methyl)-6- (hydroxymethyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3- c]pyridin-4b-ol (Cpd. No.226F),

Rac-(5aR,6S,7R,8S,8aR)-5a-(4-bromophenyl)-3-chloro-7-((dimethylamino)methyl)- 8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8- carbonitrile (Cpd. No.227F), Rac-(5aR,6S,7R,8S,8aR)-3-chloro-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)- 8a-hydroxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-b]pyridine-8- carbonitrile (Cpd. No.228F),

Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N- dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7- carboxamide (Cpd. No.229F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3- dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No.230F),

4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy- 6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No.231F),

Rac-4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8,8a-dihydroxy-1,3- dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a- yl)benzonitrile (Cpd. No.232F),

4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(2,2,2- trifluoroethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.233F),

Rac-(4bR,5R,7S,7aR)-7a-(4-(aminomethyl)phenyl)-5-(hydroxymethyl)-4-methoxy- 7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol (Cpd. No. 234F),

Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(2-oxa-6- azaspiro[3.3]heptan-6-yl)methanone (Cpd. No.235F),

Rac-4-((4bS,5R,6S,7S,7aR)-6-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-4b,5- dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.236F), Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N- methyl-N-(oxetan-3-yl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3- c]pyridine-6-carboxamide (Cpd. No.237F),

Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(oxetan-3- yl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.238F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N- (oxetan-3-yl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6- carboxamide (Cpd. No.239F),

Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((oxetan-3- ylamino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.240F),

Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((((1-methyl-1H-pyrazol- 5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.241F),

Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((((1-methyl-1H-pyrazol- 5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.242F),

4-((4bS,5R,6S,7S,7aR)-6-((tert-butyl(methyl)amino)methyl)-4b,5-dihydroxy-4- methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.243F),

Rac-4-((4bS,5R,6S,7S,7aR)-6-((cyclopropylamino)methyl)-4b,5-dihydroxy-4- methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.244F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-cyclopropyl-4b,5-dihydroxy-4- methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine- 6-carboxamide (Cpd. No.245F), Rac-4-((4bS,5R,6S,7S,7aR)-6-((cyclopropyl(methyl)amino)methyl)-4b,5- dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.246F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-N-(2-fluoroethyl)-4b,5-dihydroxy-4- methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine- 6-carboxamide (Cpd. No.247F),

4-((4bS,5R,6S,7S,7aR)-6-(((2-fluoroethyl)(methyl)amino)methyl)-4b,5-dihydroxy- 4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.248F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N- methyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H- cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide (Cpd. No.249F),

4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl((1-methyl-1H- pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH- cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.250F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxy-2- methylpropyl)-4-methoxy-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H- cyclopenta[4,5]furo[2,3-c]pyridine-6-carboxamide (Cpd. No.251F),

4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxy-2- methylpropyl)(methyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH- cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.252F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-N-(2-hydroxy-2- methylpropyl)-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3- c]pyridine-6-carboxamide (Cpd. No.253F),

4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-6-(((2-hydroxy-2- methylpropyl)amino)methyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH- cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.254F), Rac-(4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(p- tolyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No. 255F),

(4bS,5R,6S,7S,7aR)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(p-tolyl)- 5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No.256F), Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(piperidin-1- yl)methanone (Cpd. No.257F),

4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(piperidin-1- ylmethyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.258F),

Rac-4-((4bS,5R,6S,7S,7aR)-6-(((2-fluoroethyl)amino)methyl)-4b,5-dihydroxy-4- methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.259F),

Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(2- methoxyethyl)-N-methyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3- c]pyridine-6-carboxamide (Cpd. No.260F),

4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(((2- methoxyethyl)(methyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH- cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.261F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N-(2- methoxyethyl)-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6- carboxamide (Cpd. No.262F),

4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-(((2- methoxyethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile hydrochloride (Cpd. No.263F),

Rac-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)((4bS,5R,6R,7S,7aR)-7a-(4- bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H- cyclopenta[4,5] furo[2,3-c]pyridin-6-yl)methanone (Cpd. No.264F), 4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl) methyl)- 4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta [4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.265F),

Rac-((1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)((4bS,5R,6R,7S,7aR)-7a-(4- bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H- cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone (Cpd. No.266F),

Rac-4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-oxa-6-azabicyclo[3.1.1]heptan-6- yl)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH- cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.267F),

4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-4b,5- dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.268F),

Rac-(3aR,4R,4aR,9bS,9cR)-4a-(4-(difluoromethyl)phenyl)-9b-hydroxy-9-methoxy- 4-phenyl-3,3a,4,4a,9b,9c-hexahydro-2H-oxazolo[4'',5'':4',5']cyclopenta[1',2':4,5]furo[2,3- c]pyridin-2-one (Cpd. No.269F),

Rac-(4bS,5R,6R,7R,7aR)-6-amino-7a-(4-(difluoromethyl)phenyl)-4-methoxy-7- phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No. 270F),

Rac-((4bS,5R,6R,7S,7aR)-7a-(4-chlorophenyl)-4b,5-dihydroxy-4-methoxy-N,N- dimethyl-7-phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridine-6- carboxamide (Cpd. No.271F),

(4bS,5R,6S,7S,7aR)-7a-(4-Chlorophenyl)-6-((dimethylamino)methyl)-4-methoxy-7- phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No. 272F),

Rac-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)((4bS,5R,6R,7S,7aR)-7a-(4- bromophenyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,6,7,7a-tetrahydro-5H- cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)methanone (Cpd. No.273F), 4-((4bS,5R,6S,7S,7aR)-6-((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)-4b,5- dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.274F),

Rac-(3aR,4S,4aR,9bS,9cR)-4a-(4-bromophenyl)-9b-hydroxy-9-methoxy-4-phenyl- 3,3a,4,4a,9b,9c-hexahydro-2H-furo[3'',2'':4',5']cyclopenta[1',2':4,5]furo[2,3-c]pyridin-2-one (Cpd. No.275F),

Rac-4-((4bS,5R,6R,7S,7aR)-6-(2-(dimethylamino)ethyl)-4b,5-dihydroxy-4- methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.276F),

Rac-(4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-N- methyl-7-phenyl-N-(pyridin-3-ylmethyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3- c]pyridine-6-carboxamide (Cpd. No.277F),

4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-6-((methyl(pyridin-3- ylmethyl)amino)methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3- c]pyridin-7a-yl)benzonitrile (Cpd. No.278F),

Rac-((4bS,5R,6R,7S,7aR)-7a-(4-bromophenyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6-yl)(3,3- difluoropyrrolidin-1-yl)methanone (Cpd. No.279F),

4-((4bS,5R,6S,7S,7aR)-6-((3,3-difluoropyrrolidin-1-yl)methyl)-4b,5-dihydroxy-4- methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a- yl)benzonitrile (Cpd. No.280F),

Rac-((4bS,5R,6R,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-7a-(4- (trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3-c]pyridin-6- yl)(morpholino)methanone (Cpd. No.281F),

(4bS,5R,6S,7S,7aR)-4-Methoxy-6-(morpholinomethyl)-7-phenyl-7a-(4- (trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5- diol (Cpd. No.282F), Rac-(4bS,5R,6S,7S,7aR)-4-methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl- 7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3- c]pyridine-4b,5-diol (Cpd. No.283F),

(4bS,5R,6S,7S,7aR)-4-Methoxy-6-((4-methylpiperazin-1-yl)methyl)-7-phenyl-7a- (4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine- 4b,5-diol (Cpd. No.284F),

Rac-(4bS,5R,6R,7S,7aR)-N-(2,2-difluoroethyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-7a-(4-(trifluoromethyl)phenyl)-4b,6,7,7a-tetrahydro-5H-cyclopenta[4,5]furo[2,3- c]pyridine-6-carboxamide (Cpd. No.285F),

(4bS,5R,6S,7S,7aR)-6-(((2,2-Difluoroethyl)amino)methyl)-4-methoxy-7-phenyl-7a- (4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine- 4b,5-diol (Cpd. No.286F),

Rac-4-((4bS,5R,7S,7aR)-4b,5-dihydroxy-4-methoxy-5-(morpholinomethyl)-7- phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.287F),

(5aR,6S,7S,8R,8aS)-5a-(4-Cyanophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)- 8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.288F),

Rac-(4bR,7S,7aR)-4-methoxy-5-(morpholinomethyl)-7-phenyl-7a-(4- (trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridin-4b-ol (Cpd. No.289F),

4-((4bS,5R,6S,7S,7aR)-6-((tert-butylamino)methyl)-4b,5-dihydroxy-4-methoxy-7- phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No.290F),

4-((4bS,5R,6S,7S,7aR)-4b,5-dihydroxy-4-methoxy-7-phenyl-6-(((2,2,2- trifluoroethyl)amino)methyl)-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin- 7a-yl)benzonitrile (Cpd. No.291F), Rac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-bromophenyl)-3-chloro-1- methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No.292F),

Rac-(5aR,6S,7S,8R,8aS)-7-(aminomethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1- methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3- carbonitrile (Cpd. No.293F),

Rac-4-((5aR,6S,7S,8R,8aS)-7-(aminomethyl)-3-chloro-8,8a-dihydroxy-1-methoxy- 6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No.294F), and

Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-3-chloro-8,8a-dihydroxy-1-methoxy- 6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylic acid (Cpd. No.295F).

In another embodiment, the compounds according to Formula I are selected from (5aR,6S,7S,8R,8aS)-7-((Dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a- (4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3- carbonitrile (Cpd. No.147F),

Rac-(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl- 5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2- c]pyridine-8,8a-diol (Cpd. No.144F), Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7- ((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH- cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No.143F),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-8,8a- dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2- c]pyridin-5a-yl)benzonitrile (Cpd. No.196F),

4-((5aR,6S,7S,8R,8aS)-7-((Dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy- 6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No.231F), Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((diethylamino)methyl)-8,8a-dihydroxy-1- methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a- yl)benzonitrile (Cpd. No.159bF),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7- ((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H- cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No.146F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((diethylamino)methyl)-8,8a- dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c]pyridine-3-carbonitrile (Cpd. No.159cF), Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl- 7-(pyrrolidin-1-ylmethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3- carbonitrile (Cpd. No.158cF),

(4bS,5R,6S,7S,7aR)-7a-(4-(Difluoromethyl)phenyl)-6-((dimethylamino)methyl)-4- methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No.106F),

(4bS,5R,6S,7S,7aR)-6-((Dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(4- (trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5- diol (Cpd. No.107F),

or any combination of two to four compounds thereof.

In particular embodiments, a site-directed eIF4A inhibitor is a compound according to the following formula:

or is a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

Methods of testing eIF4A activity are known in the art and include ATPase assays (Pause and Sonenberg, EMBO J.11:2643-54, 1992; Abramson et al., J. Biol. Chem.

262:3826-3832, 1987; each assay of which is incorporated herein by reference in its entirety), helicase assays (Rogers et al., J. Biol. Chem.274:12236-44, 1999; Pause and Sonenberg, 1992; each assay of which is incorporated herein by reference in its entirety), and dual luciferase reporter assays (Wolfe et al., Nature 513:65-70, 2014, each assay of which is incorporated herein by reference in its entirety). (iii) mTOR Inhibitors

An "mTOR inhibitor" refers to an agent or compound that directly interacts with mTOR and may block, inactivate, reduce or minimize mTOR activity (e.g., kinase activity or translational effects), or reduce activity by promoting degradation of mTOR, by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more as compared to untreated mTOR.

In certain embodiments, a mTOR inhibitor is an allosteric inhibitor. An "allosteric mTOR inhibitor" binds to mTOR at a site other than the active site, wherein its binding induces a conformational change in mTOR so that a substrate can no longer bind mTOR or mTOR activity is reduced. Allosteric mTOR inhibitors include rapamycin (sirolimus), rapamycin-related compounds, that is compounds having structural and functional similarity to rapamycin including, e.g., rapamycin derivatives, rapamycin analogs (also referred to as rapalogs) and other macrolide compounds that inhibit mTOR activity.

Examples of allosteric mTOR inhibitors include rapamycin, everolimus, emsirolimus, temsirolimus, umirolimus, ridaforolimus (deforolimus), farnesylthiosalicylic acid, curcumin, and zotarolimus. Further examples of rapamycin analogs include 40-O-benzyl- rapamycin, 40-O-(4'- hydroxymethyl)benzyl-rapamycin, 40-O-[4'-(l,2- dihydroxyethyl)]benzyl-rapamycin, 40-O-allyl- rapamycin, 40-O-[3'-(2,2-dimethyl-l,3- dioxolan-4(S)-yl)-prop-2'-en-yl]-rapamycin, (2'E,4'S)-40-O-(4',5'-dihydroxypent-2'-en-l'- yl)-rapamycin, 40-O-(2- hydroxy)ethoxycarbonylmethyl-rapamycin, 40-O-(2- hydroxy)ethyl-rapamycin , 40-O-(3- hydroxy)propyl-rapamycin, 40-O-(6-hydroxy)hexyl- rapamycin, 40-O-[2-(2- hydroxy)ethoxy]ethyl-rapamycin, 40-O-[(3S)-2,2- dimethyldioxolan-3-yl]methyl-rapamycin, 40- 0-[(2S)-2,3-dihydroxyprop-l-yl]-rapamycin, 40-O-(2-acetoxy)ethyl-rapamycin, 40-O-(2- nicotinoyloxy)ethyl-rapamycin, 40-O-[2-(N- morpholino)acetoxy]ethyl-rapamycin, 40-O-(2-N- imidazolylacetoxy)ethyl-rapamycin, 40- O-[2-(N-methyl-N'-piperazinyl)acetoxy]ethyl- rapamycin, 39-O-desmethyl-39,40-O,O- ethylene-rapamycin, (26R)-26-dihydro-40-O-(2- hydroxy)ethyl-rapamycin, 40-O-(2- aminoethyl)-rapamycin, 40-O-(2-acetaminoethyl)-rapamycin, 40-O-(2-nicotinamidoethyl)- rapamycin, 40-O-(2-(N-methyl-imidazo-2'- ylcarbethoxamido)ethyl)-rapamycin, 40-O-(2- ethoxycarbonylaminoethyl)-rapamycin, 40-O-(2- tolylsulfonamidoethyl)-rapamycin and 40-O-[2-(4' ,5'-dicarboethoxy-l',2',3'-triazol-l'-yl)-ethyl]-rapamycin as disclosed in U.S. Patent No.5, 665,772 (incorporated by reference in its entirety) and 16-demethoxy-16- (pent-2-ynyl)oxy-rapamycin, 16-demethoxy-16-(but-2-ynyl)oxy-rapamycin, 16- demethoxy-16-(propargyl)oxy-rapamycin, 16-demethoxy- 16- (4-hydroxy-but-2-ynyl)oxy- rapamycin, 16-demethoxy- 16-benzyloxy-40-O-(2-hydroxyethyl)-rapamycin, 16- demethoxy-16-benzyloxy-rapamycin, 16-demethoxy-16-ortho- methoxybenzyl-rapamycin, 16-demethoxy-40-O-(2-methoxyethyl)-16-pent-2-ynyl)oxy-rapamycin, 39-demethoxy-40- desoxy-39-formyl-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-hydroxymethyl-42-nor- rapamycin, 39-demethoxy-40-desoxy-39-carboxy-42-nor-rapamycin, 39-demethoxy-40- desoxy-39-(4-methyl-piperazin-l-yl)carbonyl-42-nor-rapamycin, 39-demethoxy-40-desoxy- 39-(morpholin-4-yl)carbonyl-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-[N-methyl, N-(2-pyridin-2-yl-ethyl)]carbamoyl-42-nor-rapamycin and 39-demethoxy-40-desoxy-39- (p-toluenesulfonylhydrazonomethyl)-42-nor-rapamycin as disclosed in PCT Publication No. WO95/16691 (which compounds are incorporated herein by reference in their entirety), and 32-deoxo-rapamycin, 16-O-pent-2-ynyl-32-deoxo- rapamycin, 16-O-pent-2- ynyl-32-deoxo-40-O-(2-hydroxy-ethyl)-rapamycin, 16-0-pent-2-ynyl- 32-(S)-dihydro-40- O-(2-hydroxyethyl)-rapamycin, 32(S)-dihydro-40-O-(2-methoxy)ethyl- rapamycin and 32(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin as disclosed in PCT Publication No. WO 96/41807 (which compounds are incorporated herein by reference in their entirety). mTORC1 is sensitive to allosteric mTOR inhibitors such as rapamycin and its derivatives and analogs due to rapamycin’s mechanism of action. Rapamycin forms an intracellular complex with intracellular receptor FKBP12. FKBP12-rapamycin complex binds directly to the FKBP12-rapamycin binding domain of mTOR, which is amino terminal to the kinase catalytic domain. This results in a conformational change in mTORC1, which causes the scaffold protein raptor to dissociate from mTOR, in turn blocking its substrates P70 S6 kinase and to a lesser extent 4E-BP1 from accessing mTOR and being phosphorylated. Thus, allosteric mTOR inhibitors inhibit mTOR signaling without altering mTOR’s intrinsic catalytic activity. While rapamycin-FKBP12 does not bind to mTORC2, prolonged treatment with rapamycin may inhibit mTORC2 activity indirectly by interfering with assembly of mTORC2 (Sarbassov et al., 2006, Mol. Cell. 22:159-168).

In further embodiments, a mTOR inhibitor is a catalytic inhibitor. A catalytic mTOR inhibitor, also referred to as ATP-competitive mTOR inhibitor, is an agent that directly inhibits the kinase activity of mTORC1, mTORC2, or both, i.e., the agent inhibits phosphorylation activity of mTORC1, mTORC2, or both. Examples of catalytic mTOR inhibitors include BEZ235 (2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro- imidazo[4,5-c]quinolin-l-yl)-phenyl]-propionitrile) (described in PCT Publication No. WO2006/122806, which compound is incorporated herein by reference in its entirety), CCG168 (also known as AZD8055, { 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)- pyrido[2,3d]pyrimidin-7-yl]-2-methoxy-phenyl}–methanol) (described in Chresta et al., Cancer Res.70:288-298, 2010, which compound is incorporated herein by reference in its entirety), PKI-587 (l-[4-[4-(dimethylamino)piperidine-l-carbonyl]phenyl]-3-[4-(4,6- dimorpholino-l,3,5-triazin-2-yl)phenyl]urea) (described in Venkatesan et al., J. Med.

