EIF4a inhibitors

Abstract

The invention provides a compound of Formula (I) or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof and a method for treating a disease in a subject comprising administering the subject a therapeutically effective amount of a compound of Formula (I).

Description

Leydig 515882EIF4A INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority to U. S. provisional patent application no.63 / 738,225 filed on December 23, 2024, the entire disclosure of which is hereby incorporated by reference.BACKGROUND OF THE INVENTION

[0002] The initiation of translation of messenger RNA is often dependent on eukaryotic initiation factors (eIF4A. eIF4E. and eIF4G) that form a functional eIF4F complex. Changes in the activity or expression of these eukaryotic factors are a hallmark of many diseases. As a result, regulation of translation has important implications in a range of diseases.

[0003] In view of the number of pathological responses that are mediated by a functional eIF4F complex, inhibition of the eIF4F complex has therapeutic potential. As such, there remains a need to develop compounds and methods for regulating the eIF4F complex and its various member proteins.BRIEF SUMMARY OF THE INVENTION

[0004] In one aspect the invention provides a compound according to Formula (I):or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof. Also provided are methods and compositions for making compounds of Formula I, use of the compounds to modulate eIF4A and treat diseases associated with eIF4A activity, and related compositions and methods.Leydig 5158822BRIEF DESCRIPTION OF THE DRAWINGS

[0005] FIGs. 1 A and IB provide graphs illustrating the specificity for 1-4 for AGA rich (FIG. 1 A) compared to CAA rich (FIG. IB) leader sequences. Zotatifin shows much less specificity for AGA rich leader sequences.

[0006] FIGs. 2A and 2B provide a schematic illustration (FIG. 2A) of an assay used to determine the binding kinetics of eIF4A to RNA containing an AGA rich leader sequence in the presence of 1-11. 1-4. and Zotatifin, and the results of the assay (FIG. 2B).

[0007] FIGs. 3 A, 3B and 3C are graphs illustrating that compounds 1-4, 1-11 and 1-9, respectively, do not trap eIF4Al to its target mRNA while Zotatifin does. Trapping is measured by increased hydrolase activity to convert ATP to ADP.

[0008] FIGs. 4A, 4B and 4C provide graphs and associated scatter plots illustrating the effect of DMSO (control), Bortezomib, Zotatifin, and 1-4 on the populations of total lymphocytes (FIG. 4A), total B cells (FIG. 4B), and plasma B cells (FIG. 4C).

[0009] FIGs. 5A-5C are a graph of the anti-KLH IgG (FIG. 5A), total IgG (FIG. 5B), and anti-KLH IgM (FIG. 5C) concentrations in KLH-challenged rats after administration of test compounds.

[0010] FIG. 6A and 6B are images of a gel showing the results of a Western blot gel electrophoresis assay of RPMI8226 cells and peripheral blood mononuclear cells (PBMCs, referred to as “Primary” cells).DETAILED DESCRIPTION OF THE INVENTION

[0011] The invention provides a compound according to Formula (I):or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:

[0012] n is 1 or 2;Leydig 5158823

[0013] X is O, S. NH, CRnR12, N(Ci-Cs)alkyl, C(0). CH-CHR“R12. NC(0)R15. S(0) or S(O)2;

[0014] each instance of Y is independently CR8, N, NR8,0, or S;

[0015] each instance of Z is independently CR9or N;

[0016] R1is H. halogen, Ci-Cs alkyl, Ci-Cs haloalkyl. C(O)O(Ci- C8)alkyl. C(O)(Ci-C8)alkyl, SO2(Ci-C8)alkyl, C2-C8alkenyl, C2-C8alkynyl, OR14, NHR14, NR14R14, CN, [Ci-Cs alkylene] OR14, [Ci-C8alkylene]NHR14, [Ci-C8alkylene]NR14R14, C(O)R15, C(O)NHR14, C(O)NR14R14, C(O)[CI-C8alkylene]NHR14, C(O)[Ci-C8alkylene]NR14R14, CO2R14, C(S)NHR14, C(S)NR14R14. SR14. S(O)R14, SO2R14, SO2N(H)(R14), SO2NR14R14, NHC(O)R15, NR14C(O)R15, NHC(O)NHR14, NHC(O)NR14R14. NR14C(O)NHR14, NR14C(O)NR14R14, P(O)(OH)(OR14), P(O)(OR14) (OR14), aryl, heteroaryl, cycloalkyl, or heterocyclyl;

[0017] R2is H, halogen, hydroxyl, CN, Ns, SR14, Ci-C8alkyl, Ci-Cs haloalkyl, O-(Ci-C8)alkyl, O-(Ci- C8)haloalkyl, C2-C8alkynyl, NHC(O)(Ci-C8)alkyl or heteroaryl;

[0018] R3, R3a. R4. and R4aindependently are H, halogen, CN, Ci-C8alkyl, Ci-C8haloalkyl, C2-C8alkenyl, C2-C8alkynyl, OR14, NHR14, NR14R14, [Ci-Cs alkylene] OR14, [Ci-C8alkylene]NHR14, [Ci-Cs alkylene]NR14R14, C(O)R15, C(O)NHR14, C(O)NR14R14, C(O)[Ci- C8alkylene]NHR14, C(O)[Ci-C8alkylene]NR14R14, CO2R14, C(NR14)R14, C(S)NHR14, C(S)NR14R14. SR14. S(O)R4, SQ2R14. SO2NHR14, SO2NR14R14, NHC(O)R15, NR14C(O)R15, NHC(O)NHR14, NHC(O)NR14R14. NR14C(O)NHR14, NR14C(O)NR14R14. P(O)(OH)(OR14), P(O)(OR14) (OR14), aryl, heteroaryl, cycloalkyl or heterocyclyl; orR3and R3a, or R4and R4atogether form oxo or alkenyl; or R3and R4, R3aand R4a, or R3aand R2together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;