Chem.53:2636-2645, 2010, which compound is incorporated herein by reference in its entirety), GSK-2126458 (2,4-difluoro-N-{2-methoxy-5-[4-(4-pyridazinyl)-6-quinolinyl]-3- pyridinyl}benzenesulfonamide) (Knight et al., ACS Med. Chem. Lett., 2010, 1:39-43, which compound is incorporated herein by reference in its entirety), WYE-354 (described in Yu et al., Cancer Res.69:6232-6240, 2009, which compound is incorporated herein by reference in its entirety), Ku-0063794 (described in Garcia-Martinez et al., Biochem. J. 421:29-42, 2009, which compound is incorporated herein by reference in its entirety), Ku- 0068650 (Malagu et al., Bioorg. Med. Chem. Lett.19:5950-3, 2009; which compound is incorporated herein by reference in its entirety); torkinib (PP242), sapanisertib (INK128), Torin 1 (1-[4-[4-(1-Oxopropyl)-1-piperazinyl]-3-(trifluoromethyl)phenyl]-9-(3-quinolinyl)- benzo[h]-1,6-naphthyridin-2(1H)-one) (described in Thoreen et al., 2009, J. Biol. Chem. 285:8023-32, which compound is incorporated herein by reference in its entirety), and Torin 2 (9-(6-Amino-3-pyridinyl)-1-[3-(trifluoromethyl)phenyl]-benzo[h]-1,6- naphthyridin-2(1H)-one) (described in Liu et al., Cancer Res.73:2574-86, 2013, which compound is incorporated herein by reference in its entirety), and AZD2014 (described in Pike et al., 2013, Bioorg. Med. Chem. Lett.23:1212-6, which compound is incorporated herein by reference in its entirety).

(iv) RAF Inhibitors

As used herein, a“RAF inhibitor” may block, inactivate, reduce or minimize RAF activity (e.g., kinase activity or translational effects), or reduce activity by promoting degradation of RAF, by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more as compared to untreated RAF. A RAF inhibitor may inhibit the activity of A-RAF, B- RAF, C-RAF, or any combination thereof. In certain embodiments a RAF inhibitor is a BRAF inhibitor. In certain embodiments, a RAF inhibitor blocks, inactivates, reduces or minimizes the ability of RAF to phosphorylate MEK1/2. Non-limiting examples of RAF inhibitors include TAK-632, HMC95573, TAK-580 (formerly called MLN2480), INU-152, LY3009120, AZ628, LSN3074753, SB590885, CCT196969, CCT241161, DP-4978, (R)- 2-(l-(6-amino-5-chloropyrimidine-4- carboxamide)ethyl)-N-(5-chloro-4- (Mfluoromemyl)pyridin-2-yl)thiazole-5-carboxamide, sorafenib, sorafenib tosylate, and lifirafenib. As used herein, a“BRAF inhibitor” may block, inactivate, reduce or minimize BRAF activity (e.g., kinase activity or translational effects), or reduce activity by promoting degradation of BRAF, by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more as compared to untreated BRAF. A BRAF inhibitor may be selective for BRAF or may be a pan-RAF inhibitor. In certain embodiments, a BRAF inhibitor blocks, inactivates, reduces or minimizes the ability of BRAF to phosphorylate MEK1/2. In certain embodiments, a BRAF inhibitor targets a V600 mutated BRAF. Non-limiting examples of BRAF inhibitors include encorafenib, vemurafenib, dabrafenib, PLX7904, PLX8394, CEP-32496, GDC-0879, PLX-4720, ZM 336372, GW5074, NVP-BHG712, and RAF265.

(v) MEK Inhibitors

As used herein, a“MEK inhibitor” may block, inactivate, reduce or minimize MEK1 and/or MEK2 activity (e.g., kinase activity or translational effects), or reduce activity by promoting degradation of MEK1 and/or MEK2, by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more as compared to untreated MEK1 and/or MEK2. In certain embodiments, a MEK inhibitor blocks, inactivates, reduces or minimizes the ability of MEK to phosphorylate ERK1/2.

Non-limiting examples of MEK inhibitors include trametinib, selumetinib, binimetinib, PD-325901, cobimetinib, CI-1040, MEK162, AZD8330, TAK-733, GDC- 0623, refametinib, pimasertib, RO4987655, WX-544, HL-085, GDC0973, GSK1120212, AZD6244, and PD035901. (vi) Inhibitors of Immunosuppression Components

In certain embodiments, an additional therapeutic agent that may be used in combination with an eIF4E inhibitor is an inhibitor of an immunosuppression component, which may be an inhibitor of an immune checkpoint molecule or gene, a metabolic enzyme, an immunosuppressive cytokine, T_reg cells, or any combination thereof. As used herein, the term "immunosuppression component" refers to one or more cells, proteins, molecules, compounds or complexes providing inhibitory signals to assist in controlling or suppressing an immune response. For example, immunosuppression components include those molecules that partially or totally block immune stimulation; decrease, prevent or delay immune activation; or increase, activate, or up regulate immune suppression.

"Controlling or suppressing an immune response," as used herein, means reducing any one or more of antigen presentation, T cell activation, T cell proliferation, T cell effector function, cytokine secretion or production, and target cell lysis. Such modulation, control or suppression can promote or permit the persistence of a hyperproliferative disease or disorder (e.g., cancer, chronic infections).

Immune checkpoint molecules include immune checkpoint ligands such as, PD-L1, PD-L2, CD80, CD86, B7-H3, B7-H4, HVEM, adenosine, GAL9, VISTA, CEACAM-1, CEACAM-3, CEACAM-5, PVRL2, and immune checkpoint receptors such as, PD-1, CTLA-4, BTLA, KIR, LAG3, TIM3, A2aR, CD244/2B4, CD160, TIGIT, LAIR-1, and PVRIG/CD112R). Metabolic enzymes include arginase and indoleamine 2,3-dioxygenase (IDO)), and immunosuppressive cytokines include IL-10, IL-4, IL-1RA, and IL-35. In certain embodiments, an inhibitor of immunosuppression component is a compound, an antisense moleucle, a ribozyme, an RNAi molecule (e.g., siRNA), an antibody or antigen binding fragment thereof, or fusion polypeptide (e.g., Fc fusion protein).

An antibody specific for PD-1 may be pidilizumab, nivolumab, pembrolizumab, MEDI0680 (formerly AMP-514), AMP-224, or BMS-936558.

An antibody specific for PD-L1 may be MDX-1105 (BMS-936559), durvalumab (formerly MEDI4736), atezolizumab (formerly MPDL3280A), RG7446, or avelumab (formerly MSB0010718C). A compound specific for PD-L1 may be BMS-1001 or BMS- 1166.

An antibody specific for LAG3 may be relatlimab (BMS-986016), LAG525, ,IMP701, or A9H12. In certain embodiments, a LAG3 inhibitor is a LAG3-Ig fusion protein, such as IMP321. An IDO inhibitor may be levo-1-methyl tryptophan, epacadostat (INCB024360; Liu et al., Blood 115:3520-30, 2010), ebselen (Terentis et al., Biochem.49:591-600, 2010), indoximod, NLG919 (Mautino et al., American Association for Cancer Research 104th Annual Meeting 2013; Apr 6-10, 2013), 1-methyl-tryptophan (1-MT)-tira-pazamine, navoximod, GDC-0919, BMS-986205, NLG802, HTI-1090, PF-06840003, OM2983, RG- 70099, navoximod, GDC-0919, BMS-986205, NLG802, HTI-1090, PF-06840003, OM2983 (Merck/IO-Met), RG-70099, or any combination thereof. C. Methods of Altering Imunomodulatory Activity

EIF4E inhibitors as described herein can unexpectedly reduce the level of immunosuppression components (e.g., immune checkpoint molecules) involved in immune inhibitory pathways, also known as immunosuppression pathways. In certain aspects, the present disclosure provides methods for immune modulation by administering an effective amount of a eIF4E inhibitor to a subject in need thereof. Exemplary forms of immune modulation include increasing the activity of an immune cell; reducing the

down-modulation of an immune cell; inducing or enhancing an immune response;

prolonging an immune response; stimulating an antigen-specific T cell response; inhibiting an immunosuppressive signaling pathway; promoting endogenous immunity (pre-existing and de novo); inhibiting disease-associated immune resistance (e.g., cancer or an infection); enhancing a vaccine-induced immune response; or any combination thereof. In further embodiments, a subject in need of immune modulation has a hyperproliferative disorder (e.g., cancer), infection or infectious disease (e.g., viral, bacterial, protozoan infection). In particular embodiments, a subject in need of immune modulation has a hyperproliferative disorder associated with immune resistance (e.g., cancer) or an infectious disease (e.g., chronic infection) associated with immune resistance. In any of the aforementioned embodiments, the subject being treated is human.

An exemplary immune inhibitory or suppressive pathway (modulated by eIF4E inhibitors of this disclosure) is mediated by Programmed cell death protein 1, also known as PD-1 or CD279, which is a cell surface receptor belonging to the immunoglobulin superfamily and is expressed on T cells (CD8+ effector T cells, CD4+ helper T cells, Tregs, or any combination thereof), natural killer (NK) cells, macrophages, dendritic cells, and B cells. PD-1 binds to two ligands, PD-L1 (also known as B7-H1 or CD274) and PD-L2 (also known as BC-DC or CD273). eIF4E inhibitors of this disclosure also reduce the levels of PD-L1.

By way of background, PD-1 and its ligands primarily act to regulate inflammatory responses in tissues by T cells recognizing antigen in peripheral tissues. PD-1 expression is induced on activated T cells and inflammatory signals in the tissues induce expression of PD-1 ligands on, for example, antigen presenting cells. Upon ligand binding, PD-1 inhibits kinases involved in T cell activation via SHP2 phosphatase, resulting in inhibition of TCR-mediated activation, expansion, cytokine production, and acquisition of effector functions of CD8+ effector T cells. PD-1-mediated dampening of the immune response protects peripheral tissues from damage and helps maintain self-tolerance. IFNg secretion is a signal for PD-L1 induction, which is predominantly made by T helper 1 (T_H1) cells. Activity of PD-1 receptor signaling may be detected by examining T cell proliferation and cytokine production (e.g., IFNg, IL-2), using methods known in the art.

PD-1 is also highly expressed on Treg cells, and PD-1-mediated signaling in Treg cells may result in further suppression of effector immune responses by promoting T_reg development and function (Francisco et al., Immunol. Rev.236:219, 2010). PD-1 signaling may also dampen NK cell activation and cytotoxicity and antibody production via its effects on NK cells and B cells (Benson et al., Blood 116:2286, 2010; Thibult et al., Int. Immunol.25:129, 2013).

High levels of persistent PD-1 expression, which may occur as a result of chronic antigen exposure (e.g., cancer, chronic infection) may induce a state of exhaustion and anergy among cognate antigen-specific T cells (Barber et al., Nature 438:682, 2006).

Down-regulation of the immune response, e.g., T cell response, by PD-1 signaling may facilitate persistence of cancer or infection. PD-1 ligands are commonly upregulated on the surface of cancer cells of numerous tumors and tumor infiltrating lymphocytes (TILs), which limit local anti-tumor T cell responses. Up-regulation of PD-L1 expression has been found on melanoma, ovarian cancer, lung cancer, renal cancer, breast cancer, and many other cancers, and has been associated with poor prognosis (reviewed in Pardoll, supra). PD-L2 up-regulation has been also reported on certain B cell lymphomas (Id.).

Certain immunosuppression components, such as immune checkpoint proteins like PD-1, TIM3, IDO, or LAG3, may also play a role in persistence of chronic infections. PD- 1 has been shown to be upregulated on T cells of HIV infected patients, which correlates with viral load and T cell exhaustion, resulting in decreased cellular proliferation, cytotoxic function, and cytokine secretion (reviewed in Eichbaum, Curr. Med. Chem.18:3971, 2011 and Hofmeyer et al., J. Biomed. Biotech.2011:451694, 2011). PD-1 mediated T cell exhaustion is also important in the persistence of other chronic infections, such as hepatitis B virus, hepatitis C virus, and LCMV, and is implicated in persistence or reactivation of bacterial infection (e.g., Helicobacter pylori, Mycobacterium), trypanosomal infection (e.g., Leishmania donovani), parasitic protozoan infection (e.g., Toxoplasma gondii), helminth infection (e.g., Schistosoma mansoni), and herpes simplex virus 1 infection (e.g., HSV1) (Hofmeyer et al., supra). Increased IDO activity has been observed in chronic viral infections, such as HIV, hepatitis, and herpes simplex virus (reviewed in Mehraj and Routy, Int. J. Tryptophan Res.8:41). Elevated LAG3 expression is associated with persistence of chronic infections, such as Mycobacterium tuberculosis (Phillips et al., 2017, PLOS One 12:e0180413) and hepatitis B virus (Ye et al., 2017, Medicine 96:e5275).

Similarly, TIM3 is involved in T cell exhaustion during chronic infection, such as

Mycobacterium tuberculosis infection (Jayaraman et al., 2016, PLOS Pathog.

12:e1005490) and hepatitis C virus (Golden-Mason et al., 2009, J. Virol.83:9122).

Another exemplary immunosuppression component is lymphocyte activation gene 3 (LAG3, also known as CD223), which is highly expressed on T_reg cells and has a role in enhancing the immunosuppressive activity of Treg cells (Goldberg and Drake, Curr. Top. Microbiol. Immunol.344:269, 2011). LAG3 also directly inhibits CD8⁺ effector T cells, independently of the effect via Treg cells (Grosso et al., J. Clin. Invest.117:3383, 2007). LAG3 is also expressed on activated CD4⁺ and CD8⁺ T lymphocytes where it associates with the CD3–TCR complex at the cell surface and negatively regulates signal transduction (Hannier et al., J. Immunol.161:4058, 1998; Darlington et al., J. Exp. Med.195:1337, 2002). The role of LAG3 in the down regulation of T cell responses is well established (Matsuzaki et al., Proc. Nat'l. Acad. Sci. USA 107:7875, 2010), and there is increasing evidence of its involvement in regulatory function of tumor-infiltrated T cells in cancer, such as Hodgkin’s lymphomas (Gandhi et al., Blood 108:2280, 2006) and prostate cancer (Sfanos et al., Clin. Cancer Res.14:3254, 2008). The ligand for LAG3, MHC/HLA class II molecules, are upregulated on some epithelial cancers (e.g., melanoma), and tumor infiltrating macrophages and dendritic cells. There are several LAG3 inhibitors in development, and even LAG3 antibodies that do not block LAG3-MHC class II binding are still able to enhance T cell proliferation and effector function (reviewed in Pardoll, supra).

Another exemplary immunosuppression component is T cell immunoglobulin and mucin domain 3 (TIM3, also known as HAVCR2), which is expressed on the surface of IFNg producing CD4 and CD8 T cells, Treg cells, and innate immune cells and is a negative regulator of type 1 immunity (reviewed in Anderson et al., supra). TH1 cells, characterized by IFNg production, are important for anti-cancer and anti-viral immune responses. TIM3 binds to multiple ligands, including galectin 9, phosphatidylserine, CEACAM1, and HMGB1. Galectin 9 is upregulated in various types of cancer. TIM3 expression is associated with CD8 T cells that exhibit dysfunctional/exhausted phenotype in chronic viral infections and cancer (reviewed in Anderson et al., supra). Blockade of TIM3 improves T cell proliferation and effector function (Golden-Mason et al., 2009, J. Virol.83:9122-130; McMahan et al., 2010, J. Clin. Invest.120:4546-557; Nebbia et al., 2012, PLOS One 7:e47648; Wu et al., 2011, Vriol. J.8:113; Fourcade et al., 2010, J. Exp. Med.207:2175-186; Yang et al., 2012, J. Clin. Invest.122:1271-282). TIM3 is also upregulated on FOXP3+ T reg cells that are present in pathological tissue sites, e.g., tumor site or tissue graft site, and may also have a role in regulating FOXP3+ T reg cells. TIM3+ Treg cells may have superior suppressive function as compared to TIM3+ Treg cells, e.g., expressing higher levels of IL10, granzymes, perforin, and FOXP3 (Gautron et al., 2014, Eur. J. Immunol.44:2703-11; Gupta et al., 2012, J. Clin. Invest.122:2395-404; Sakuishi et al., 2013, OncoImmunol.2:e23849). Yet another exemplary immunosuppresion component is a metabolic enzyme, indoleamine 2,3-dioxygenase (IDO), which is expressed in infiltrating myeloid cells (dendritic cells, monocytes, and macrophages) (Mellor and Munn, Nat. Rev. Immunol. 4:762-74, 2004). IDO is also expressed by cancer cells in a range of tumor types and may inhibit immune response to tumors (Munn, Update Cancer Ther.1:175-185, 2006). IDO is the first and rate limiting catabolic enzyme in the“kynurenine”degradation pathway of tryptophan. IDO catalyzes the breakdown of tryptophan to N-formyl-kynurenine. IDO is induced by IFNg and inhibits immune response through local depletion of tryptophan, which is essenital for anabolic functions in lymphocytes, particularly T cells (Mellor, Biochem. Biophys. Res. Comm.338:20-4, 2005). IDO can also exert immunoregulatory functions via generation of kynurenines, which stimulate pro-inflammatory T cell apoptosis. (reviewed in Mgongue et al., 2015,Vaccines 3:703-29).