[0019] R3and R6are each independently aryl, heteroaryl, cycloalkyl, or heterocyclyl;

[0020] R7is H, halogen, Ci-Cs alkyl, Ci-Cs haloalkyl, C(O)O(Ci- C8)alkyl, C(O)(Ci-Cs alkyl), SO2(Ci-C8alkyl), C2-Cs alkenyl, C2-C8alkynyl, OR14, NHR14, NR14R14, CN, [Ci-C8alkylene]OR14. [Ci-C8alkylene]NHR14, [Ci-Cs alkylene]NR14R14, C(O)R15, C(O)NHR14, C(O)NR14R4, C(O)[Ci-C8alkylene]NHR4, C(O)[Ci-C8alkylene]NR14R14, CO2R14, C(S)NHR14, C(NR14)R14, C(S)NR14R14, SR14, S(O)R14, SO2R14, SO2N(H)(R14), SO2NR14R14, NHC(O)R15, NR14C(O)R15, NHC(0)NHR14, NHC(O)NR14R14, NR14C(O)NHR14, NR14C(O)NR14R14, P(O)(OH)(OR14), P(O)(OR14) (OR14), aryl, heteroaryl, cycloalkyl, or heterocyclyl;Leydig 5158824

[0021] each R8and each R9are each independently a hydrogen, hydroxyl, halogen. CN, SR10, Ci-Cs alkyl, Ci-Cs alkoxy, Ci-Cs haloalkyl, Ci-Cs heteroalkyl, C2-C8 alkenyl, C2-Cs alkynyl, aryl, heterocyclyl or heteroaryl;

[0022] R10is hydrogen, halogen, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-Cs haloalkyl, Ci-Cs heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;

[0023] R11and R12independently are H, CN, halogen, OR13, SR13, Ci-Cs alkyl, NH(R13) orNR13R13;

[0024] each R13is independently H, Ci-Cs alkyl, Ci-Cs haloalky l, cycloalkyl, heterocyclyl, [Ci-Cs alkylene] heterocyclyl, aryl, [Ci-Cs alkylene] aryl, heteroaryl, or [Ci-Cs alkylene] heteroaiyl;

[0025] each R14is independently H, Ci-Cs alkyl, Ci-Cs haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, [Ci-Cs alkylene] cycloalkyl, [Ci-Cs alkydene] heterocyclyl, [Ci-Cs alkylene] aryl, [Ci-Cs alkylene] heteroaryl, [Ci-Cs alkyd ene] -OR15, O(Ci-C )alkyl, O(Ci-C8)haloalkyl. O(cycloalkyl). O(heterocyclyl), O(aryl), or O(heteroaryl); or wherein two R14groups together with a nitrogen atom to which they are both attached (e.g., NR14R14, [Ci-Cs alkylene]NR14R14, C(O)NR14R14, C(O)[Ci-Cs alkylene]NR14R14, C(S)NR14R14, SO2NR14R14, NHC(O)NR14R14or NR14C(O)NR14R14) optionally form a heterocyclyl ring;

[0026] each R15is independently H, (Ci-Cs)alkyl, (Ci-Cs)haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl O(Ci-Cs)alkyl, O(Ci-Cs)haloalkyl, O(cycloalkyl), O(heterocyclyl), O(aryl), or O(heteroaryl);

[0027] wherein any alky 1, alkenyl, cycloalkyl, heterocyclyl, heteroaryl or ary l is optionally substituted with 1, 2, or 3 groups selected from OH, CN, SH, SO2NH2, SO2(Ci-C4)alkyl. SO2NH(Ci-C4)alkyl. halogen, NH2, NH(Ci-C4)alkyl, N[(Ci-C4)alky 1]2. C(O)NH2, COOH, COOMe, acetyl, (Ci-C8)alkyl, O(Ci-C8)alkyl, O(Ci-C8)haloalkyl, (C2-Cs)alkenyl, (C2- Cs)alkyny 1, haloalkyl, thioalkyl, cyanomethy dene, alky daminyl, NH2-C(O)-alkylene, NH(Me)- C(O)-alkylene, CH2-C(O)-(Ci-C6)alkyd, C(O)-(Ci-C6)alkyd, alkylcarbony daminyl, CH2- [CH(0H)]m-(CH2)P-0H, CH2-[CH(OH)]m-(CH2)P-NH2, or CH2-aryl-alkoxy; or wherein any alkyl, cycloalkyl or heterocyclyl is optionally substituted with oxo; wherein "m" and"p" are 1, 2, 3, 4, 5 or 6. Any unspecified positions are considered to be hydrogen.

[0028] As used herein, “alky l’' or “alkylene"’ refers to a substituted or unsubstituted hydrocarbon chain. The alkyd group can have any number of carbon atoms (e.g., Ci-Ci2alkyl, Ci-Cs alkyl, Ci-Ce alkyl, Ci-C4alkyl, Ci-C2alkyl, etc.). The alkyl or alkylene can be saturated, or can be unsaturated (e g., to provide an alkenyl or alkynyl), and can be linear,Leydig 5158825branched, straight-chained, cyclic (e.g., C3-C12 alkyl, C3-C8 alkyl, C3-C6 alkyl, C3-C5 cycloalkyl or cycloalkenyl), or a combination thereof. Cyclic groups can be monocyclic, fused to form bicyclic or tricyclic groups, linked by a bond, or spirocyclic. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0029] As used herein, the term “haloalkyl group” refers to an alkyl group as described herein further comprising halogen atoms (e.g., 1, 2, 3, 4, 5 or 6 halogen atoms), such as F, Cl, Br, and I.

[0030] As used herein, the term “heteroalky l group” refers to an alkyl group as described further comprising heteroatoms (e g., N. O, or S). A heteroalkyl group typically comprises 1-6 or 1-3 heteroatoms (e.g., 1, 2, 3, 4, 5, or 6 heteroatoms). Examples of heteroalkyl groups are alkoxy groups, alkylamine and aminoalkyl groups, ethereal groups, thioalkyl groups, or thioethereal groups. Heteroalkyl groups can be straight-chain or branched, and include cyclic groups. Thus, for instance, a “heterocyclyl group” can be a cycloalkyl group, described herein, containing 1-6 or 1-3 heteroatoms (e.g. 1, 2, 3, 4, 5, or 6 heteroatoms) chosen from N, O, and S (or combination thereof).

[0031] As used herein, the term “alkenyl group” refers to a branched or straight-chained unsaturated hydrocarbon group having at least one double bond, and having the specified number of carbon atoms, usually from 2 to 8 or 2-6.

[0032] As used herein, the term "alkynyl group” refers to a branched or straight-chained unsaturated hydrocarbon group having at least one triple bond, and having the specified number of carbon atoms, usually from 2 to 8 or 2 to 6.

[0033] The term “aryl” refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can include, for instance, 5, 6. 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 5 to 10, 5 to 12, or 5 to 14 ring members. Ary l groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl, biphenyl, pyrrolyl. furanyl, thiophenyl, imadozolyl. In some embodiments, the ary l group comprises an alkylene linking group so as to form an arylalkyl group (e.g., a benzyl group). Some aryl groups have from 6 to 12 or 6 to 10 ring members, such as phenyl, naphthyl or biphenyl. In some embodiments, the aryl substituent can comprise one or more heteroatoms (e g., oxygen, nitrogen, and sulfur), thereby proving a heteroaryl group. In some embodiments, the heteroaryl can comprise 5 to 12 carbon atoms with at least one aromatic ring and further comprising 1-6 or 1-3 heteroatoms chosen fromN, O, and S.Leydig 5158826

[0034] As used herein, the term "substituted ' can mean that one or more hydrogens on the designated atom or group (e.g., substituted alkyl group or substituted aryl group) are replaced with another group provided that the designated atom’s normal valence is not exceeded. For example, when the substituent is oxo (i.e., =0), then two hydrogens on the atom are replaced. Substituent groups can include one or more of a hydroxyl, an amino (e.g., primary, secondary, or tertiary), an aldehyde, a carboxylic acid, an ester, an amide, a ketone, nitro, an urea, a guanidine, cyano, fluoroalkyl (e.g., trifluoromethane), halo (e.g., fluoro), aryl (e.g., phenyl), heterocyclyl or heterocyclic group (i.e., cyclic group, e.g., aromatic (e.g., heteroaryl) or non-aromatic where the cyclic group has one or more heteroatoms), oxo, or combinations thereof. Combinations of substituents and / or variables are permissible provided that the substitutions do not significantly adversely affect synthesis or use of the compound.

[0035] In some embodiments of Formula I, X is O, N, S, S(O), or S(O)2. In some embodiments, X is O, N. or S. In still other embodiments, X is O.

[0036] In some embodiments, each instance of Y is independently CR8or N, optionally wherein each instance of R8is hydrogen, halogen, or methyl.

[0037] In some embodiments, each instance of Z is independently CH or N.

[0038] In some embodiments, R1is OR14, such as a hydroxy or alkoxy group. In some embodiments, R1is a C1-C3 alkoxy (e.g., methoxy).

[0039] In some embodiments, R2is a hydroxyl group.

[0040] In some embodiments, R3ais hydrogen. In some embodiments R3is hydroxyl. In some embodiments, Rjais hydrogen and R3is hydroxyl.

[0041] In some embodiments, R4ais hydrogen. In some embodiments. R4is hydrogen; C(O)OH; or an alkyl, optionally substituted with a hydroxyl. In some embodiments, R4is C(O)NR14R14, CO2R14, [Ci-Cs alkylene] OR14, C(NR14)R14, or CH2NR14R14. In some embodiments, R4 is one of the following:Leydig 5158827

[0042] In some embodiments, R5is aryl, optionally phenyl. In some embodiments, R6is aryl or substituted aryl, such as phenyl or substituted phenyl. In some embodiments, R6is aryl substituted with a C1-C3 alkoxy (e.g., methoxy) or CN. In some embodiments, R6is phenyl substituted with C1-C3 alkoxy (e.g., methoxy) or CN.

[0043] In some embodiments, R7is hydrogen.

[0044] In some embodiments, R8is hydrogen, halogen, Ci-Cs alkyl (e.g, C1-C3 alkyl, such as methyl), Ci-Cs alkoxy (e.g., C1-C3 alkoxy, such as methoxy).

[0045] In some embodiments, R9is hydrogen.

[0046] Any of the foregoing embodiments can be used in combination.

[0047] In some embodiments, the compound of Formula I is a compound of Formula I A:or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X, Y, Z, n, R1, R2, R3, R3a. R4. R4a, R5, R6, and R7are as defined with respect to Formula I. including any and all embodiments thereof.Leydig 515882

[0048] In some embodiments of Formula IA, X is O, N. S, S(O), or S(O)2. In some embodiments, X is O, N, or S. In still other embodiments, X is O.

[0049] In some embodiments, each instance of Y is independently CR8or N, optionally wherein each instance of R8is hydrogen, halogen, or methyl.

[0050] In some embodiments, each instance of Z is independently CH or N.

[0051] In some embodiments, R1is OR14, wherein R14is as defined with respect to Formula I. In some embodiments, R1is a hydroxy or alkoxy group. In some embodiments, R1is a C1-C3 alkoxy (e.g., methoxy).

[0052] In some embodiments, R2is a hydroxyl group.