The present disclosure provides methods of treating disease by reducing the down-modulation of an immune cell, comprising administering an effective amount of an eIF4E inhibitor to a subject (e.g., human) in need thereof. In certain embodiments, the present disclosure provides methods of reducing or blocking PD-1, PD-L1, TIM3, LAG3, or IDO signaling for use in enhancing an immune response or reducing the down- modulation of an immune cell against a hyperproliferative disorder (e.g., cancer) or an infection or infectious disease. In certain aspects, the present disclosure provides a method of reducing levels or activity of PD-1, PD-L1, TIM3, LAG3, IDO, or combinations thereof, by administering a therapeutically effective amount of an eIF4E inhibitor to a subject in need of an induced or enhanced immune response or a reduction in the down-modulation or suppression of an immune cell. In certain embodiments, an eIF4E inhibitor is used to induce or enhance an immune response or reduce the down-modulation or suppression of an immune cell in a subject having cancer or a chronic infection. In further embodiments, an eIF4E inhibitor is any one of the compounds of Formula I, II, III, IV, V, or VI. In still further embodiments, the induced or enhanced immune response comprises an antigen- specific T cell response, or the reduced down-modulation or suppression is of an antigen- specific T cell. In particular embodiments, the method further comprises administering an inhibitor of an immunosuppression component, such as an antibody or binding fragment thereof, a fusion protein (e.g., Fc fusion), siRNA, compound, or the like, which may be inhibitors of PD-1, PD-L1, TIM3, LAG3, IDO, or combinations thereof.

In still further embodiments, the present disclosure provides a method of treating disease associated with PD-1-mediated, PD-L1-mediated, TIM3-mediated, LAG3- mediated, or IDO-mediated immune resistance, comprising administering an effective amount of an eIF4E inhibitor to a subject in need thereof.

In any of the aforementioned embodiments, an eIF4E inhibitor can be any compound having a structure of Formula I, II, III, IV, V or VI. In still further

embodiments, the induced or enhanced immune response is an antigen-specific T cell response. In particular embodiments, the method further comprises administering an inhibitor of an immunosuppression component, such as a compound, antibody, or binding fragment thereof, a fusion protein, siRNA, or the like.

In yet further embodiments, the present disclosure provides a method of inhibiting an immunosuppressive signaling pathway associated with dysregulated immune checkpoint proteins, such as PD-1, PD-L1, TIM3, LAG3, IDO, or combinations thereof, comprising administering an effective amount of an eIF4E inhibitor to a subject in need thereof. In certain embodiments, an eIF4E inhibitor is any compound having a structure of Formula I, II, III, IV, V, or VI. In still further embodiments, an induced or enhanced immune response is an antigen-specific T cell response. In particular embodiments, the method further comprises administering an inhibitor of an immunosuppression signal, such as an antibody or binding fragment thereof, a fusion protein, siRNA, compound or the like.

In more embodiments, the present disclosure provides a method of inhibiting a dysregulated PD-1, PD-L1, LAG3, TIM3, IDO, or any combination thereof,

immunosuppressive signaling pathway, comprising administering an effective amount of an eIF4E inhibitor to a subject in need thereof. In certain embodiments, an eIF4E inhibitor is any compound having a structure of Formula I, II, III, IV, V or VI. In more

embodiments, the method inhibits an immunosuppression component, such as a PD-1, PD- L1, TIM3, LAG3, and/or IDO, of immunosuppressive signaling pathways, to correct dysregulated or inappropriate immune suppression and promote endogenous immunity (e.g., pre-existing or de novo). In certain embodiments, this disclosure provides a method of inhibiting an immunosuppression component to promote endogenous immunity, comprising administering an effective amount of an eIF4E inhibitor and an

immunosuppression inhibitor to a subject in need thereof, wherein (a) the eIF4E inhibitor primes antigen-specific T cells for response to antigen in the presence of the

immunosuppression inhibitor, or (b) the eIF4E inhibitor enhances or prolongs the effect of the immunosuppression inhibitor in promoting endogenous immunity. In still further embodiments, the induced or enhanced immune response is an antigen-specific T cell response. In particular embodiments, the method further comprises administering an inhibitor of an immunosuppression component, such as an antibody or binding fragment thereof, a fusion protein, siRNA, compound or the like.

The methods of use of an eIF4E inhibitor described herein may be optionally used in combination with an inhibitor targeting an immunosuppression component or production of an immunosuppression component. Exemplary immunosuppression component targets include PD-1, PD-L1, PD-L2, CTLA4, CD80, CD86, B7-H3, B7-H4, HVEM, BTLA, KIR, LAG3, GAL9, TIM3, 2B4, adenosine, A2aR, TGFb, IL-10, IL-35, arginase, IDO, or immunosuppressive cytokines (e.g., IL-10). An immunosuppression component inhibitor may be a compound, an antibody, an antibody fragment or fusion polypeptide (e.g., Fc fusion protein, such as CTLA4-Fc or LAG3-Fc), an antisense molecule, a ribozyme or RNAi molecule, or a low molecular weight organic molecule.

In certain embodiments, an inhibitor of an immunosuppression component is an antibody or binding fragment thereof, fusion protein, compound, or siRNA specific for PD- 1, PD-L1, PD-L2, CTLA4, CD80, CD86, B7-H3, B7-H4, HVEM, BTLA, KIR, LAG3, GAL9, TIM3, 2B4, adenosine, A2aR, TGFb, IL-10, IL-35, arginase, IDO, or any combination thereof.

In certain embodiments, an eIF4E inhibitor is used in combination with a PD-1 specific antibody or binding fragment thereof, such as pidilizumab, nivolumab, pembrolizumab, MEDI0680 (formerly AMP-514), MK-3475, AMP-224, BMS-936558 or any combination thereof. In further embodiments, an eIF4E inhibitor is used in combination with a PD-L1 specific antibody or binding fragment thereof, such as BMS- 936559, durvalumab (MEDI4736), atezolizumab (MPDL3280A), avelumab

(MSB0010718C), RG7446, or any combination thereof. In yet further embodiments, an eIF4E inhibitor is used in combination with a LAG3 specific antibody or binding fragment thereof, such as LAG525, IMP321, IMP701, 9H12, BMS-986016, or any combination thereof. In yet further emobidments, an eIF4E inhibitor is used in combination with a TIM3 specific antibody or binding fragment thereof, such as TSR-022, MBG453, or both. In yet further embodiments, an eIF4E inhibitor is used in combination with an IDO inhibitor compound, such as levo-1-methyl tryptophan, epacadostat, ebselen, indoximod, NLG919, 1-methyl-tryptophan (1-MT)-tira-pazamine, navoximod, GDC-0919, BMS- 986205, NLG802, HTI-1090, PF-06840003, OM2983, RG-70099, or any combination thereof. In still more embodiments, an eIF4E inhibitor is used in combination with a PD-1 inhibitor and a LAG3 inhibitor. In other embodiments, an eIF4E inhibitor is used in combination with a PD-L1 inhibitor and a LAG3 inhibitor. In yet other embodiments, an eIF4E inhibitor is used in combination with a PD-1 inhibitor and a TIM3 inhibitor, or a PD-L1 inhibitor and a TIM3 inhibitor. In yet other embodiments, an eIF4E inhibitor is used in combination with a PD-1 inhibitor and an IDO inhibitor, or a PD-L1 inhibitor and an IDO inhibitor. In still more embodiments, an eIF4E inhibitor is used in combination with a PD-1 inhibitor, a LAG3 inhibitor, and a TIM3 inhibitor, or a PD-L1 inhibitor, a LAG3 inhibitor, and a TIM3 inhibitor. In still more embodiments, an eIF4E inhibitor is used in combination with a PD-1 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, and an IDO inhibitor, or a PD-L1 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, and an IDO inhibitor. Other combinations of inhibitors comprising PD-1, PD-L1, TIM3, LAG3, and IDO are also contemplated.

Cytotoxic T-lymphocyte associated protein 4 (CTLA4), also known as CD152, is a receptor exclusively expressed by T cells and acts as a negative regulator of T cell activation. CTLA4 primarily counteracts the activity of the T cell co-stimulatory receptor CD28. CTLA4 and CD28 share the same ligands CD80 (also known as B7.1) and CD86 (also known as B7.2), which are expressed on the surface of antigen presenting cells.

Engagement of CD28 by CD80 or CD86 activates T cell proliferation and IL-2 production only if the T cell receptor has bound its cognate antigen. T cell activation through TCR and CD28 induces expression of CTLA4. CTLA4 has a higher affinity for both its ligands than CD28. Not wishing to be bound by theory, it is suggested that CTLA4 dampens T cell activation by outcompeting CD28 for ligand binding and delivery of inhibitory signals to the T cell (reviewed in Pardoll, supra). CTLA4 is expressed on multiple T cell subsets, and signaling may down-modulate activity of CD8+ effector T cells, CD4+ helper T cells, and enhance T_reg activity.

In certain embodiments, an eIF4Especific inhibitor is used in combination with an inhibitor of CTLA4. In particular embodiments, an eIF4E inhibitor is used in combination with a CTLA4 specific antibody or binding fragment thereof, such as ipilimumab, tremelimumab, CTLA4-Ig fusion proteins (e.g., abatacept, belatacept), or any combination thereof.

Other B7 family inhibitory ligands, such as B7-H3 (also known as CD276) and B7- H4 (also known as B7-S1, B7x, and VCTN1), may have an immune inhibitory role (Yi et al., Immunol. Rev.229:145, 2009). The receptors for B7-H3 and B7-H4 have not yet been identified. But, B7-H3 and B7-H4 are upregulated on tumor cells and tumor-infiltrating cells (He et al., Clin. Dev. Immunol.2011:695834, 2011).

In more embodiments, an eIF4E inhibitor is used in combination with a B7-H3 specific antibody or binding fragment thereof, such as MGA271, 376.96, or both. A B7-H4 antibody binding fragment may be a scFv or fusion protein thereof, as described in, for example, Dangaj et al., Cancer Res.73:4820, 2013.

CD244, also known as Natural Killer Cell Receptor 2B4, is a cell surface receptor expressed on natural killer cells, gd T cells, and memory CD8+ (ab) T cells. The ligand for CD244 is CD48, which is expressed on hematopoietic cells. CD244 signaling is thought to modulate NK-cell cytolytic activity in both an activating and inhibitory manner, depending on expression level of CD244 and degree of cross-linking (Chlewicki et al., J. Immunol. 180:8159, 2008).

B and T lymphocyte attenuator (BLTA, also known as CD272) is an inhibitor receptor whose expression is induced during T cell activation. Its ligand is herpesvirus entry mediator (HVEM, also known as TNFRSF14). HVEM is widely expressed in multiple tissue/cell types. HVEM is also upregulated on certain tumor types, including for example, melanoma, lymphoma, prostate cancer, colorectal cancer, urothelial cancer, and tumor infiltrating lymphocytes. BTLA-HVEM trans-interaction results in inhibitor effects on T cell (reviewed by Shui et al., J. Leukoc. Biol.89:517, 2011). Cis-binding of HVEM- BTLA on T cells may also have an inhibitory function, which is stabilized by soluble LIGHT (also known as TNFSF14 or CD258) (Shui et al., supra).

Adenosine A2a receptor (A2aR) inhibits T cell response by inducing T cell anergy and by promoting expression of FOXP3 in CD4+ T cells and develop into Treg cells (Zarek et al., Blood 111:251, 2008). The ligand for A2aR is adenosine. Adenosine is released during cell death (e.g., tumors, viral infection).

Killer cell immunoglobulin-like receptors (KIR, also known as CD158) are cell surface proteins found on natural killer cells and a subset of T cells. KIR interact with a MHC class I molecule, which suppresses cytotoxicity activity of the NK cell. Individual KIR recognize distinct subsets of MHC class I allotypes. In certain embodiments, an eIF4E inhibitor is used in combination with an inhibitor of KIR, such as lirilumab (BMS- 986015).

Inhibitory cytokines, including TGFb, IL-10, and IL-35, may inhibit immune response by suppressing TH1 type response, promoting Treg cell development, (Bettini and Vignali, Curr. Opin. Immunol.21:612, 2009).

The metabolism of arginine to ornithine and urea is catalyzed by arginase I and arginase II, encoded by two distinct genes located in the cytoplasm and mitochondria. Ornithine is the main substrate for the production of polyamines that are required for cell cycle progression. Arginine can also be metabolized by inducible nitric oxide synthase to produce citrulline and nitric oxide, which plays an important role in cytotoxic mechanisms. Arginase can also cause T cell anergy by decreasing expression of CD3z chain (Rodriguez et al., Cancer Res.64:5839, 2004). Arginase is produced by myeloid derived suppressor cells, and expression has been observed in several tumor cell lines (Rodriguez and Ochoa, Immunol. Rev.222:180-191, 2008).

In certain embodiments, an eIF4E inhibitor is used in combination with an arginase inhibitor, such as N(omega)-Nitro-L-arginine methyl ester (L-NAME), N‐omega‐hydroxy‐ nor‐l‐arginine (nor‐NOHA), L-NOHA, 2(S)-amino-6-boronohexanoic acid (ABH), S-(2- boronoethyl)-L-cysteine (BEC), or any combination thereof.

In certain embodiments, an eIF4E inhibitor is used in combination with agents that target other immunomodulatory molecules. For example, an eIF4E inhibitor can be used in combination with an anti-CD137 (4-1BB) antibody (such as urelumab), an anti-CD134 (OX-40) antibody (such as MDI6469 (an OX-40 agonist)), lenalidomide, pomalidomide, or combinations thereof.

A wide variety of hyperproliferative disorders, including solid tumors and leukemias, are amenable to the immune modulating compositions and methods disclosed herein. Exemplary cancers that may be treated by immune modulation of this disclosure include adenocarcinoma of the breast, prostate, and colon; all forms of bronchogenic carcinoma of the lung; myeloid; melanoma; hepatoma; neuroblastoma; papilloma;

apudoma; choristoma; branchioma; malignant carcinoid syndrome; carcinoid heart disease; and carcinoma (e.g., Walker, basal cell, basosquamous, Brown-Pearce, ductal, Ehrlich tumor, Krebs 2, merkel cell, mucinous, non-small cell lung, oat cell, papillary, scirrhous, bronchiolar, bronchogenic, squamous cell, and transitional cell). Additional representative cancers that may be treated include histiocytic disorders; histiocytosis malignant;

immunoproliferative small intestinal disease; plasmacytoma; reticuloendotheliosis;

melanoma; chondroblastoma; chondroma; chondrosarcoma; fibroma; fibrosarcoma; giant cell tumors; histiocytoma; lipoma; liposarcoma; mesothelioma; myxoma; myxosarcoma; osteoma; osteosarcoma; chordoma; craniopharyngioma; dysgerminoma; hamartoma;

mesenchymoma; mesonephroma; myosarcoma; ameloblastoma; cementoma; odontoma; teratoma; thymoma; and trophoblastic tumor. Exemplary hematological malignancies include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), chronic eosinophilic leukemia (CEL), myelodysplastic syndrome (MDS), Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL) (e.g., follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukemia), or multiple myeloma (MM).

Still further exemplary hyperproliferative disorders include adenoma; cholangioma; cholesteatoma; cyclindroma; cystadenocarcinoma; cystadenoma; granulosa cell tumor; gynandroblastoma; hepatoma; hidradenoma; islet cell tumor; Leydig cell tumor; sertoli cell tumor; thecoma; leimyoma; leiomyosarcoma; myoblastoma; myomma; myosarcoma;

rhabdomyoma; rhabdomyosarcoma; ependymoma; ganglioneuroma; glioma;

medulloblastoma; meningioma; neurilemmoma; neuroblastoma; neuroepithelioma;

neurofibroma; neuroma; paraganglioma; paraganglioma nonchromaffin; angiokeratoma; angiolymphoid hyperplasia with eosinophilia; angioma sclerosing; angiomatosis;

glomangioma; hemangioendothelioma; hemangioma; hemangiopericytoma;

hemangiosarcoma; lymphangioma; lymphangiomyoma; lymphangiosarcoma; pinealoma; carcinosarcoma; chondrosarcoma; cystosarcoma phyllodes; fibrosarcoma;

hemangiosarcoma; leiomyosarcoma; leukosarcoma; liposarcoma; lymphangiosarcoma; myosarcoma; myxosarcoma; ovarian carcinoma; rhabdomyosarcoma; sarcoma; neoplasms; nerofibromatosis; and cervical dysplasia.

In particular aspects, the present disclosure provides methods for increasing the activity of an immune cell by administering an effective amount of an eIF4E inhibitor to a subject having a solid tumor, melanoma, non-small cell lung cancer, renal cell carcinoma, renal cancer, a hematological cancer, prostate cancer, castration-resistant prostate cancer, colon cancer, rectal cancer, gastric cancer, esophageal cancer, bladder cancer, head and neck cancer, thyroid cancer, breast cancer, triple-negative breast cancer, ovarian cancer, cervical cancer, lung cancer, urothelial cancer, pancreatic cancer, glioblastoma, hepatocellular cancer, myeloma, multiple myeloma, leukemia, Hodgkin's lymphoma, non- Hodgkin's lymphoma, myelodysplastic syndrome, brain cancer, CNS cancer, malignant glioma, or any combination thereof. In other aspects, the present disclosure provides methods for reducing the down- modulation of an immune cell by administering an effective amount of an eIF4E inhibitor to a subject having a solid tumor, melanoma, non-small cell lung cancer, renal cell carcinoma, renal cancer, a hematological cancer, prostate cancer, castration-resistant prostate cancer, colon cancer, rectal cancer, gastric cancer, esophageal cancer, bladder cancer, head and neck cancer, thyroid cancer, breast cancer, triple-negative breast cancer, ovarian cancer, cervical cancer, lung cancer, urothelial cancer, pancreatic cancer, glioblastoma, hepatocellular cancer, myeloma, multiple myeloma, leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myelodysplastic syndrome, brain cancer, CNS cancer, malignant glioma, or any combination thereof.