[0053] In some embodiments, R3ais hydrogen. In some embodiments R3is hydroxyl. In some embodiments, R3ais hydrogen and R3is hydroxyl.

[0054] In some embodiments, R4ais hydrogen. In some embodiments, R4is hydrogen; C(O)OH; or an alkyl, optionally substituted with a hydroxyl. In some embodiments, R4is C(O)NR14R14, CO2R14, [Ci-Cs alkylene] OR14. C(NR14)R14, or CH2NR14R14. In some embodiments, R4 is one of the following:

[0055] In some embodiments, R5is aryl, optionally phenyl. In some embodiments, R6is aryl or substituted ar l, such as phenyl or substituted phenyl. In some embodiments, R6is aryl substituted with a C1-C3 alkoxy (e.g., methoxy) or CN. In some embodiments, R6is phenyl substituted with C1-C3 alkoxy (e.g., methoxy) or CN.

[0056] In some embodiments, R7is hydrogen.Leydig 5158829

[0057] In some embodiments, R8is hydrogen, halogen, Ci-Cs alkyl (e.g, C1-C3 alkyl, such as methyl), Ci-Cs alkoxy (e.g., C1-C3 alkoxy, such as methoxy).

[0058] In some embodiments, R9is hydrogen.

[0059] Any of the foregoing embodiments can be used in combination.

[0060] In some embodiments, the compound of Formula I is a compound of Formula II or IIA:or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R3a, R4, R4'1, R5, R6, R7and R8, are as defined with respect to Formula I, including any and all embodiments thereof.

[0061] In some embodiments of Formula 11 or 11A, X is O, N, S, S(O), or S(O)2. In some embodiments, X is O, N, or S. In still other embodiments, X is O.

[0062] In some embodiments, R1is OR14, wherein R14is as defined with respect to Formula I. In some embodiments, R1is a hydroxy or alkoxy group. In some embodiments, R1is a C1-C3 alkoxy (e.g., methoxy).

[0063] In some embodiments, R2is a hydroxyl group.Leydig 51588210

[0064] In some embodiments, R3ais hydrogen. In some embodiments R3is hydroxyl. In some embodiments, R3ais hydrogen and R3is hydroxyl.

[0065] In some embodiments, R4ais hydrogen. In some embodiments, R4is hydrogen; C(O)OH; or an alkyl, optionally substituted with a hydroxyl. In some embodiments, R4is C(O)NR14R14, CO2R14, [Ci-Cs alkylene] OR14. C(NR14)R14, or CH2NR14R14. In some embodiments, R.4 is one of the following:

[0066] In some embodiments, R5is aryl, optionally phenyl. In some embodiments, R6is aryl or substituted ar l, such as phenyl or substituted phenyl. In some embodiments, R6is aryl substituted with a C1-C3 alkoxy (e.g., methoxy) or CN. In some embodiments, R6is phenyl substituted with C1-C3 alkoxy (e.g., methoxy) or CN.

[0067] In some embodiments, R7is hydrogen.

[0068] In some embodiments, R8is hydrogen, halogen, Ci-Cs alkyl (e.g, C1-C3 alkyl, such as methyl), Ci-Cs alkoxy (e.g., C1-C3 alkoxy, such as methoxy).

[0069] Any of the foregoing embodiments can be used in combination.

[0070] In some embodiments, the compound of Formula l is a compound of Formula III or IIIA:Leydig 51588211or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R16is Ci-C3 alkoxy (e.g., methoxy) or CN, and X, Y, Z, n, R1, R2, R3, R3a, R4, R4a, and R7are as defined with respect to Formula I, including any and all embodiments thereof.

[0071] In some embodiments of Formula III or IIIA, X is O, N, S, S(O), or S(O)2. In some embodiments, X is O, N, or S. In still other embodiments, X is O.

[0072] In some embodiments, each instance of Y is independently CR8or N, optionally wherein each instance of R8is hydrogen, halogen, or methyl.

[0073] In some embodiments, each instance of Z is independently CH or N.

[0074] In some embodiments, R1is OR14, wherein R14is as defined with respect to Formula I. In some embodiments. R1is a hydroxy or alkoxy group. In some embodiments, R1is a C1-C3 alkoxy (e.g., methoxy).

[0075] In some embodiments, R2is a hydroxyl group.Leydig 51588212

[0076] In some embodiments, R3ais hydrogen. In some embodiments R3is hydroxyl. In some embodiments, R3ais hydrogen and R3is hydroxyl.

[0077] In some embodiments, R4ais hydrogen. In some embodiments, R4is hydrogen; C(O)OH; or an alkyl, optionally substituted with a hydroxyl. In some embodiments, R4is C(O)NR14R14, CO2R14, [Ci-Cs alkylene] OR14. C(NR14)R14, or CH2NR14R14, wherein R14is as defined with respect to Formula I. In some embodiments, R4 is one of the following:

[0078] In some embodiments, R7is hydrogen.

[0079] In some embodiments, R8is hydrogen, halogen, Ci-Cs alkyl (e.g, C1-C3 alkyl, such as methyl), Ci-Cs alkoxy (e.g., C1-C3 alkoxy, such as methoxy).

[0080] In some embodiments, R9is hydrogen.

[0081] Any of the foregoing embodiments can be used in combination.

[0082] In some embodiments, the compound of Formula l is a compound of Formula IV or Formula IVA:Leydig 515882or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein X, R1and R4are as defined with respect to Formula I, including any and all embodiments thereof.

[0083] In some embodiments of Formula IV or IVA, X is O, N, S, S(O), or S(O)2. In some embodiments, X is O, N, or S. In still other embodiments, X is O.

[0084] In some embodiments, R1is OR14, wherein R14is as defined with respect to Formula I. In some embodiments, R1is a hydroxy or alkoxy group. In some embodiments, R1is a C1-C3 alkoxy (e.g., methoxy).