In still other aspects, the present disclosure provides methods for inducing, enhancing, or prolonging an immune response by administering an effective amount of an eIF4E inhibitor to a subject having a solid tumor, melanoma, non-small cell lung cancer, renal cell carcinoma, renal cancer, a hematological cancer, prostate cancer, castration- resistant prostate cancer, colon cancer, rectal cancer, gastric cancer, esophageal cancer, bladder cancer, head and neck cancer, thyroid cancer, breast cancer, triple-negative breast cancer, ovarian cancer, cervical cancer, lung cancer, urothelial cancer, pancreatic cancer, glioblastoma, hepatocellular cancer, myeloma, multiple myeloma, leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myelodysplastic syndrome, brain cancer, CNS cancer, malignant glioma, or any combination thereof.

In yet other aspects, the present disclosure provides methods for stimulating an antigen-specific T cell response by administering an effective amount of an eIF4E inhibitor to a subject having a solid tumor, melanoma, non-small cell lung cancer, renal cell carcinoma, renal cancer, a hematological cancer, prostate cancer, castration-resistant prostate cancer, colon cancer, rectal cancer, gastric cancer, esophageal cancer, bladder cancer, head and neck cancer, thyroid cancer, breast cancer, triple-negative breast cancer, ovarian cancer, cervical cancer, lung cancer, urothelial cancer, pancreatic cancer, glioblastoma, hepatocellular cancer, myeloma, multiple myeloma, leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myelodysplastic syndrome, brain cancer, CNS cancer, malignant glioma, or any combination thereof. In certain embodiments, a stimulated antigen-specific T cell response is specific for a tumor-associated antigen (TAA).

In more aspects, the present disclosure provides methods for inhibiting an immunosuppressive signaling pathway by administering an effective amount of an eIF4E inhibitor to a subject having a solid tumor, melanoma, non-small cell lung cancer, renal cell carcinoma, renal cancer, a hematological cancer, prostate cancer, castration-resistant prostate cancer, colon cancer, rectal cancer, gastric cancer, esophageal cancer, bladder cancer, head and neck cancer, thyroid cancer, breast cancer, triple-negative breast cancer, ovarian cancer, cervical cancer, lung cancer, urothelial cancer, pancreatic cancer, glioblastoma, hepatocellular cancer, myeloma, multiple myeloma, leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myelodysplastic syndrome, brain cancer, CNS cancer, malignant glioma, or any combination thereof. In certain embodiments, an immunosuppressive signal involves PD-1, PD-L1, PD-L2, CTLA4, CD80, CD86, B7-H3, B7-H4, HVEM, BTLA, KIR, LAG3, GAL9, TIM3, 2B4, adenosine, A2aR, TGFb, IL-10, IL-35, or any combination thereof. In certain embodiments, an immunosuppressive signal involves one or more dysregulated immune checkpoint proteins resulting in a subject having disease-associated immune resistance, wherein the subject is in need of treatment with an eIF4E inhibitor to modulate the inappropriate immunosuppressive signaling pathway(s) in order to induce or enhance an immune response against the disease (e.g., cancer). In particular embodiments, an immunosuppression component associated with immune resistance is PD-1, PD-L1, LAG3, TIM3, IDO or combinations thereof. In certain embodiments, an inhibited immunosuppressive signaling pathway is a PD-1 pathway, a TIM3 pathway, a LAG3 pathway, or an IDO pathway. For example, an eIF4E inhibitor can down-regulate expression of or indirectly inhibit PD-1, PD-L1, LAG3, TIM3, IDO, or all five, thereby inhibiting these immunosuppression pathways.

In further aspects, the present disclosure provides methods for promoting endogenous anti-cancer immunity by administering an effective amount of an eIF4E inhibitor to a subject having a solid tumor, melanoma, non-small cell lung cancer, renal cell carcinoma, renal cancer, a hematological cancer, prostate cancer, castration-resistant prostate cancer, colon cancer, rectal cancer, gastric cancer, esophageal cancer, bladder cancer, head and neck cancer, thyroid cancer, breast cancer, triple-negative breast cancer, ovarian cancer, cervical cancer, lung cancer, urothelial cancer, pancreatic cancer, glioblastoma, hepatocellular cancer, myeloma, multiple myeloma, leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myelodysplastic syndrome, brain cancer, CNS cancer, malignant glioma, or any combination thereof. The term“endogenous” refers to an anti-cancer immune response that is present in the subject, as opposed to being acquired exogenously, for example, via immunoglobulin therapy, adoptive T cell therapy, genetically modified T cell therapy (e.g., chimeric antigen receptor, recombinant T cell receptor). In certain embodiments, the endogenous anti-cancer immunity that is promoted comprises an antigen-specific T cell response.

In still further aspects, the present disclosure provides methods for inhibiting disease-associated immune resistance by administering an effective amount of an eIF4E inhibitor to a subject having a solid tumor, melanoma, non-small cell lung cancer, renal cell carcinoma, renal cancer, a hematological cancer, prostate cancer, castration-resistant prostate cancer, colon cancer, rectal cancer, gastric cancer, esophageal cancer, bladder cancer, head and neck cancer, thyroid cancer, breast cancer, triple-negative breast cancer, ovarian cancer, cervical cancer, lung cancer, urothelial cancer, pancreatic cancer, glioblastoma, hepatocellular cancer, myeloma, multiple myeloma, leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myelodysplastic syndrome, brain cancer, CNS cancer, malignant glioma, or any combination thereof. In certain embodiments, the disease-associated immune resistance is mediated by a PD-1, PD-L1, TIM3, LAG3, IDO immune suppression signaling pathway. In particular embodiments, inhibition of immune resistance comprises down-regulating, reducing expression, or indirectly inhibiting PD-1, PD-L1, LAG3, TIM3, IDO, or combinations thereof.

The compositions and methods for immune modulation as described herein may also be used in the context of an infection or infectious disease (e.g., viral, bacterial, fungal, parasitic, protozoan, helminth). In certain aspects, the present disclosure provides methods for (1) increasing the activity of an immune cell; (2) reducing the down-modulation of an immune cell; (3) inducing, enhancing, or prolonging an immune response; (4) stimulating an antigen-specific T cell response; (5) inhibiting an immunosuppressive signaling pathway; (6) promoting endogenous anti-infectious agent immunity; (7) enhancing vaccine-induced immune response; or (8) inhibiting disease-associated immune resistance; by administering an effective amount of an eIF4E inhibitor to a subject (e.g., human) having an infection, such as a chronic infection.

Infectious diseases include those associated with infectious agents and include any of a variety of bacteria (e.g., pathogenic E. coli, S. typhimurium, P. aeruginosa, B.

anthracis, C. botulinum, C. difficile, C. perfringens, H. pylori, V. cholerae, Listeria spp., Rickettsia spp., Chlamydia spp., Staphylococci, Streptococci, Pneumonococci,

Meningococci, or the like), mycobacteria, and parasites (including any known parasitic member of the Protozoa, trypanosome, malaria, Giardia, toxoplasma). Infectious viruses include eukaryotic viruses, such as adenovirus, bunyavirus, cytomegalovirus, enterovirus, Epstein-Barr virus, flavivirus (e.g., hepatitis C virus (HCV), hepatitis B virus (HBV), hepatitis A virus, hepatitis E virus, Japanese encephalitis virus), herpes virus, papovavirus, papillomavirus (e.g., HPV), paramyxovirus (e.g., measles virus, mumps virus), picornavirus (e.g., rhinovirus), poliovirus, rubella virus, rhabdovirus (e.g., Rabies), orthomyxovirus (e.g., influenza), poxvirus (e.g., Vaccinia), reovirus, retrovirus, lentivirus (e.g., human immunodeficiency virus, HIV), human T leukemia virus (HTLV1, HTLV2), varicella-zoster virus, zoonotic viruses (e.g., severe acute respiratory syndrome (SARS), Ebola virus, and West Nile virus), or the like. Infectious fungi include, for example, Candida, Cryptococcus, and Aspergillus. In certain embodiments, methods for increasing the activity or reducing the down-modulation of an immune cell, comprises administering an effective amount of an eIF4E inhibitor of this disclosure to a subject infected with a cytosolic pathogen whose antigens are processed and displayed with MHC or HLA class I molecules.

In any of the aforementioned embodiments, an immune cell is a lymphocyte, such as a T cell (e.g., CD8⁺ effector T cell, CD4⁺ helper T cell, or regulatory T cell), natural killer cell, dendritic cell, myeloid cell (such as a monocyte, macrophage, eosinophil, mast cell, basophil, or granulocyte), or any combination thereof. In particular embodiments, immune cells are T cells, such as a CD8+ effector T cells (also known as cytotoxic T lymphocytes or CTLs).

In any of the aforementioned embodiments, an immune response is mediated by a T cell, natural killer cell, dendritic cell, myeloid cell, or any combination thereof. In certain embodiments, an immune response is mediated by T cells, such as a CD8+ effector T cells.

In any of the aforementioned embodiments, immune resistance is resistance to a T cell, natural killer cell, dendritic cell, myeloid cell, or any combination thereof. In certain embodiments, immune resistance is mediated against T cells, such as a CD8+ effector T cells.

An increase in activity or induction, enhancement, prolonging, or stimulation of an immune cell or immune response, or inhibition of an immunosuppressive signaling pathway or immune resistance in any aspect of the compositions and methods described herein may be measured using methods known in the art, for example, by measuring immune cell proliferation, immune cell activity/effector function, immune cell persistence, antibody production, or cytokine production. By way of example, increased T cell activity may be demonstrated by increased T cell proliferation (³H-thymidine incorporation assay, CFSE dilution assay), enhanced T cell co-stimulation, expression of T cell activation cell surface markers (flow cytometry), cytolytic activity (⁵¹Chromium release assay), increased IFNg or IL-2 secretion (ELISA, flow cytometry) in the presence and absence of an eIF4E inhibitor.

In further aspects, the present disclosure provides methods for promoting an enhanced antigen-specific immune response, wherein the method comprises administering to a subject in need thereof an effective amount of an eIF4E inhibitor and an antigen (e.g., a vaccine), wherein an antigen-specific immune response is more effective in combination with an eIF4E inhibitor than in the absence of treatment with an eIF4E inhibitor. The efficacy of an antigen-specific immune response may be ascertained, for example, by immune cell activation, immune cell effector function, immune cell proliferation, immune cell survival, immune cell, immune cell cytokine production, using methods known in the art. In certain embodiments, an antigen-specific immune response is a T cell response. As used herein the term "vaccine" refers to a biological preparation that induces an antigen- specific immune response. A vaccine comprises an antigen, which may be a peptide, polypeptide or protein, or immunogenic fragments thereof; a glycoprotein or immunogenic fragments thereof; a nucleic acid encoding a peptide, polypeptide, protein, or glycoprotein, or immunogenic fragments thereof; a glycolipid; a carbohydrate or carbohydrate comprising molecule; a lipid molecule; or a cell or cell preparation. In certain

embodiments, a vaccine comprises a polynucleotide that encodes an antigen; a recombinant expression vector comprising the polynucleotide; an immune cell or other cell into which an antigen or a polynucleotide encoding the antigen has been introduced, a cell (live, attenuated, or killed), a cell membrane preparation, a cell organelle preparation, or an exosome of a cell. A vaccine may be prophylactic or therapeutic. A vaccine may be directed to an infectious agent or to an endogenous cell (e.g., a cancer cell). In certain embodiments, a vaccine is specific for a cancer cell antigen or tumor-associated antigen. In certain embodiments, a vaccine antigen comprises a MHC (HLA) class I epitope, a MHC (HLA) class II epitope, or a combination thereof.

An eIF4E inhibitor of this disclosure, or pharmaceutically acceptable salt thereof, may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents or regimens. Such combination therapy includes

administration of a single pharmaceutical dosage formulation that contains an eIF4E inhibitor of this disclosure and one or more additional active agents (e.g., inhibitor of an immunosuppression component), as well as administration of eIF4E inhibitors of this disclosure and each active agent in its own separate pharmaceutical dosage formulation. For example, en eIF4E inhibitor of this disclosure and another active agent can be administered to the patient together in a single oral dosage composition, such as a tablet or capsule or liquid, or each agent may be administered in separate oral dosage formulations, or each agent may administered by different routes of administration (e.g., oral and parenteral). An additional active agent may be one accepted in the art as a standard treatment for a particular disease state or disorder, such as in cancer or infection (e.g., vaccine, chemotherapeutic) or a newly emerging therapy (e.g., antibodies against one or more immunosuppression components). When separate dosage formulations are used, an eIF4E inhibitor of this disclosure and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens. Administration of an eIF4E inhibitor of this disclosure may be as a single dose, or administration may occur several times wherein a plurality of doses is given to a subject in need thereof.

In certain embodiments, a combination comprising an eIF4E inhibitor and an inhibitor of an immunosuppression component, each of which may be administered serially (sequentially), concurrently or simultaneously, is used to treat a disease (such as cancer or an infection) in a subject (e.g., human). For example, a combination useful for treating a cancer or an infectious disease my comprise an eIF4E inhibitor (e.g., an eIF4E inhibitor of Formula I, II, III, IV, V, or VI) combined with (a) an antibody specific for PD-1, such as pidilizumab, nivolumab, or pembrolizumab; (b) an antibody specific for PD-L1, such as avelumab, atezolizumab, druvalumab, RG7446, or MDX-1105; (c) an antibody specific for TIM3, such as TSR-022 or MBG453; (d) an antibody specific for LAG3, such as LAG525, IMP321, IMP701, 9H12, or BMS-986016; (e) an IDO inhibitor compound , such as levo-1- methyl tryptophan, epacadostat, ebselen, indoximod, NLG919, 1-methyl-tryptophan (1- MT)-tira-pazamine, navoximod, GDC-0919, BMS-986205, NLG802, HTI-1090, PF- 06840003, OM2983, or RG-70099; (f) a chemotherapeutic agent, such as a MNK-specific inhibitor, an eIF4A inhibitor, a BRAF inhibitor, a MEK inhibitor, a mTOR inhibitor, a VEGF inhibitor, a VEGFR inhibitor, a tyrosine kinase inhibitor, an anti-mitotic agent, vemurafenib, dabrafenib, trametinib, cobimetinib, sunitinib, erlotinib, paclitaxel, or docetaxel; (g) anti-CD137 (4-1BB) antibody, such as urelumab; (h) an anti-CD134 (OX- 40) antibody, such as MDI6469 (an OX-40 agonist); (i) lenalidomide or pomalidomide; or any combination thereof. In any of the aforementioned embodiments, the method of treatment or immune modulation comprises use of the combination further comprising a chemotherapeutic agent, wherein each component of the combination may be administered serially (sequentially), concurrently or simultaneously, as described herein. For example, any one of the eIF4E inhibitors can be combined with an inhibitor of an immunosuppression component, such as (a) an antibody specific for PD-1, such as pidilizumab, nivolumab, or pembrolizumab; (b) an antibody specific for PD-L1, such as MDX-1105, BMS-936559, MEDI4736,

MPDL3280A, or MSB0010718C; (c) an antibody specific for LAG3, such as BMS- 986016; (d) an antibody specific for TIM3, such as TSR-022 or MBG453; (e) an IDO inhibitor compound , such as levo-1-methyl tryptophan, epacadostat, ebselen, indoximod, NLG919, 1-methyl-tryptophan (1-MT)-tira-pazamine, navoximod, GDC-0919, BMS- 986205, NLG802, HTI-1090, PF-06840003, OM2983, or RG-70099; (f) lenalidomide or pomalidomide; (g) anti-CD137 (4-1BB) antibody, such as urelumab; and a

chemotherapeutic agent, such as MNK-specific inhibitor, an eIF4A inhibitor, a BRAF inhibitor, a MEK inhibitor, a mTOR inhibitor, a VEGF inhibitor, a VEGFR inhibitor, a tyrosine kinase inhibitor, an anti-mitotic agent, vemurafenib, dabrafenib, trametinib, cobimetinib, sunitinib, erlotinib, paclitaxel, docetaxel, or the like.

In any of the aforementioned embodiments, the method of treatment or immune modulation comprises use of the combination further comprising an immunotherapeutic agent targeting a disease antigen. In certain embodiments, an immunotherapeutic agent is an adoptive immunotherapeutic agent, such as T cell containing a T cell receptor (TCR) or chimeric antigen receptor (CAR) specific for a cancer antigen (e.g., a tumor-associated antigen (TAA)) or an antigen expressed on an infected cell or both. For example, the eIF4E inhibitor may be administered with a T cell containing a CAR or TCR specific for a cancer antigen (e.g., a tumor-associated antigen (TAA)), such as CD3, CEACAM6, c-Met, EGFR, EGFRvIII, ErbB2, ErbB3, ErbB4, EphA2, IGF1R, GD2, O-acetyl GD2, O-acetyl GD3, GHRHR, GHR, FLT1, KDR, FLT4, CD44v6, CD151, CA125, CEA, CTLA-4, GITR, BTLA, TGFBR2, TGFBR1, IL6R, gp130, Lewis A, Lewis Y, TNFR1, TNFR2, PD1, PD-L1, PD-L2, HVEM, MAGE-A, mesothelin, NY-ESO-1, PSMA, RANK, ROR1, TNFRSF4, CD40, CD137, TWEAK-R, LTbR, LIFRb, LRP5, MUC1, OSMRb, TCRa, TCRb, CD19, CD20, CD22, CD25, CD28, CD30, CD33, CD52, CD56, CD80, CD81, CD86, CD123, CD171, CD276, B7H4, TLR7, TLR9, PTCH1, PTCH1, Robo1, a- fetoprotein (AFP), Frizzled, OX40 (also referred to as CD134), or CD79b. In certain embodiments, an immunotherapeutic agent is a monoclonal antibody, antigen binding fragment thereof, or antibody fusion protein that bind to a cancer antigen (e.g., tumor associated antigen) or an antigen on an infected cell or both. Exemplary cancer antigens include CD3, CEACAM6, c-Met, EGFR, EGFRvIII, ErbB2, ErbB3, ErbB4, EphA2, IGF1R, GD2, O-acetyl GD2, O-acetyl GD3, GHRHR, GHR, FLT1, KDR, FLT4, CD44v6, CD151, CA125, CEA, CTLA-4, GITR, BTLA, TGFBR2, TGFBR1, IL6R, gp130, Lewis A, Lewis Y, TNFR1, TNFR2, PD1, PD-L1, PD-L2, HVEM, MAGE-A, mesothelin, NY- ESO-1, PSMA, RANK, ROR1, TNFRSF4, CD40, CD137, TWEAK-R, LTbR, LIFRb, LRP5, MUC1, OSMRb, TCRa, TCRb, CD19, CD20, CD22, CD25, CD28, CD30, CD33, CD52, CD56, CD80, CD81, CD86, CD123, CD171, CD276, B7H4, TLR7, TLR9, PTCH1, PTCH1, Robo1, a-fetoprotein (AFP), Frizzled, OX40 (also referred to as CD134), and CD79b. In certain embodiments, each component of the combination may be administered serially (sequentially), concurrently or simultaneously, as described herein. For example, an eIF4E inhibitor, e.g. a compound of Formula I, II, III, IV, V or VI can be combined with an inhibitor of an immunosuppression component, such as (a) an antibody specific for PD- 1, such as pidilizumab, nivolumab, or pembrolizumab; (b) an antibody specific for PD-L1, such as MDX-1105, BMS-936559, MEDI4736, MPDL3280A, or MSB0010718C; (c) an antibody specific for LAG3, such as BMS-986016; (d) an antibody specific for TIM3, such as TSR-022 or MBG453; (e) an IDO inhibitor compound , such as levo-1-methyl tryptophan, epacadostat, ebselen, indoximod, NLG919, 1-methyl-tryptophan (1-MT)-tira- pazamine, navoximod, GDC-0919, BMS-986205, NLG802, HTI-1090, PF-06840003, OM2983, or RG-70099 (f) an anti-CD134 (OX-40) antibody, such as MDI6469 (an OX-40 agonist); (g) lenalidomide or pomalidomide; or (h) anti-CD137 (4-1BB) antibody, such as urelumab; and a T cell containing a TCR or CAR specific for a cancer antigen (e.g., a tumor-associated antigen (TAA)), such as CD3, CEACAM6, c-Met, EGFR, EGFRvIII, ErbB2, ErbB3, ErbB4, EphA2, IGF1R, GD2, O-acetyl GD2, O-acetyl GD3, GHRHR, GHR, FLT1, KDR, FLT4, CD44v6, CD151, CA125, CEA, CTLA-4, GITR, BTLA, TGFBR2, TGFBR1, IL6R, gp130, Lewis A, Lewis Y, TNFR1, TNFR2, PD1, PD-L1, PD-L2, HVEM, MAGE-A, mesothelin, NY-ESO-1, PSMA, RANK, ROR1, TNFRSF4, CD40, CD137, TWEAK-R, LTbR, LIFRb, LRP5, MUC1, OSMRb, TCRa, TCRb, CD19, CD20, CD22, CD25, CD28, CD30, CD33, CD52, CD56, CD80, CD81, CD86, CD123, CD171, CD276, B7H4, TLR7, TLR9, PTCH1, PTCH1, Robo1, a-fetoprotein (AFP), Frizzled, OX40 (also referred to as CD134), or CD79b; a T cell containing a TCR or CAR specific for an antigen expressed on infected cells, such as molecules from an adenovirus, bunyavirus, herpesvirus (e.g., Epstein Barr Virus, cytomegalocvirus), papovavirus, papillomavirus (e.g., human papilloma virus, HPV), paramyxovirus, picornavirus, rhabdovirus (e.g., Rabies), orthomyxovirus (e.g., influenza), poxvirus (e.g., Vaccinia), reovirus, retrovirus, lentivirus (e.g., human immunodeficiency virus, HIV), flavivirus (e.g., Hepatitis C virus, HCV; Hepatitis B virus, HBV); an antibody or antigen binding fragment thereof that is specific for a cancer antigen, such as CD3, CEACAM6, c-Met, EGFR, EGFRvIII, ErbB2, ErbB3, ErbB4, EphA2, IGF1R, GD2, O-acetyl GD2, O-acetyl GD3, GHRHR, GHR, FLT1, KDR, FLT4, CD44v6, CD151, CA125, CEA, CTLA-4, GITR, BTLA, TGFBR2, TGFBR1, IL6R, gp130, Lewis A, Lewis Y, TNFR1, TNFR2, PD1, PD- L1, PD-L2, HVEM, MAGE-A, mesothelin, NY-ESO-1, PSMA, RANK, ROR1, TNFRSF4, CD40, CD137, TWEAK-R, LTbR, LIFRb, LRP5, MUC1, OSMRb, TCRa, TCRb, CD19, CD20, CD22, CD25, CD28, CD30, CD33, CD52, CD56, CD80, CD81, CD86, CD123, CD171, CD276, B7H4, TLR7, TLR9, PTCH1, PTCH1, Robo1, a-fetoprotein (AFP), Frizzled, OX40 (also referred to as CD134), or CD79b; or an antibody binding specific for an antigen expressed on infected cells, such as molecules from an adenovirus, bunyavirus, herpesvirus (e.g., Epstein Barr Virus, cytomegalocvirus), papovavirus, papillomavirus (e.g., human papilloma virus, HPV), paramyxovirus, picornavirus, rhabdovirus (e.g., Rabies), orthomyxovirus (e.g., influenza), poxvirus (e.g., Vaccinia), reovirus, retrovirus, lentivirus (e.g., human immunodeficiency virus, HIV), flavivirus (e.g., Hepatitis C virus, HCV; Hepatitis B virus, HBV). In further embodiments, one or more doses of an eIF4E inhibitor are administered serially (sequentially), concurrently or simultaneously with one or more doses of an inhibitor of an immunosuppression component and optionally one or more doses of a chemotherapeutic agent or a T cell containing a TCR or CAR specific for a TAA or an antigen expressed on an infected cell. In still further embodiments, multiple doses of an eIF4E inhibitor are administered serially (sequentially), concurrently or simultaneously with multiple doses of an inhibitor of an immunosuppression component and multiple doses of a chemotherapeutic agent. In still further embodiments, multiple doses of an eIF4E inhibitor are administered serially (sequentially), concurrently or simultaneously with one to about four doses of an inhibitor of an immunosuppression component and one to about four doses of a chemotherapeutic agent. In all the above embodiments, an eIF4E inhibitor may be administered first or an inhibitor of an immunosuppression component may be administered first or a chemotherapeutic agent may be administered first.

The combinations may be presented as a combination kit. The phrase "combination kit" or "kit of parts," as used herein, means one or more pharmaceutical compositions that are used to administer an eIF4E inhibitor, an inhibitor of an immunosuppression component, and optionally a chemotherapeutic agent according to this disclosure. When an eIF4E inhibitor and an inhibitor of an immunosuppression component are administered simultaneously, the combination kit can contain an eIF4E inhibitor and an inhibitor of an immunosuppression component in a single pharmaceutical composition or in separate pharmaceutical compositions, such as a tablet, vial or both, and a chemotherapeutic agent in a vial. When an eIF4E inhibitor and a chemotherapeutic agent are administered simultaneously, the combination kit can contain an eIF4E inhibitor and a chemotherapeutic agent in a single pharmaceutical composition or in separate pharmaceutical compositions, such as a tablet, vial or both, and an inhibitor of an immunosuppression component in a vial. When an eIF4E inhibitor and an inhibitor of an immunosuppression component and/or optionally a chemotherapeutic agent are not administered simultaneously, the combination kit will contain an eIF4E inhibitor, an inhibitor of an immunosuppression component and optionally a chemotherapeutic agent in separate pharmaceutical compositions, wherein an eIF4E inhibitor, an inhibitor of an immunosuppression component and optionally a chemotherapeutic agent are either in a single package, or are in separate pharmaceutical compositions in separate packages.

In one aspect, there is provided a kit of parts comprising the following components: (a) an eIF4E inhibitor in a pharmaceutically acceptable carrier, diluent or excipient; (b) an inhibitor of an immunosuppression component in a pharmaceutically acceptable carrier, diluent or excipient; and optionally (c) a chemotherapeutic agent in a pharmaceutically acceptable carrier, diluent or excipient.

In certain embodiments, a kit of parts comprises the following components: (a) an eIF4E inhibitor in a pharmaceutically acceptable carrier, diluent or excipient; (b) an inhibitor of an immunosuppression component in a pharmaceutically acceptable carrier, diluent or excipient; and optionally (c) a chemotherapeutic agent in a pharmaceutically acceptable carrier, diluent or excipient, wherein the components are provided in a form that is suitable for sequential, separate and/or simultaneous administration.

In certain embodiments, a kit of parts comprises: (1) a first container comprising an eIF4E inhibitor in a pharmaceutically acceptable carrier, diluent or excipient; and (2) a second container comprising an inhibitor of an immunosuppression component in a pharmaceutically acceptable carrier, diluent or excipient, and optionally (3) a third container comprising a chemotherapeutic agent in a pharmaceutically acceptable carrier, diluent or excipient. A combination kit can also be provided with instruction, such as dosage and administration instructions. Such dosage and administration instructions can be of the kind that are provided to a doctor, for example, by a drug product label or they can be of the kind that are provided by a doctor, such as instructions to a patient.

The term "loading dose," as used herein, should be understood to mean a single dose or short duration regimen of an eIF4E inhibitor or an inhibitor of an

immunosuppression component or a chemotherapeutic agent having a dosage higher than the maintenance dose administered to a subject to, for example, rapidly increase the blood concentration level of the drug. In certain embodiments, a short duration regimen for use as described herein will be from one to about 14 days; from one to about seven days; from one to about three days; for about three days; for about two days; or for one day. In some embodiments, a "loading dose" can increase the blood concentration of a compound (e.g., eIF4E inhibitor of this disclosure) to a therapeutically effective level. In some

embodiments, a "loading dose" can increase the blood concentration of a compound (e.g., eIF4E inhibitor of this disclosure) to a therapeutically effective level in conjunction with a maintenance dose of the compound. The "loading dose" can be administered once per day, or more than once per day (e.g., up to four times per day). In certain embodiments, a "loading dose" is administered once a day. In some embodiments, a loading dose will be an amount from two to about 100 times the maintenance dose; from about two to about ten times; from about two to about five times; or from about two times to about three times; about four times; or about five times. In other embodiments, a loading dose will be administered from one to about seven days; from one to about five days; from one to about three days; for one day; for about two days; for about three days, followed by a

maintenance dosing protocol.

The term "maintenance dose," as used herein, will be understood to mean a dose that is serially administered (i.e.; at least twice), which is intended to either slowly raise blood concentration levels of the compound (e.g., eIF4E inhibitor of this disclosure) to a therapeutically effective level, or to maintain such a therapeutically effective level over a desired period of time (e.g., hours, days, weeks, months, years). In certain embodiments, a maintenance dose is administered once or twice per day, and the daily maintenance dose is lower than the total daily loading dose.

In any of the previously aforementioned embodiments, the method comprises administering an eIF4E inhibitor and optionally a compound that induces or enhances an anti-cancer response. In certain embodiments, an induced or enhanced anti-cancer response is an anti-tumor response. In further embodiments, a therapy that induces or enhances an anti-cancer response is a vaccine, surgery, radiation, an inhibitor of an immunosuppression component, a tyrosine kinase inhibitor, a cytotoxic agent, a chemotherapeutic agent, an RNA interference agent, a cytokine, or any combination thereof. In certain embodiments, a therapy that induces or enhances an anti-cancer response is a chemotherapeutic agent, such as a eIF4A inhibitor, MNK inhibitor, mTOR inhibitor, B-Raf inhibitor, a MEK inhibitor, a VEGF inhibitor, or a VEGFR inhibitor.

In certain embodiments, a combination therapy method comprises administering an eIF4E inhibitor and further administering a radiation treatment or a surgery to a subject. Radiation therapy includes X-ray therapies, such as gamma-irradiation, and

radiopharmaceutical therapies. Surgeries and surgical techniques appropriate to treating a given cancer or non-inflamed solid tumor may be used in a subject in combination with an eIF4E inhibitor of this disclosure.

As used herein the term "RNA interference agent" (RNAi agent), refers to a short single or double-stranded RNA polynucleotide capable of decreasing or inhibiting expression of a target gene, typically by cleavage of the target mRNA molecule. Non- limiting examples of RNAi agents include short interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), and PIWI-interacting RNA (piRNA). Another cancer therapy approach involves reducing expression of oncogenes and other genes needed for growth, maintenance, proliferation, and immune evasion by cancer cells. RNA interference agents, such as microRNAs (miRNAs) and small inhibitory RNAs (siRNAs), provide an approach for knocking down expression of cancer genes. See, e.g., Larsson et al., Cancer Treat. Rev.16:128, 2017.

Cytokines can be used to manipulate host immune response towards anticancer activity. See, e.g., Floros and Tarhini, Semin. Oncol.42:539, 2015. Cytokines useful for promoting anticancer or antitumor response include, for example, IFN-a, IL-2, IL-3, IL-4, IL-10, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-21, IL-24, and GM-CSF, singly or in any combination.

In certain embodiments, an eIF4E inhibitor is used in combination with a BRAF inhibitor, such as encorafenib, vemurafenib, dabrafenib, PLX7904, PLX8394, CEP-32496, GDC-0879, PLX-4720, ZM 336372, GW5074, NVP-BHG712, RAF265, sorafenib, vemurafenib, dabrafenib, TAK-632, HMC95573, TAK-580 (formerly called MLN2480), INU-152, LY3009120, AZ628, LSN3074753, SB590885, CCT196969, CCT241161, DP- 4978, (R)-2-(l-(6-amino-5-chloropyrimidine-4- carboxamide)ethyl)-N-(5-chloro-4- ĨMfluoromemyl)pyridin-2-yl)thiazole-5-carboxamide, sorafenib tosylate, lifirafenib, or any combination thereof. In further embodiments, an eIF4E inhibitor is used in combination with a BRAF inhibitor and a PD-1 specific antibody or binding fragment thereof. In still further embodiments, an eIF4E inhibitor is used in combination with a BRAF inhibitor and a PD-L1 specific antibody or binding fragment thereof. In yet further embodiments, an eIF4E inhibitor is used in combination with a BRAF inhibitor and a LAG3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a BRAF inhibitor and a TIM3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a BRAF inhibitor and an IDO inhibitor compound.

In certain embodiments, an eIF4E inhibitor is used in combination with a MEK inhibitor, such as trametinib, selumetinib, binimetinib, PD-325901, cobimetinib, CI-1040, MEK162, AZD8330, TAK-733, GDC-0623, refametinib, pimasertib, RO4987655, WX- 544, HL-085, GDC0973, GSK1120212, AZD6244, PD035901, or any combination thereof. In further embodiments, an eIF4E inhibitor is used in combination with a MEK inhibitor and a PD-1 specific antibody or binding fragment thereof. In still further embodiments, an eIF4E inhibitor is used in combination with a MEK inhibitor and a PD- L1 specific antibody or binding fragment thereof. In yet further embodiments, an eIF4E inhibitor is used in combination with a MEK inhibitor and a TIM3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a MEK inhibitor and a LAG3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a MEK inhibitor and an IDO inhibitor compound.

In certain embodiments, an eIF4E inhibitor is used in combination with a VEGF inhibitor, such as bevacizumab, ranibizumab, AZD2171, cannbidiol, THC, or any combination thereof. In further embodiments, an eIF4E inhibitor is used in combination with a VEGF inhibitor and a PD-1 specific antibody or binding fragment thereof. In still further embodiments, an eIF4E inhibitor is used in combination with a VEGF inhibitor and a PD-L1 specific antibody or binding fragment thereof. In yet further embodiments, an eIF4E inhibitor is used in combination with a VEGF inhibitor and a LAG3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a VEGF inhibitor and a TIM3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a VEGF inhibitor and an IDO inhibitor compound.

In certain embodiments, an eIF4E inhibitor is used in combination with a VEGFR inhibitor, such as axitinib, sunitinib, vatalanib, sorafenib, GW-786034, CP-547632, AG- 013736, lenvatinib, motesanib, pazopanib, regorafenib, ramucirumab, CDP-791, or any combination thereof . In further embodiments, an eIF4E inhibitor is used in combination with a VEGFR inhibitor and a PD-1 specific antibody or binding fragment thereof. In still further embodiments, an eIF4E inhibitor is used in combination with a VEGFR inhibitor and a PD-L1 specific antibody or binding fragment thereof. In yet further embodiments, an eIF4E inhibitor is used in combination with a VEGFR inhibitor and a LAG3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a VEGFR inhibitor and a TIM3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a VEGFR inhibitor and an IDO inhibitor compound.

In certain embodiments, an eIF4E inhibitor is used in combination with a tyrosine kinase inhibitor, such as imatinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, pazopanib, vandetanib, dasatinib, or any combination thereof. In further embodiments, an eIF4E inhibitor is used in combination with a tyrosine kinase inhibitor and a PD-1 specific antibody or binding fragment thereof. In still further embodiments, an eIF4E inhibitor is used in combination with a tyrosine kinase inhibitor and a PD-L1 specific antibody or binding fragment thereof. In yet further embodiments, an eIF4E inhibitor is used in combination with a tyrosine kinase inhibitor and a TIM3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a tyrosine kinase inhibitor and a LAG3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a tyrosine kinase inhibitor and an IDO inhibitor compound.