[0085] In some embodiments, R4is hydrogen; C(O)OH; or an alkyl, optionally substituted with a hydroxyl. In some embodiments, R4is C(O)NR14R14, CO2R14. [Ci-Cs alkylene]OR14. C(NR14)R14, or CH2NR14R14. In some embodiments, R4 is one of the following:Leydig 51588214

[0086] Illustrative examples of the compounds of Formula (I) are as follows:1-4 1-51-6Leydig 515882151-16 1-17 1-18Leydig 515882161-27Leydig 515882Leydig 51588218as well as stereoisomers, tautomers, or pharmaceutically acceptable salts of the foregoing compounds. Additional examples include the compounds provided in Appendix I, as well as stereoisomers, tautomers, and pharmaceutically acceptable salts thereof.

[0087] In some embodiments the compound of Formula I is a compound having the structure:or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments the compound of Formula I is a compound having the structure:Leydig 51588219or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments the compound of Formula I is a compound having the structure:or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments the compound of Formula I is a compound having the structure:Leydig 51588220or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments the compound of Formula I is a compound having the structure:or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments the compound of Formula I is a compound having the structure:Leydig 515882or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments the compound of Formula I is a compound having the structure:or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments the compound of Formula I is a compound having the structure:Leydig 51588222or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments the compound of Formula I is a compound having the structure:or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments the compound of Formula I is a compound having the structure:or a pharmaceutically acceptable salt thereof.Leydig 51588223

[0097] In some embodiments the compound of Formula I is a compound having the structure:or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments the compound of Formula I is a compound having the structure:or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments the compound of Formula I is a compound having the structure:Leydig 51588224or a pharmaceutically acceptable salt thereof.

[0100] Also provided herein is a method of inhibiting eIF4A activity, the method comprising contacting eIF4A with a compound of Formula I. Without wishing to be bound by any particular theory or mechanism of action, it is believed that the compounds of Formula I provided herein bind to eIF4A and / or otherwise prevent eIF4A from binding target mRNA and / or forming an active translation complex.

[0101] The method can be used for any purpose, but is believed to be particularly useful for inhibiting IgG secretion by plasma B cells. In some embodiments, the method can be used to inhibit IgG secretion by plasma B cells to a greater extent than other B cells (e.g., naive and memory B cells). Without wishing to be bound by any particular theory' or mechanism of action, it is believed that the inhibition of IgG secretion by plasma B cells might be due to a reduction in the population of plasma B cells, possibly by’ inhibiting the production of plasma B cells from germinal centers and / or by killing plasma B cells. Thus, in some embodiments, the method can be a method of reducing the number or concentration of plasma B cells in a mammal, particular a human. In further embodiments, the method reduces the number or concentration of plasma B cells in a mammal, particularly a human, to a greater extent than other B cells (e.g., naive and memory B cells) or other lymphocytes.

[0102] In some embodiments, the compounds provided herein are used for treating autoimmune or inflammatory' diseases or disorders, particularly those associated with eIF4A activity or plasma B cell activity (e.g., plasma B cell secretion of IgG). Examples of inflammatory’ or autoimmune diseases and disorders include, for example, arthritis, rheumatoid arthritis, including TNF-refractory rheumatoid arthritis, Sjogren’s Syndrome,Leydig 51588225asthma, Chronic obstructive pulmonary disease (COPD), pelvic inflammatory disease. Behcet disease, Alzheimer’s Disease, inflammatory bowel disease including Crohn’s disease and ulcerative colitis, Peyronie’s Disease, celiac disease, gallbladder disease, Pilonidal disease, peritonitis, psoriasis, psoriatic arthritis, contact hypersensitivity, allergic disease, eosinophilia, eosinophilic esophagitis, vasculitis, antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis, surgical adhesions, stroke, Type I Diabetes, lyme disease, arthritis, meningoencephalitis, autoimmune or noninfectious uveitis, immune mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis, lupus (such as systemic lupus erythematosus and chronic discoid lupus erythematosus) and Guillain-Barr syndrome, Atopic dermatitis, polymyositis, dermatomyositis, autoimmune hepatitis, fibrosing alveolitis. Grave’s disease, IgA nephropathy, primary membranous nephropathy, idiopathic thrombocytopenic purpura, Meniere's disease, pemphigus, pemphigus vulgaris, pemphigoid, primary biliary cholangitis, hepatitis, sarcoidosis, scleroderma (localized scleroderma, systemic scleroderma, and progressive systemic scleroderma). Granulomatosis with polyangiitis, other autoimmune disorders, cholangitis, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, heart disease including ischemic diseases such as myocardial infarction as well as atherosclerosis, periarteritis nodosa (polyarteritis nodosa and microscopic polyangiitis), allergic granulomatous angiitis, hypersensitivity angiitis, aortitis syndrome (Takayasu arteritis), temporal arteritis, intravascular coagulation, bone resorption, osteoporosis, osteoarthritis, periodontitis, including chronic periodontitis, and hypochlorhydria, Still’s disease, Cogan’s syndrome, RS3PE, polymyalgia rheumatica, fibromyalgia syndrome, antiphospholipid antibody syndrome, eosinophilic fasciitis, Guillain-Barre syndrome, chronic idiopathic demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis, chronic atrophic gastritis, Goodpasture’s syndrome, rapidly progressive glomerulonephritis, megaloblastic anemia, hemolytic anemia (e.g., warm autoimmune hemolytic anemia), autoimmune neutropenia, Hashimoto’s thyroiditis, thyroid eye disease, autoimmune adrenal insufficiency, primary hypothyroidism, idiopathic Addison’s disease (chronic adrenal insufficiency), herpes gestationis, linear IgA bullous skin disease, epidermolysis bullosa acquisita, alopecia areata, vitiligo, Harada disease, autoimmune optic neuropathy, idiopathic azoospermia, recurrent fetal loss (e.g., recurrent miscarriage or abortion), infertility related to lack of fetal-matemal tolerance, or respiratory diseases, such as asthma and ARDS (acute respiratory distress syndrome).Leydig 51588226