As used herein the term "cytotoxic agent," refers to any agent that inhibits cell growth, inhibits cell proliferation, leads to cell death or the like. In certain embodiments, an eIF4E inhibitor is used in combination with a cytotoxic agent, such as actinomycin, belomycin, plicamycin, mitomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, pirarubucin, aclarubicin, mitoxantrone, or a combination thereof. An anti-mitotic agent, or anti-microtubule agent, may be paclitaxel, docetaxel, vinblastine, vincristine, vindesine, vinorelbine, or a combination thereof. In further embodiments, an eIF4E inhibitor is used in combination with a cytotoxic agent and a PD-1 specific antibody or binding fragment thereof. In still further embodiments, an eIF4E inhibitor is used in combination with a cytotoxic agent and a PD-L1 specific antibody or binding fragment thereof. In yet further embodiments, an eIF4E inhibitor is used in combination with a cytotoxic agent and a TIM3 specific antibody or binding fragment thereof, or fusion protein. In yet further

embodiments, an eIF4E inhibitor is used in combination with a cytotoxic agent and a LAG3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a cytotoxic agent and an IDO inhibitor compound.

In certain embodiments, immune modulation by an eIF4E inhibitor is used with at least one anti-cancer agent. Anti-cancer agents include chemotherapeutic drugs. A chemotherapeutic agent includes, for example, an inhibitor of chromatin function, a topoisomerase inhibitor, a microtubule inhibiting drug, a DNA damaging agent, an antimetabolite (such as folate antagonists, pyrimidine analogs, purine analogs, and sugar- modified analogs), a DNA synthesis inhibitor, a DNA interactive agent (such as an intercalating agent), a DNA repair inhibitor, and targeted, cytostatic agents that inhibit a target molecule involved in carcinogenesis and tumor growth. In certain embodiments, a chemotherapeutic is a MNK inhibitor, an eIF4A inhibitor, a B-Raf inhibitor, a MEK inhibitor, a VEGF inhibitor, a VEGFR inhibitor, a mTOR inhibitor, a tyrosine kinase inhibitor, an anti-mitotic agent, or any combination thereof. In a specific embodiment, the chemotherapeutic is vemurafenib, dabrafenib, trametinib, cobimetinib, sunitinib, erlotinib, paclitaxel, docetaxel, or any combination thereof. In further embodiments, an eIF4E inhibitor is used in combination with a chemotherapeutic agent and a PD-1 specific antibody or binding fragment thereof. In still further embodiments, an eIF4E inhibitor is used in combination with a chemotherapeutic agent and a PD-L1 specific antibody or binding fragment thereof. In yet further embodiments, an eIF4E inhibitor is used in combination with a chemotherapeutic agent and a TIM3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a chemotherapeutic agent and a LAG3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a chemotherapeutic agent and an IDO inhibitor compound.

Chemotherapeutic agents include, for example, the following groups: anti- metabolites/anti-cancer agents, such as pyrimidine analogs (5-fluorouracil, floxuridine, capecitabine, gemcitabine and cytarabine) and purine analogs, folate antagonists and related inhibitors (methotrexate, pemetrexed, mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine)); antiproliferative/antimitotic agents including natural products such as vinca alkaloids (vinblastine, vincristine, and vinorelbine), microtubule disruptors such as taxane (paclitaxel, docetaxel), vincristin, vinblastin, nocodazole, epothilones, eribulin and navelbine; epidipodophyllotoxins (etoposide, teniposide); DNA damaging agents (actinomycin, amsacrine, anthracyclines, bleomycin, busulfan, camptothecin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin, procarbazine, taxol, taxotere, temozolamide, teniposide,

(mithramycin) and mitomycin; enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents; antiproliferative/antimitotic alkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine and thiotepa), alkylsulfonates (busulfan), nitrosoureas (carmustine (BCNU) and analogs, streptozocin), triazenes (dacarbazine (DTIC)); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory agents; antisecretory agents (breveldin); immunosuppressives (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); anti-angiogenic compounds (TNP470, genistein, pomalidomide) and growth factor inhibitors (vascular endothelial growth factor (VEGF) inhibitors, such as ziv-aflibercept; fibroblast growth factor (FGF) inhibitors); inhibitors of apoptosis protein (IAP) antagonists (birinapant); histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, chidamide, panobinostat, mocetinostat, abexinostat, belinostat, entinostat, resminostat, givinostat, quisinostat, SB939); proteasome inhibitors (ixazomib); angiotensin receptor blocker; nitric oxide donors; anti-sense oligonucleotides; antibodies (trastuzumab, panitumumab, pertuzumab, cetuximab, adalimumab, golimumab, infliximab, rituximab, ocrelizumab, ofatumumab, obinutuzumab, alemtuzumab, abciximab, atlizumab, daclizumab, denosumab, efalizumab, elotuzumab, rovelizumab, ruplizumab, ustekinumab, visilizumab, gemtuzumab

(flavopiridol, roscovitine, bryostatin-1) and differentiation inducers (tretinoin); mTOR inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), amsacrine, camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan (CPT- 11) and mitoxantrone, topotecan, irinotecan), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, and prenisolone); PARP inhibitors (niraparib, olaparib); focal adhesion kinase (FAK) inhibitors (defactinib (VS-6063), VS- 4718, VS-6062, GSK2256098); growth factor signal transduction kinase inhibitors (cediranib, galunisertib, rociletinib, vandetanib, afatinib, EGF816, AZD4547); c-Met inhibitors (capmatinib, INC280); ALK inhibitors (ceritinib, crizotinib); mitochondrial dysfunction inducers, toxins such as Cholera toxin, ricin, Pseudomonas exotoxin,

Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin, and caspase activators; and chromatin disruptors.

In certain embodiments, an eIF4E inhibitor is used in combination with a MNK specific inhibitor, such as a compound provided in Section B (i) of the present disclosure. In further embodiments, an eIF4E inhibitor is used in combination with a a MNK specific inhibitor and a PD-1 specific antibody or binding fragment thereof. In still further embodiments, an eIF4E inhibitor is used in combination with a MNK specific inhibitor and a PD-L1 specific antibody or binding fragment thereof. In yet further embodiments, an eIF4E inhibitor is used in combination with a MNK specific inhibitor and a TIM3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a MNK specific inhibitor and a LAG3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a MNK specific inhibitor and an IDO inhibitor compound.

In certain embodiments, an eIF4E inhibitor is used in combination with an eIF4A specific inhibitor, such as a compound provided in Section B (ii) of the present disclosure. In further embodiments, an eIF4E inhibitor is used in combination with an eIF4A inhibitor and a PD-1 specific antibody or binding fragment thereof. In still further embodiments, an eIF4E inhibitor is used in combination with an eIF4A inhibitor and a PD-L1 specific antibody or binding fragment thereof. In yet further embodiments, an eIF4E inhibitor is used in combination with an eIF4A inhibitor and a TIM3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with an eIF4A inhibitor and a LAG3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with an eIF4A inhibitor and an IDO inhibitor compound.

In certain embodiments, an eIF4E inhibitor is used in combination with an mTOR inhibitor, such as a compound provided in Section B (iii) of the present disclosure. In further embodiments, an eIF4E inhibitor is used in combination with a mTOR inhibitor and a PD-1 specific antibody or binding fragment thereof. In still further embodiments, an eIF4E inhibitor is used in combination with a mTOR inhibitor and a PD-L1 specific antibody or binding fragment thereof. In yet further embodiments, an eIF4E inhibitor is used in combination with a mTOR inhibitor and a TIM3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a mTOR inhibitor and a LAG3 specific antibody or binding fragment thereof, or fusion protein. In yet further embodiments, an eIF4E inhibitor is used in combination with a mTOR inhibitor and an IDO inhibitor compound.

In certain embodiments, a therapy that induces or enhances an anti-cancer response, for example, a vaccine, an inhibitor of an immunosuppression signal, a B-Raf inhibitor, a MEK inhibitor, a VEGF inhibitor, a VEGFR inhibitor, a tyrosine kinase inhibitor, a cytotoxic agent, a chemotherapeutic, or any combination thereof, is used in combination with an eIF4E inhibitor in the immune modulation methods described herein, wherein the therapy that induces or enhances an anti-cancer response does not antagonize, reduce, diminish, or decrease the inhibitory activity of an eIF4E inhibitor on one or more inhibitory immune checkpoint molecules. An antagonistic combination with an eIF4E inhibitor may be ascertained by measuring the level of T cell activation as a readout of the inhibitory activity of an eIF4E inhibitor, with and without the therapy that induces or enhances anti- cancer response, on one or more inhibitory immune checkpoint molecules. In certain embodiments, a combination of an eIF4E inhibitor and a therapy that induces or enhances anti-cancer response will not antagonize the inhibitory activity of the eIF4E inhibitor against one or more inhibitory immune checkpoint molecules or will only decrease the inhibitory activity of the eIF4E inhibitor against one or more inhibitory immune checkpoint molecules by less than about 25%, 20%, 15%, 10%, 5%, 2%, 1%, 0.5%, 0.25%, or 0.1%. In the context of infection or infectious disease, immune modulation by an eIF4E inhibitor is used in combination with anti-infective agents, including antiviral agents (e.g., anti-HIV agents), antibiotic agents, antimicrobial agents, anti-parasitic agents, or anti- fungal agents. Examples of anti-HIV drugs include, for example, reverse transcriptase inhibitors (e.g., AZT, ddl, 3TC, and d4T), protease inhibitors (e.g., saquinavir mesylate, ritonavir, nelfinavir mesylate, amprenavir, delavirdine mesylate, saquinavir, and lopinavir/ritonavir) or CCR5 receptor antagonists. Antiviral agents include, for example, anti-herpesvirus agents, anti-influenza virus agents, interferon-a and b, or various immunoglobulins.

Immune modulation by an eIF4E inhibitor may be used together with an anti-viral vaccine, an anti-bacterial vaccine, an anti-fungal vaccine, an anti-parasitic vaccine, or made as a formulation with such vaccines. Vaccines for infectious disease include, for example, poliovaccine, measles vaccine, Japanese encephalitis vaccine, BCG vaccine, triple vaccine, mumps virus vaccine, varicella virus vaccine, influenza vaccine, hepatitis A vaccine, hepatitis B vaccine, HIV vaccine, malaria vaccine, and cholera vaccine.

A "subject in need thereof" refers to a subject at risk of, or suffering from, a disease, disorder or condition (e.g., hyperproliferative disorder like cancer, chronic infection) that is amenable to treatment or amelioration with a compound or a composition thereof provided herein. Subjects in need of administration of therapeutic agents as described herein include subjects suspected of having a cancer, subjects presenting with an existing cancer, subjects receiving a cancer vaccine, subjects suspected of being infected with an infectious agent, subjects presenting with an infection or infectious disease, or subjects receiving a vaccine against an infectious agent. A subject may be any organism capable of developing cancer or being infected, such as humans, pets, livestock, show animals, zoo specimens, or other animals. For example, a subject may be a human, a non- human primate, dog, cat, rabbit, horse, or the like. In certain embodiments, a subject in need is a human. In particular embodiments, a subject in need has a disease, such as cancer or chronic infection, associated with immune resistance. In any of the aforementioned embodiments, a pharmaceutical composition comprising an eIF4E inhibitor (e.g., as compound of structure (II)) is administered to a subject in an amount sufficient to inhibit eIF4E-specific activity and reduce

immunosuppression, and preferably with acceptable toxicity to the same. Appropriate concentrations and dosages can be readily determined by one skilled in the art.

An eIF4E inhibitor, or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy.

"Effective amount" or "therapeutically effective amount" refers to that amount of an eIF4E inhibitor described herein which, when administered to a mammal (e.g., human), is sufficient to effect relief from immune suppression, as defined herein, to aid in treating a disease in the mammal, such as a human. The amount of an eIF4E inhibitor that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure. When referring to an individual active ingredient, administered alone, a therapeutically effective dose refers to that ingredient alone. When referring to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered serially, concurrently or simultaneously.

The therapeutic eIF4E inhibitors and pharmaceutical compositions thereof that increase the activity of an immune cell; induce, enhance, or prolong an immune response; stimulate an antigen-specific T cell response; inhibit an immunosuppressive signaling pathway; promote endogenous anti-cancer or anti-infectious agent immunity; or inhibit immune resistance of cancer cells or infectious agents/infected cells provided herein are administered to a subject who has or is at risk of developing a cancer, infection, or infectious disease at a therapeutically effective amount or dose. Such a dose may be determined or adjusted depending on various factors including the specific therapeutic agents or pharmaceutical compositions, the routes of administration, the subject’s condition, that is, stage of the disease, viral/bacterial/fungal/parasite load, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Similarly, the dose of the therapeutic for treating a disease or disorder may be determined according to parameters understood by a person skilled in the medical art.

An example where monotherapy may be sufficient as an anti-cancer therapy is in the context of a patient with a strong, endogenous (pre-existing) anti-cancer immune response. For example, a tumor may have a large population of antigen specific tumor infiltrating lymphocytes (TILs). But, an active anti-cancer immune response within the tumor microenvironment may induce tumor cells and tumor-associated macrophages to express immune inhibitory signals (e.g., PD-L1) that down-modulate the anti-cancer immune response. Addition of an inhibitor of an immunosuppression signal, such as an eIF4E inhibitor, may inhibit the tumor’s adaptive immune resistance mechanism and allow tumor regression via the endogenous anti-cancer immune response (e.g., TILs). In certain embodiments, a monotherapy that promotes an anti-cancer response may be an eIF4E inhibitor, a vaccine, a B-Raf inhibitor, a MEK inhibitor, a mTOR inhibitor, a VEGF inhibitor, a VEGFR inhibitor, an eIF4A inhibitor, a MNK specific inhibitor, a tyrosine kinase inhibitor, a cytotoxic agent, a chemotherapeutic, or any combination thereof. In certain embodiments, an inhibitor of an immunosuppression signal component is an inhibitor of PD-1, PD-L1, PD-L2, CTLA4, CD80, CD86, B7-H3, B7-H4, HVEM, BTLA, KIR, LAG3, GAL9, TIM3, 2B4, adenosine, A2aR, TGFb, IL-10, IL-35, arginase, IDO, or any combination thereof.

In other examples, a combination therapy may be useful in the context of a patient with a weak, endogenous anti-cancer immune response. For example, a tumor environment may have lower numbers of TILs because the tumor might be less immunogenic. A therapy that induces or enhances an anti-cancer response de novo can promote or increase the endogenous anti-cancer immune response. But, as with the single therapy, the efficacy of this anti-cancer immune response may be limited by up-regulation of immunosuppression signal components (e.g., PD-L1). For example, combining a therapy that induces or enhances an anti-cancer response (“prime”) with an inhibitor of an immunosuppression signal (“boost”) may induce promote or improve the likelihood of tumor regression. Alternatively, a combination therapy may comprise an inhibitor of an immunosuppression signal component (“prime”) with an agent that induces or enhances an anti-cancer response (“boost”) may induce or promote or improve the likelihood of tumor regression. Combining a therapy that induces or enhances an anti-cancer response

(“prime”) with an inhibitor or down-regulator of an immunosuppression signal component (“boost”) may induce tumor regression by allowing an endogenous anti-tumor immune response to function as such. In certain embodiments, a combination therapy that induces or enhances or promotes an anti-cancer response may be an eIF4E inhibitor used with one or more of the following: a vaccine, a B-Raf inhibitor, a MEK inhibitor, a mTOR inhibitor, a VEGF inhibitor, a VEGFR inhibitor, an eIF4A inhibitor, a MNK specific inhibitor, a tyrosine kinase inhibitor, a cytotoxic agent, a chemotherapeutic, or any combination thereof. In certain embodiments, an inhibitor of an immunosuppression signal component is an inhibitor of PD-1, PD-L1, PD-L2, CTLA4, CD80, CD86, B7-H3, B7-H4, HVEM, BTLA, KIR, LAG3, GAL9, TIM3, 2B4, adenosine, A2aR, TGFb, IL-10, IL-35, arginase, or IDO. In certain embodiments, a combination therapy comprises a“prime” and a“boost” treatment, wherein each treatment is administered to a subject simultaneously or concurrently. In other embodiments, the“boost” treatment is administered sequentially after the“prime” treatment.

Generally, a therapeutic agent is administered at a therapeutically effective amount or dose. A therapeutically effective amount or dose will vary according to several factors, including the chosen route of administration, formulation of the composition, patient response, severity of the condition, the subject's weight, and the judgment of the prescribing physician. The dosage can be increased or decreased over time, as required by an individual patient. In certain instances, a patient initially is given a low dose, which is then increased to an efficacious dosage tolerable to the patient. In addition, a patient may be given a plurality of doses over a determined period of time and in particular time increments (such as daily, weekly, biweekly, monthly, quarterly, biannually, annually or the like). Determination of an effective amount or dosing regimen is well within the capability of those skilled in the art.

When referring to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered serially or simultaneously (in the same formulation or concurrently in separate formulations). The most effective doses may generally be determined using experimental models and/or clinical trials. Design and execution of pre-clinical and clinical studies for a therapeutic agent (including when administered for prophylactic benefit) described herein are well within the skill of a person skilled in the relevant art.

The route of administration of a therapeutic agent can be oral, intraperitoneal, transdermal, subcutaneous, by intravenous or intramuscular injection, by inhalation, topical, intralesional, infusion; liposome-mediated delivery; topical, intrathecal, gingival pocket, rectal, intrabronchial, nasal, transmucosal, intestinal, ocular or otic delivery, or any other methods known in the art.

EXAMPLES EXAMPLE 1

EFFECT OF EIF4E INHIBITION ON T CELL IMMUNE CHECKPOINT MARKERS Reagents

A375 cells were purchased from ATCC (Manassas, VA) and were maintained in DMEM supplemented with 10% fetal bovine serum. HAP-1 and the HAP-1-R (harboring a knock-in mutation conferring eIF4Ei resistance) were purchased from Horizon Discovery (Cambridge, UK) and were maintained in IMEM supplemented with 10% fetal bovine serum. Primary T cells were isolated from buffy coat preparations obtained from donors with informed consent (San Diego Blood Bank, San Diego CA).