[0103] In some embodiments, the disease or disorder is psoriasis, psoriatic arthritis, rheumatoid arthritis, contact hypersensitivity, allergic disease, eosinophilia, eosinophilic esophagitis, respiratory diseases such as asthma and ARDS (acute respiratory' distress syndrome), chronic rhinosinusitis (e g., with nasal polyps), Giant Cell Arteritis, Polymyalgia Rheumatica, Primary Sjogren’s Syndrome, TNF-refractory Rheumatoid Arthritis, Alopecia Areata, Primary Biliary Cholangitis (PBC), Graft vs Host Disease (GvHD), Vitiligo, ANCA Vasculitis, Type 1 Diabetes, inflammatory' bowel disease including Crohn's disease and ulcerative colitis, asthma, chronic spontaneous urticaria, chronic periodontitis, recurrent fetal loss, celiac disease, transplant rejection orNoninfectious Uveitis.

[0104] In some embodiments, the disease or disorder is thyroid eye disease, neuromyelitis optica, Grave’s disease, Sjogren’s disease, chronic rhinosinusitis (e g., with nasal polyps), moderate-to-severe asthma, chronic spontaneous urticaria, pemphigus vulgaris, multiple sclerosis, myasthenia gravis, chronic idiopathic demyelinating polyneuropathy, idiopathic thrombocytopenia purpura, warm autoimmune hemolytic anemia, systemic lupus erythematosus, or primary membranous nephropathy. In some embodiments, the disease or disorder is IgA nephropathy.

[0105] In some embodiments, the compounds disclosed herein may be used in to treat diseases characterized by uncontrolled cell growth, proliferation and / or survival, particularly those mediated by eIF4A. In some embodiments, the disease or disorder is a fibrotic disease or disorder, such as viral hepatitis, hepatic fibrosis, liver fibrosis, renal fibrosis, schistosomiasis, steatohepatitis (alcoholic or non-alcoholic (NASH)), cirrhosis, idiopathic pulmonary fibrosis (IPF), systemic sclerosis (scleroderma), nephrogenic systemic fibrosis (NSF), diabetes, untreated hypertension, heart attack, hypertension, atherosclerosis, restenosis, macular degeneration, retinal and vitreal retinopathy, keloids, hypertrophic scars, Crohn's disease and Alzheimer's disease.

[0106] In some embodiments, the cell proliferative disease or disorder is 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 types of cancers that may be treated include: histiocytic disorders; leukemia; histiocytosis malignant; Hodgkin's disease; immunoproliferative small;Leydig 51588227non-Hodgkin's lymphoma; T-cell lymphoma, B-cell lymphoma, hairs’ cell lymphoma, Burkitt's lymphoma, multiple myeloma, diffuse large B-cell lymphoma; 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; trophoblastic tumor, adenoma; cholangioma; cholesteatoma; cyclindroma; cystadenocarcinoma; cystadenoma; granulosa cell tumor; gynandroblastoma; hepatoma; hidradenoma; islet cell tumor; Leydig cell tumor; papilloma; sertoli cell tumor; theca cell tumor; 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, colon cancer, colorectal cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, acute myeloid leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, primary and secondary CNS cancer, including malignant glioma and glioblastoma, renal cancer, prostate cancer, including castration-resistant prostate cancer, ovarian cancer, or breast cancer, including triple negative, HER2 positive, or hormone receptor positive breast cancers.

[0107] As used herein, the terms “treat’", “treating” or “treatment"’ in reference to a disease means to reduce the severity of the disease or one or more symptoms of the disease to any extent, or to slow the onset or progression of the disease or one or more symptoms thereof to any degree.

[0108] The compounds of the present invention may be formulated into pharmaceutical compositions prior to administration to a subject. Accordingly, one aspect of the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient. In accordance with another aspect of the invention, aLeydig 51588228process is provided for the preparation of a pharmaceutical composition including admixing a compound described above or salts thereof, solvates etc thereof, with one or more pharmaceutically acceptable excipient.

[0109] As used herein, “pharmaceutically acceptable excipient'’ means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient may be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a subject and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.

[0110] The compounds of the invention and the pharmaceutically acceptable excipient or excipients may be formulated into a dosage form adapted for administration to the subject by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration (including buccal or sublingual) such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration (including subcutaneous, intramuscular, intravenous or intradermal) such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) nasal inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration (including buccal, sublingual or transdermal) such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels. Such compositions may be prepared by any methods known in the art of pharmacy, for example by bringing into association a compound described above with the carrier(s) or excipient(s).

[0111] Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

[0112] Suitable pharmaceutically acceptable excipients may vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability’ to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. CertainLeydig 51588229pharmaceutically acceptable excipients may be chosen for their ability to facilitate carrying or transporting the compound or compounds of the invention once administered to the subject from an organ, or a portion of the body, to another organ, or a portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.

[0113] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much the excipient is present in the formulation and what other ingredients are present in the formulation.

[0114] Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington 's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0115] The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0116] In one embodiment, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a therapeutically effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. com starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder.Suitable binders include starch (e.g. com starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and celluloseLeydig 51588230and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

[0117] In one embodiment, the pharmaceutical composition comprises a compoundor a pharmaceutically acceptable salt thereof.

[0118] In one embodiment, the pharmaceutical composition comprises a compoundor a pharmaceutically acceptable salt thereof.