For flow cytometry analyses, the fluorescein isothiocyanate (FITC)-conjugated CD3, allophycocyanin (APC)-conjugated PD-1, and phycoerythrin (PE)-conjugated PD-L1 antibodies were purchased from BioLegend (San Diego, CA). The APC-conjugated LAG3 and PE-conjugated TIM-3 antibodies were purchased from eBioScience (San Diego, CA). For immunoblotting analyses, the IDO, PD-L1, STAT1, and actin antibodies were purchased from Cell Signaling Technology (Danvers, MA). The tubulin antibody was purchased from Sigma (St. Louis, MO). BD Horizon Fixable Viability Stain and BD BD CytoFix™ were purchased from (BD Biosciences, San Jose, CA).

eIF4E Inhibitor Compounds:

Compound 296F according to the following structure:

Compound X according to the following structure:

Compound 470F according to the following structure:

Analysis of T cell checkpoint markers

Primary T cells were isolated from buffy coat preparations using the MojoSort Human CD3 T cell isolation kit (Biolegend, San Diego, CA). T cells were activated by incubation with anti-CD3/CD28 beads at a 2:1 ratio (Miltenyi Biotec, San Diego CA) in the absence or presence of Compound 296F. At 24 h post-stimulation, cells were harvested and analyzed by immunoblotting or flow cytometry. For immunoblotting, whole cell lysates were separated by SDS-PAGE and immunoblotted with the indicated antibodies followed by detection using an Odyssey Infrared Imager (LI-COR Biosciences, Lincoln NE). For flow cytometry analyses, cells were incubated with Horizon Fixable Viability Stain (BD Biosciences, San Jose CA) for 15 min at 4^o C, and washed with flow staining buffer (1x PBS, 4% FBS and 1mM EDTA). Cells were then incubated with human BD FcR Block (BD Biosciences) and stained for CD3 and PD-1, LAG3, TIM-3 or PD-L1 antibodies for 30 minutes at 4^o C, washed two times with flow staining buffer, and fixed with BD CytoFix™ (BD Biosciences) for 20 minutes at 4^o C. After fixation, cells were washed in flow staining buffer and assessed for fluorescence using a Attune NXT flow cytometer (ThermoFisher) and data was analyzed by FlowJo 10.1 (FloJo, Ashland OR). Analysis of IFN-gamma stimulated IDO and PD-L1 expression

HAP-1, HAP-1-R, or A375 cells were stimulated with 20 ng/ml IFN-gamma alone or in the presence of eIF4E inhibitors for 24h. HAP-1 and HAP-1-R cells were harvested and analyzed for PD-L1 expression by flow cytometry. Whole cell lysates from A375 cells were analyzed by immunoblotting for IDO, STAT-1, PD-L1, tubulin, and actin expression. Additionally, supernatants from A375 cells were analyzed for L-kynurenine levels by LC- MS/MS.

Analysis of T cell checkpoint markers

To assess whether eIF4E inhibition affected key checkpoint proteins in T cells, primary T cells were stimulated via anti-CD3/CD28 beads in the absence or presence of eIF4E inhibitors and expression of PD-1, LAG3, TIM-3, and PD-L1 was analyzed by flow cytometry after 24 h. PD-1 expression was stimulated by anti-CD3/CD28 crosslinking and was inhibited by Compound 296F in a dose-dependent manner (Fig.1A). Similar results were observed with LAG3 (Fig.1B), TIM-3 (Fig.1C) and PD-L1 (Fig.1D), which were all stimulated by anti-CD3/CD28 crosslinking and showed dose-dependent inhibition by Compound 296F. Importantly, the inhibition of checkpoint protein expression did not occur due to compromised T cell activation or cell viability, as CD69 expression or cell viability was unchanged (Fig.1E). These results demonstrate that eIF4E inhibitors are able to suppress expression of key checkpoint proteins in activated T cells.

Analysis of IFN-gamma stimulated IDO and PD-L1 expression

Compound 296F was also tested for the ability to inhibit IFN-gamma-stimulated PD-L1 expression (Fig.2). PD-L1 was induced in HAP-1 cells treated with IFN-gamma, and this induction was blocked by Compound 296F in a dose-dependent manner. A parallel experiment in HAP-1-R cells, which express a mutant eIF4E allele engineered to be resistant to Compound 296F, also showed IFN-gamma-stimulated PD-L1 expression. However, Compound 296F did not inhibit PD-L1 expression in HAP-1-R cells, confirming that the observed effect in HAP-1 cells was due to eIF4E inhibition.

Next, the effect of multiple eIF4E inhibitors (Compounds 296F, X, and 470F–on additional IFN-gamma-stimulated proteins, such as IDO and STAT1 was examined in the melanoma cell line A375. Stimulation of A375 cells with IFN-gamma robustly enhanced the expression of IDO, STAT1 and PD-L1 (Fig.3A). Treatment of cells with Compounds 296F, X and 3 inhibited IDO, STAT1 and PD-L1 expression in a dose-dependent manner. Furthermore, L-kynurenine levels in the growth media were reduced in a dose-dependent manner by Compounds 296F, X, and 470F, which is consistent with the observed reduction in IDO expression (Fig.3B). Taken together, these results demonstrate the eIF4E inhibitors can inhibit IFN-gamma-stimulated expression of PD-L1, STAT1 and IDO.

T cell checkpoint receptors such as PD-1, LAG3 and TIM-3 play important roles in restraining normal immune function and are frequently engaged by tumor cells to facilitate evasion from the immune response. Here, we demonstrate that eIF4E inhibition can downregulate checkpoint receptors in T cells, such as PD-1, LAG3 and TIM-3. eIF4E inhibitors can also downregulate PD-L1, the ligand for PD-1, in T cells or in interferon gamma-stimulated tumor cells. Finally, we show that eIF4E can inhibit the STAT1-IDO axis, which is responsible for generating the immunosuppresive catabolite kynurenine. Taken together, these results suggest that eIF4E inhibition can be used as a strategy to enhance the anti-tumor immune response as both a monotherapy and in combination with agents that activate anti-cancer immune response (e.g. immune checkpoint inhibitors). The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.

These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMS at is claimed is: 1. A method of inducing or enhancing an immune response, comprising

inistering a therapeutically effective amount of an eIF4E inhibitor to a subject, thereby cing or enhancing the immune response. 2. The method of claim 1, wherein the subject in need of induced or enhancedmune response has a disease associated with immune resistance. 3. The method of claim 2, wherein the disease associated with immune resistance is ncer or an infection. 4. The method of claim 3, wherein the cancer is a solid tumor, melanoma, non-small lung cancer, renal cell carcinoma, renal cancer, a hematological cancer, prostate cancer, ration-resistant prostate cancer, colon cancer, rectal cancer, gastric cancer, esophageal cer, bladder cancer, head and neck cancer, thyroid cancer, breast cancer, triple-negative st cancer, ovarian cancer, cervical cancer, lung cancer, urothelial cancer, pancreatic cancer, blastoma, hepatocellular cancer, myeloma, multiple myeloma, leukemia, Hodgkin's phoma, non-Hodgkin's lymphoma, myelodysplastic syndrome, brain cancer, CNS cancer, gnant glioma, or any combination thereof. 5. The method of claim 3, wherein the infection is a viral, bacterial, fungal, or sitic infection. 6. The method of claim 5, wherein the viral infection is an infection by a flavivirus, es virus, hepatitis virus, papillomavirus, paramyxovirus, retrovirus, lentivirus, or

cella-zoster virus.

7. The method of claim 5, wherein the viral infection is an infection by a hepatitis C s (HCV), hepatitis B virus (HBV), hepatitis A virus, hepatitis E virus, Japanese encephalitis s, or human immunodeficiency virus (HIV). 8. The method of any one of claims 5-7, wherein the method further comprises inistering an inhibitor of an immunosuppression component, an anti-infective agent, or both. 9. The method of claim 8, wherein the inhibitor of an immunosuppression ponent is a small molecule, antibody, or siRNA. 10. The method of claim 9, wherein the small molecule, antibody, or siRNA is ific for PD-1, PD-L1, LAG3, TIM3, IDO, PD-L2, CTLA4, KIR, CD244, B7-H3, B7-H4,LA, HVEM, GAL9, A2aR, TGFb, IL-10, IL-35, arginase, or any combination thereof. 11. The method of claim 10, wherein the antibody specific for PD-1 is pidilizumab, lumab, pembrolizumab, or any combination thereof. 12. The method of claim 10, wherein the antibody specific for PD-L1 is avelumab, olizumab, durvalumab, MDX-1105 (BMS-936559), or any combination thereof. 13. The method of claim 10, wherein the antibody specific for LAG3 is BMS-986016. 14. The method of claim 18, wherein the antibody specific for TIM3 is TSR-022,G453, or both. 15. The method of claim 18, wherein the small molecule inhibitor of IDO is ximod, epacadostat, navoximod, GDC-0919, BMS-986205, NLG802, HTI-1090, PF-40003, OM2983, RG-70099, or any combination thereof.

16. The method of claim 3 or 4, wherein the method further comprises administeringerapy that induces or enhances an anti-cancer response. 17. The method of claim 4, wherein the induced or enhanced anti-cancer response is nti-tumor response. 18. The method of claim 16 or 17, wherein the therapy that induces or enhances an-cancer response is a vaccine, an inhibitor of an immunosuppression component, a radiationapy, surgery, a chemotherapeutic agent, an immunotherapeutic agent targeting a diseasegen, or any combination thereof. 19. The method of claim 18, wherein the inhibitor of an immunosuppression ponent is a small molecule, antibody, or siRNA. 20. The method of claim 19, wherein the small molecule, antibody, or siRNA is ific for PD-1, PD-L1, LAG3, TIM3, IDO, PD-L2, CTLA4, KIR, CD244, B7-H3, B7-H4,LA, HVEM, GAL9, A2aR, TGFb, IL-10, IL-35, arginase, or any combination thereof. 21. The method of claim 20, wherein the antibody specific for PD-1 is pidilizumab, lumab, pembrolizumab, or any combination thereof. 22. The method of claim 20, wherein the antibody specific for PD-L1 is avelumab, olizumab, durvalumab, MDX-1105 (BMS-936559), or any combination thereof. 21. The method of claim 20, wherein the antibody specific for LAG3 is BMS-986016. 22. The method of claim 20, wherein the antibody specific for TIM3 is TSR-022,G453, or both.

23. The method of claim 20, wherein the small molecule inhibitor of IDO is ximod, epacadostat, navoximod, GDC-0919, BMS-986205, NLG802, HTI-1090, PF- 40003, OM2983, RG-70099, or any combination thereof. 24. The method of claim 18, wherein the chemotherapeutic is a MNK specific bitor, an eIF4A inhibitor, a mTOR inhibitor, a B-Raf inhibitor, a MEK inhibitor, a VEGF bitor, a VEGFR inhibitor, a tyrosine kinase inhibitor, an anti-mitotic agent, or any bination thereof. 25. The method of claim 18, wherein the chemotherapeutic is vemurafenib, afenib, trametinib, cobimetinib, sunitinib, erlotinib, paclitaxel, docetaxel, or any

bination thereof. 26. The method of any one of claims 4 to 25, wherein the eIF4E inhibitor and the apy that induces or enhances the anti-cancer response are administered simultaneously, currently, sequentially, or any combination thereof. 27. The method of any one of claims 1 to 26, wherein the induced or enhancedmune response is an antigen-specific T cell response. 28. The method of any one of claims 1 to 27, wherein the eIF4E inhibitor reduces the ession of PD-1, PD-L1, LAG3, TIM-3, IDO, or any combination thereof. 29. The method of claim 28, wherein the expression of PD-1, PD-L1, LAG3, TIM-3, ny combination thereof is reduced in a T cell. 30. The method of claim 28, wherein the expression of PD-L1, IDO, or both is ced in an antigen presenting cell or a disease-associated cell.

31. The method of any one of claims 1 to 30, wherein the eIF4E inhibitor reduces or imizes the ability of eIF4E to initiate cap-dependent protein translation. 32. A method of inhibiting an immunosuppressive signaling pathway, comprising inistering a therapeutically effective amount of an eIF4E inhibitor to a subject, thereby biting an immunosuppressive signaling pathway. 33. The method of claim 32, wherein inhibiting the immunosuppressive signaling way promotes pre-existing endogenous immunity or promotes de novo endogenousmunity. 34. The method of claim 32 or 33, wherein the subject in need of relief from themunosuppressive signaling pathway has cancer or an infection. 35. The method of any one of claims 32-34, wherein the immunosuppressive aling pathway is a PD-1, TIM-3, IDO, LAG3, or any combination thereof,

munosuppressive signaling pathway. 36. The method of claim 34, wherein the cancer is a solid tumor, melanoma, non- ll cell lung cancer, renal cell carcinoma, renal cancer, a hematological cancer, prostate cer, castration-resistant prostate cancer, colon cancer, rectal cancer, gastric cancer,phageal cancer, bladder cancer, head and neck cancer, thyroid cancer, breast cancer, triple- ative breast cancer, ovarian cancer, cervical cancer, lung cancer, urothelial cancer, pancreatic cer, glioblastoma, hepatocellular cancer, myeloma, multiple myeloma, leukemia, Hodgkin's phoma, non-Hodgkin's lymphoma, myelodysplastic syndrome, brain cancer, CNS cancer, gnant glioma, or any combination thereof. 37. The method of claim 34, wherein the infection is a viral, bacterial, fungal, or sitic infection.

38. The method of claim 37, wherein the viral infection is an infection by a flavivirus, es virus, hepatitis virus, papillomavirus, paramyxovirus, retrovirus, lentivirus, or varicella- er virus. 39. The method of claim 37, wherein the viral infection is an infection by a hepatitis rus (HCV), hepatitis B virus (HBV), hepatitis A virus, hepatitis E virus, Japanese

ephalitis virus, or human immunodeficiency virus (HIV). 40. The method of any one of claims 37-39, wherein the method further comprises inistering an inhibitor of an immunosuppression component, an anti-infective agent, or both. 41. The method of claim 40, wherein the inhibitor of an immunosuppression ponent is a small molecule, antibody, or siRNA. 42. The method of claim 41, wherein the small molecule, antibody, or siRNA is ific for PD-1, PD-L1, LAG3, TIM3, IDO, PD-L2, CTLA4, KIR, CD244, B7-H3, B7-H4,LA, HVEM, GAL9, A2aR, TGFb, IL-10, IL-35, arginase, or any combination thereof. 43. The method of claim 42, wherein the antibody specific for PD-1 is pidilizumab, lumab, pembrolizumab, or any combination thereof. 44. The method of claim 42, wherein the antibody specific for PD-L1 is avelumab, olizumab, durvalumab, MDX-1105 (BMS-936559), or any combination thereof. 45. The method of claim 42, wherein the antibody specific for LAG3 is BMS-986016. 46. The method of claim 42, wherein the antibody specific for TIM3 is TSR-022,G453, or both.

47. The method of claim 42, wherein the small molecule inhibitor of IDO is ximod, epacadostat, navoximod, GDC-0919, BMS-986205, NLG802, HTI-1090, PF-40003, OM2983, RG-70099, or any combination thereof. 48. The method of any one of claims 32-36, wherein the method further comprises inistering a therapy that induces or enhances an anti-cancer response. 49. The method of claim 48, wherein the induced or enhanced anti-cancer response is nti-tumor response. 50. The method of claim 48 or 49, wherein the therapy that induces or enhances an-cancer response is a vaccine, an inhibitor of an immunosuppression component, a radiationapy, surgery, a chemotherapeutic agent, an immunotherapeutic agent targeting a diseasegen, or any combination thereof. 51. The method of claim 50, wherein the inhibitor of an immunosuppression ponent is a small molecule, antibody, or siRNA. 52. The method of claim 51, wherein the small molecule, antibody, or siRNA is ific for PD-1, PD-L1, LAG3, TIM3, IDO, PD-L2, CTLA4, KIR, CD244, B7-H3, B7-H4,LA, HVEM, GAL9, A2aR, TGFb, IL-10, IL-35, arginase, or any combination thereof. 53. The method of claim 52, wherein the antibody specific for PD-1 is pidilizumab, lumab, pembrolizumab, or any combination thereof. 54. The method of claim 52, wherein the antibody specific for PD-L1 is MDX-1105,S-936559, MEDI4736, MPDL3280A, MSB0010718C, or any combination thereof. 55. The method of claim 52, wherein the antibody specific for LAG3 is BMS-986016.

56. The method of claim 52, wherein the antibody specific for TIM3 is TSR-022,G453, or both. 57. The method of claim 52, wherein the small molecule inhibitor of IDO is ximod, epacadostat, navoximod, GDC-0919, BMS-986205, NLG802, HTI-1090, PF-40003, OM2983, RG-70099, or any combination thereof. 58. The method of claim 50, wherein the chemotherapeutic is a MNK specificbitor, an eIF4A inhibitor, a mTOR inhibitor, a B-Raf inhibitor, a MEK inhibitor, a VEGFbitor, a VEGFR inhibitor, a tyrosine kinase inhibitor, an anti-mitotic agent, or anybination thereof. 59. The method of claim 50, wherein the chemotherapeutic is vemurafenib, afenib, trametinib, cobimetinib, sunitinib, erlotinib, paclitaxel, docetaxel, or anybination thereof. 60. The method of any one of claims 48 to 59, wherein the eIF4E inhibitor and theapy that induces or enhances the anti-cancer response are administered simultaneously,currently, sequentially, or any combination thereof. 61. The method of any one of claims 32 to 60, wherein the eIF4E inhibitor reduces expression of PD-1, PD-L1, LAG3, TIM-3, IDO, or any combination thereof. 62. The method of claim 61, wherein the expression of is reduced in a T cell. 63. The method of claim 61, wherein the expression of is reduced in an antigenenting cell or a disease-associated cell.

64. The method of any one of claims 32 to 63, wherein the eIF4E inhibitor reduces or imizes the ability of eIF4E to initiate cap-dependent protein translation. 65. A method of reducing PD-1, PD-L1, activity, LAG3 activity, TIM-3 activity, IDO vity, or any combination thereof, comprising contacting a cell with an effective amount of an 4E inhibitor to increase immune cell activity or reduce down-modulation of immune cells. 66. The method of any one of claims 1 to 65, wherein the subject is human. 67. The method of any one of claims 1 to 66, wherein the eIF4E inhibitor is an 4G1 peptide, a modified eIF4G1 peptide, a cross-linked eIF4G1 peptide, or briciclib.

ereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:

X¹ is CR², -C-L¹-Y or N;

X², X⁵ and X⁶ are independently CR² or N,

wherein X⁵ and X⁶ together with 3 or 4 carbon or nitrogen atoms combine to form or 6-membered cycloalkyl or heterocyclyl,

or when X² is CR², R¹ and R² together with the atoms they attached to form a 6- mbered aryl or heteroaryl;

X³ is C, or X³ is C or N when X⁴ is a bond; X⁴ is a bond, CR² or N,

wherein X⁴ and X⁵ together with 3 or 4 carbon or nitrogen atoms combine to form or 6-membered heteroaryl;

Q is H or–L¹-Y;

L¹ is–(CH2)–,–(CH2)2–,–(CH2)3–,–CH((C1-C8)alkyl)(CH2)–,–CH((C1- lkyl)(CH₂)₂–,–(CH₂)₂-O–,–CH₂CH=CH–,–CH₂CºC– or–CH₂(cyclopropyl)–;

Y is

Ring B is a six-membered aryl, heteroaryl or heterocyclyl;

R¹ is H, OH, halo, CN, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C6)cycloalkyl or NR⁵R⁵; R² is independently H, halo, CN, NO, NO₂, CºH, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, SR⁵, OR⁵, NHR⁵, NR⁵R⁵, [(C1-C8)alkylene]heterocyclyl, [(C1-C8)alkylene]heteroaryl, [(C1- lkylene]NHR⁵, [(C1-C8)alkylene]NR⁵R⁵, [(C1-C8)alkylyne]NR⁵R⁵, C(O)R⁵, C(O)OR⁵, )NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO₂R⁵, SO₂NHR⁵, SO₂NR⁵R⁵, NH(CO)R⁶, NR⁵(CO)R⁶, , heteroaryl, cycloalkyl or heterocyclyl;

R³ is independently OH, halo, CN, NO2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy,H, NHR⁷, NR⁷R⁷, CO2H, CO2R⁷, [(C1-C3)alkylene] (C1-C3)alkoxy, [(C1-C3)alkylene]CO2H, C₅)cycloalkyl, =O. =S, SR⁷, SO₂R⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁴ is H, OH, halo, CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, SR⁷ or Z, wherein

Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl;

L² is -C(R⁶)(R⁶)-, -C(R⁶)(R⁶)C(R⁶)(R⁶)-, -C(R⁶)=C(R⁶)-, -N(R⁵)C(R⁶)(R⁶)-, - R⁶)(R⁶)-, -C(=O)-, -C(=O)N(R⁵)C(R⁶)(R⁶)- or a bond;

R⁵ is independently H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C5)cycloalkyl, CO2H, [(C1- lkylene]heteroaryl, [(C₁-C₃)alkylene]aryl, [(C₁-C₃)alkylene]CO₂H, heterocyclyl, aryl or roaryl,

or wherein two R⁵ substituents together with a nitrogen atom form a 4-, 5-, 6- or membered heterocyclyl;

R⁶ is independently H, OH, halo, CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, R⁷, NR⁷R⁷, CO2H, [(C1-C3)alkylene]CO2H, (C3-C5)cycloalkyl, SR⁷, NH(CO)R⁷ or

(CO)R⁷;

R⁷ is independently H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl, heterocyclyl, aryl or roaryl;

R⁸ is H, OH, CO₂H, CO₂R⁷, CF₂C(R⁶)₂OH, C(R⁶)₂OH, C(CF₃)₂OH, SO₂H, SO₃H, SO₂C(R⁶)₃, CF₂SO₂N(H)R⁵, SO₂N(H)R⁵, SO₂N(H)C(O)R⁶, C(O)N(H)SO₂R⁵, C(O)haloalkyl, )N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, C(O)NR⁵C(O)N(R⁵)2, P(O)(OR⁵)OH,

)(O)N(H)R⁵, P(O)(C(R⁶)3)C(R⁶)3, B(OH)2, heterocyclyl or heteroaryl;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally tituted with 1, 2 or 3 groups selected from OH, CN, SH, SCH₃, SO₂CH_3, SO₂NH₂,

NH(C₁-C₄)alkyl, halogen, NH₂, NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, NH(aryl), C(O)NH₂, )NH(alkyl), CH2C(O)NH(alkyl), COOH, COOMe, acetyl, (C1-C8)alkyl, (C1-C8)haloalkyl, 1-C₈)alkyl, O(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, thioalkyl, cyanomethylene, laminyl, alkylene-C(O)NH2, alkylene-C(O)-NH(Me), NHC(O)alkyl, CH2-C(O)-(C1- lkyl, C(O)-(C1-C8)alkyl and alkylcarbonylaminyl, or a cycloalkyl, heterocyclyl, aryl or roaryl optionally substituted with OH, halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, O(C₁- lkyl or O(C1-C8)haloalkyl,

wherein when X⁴ is a bond ring A forms a 5-membered heteroaryl wherein X¹, X⁵ and X⁶ in addition to the above defined substituents be NR², and X¹ can in addition be -N-L¹- nd

wherein either

69. The method of any one of claims 1-66, wherein the eIF4E inhibitor is a compoundording to Formula II:

ereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:

X² and X⁵ are independently CR² or N,

or when X² is CR², R¹ and R² together with the atoms they attached to form a 6-mbered aryl or heteroaryl;

L¹ is–(CH₂)–,–(CH₂)₂–,–(CH₂)₃–,–CH((C₁-C₈)alkyl)(CH₂)–,–CH((C₁- lkyl)(CH2)2–,–(CH2)2-O–,–CH2CH=CH–,–CH2CºC– or–CH2(cyclopropyl)–;

Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl; R¹ is H, OH, halo, CN, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C6)cycloalkyl or NR⁵R⁵; R² is independently H, halo, CN, NO, NO2, CºH, (C1-C8)alkyl, (C1-C8)haloalkyl, SR⁵, OR⁵, NHR⁵, NR⁵R⁵, [(C₁-C₈)alkylene]heterocyclyl, [(C₁-C₈)alkylene]heteroaryl, [(C₁- lkylene]NHR⁵, [(C1-C8)alkylene]NR⁵R⁵, [(C1-C8)alkylyne]NR⁵R⁵, C(O)R⁵, C(O)OR⁵, )NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO2R⁵, SO2NHR⁵, SO2NR⁵R⁵, NH(CO)R⁶, NR⁵(CO)R⁶, , heteroaryl, cycloalkyl or heterocyclyl;

R³ is independently OH, halo, CN, NO₂, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)alkoxy,H, NHR⁷, NR⁷R⁷, CO2H, CO2R⁷, [(C1-C3)alkylene] (C1-C3)alkoxy, [(C1-C3)alkylene]CO2H, C5)cycloalkyl, =O. =S, SR⁷, SO2R⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁵ is independently H, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₃-C₅)cycloalkyl, CO₂H, [(C₁- lkylene]heteroaryl, [(C1-C3)alkylene]aryl, [(C1-C3)alkylene]CO2H, heterocyclyl, aryl or roaryl,

or wherein two R⁵ substituents together with a nitrogen atom form a 4-, 5-, 6-, or 7-mbered heterocyclyl;

R⁶ is independently H, OH, halo, CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy,R⁷, NR⁷R⁷, CO₂H, [(C₁-C₃)alkylene]CO₂H, (C₃-C₅)cycloalkyl, SR⁷, NH(CO)R⁷ or

(CO)R⁷;

R⁷ is independently H, (C1-C8)alkyl, (C1-C8)haloalkyl, cycloalkyl, heterocyclyl, aryl or roaryl;

R⁸ is H, OH, CO₂H, CO₂R⁷, CF₂C(R⁶)₂OH, C(R⁶)₂OH, C(CF₃)₂OH, SO₂H, SO₃H, SO2C(R⁶)3, CF2SO2N(H)R⁵, SO2N(H)R⁵, SO2N(H)C(O)R⁶, C(O)N(H)SO2R⁵, C(O)haloalkyl, )N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, C(O)NR⁵C(O)N(R⁵)2, P(O)(OR⁵)OH,

)(O)N(H)R⁵, P(O)(C(R⁶)₃)C(R⁶)₃, B(OH)₂, heterocyclyl or heteroaryl;

m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3; wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally tituted with 1, 2 or 3 groups selected from OH, CN, SH, SCH3, SO2CH3, SO2NH2,

NH(C₁-C₄)alkyl, halogen, NH₂, NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, NH(aryl), C(O)NH₂, )NH(alkyl), CH2C(O)NH(alkyl), COOH, COOMe, acetyl, (C1-C8)alkyl, (C1-C8)haloalkyl, 1-C8)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, thioalkyl, cyanomethylene, laminyl, alkylene-C(O)NH₂, alkylene-C(O)-NH(Me), NHC(O)alkyl, CH₂-C(O)-(C₁- lkyl, C(O)-(C₁-C₈)alkyl and alkylcarbonylaminyl, or a cycloalkyl, heterocyclyl, aryl or roaryl optionally substituted with OH, halogen, (C1-C8)alkyl, (C1-C8)haloalkyl, O(C1- lkyl or O(C1-C8)haloalkyl. 70. The method of any one of claims 1-66, wherein the eIF4E inhibitor is a compoundording to formula III:

ereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:

L¹ is–(CH₂)–,–(CH₂)₂–,–(CH₂)₃–,–CH((C₁-C₈)alkyl)(CH₂)–,–CH((C₁- lkyl)(CH₂)₂–,–(CH₂)₂-O–,–CH₂CH=CH–,–CH₂CºC– or–CH₂(cyclopropyl)–;

L² is -C(R⁶)(R⁶)-, -C(R⁶)(R⁶)C(R⁶)(R⁶)-, -C(R⁶)=C(R⁶)-, -N(R⁵)C(R⁶)(R⁶)-,

(R⁶)(R⁶)-, -C(=O)-, -C(=O)N(R⁵)C(R⁶)(R⁶)- or a bond;

Ring C is a heteroaryl;

R¹ is H, OH, halo, CN, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C6)cycloalkyl or NR⁵R⁵; R² is independently H, halo, CN, NO, NO2, CºH, (C1-C8)alkyl, (C1-C8)haloalkyl, SR⁵, OR⁵, NHR⁵, NR⁵R⁵, [(C1-C8)alkylene]heterocyclyl, [(C1-C8)alkylene]heteroaryl, [(C1- lkylene]NHR⁵, [(C₁-C₈)alkylene]NR⁵R⁵, [(C₁-C₈)alkylyne]NR⁵R⁵, C(O)R⁵, C(O)OR⁵, )NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO2R⁵, SO2NHR⁵, SO2NR⁵R⁵, NH(CO)R⁶, NR⁵(CO)R⁶, , heteroaryl, cycloalkyl or heterocyclyl;

R³ is independently OH, halo, CN, NO₂, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)alkoxy,H, NHR⁷, NR⁷R⁷, CO₂H, CO₂R⁷, [(C₁-C₃)alkylene] (C₁-C₃)alkoxy, [(C₁-C₃)alkylene]CO₂H, C5)cycloalkyl, =O. =S, SR⁷, SO2R⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁵ is independently H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C5)cycloalkyl or heterocyclyl; R⁶ is independently H, OH, halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy,R⁷, NR⁷R⁷, CO2H, [(C1-C3)alkylene]CO2H, (C3-C5)cycloalkyl, SR⁷, NH(CO)R⁷ or

(CO)R⁷;

R⁸ is H, OH, CO2H, CO2R⁷, CF2C(R⁶)2OH, C(R⁶)2OH, C(CF3)2OH, SO2H, SO3H, SO₂C(R⁶)₃, CF₂SO₂N(H)R⁵, SO₂N(H)R⁵, SO₂N(H)C(O)R⁶, C(O)N(H)SO₂R⁵, C(O)haloalkyl, )N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, C(O)NR⁵C(O)N(R⁵)₂, P(O)(OR⁵)OH,

)(O)N(H)R⁵, P(O)(C(R⁶)3)C(R⁶)3, B(OH)2, heterocyclyl or heteroaryl;

R⁹ is H, (C1-C8)alkyl, (C1-C8)haloalkyl, cycloalkyl or heterocyclyl;

m is 0, 1, or 2;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally tituted with 1, 2 or 3 groups selected from OH, CN, SH, SCH3, SO2CH3, SO2NH2,

NH(C1-C4)alkyl, halogen, NH2, NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, NH(aryl), C(O)NH2, )NH(alkyl), CH₂C(O)NH(alkyl), COOH, COOMe, acetyl, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, 1-C₈)alkyl, O(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, thioalkyl, cyanomethylene, laminyl, alkylene-C(O)NH2, alkylene-C(O)-NH(Me), NHC(O)alkyl, CH2-C(O)-(C1- lkyl, C(O)-(C1-C8)alkyl and alkylcarbonylaminyl. 71. The method of any one of claims 1-66, wherein the eIF4E inhibitor is a compound cted from:

Compound X according to the structure

; and

Compound Y according to the structure;

. 72. A combination, comprising an eIF4E inhibitor and an inhibitor of an

munosuppression component. 73. The combination of claim 72, wherein the inhibitor of an immunosuppression ponent is a small molecule, antibody, or siRNA. 74. The combination of claim 73, wherein the small molecule, antibody, or siRNA is ific for PD-1, PD-L1, TIM3, LAG3, IDO, PD-L2, CTLA4, KIR, CD244, B7-H3, B7-H4,LA, HVEM, GAL9, A2aR, or any combination thereof.

75. The combination of claim 74, wherein the antibody specific for PD-1 islizumab, nivolumab, pembrolizumab, or any combination thereof. 76. The combination of claim 74, wherein the antibody specific for PD-L1 isumab, atezolizumab, durvalumab, MDX-1105 (BMS-936559), or any combination thereof. 77. The method of claim 74, wherein the antibody specific for LAG3 is BMS-986016. 78. The method of claim 74, wherein the antibody specific for TIM3 is TSR-022,G453, or both. 79. The method of claim 74, wherein the small molecule inhibitor of IDO isximod, epacadostat, navoximod, GDC-0919, BMS-986205, NLG802, HTI-1090, PF-40003, OM2983, RG-70099, or any combination thereof. 80. The combination of any one of claims 72-79, further comprising a therapy thatces or enhances an anti-cancer response. 81. The combination of claim 79, wherein the induced or enhanced anti-canceronse is an anti-tumor response. 82. The combination of claim 80 or 81, wherein the therapy that induces or enhancesnti-cancer response is vaccine, a further inhibitor of an immunosuppression component, aation therapy, surgery, a chemotherapeutic agent, an immunotherapeutic agent targeting aase antigen, or any combination thereof. 83. The combination of claim 82, wherein the chemotherapeutic agent is a MNKific inhibitor, an eIF4A inhibitor, a mTOR inhibitor, a B-Raf inhibitor, a MEK inhibitor, a GF inhibitor, a VEGFR inhibitor, a tyrosine kinase inhibitor, an anti-mitotic agent, or any bination thereof. 84. The combination of claim 82, wherein the chemotherapeutic agent is

urafenib, dabrafenib, trametinib, cobimetinib, sunitinib, erlotinib, paclitaxel, docetaxel, or combination thereof. 85. The combination of claim 82, wherein the further inhibitor of an

munosuppression component is a small molecule, antibody, or siRNA specific for PD-1, L1, TIM3, LAG3, IDO, PD-L2, CTLA4, KIR, CD244, B7-H3, B7-H4, BTLA, HVEM, L9, A2aR, or any combination thereof. 86. The combination of claim 85, wherein the antibody specific for PD-1 is lizumab, nivolumab, pembrolizumab, or any combination thereof. 87. The combination of claim 85, wherein the antibody specific for PD-L1 is

X-1105, BMS-936559, MEDI4736, MPDL3280A, MSB0010718C, or any combination eof. 88. The combination of claim 85, wherein the antibody specific for LAG3 is BMS- 016. 89. The combination of claim 85, wherein the antibody specific for TIM3 is TSR-022, G453, or both. 90. The combination of claim 85, wherein the small molecule inhibitor of IDO is ximod, epacadostat, navoximod, GDC-0919, BMS-986205, NLG802, HTI-1090, PF- 40003, OM2983, RG-70099, or any combination thereof.

91. A combination, comprising an eIF4E inhibitor, an inhibitor of anmunosuppression component, and a chemotherapeutic agent. 92. The combination of claim 91, wherein the inhibitor of the immunosuppression ponent is an antibody specific for PD-1 selected from pidilizumab, nivolumab, or

brolizumab. 93. The combination of claim 91, wherein the inhibitor of the immunosuppression ponent is an antibody specific for PD-L1 selected from MDX-1105, BMS-936559,

DI4736, MPDL3280A, or MSB0010718C. 94. The combination of claim 91, wherein the inhibitor of the immunosuppression ponent is a LAG3 specific antibody BMS-986016. 95. The combination of claim 91, wherein the inhibitor of the immunosuppression ponent is an antibody specific for TIM3 selected from TSR-022, MBG453, or both. 96. The combination of claim 91, wherein the inhibitor of the immunousppression ponent is a small molecule inhibitor of IDO selected from indoximod, epacadostat, oximod, GDC-0919, BMS-986205, NLG802, HTI-1090, PF-06840003, OM2983, RG-70099, ny combination thereof. 97. The combination of any one of claims 91 to 96, wherein the chemotherapeutic nt is a MNK specific inhibitor, an eIF4A inhibitor, vemurafenib, dabrafenib, trametinib, metinib, sunitinib, erlotinib, paclitaxel, docetaxel, or any combination thereof. 98. The combination of any one of claims 91 to 96, wherein the chemotherapeutic nt is dabrafenib and trametinib.

99. The combination of any one of claims 72 to 98, wherein the combination furtherprises a T cell containing a chimeric antigen receptor specific for a cancer antigen orctious disease antigen. 100. A kit comprising a combination of claim 72 or a combination of claim 91.