[0119] In one embodiment, the pharmaceutical composition comprises a compound having the structure ofLeydig 51588231or a pharmaceutically acceptable salt thereof.

[0120] In one embodiment, the pharmaceutical composition comprises a compound having the structure ofor a pharmaceutically acceptable salt thereof.

[0121] In one embodiment, the pharmaceutical composition comprises a compound having the structure ofLeydig 51588232or a pharmaceutically acceptable salt thereof.

[0122] In one embodiment, the pharmaceutical composition comprises a compound having the structure ofor a pharmaceutically acceptable salt thereof.

[0123] In one embodiment, the pharmaceutical composition comprises a compound having the structure ofLeydig 51588233or a pharmaceutically acceptable salt thereof.

[0124] In one embodiment, the pharmaceutical composition comprises a compound having the structure ofor a pharmaceutically acceptable salt thereof.

[0125] In one embodiment, the pharmaceutical composition comprises a compound having the structure ofLeydig 51588234or a pharmaceutically acceptable salt thereof.

[0126] In one embodiment, the pharmaceutical composition comprises a compound having the structure ofor a pharmaceutically acceptable salt thereof.

[0127] In one embodiment, the pharmaceutical composition comprises a compound having the structure ofLeydig 51588235or a pharmaceutically acceptable salt thereof.

[0128] In one embodiment, the pharmaceutical composition comprises a compoundor a pharmaceutically acceptable salt thereof.

[0129] In one embodiment, the pharmaceutical composition comprises a compound having the structure ofLeydig 51588236or a pharmaceutically acceptable salt thereof.

[0130] The disclosure further provides a method of preparing a compound of Formula I as provided herein. In one embodiment, the disclosure provides a method of preparing a compound of Formula I having the structure of Formula (VI). the method comprising combining a compound of Formula (V) with a compound of Formula (VII):H NR14R14Leydig 51588237wherein, in Formula (V), (VII), and (VI), R1, R2, R3, R3a, R5, R6, R7, R8, R9, and R14, are as previously defined including any and all embodiments thereof. In some embodiments, the method comprises combining a compound of Formula (V-A) with a compound of Formula (VII) to provide a compound of Formula (VII- A):Leydig 51588238wherein, in Formula (V-A), (VII), and (V1I-A), R1, R2, R3, R3a, R5, R6, R7, R8, R9, and R14, are as defined in any of the preceding claims. In some embodiments, the method comprises further reducing the compound thus produced. For instance, the method can comprise reducing the compound of Formula (VII- A) to provide a compound of Formula (VIII):Leydig 515882SYNTHESIS EXAMPLES

[0131] These following examples illustrate the synthesis of various compounds of Formula I described herein. The methods set forth herein as well as any and all intermediate compounds used in such methods are considered additional aspects and embodiments of the invention. The structures of compounds identified in these examples are as set forth in the schematics and as provided in Appendix I.SYNTHESIS EXAMPLE 1

[0132] (10S,llR,12R,13S,14R)-10,ll-dihydroxy-14-(4-methoxyphenyl)-N, N-dimethyl-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-12-carboxamide (1-1 and 1-2)Leydig 51588240

[0133] Step 1. 6-chloro-N,4-dimethoxy-N-methylnicotinamide

[0134] A solution of 6-chloro-4-methoxypyridine-3-carboxylic acid (30.00 g, 159.00 mmol), N, O-dimethylhydroxylamine (11.72 g, 191.91 mmol), HOBT (25.93 g, 191.91 mmol), EDCI (36.79 g, 191.91 mmol), and DIEA (41.34 g, 319.86 mmol) in DCM (1 L) was stirred for 3h at 25°C under N2. The reaction mixture was poured into saturated ammonium chloridesilution (1.5 L), then extracted with EtOAc (3 x 1.5 L) and dried over anhydrous Na2SO4. The residue was concentrated under reduced pressure to afford 6-chloro-N,4-dimethoxy-N-methylpyridine-3-carboxamide (32 g, 86.75%) as a yellow solid. LCMS (ES, m / z): 231 [M+H]+.

[0135] Step 2. l-(6-chloro-4-methoxypyridin-3-yl)ethan-l-one

[0136] A solution of 6-chloro-N,4-dimethoxy-N-methylpyridine-3-carboxamide (32.00 g, 138.73 mmol) in THF (500 mL) was added MeMgBr (55.50 ml, 166.48 mmol) dropwise at -78°C under N2. The resulting mixture was stirred for 2h at -78°C. The reaction mixture was poured into saturated ammonium chloride solution (saq., 1 L), then extracted with EtOAc (3 x 1 L) and dried over anhydrous Na2SO4. The residue was concentrated under reduced pressure to afford l-(6-chloro-4-methoxypyridin-3-yl)ethanone (25 g, 97.08%) as a yellow solid. LCMS (ES, m / z): 187 [M+H]+.Leydig 51588241

[0137] Step 3. l-(6-chloro-4-hydroxypyridin-3-yl)ethan-l-one

[0138] A solution of l-(6-chloro-4-hydroxypyridin-3-yl)ethanone (25.00 g, 145.70 mmol) in HC1(6M) (200 mL) and HOAc (100 mL) was stirred for 0.5h at 100°C. The residue was diluted with water (500 ml), then adjusted to pH 6~7 with NaOH(saq ). The resulting mixture was extracted with EtOAc (3 x 500 ml) and dried over anhydrous Na2SO4. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford l-(6-chloro-4-hydroxypyridin-3-yl)ethanone (15.5 g, 62.00%) as a off-white solid. LCMS (ES, m / z): 172 [M+H]+.

[0139] Step 4. (E)-l-(6-chloro-4-hydroxypyridin-3-yl)-3-(4-methoxyphenyl)prop-2-en-l-one

[0140] A solution of l-(6-chloro-4-hydroxypyridin-3-yl)ethanone (15.50 g, 90.33 mmol) and anisaldehyde (12.30 g. 90.33 mmol) in MeOH (300 mL) was added NaOH (10.84 g, 271.01 mmol), then stirred for 3h at 60°C. The residue was diluted with water (500 ml), then adjusted to pH 6~7 with HC1 (6M). The isolated solid was collected by filtration to afford (2E)-l-(6-chloro-4-hydroxypyridin-3-yl)-3-(4-methoxyphenyl)prop-2-en-l-one (15.5 g, 59.22%) as a off-white solid. LCMS (ES, m / z): 290 [M+H]+.

[0141] Step 5. (E)-l-(6-chloro-4-hydroxypyridin-3-yl)-3-(4-methoxyphenyl)prop-2-en-l-one

[0142] A solution of (2E)-l-(6-chloro-4-hydroxypyridin-3-yl)-3-(4-methoxyphenyl)prop-2-en-l-one (1.50 g, 5.17 mmol) in MeOH (30 mL) was added H2O2(30%) (1.29 g, 11.38 mmol) and NaOH (0.62 g, 15.531 mmol), then stirred for Ih at 25°C. The residue was diluted with water (100 ml), then adjusted to pH 6~7 with HC1(6M). The isolated solid was collected by filtration to afford 7-chloro-3-hydroxy-2-(4-methoxyphenyl)pyrano[3,2-c]pyridin-4-one (300 mg, 19.08%) as a off-white solid. LCMS (ES, m / z): 304 [M+H]+.

[0143] Step 6. methyl (3R,4R,5S)-8-chloro-5-hydroxy-2-(4-methoxyphenyl)-10-oxo-3-phenyl-2,3.4.5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate

[0144] A solution of 7-chloro-3-hydroxy-2-(4-methoxyphenyl)pyrano[3,2-c]pyridin-4-one (270 mg, 0.88 mmol), methyl cinnamate (1.44 g, 8.89 mmol) in DCM (8 mL), ACN (8 mL) and MeOH (8 mL) was stirred for 5h at 25°C under the light of 365 nm. The resulting mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with PE / EtOAc (3:1) to afford methyl (IS, 10S, 1 lR)-5-chloro-l-hydroxy-9-(4-methoxyphenyl)-12-oxo-10-Leydig 51588242phenyl-8-oxa-4-azatricyclo[7.2.1.0A{2,7[]dodeca-2,4,6-triene-l 1-carboxylate (370 mg, 89.33%) as a off-white solid. LCMS (ES, m / z): 466 [M+H]+.

[0145] Step 7. methyl (2R,4R,5S,6R)-10-chloro-2-hydroxy-6-(4-methoxyphenyl)-3-oxo-5-phenyl-7-oxa-l 1 -azatri cyclo[6.4.0.0A{2, 6}]dodeca-l(12), 8, 10-triene-4-carboxylate

[0146] A solution of methyl (lS,10S, HR)-5-chloro-l-hydroxy-9-(4-methoxyphenyl)-12-oxo-10-phenyl-8-oxa-4-azatricyclo[7.2.1.0A{2,7}]dodeca-2,4,6-triene-l 1-carboxylate (350 mg, 0.75 mmol) and NaOMe (48 mg, 0.90 mmol) in MeOH (5 mL) was stirred for 2h at 110°C. The reaction mixture was poured into saturated ammonium chloride solution (saq., 10 ml), extracted with EtOAc (3 x 10 ml) and dried over anhydrous Na2SO4. The residue was concentrated under reduced pressure to afford methyl (2R,4R,5S,6R)-10-chloro-2-hydroxy-6-(4-methoxyphenyl)-3-oxo-5-phenyl-7-oxa-l 1 -azatri cyclo[6.4.0.0A{2, 6}] dodeca- 1(12), 8,10-triene-4-carboxylate (350 mg, 100.00%) as a yellow solid. LCMS (ES, m / z): 467 [M+H]+.

[0147] Step 8. methyl (5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-l-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4.5]furo[3,2-c]pyridine-7-carboxylate

[0148] A solution of methyl (2R,4R,5S,6R)-10-chloro-2-hydroxy-6-(4-methoxyphenyl)-3-oxo-5-phenyl-7-oxa-ll-azatricyclo[6.4.0.0A{2,6)]dodeca-l(12),8,10-triene-4-carboxylate (350 mg, 0.75 mmol) in AcOH (4 mL) and ACN (4 mL) was added slowly STAB (191 mg, 0.90 mmol) at 0°C, then was stirred for Ih at 0°C. The reaction mixture was diluted with water (20 ml), extracted with EtOAc (3 x 20 ml) and dried over anhydrous Na2SO4. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with PE / EtOAc (3: 1) to afford methyl (2S,3R,4R,5S.6R)-10-chloro-2.3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-l l-azatricyclo[6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-4-carboxylate (100 mg, 28.45%) as a off-white solid. LCMS (ES, m / z): 469 [M+H]+.

[0149] Step 9. methyl (5aR,6S,7R,8R,8aS)-3-((tert-butoxycarbonyl)amino)-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate

[0150] A solution of methyl (2S,3R,4R,5S,6R)-10-chloro-2,3-dihydroxy-6-(4-methoxypheny l)-5-phenyl-7-oxa-ll -azatri cyclo[6.4.0.0A{2, 6}]dodeca-l(12), 8, 10-triene-4-carboxylate (90 mg, 0.19 mmol), Pd2(dba)s (35 mg, 0.03 mmol), XantPhos (22 mg, 0.03 mmol), CS2CO3 (125 mg, 0.38 mmol) in 1,4-dioxane (3 mL) was stirred for 2h at 100°C. The reaction mixture was diluted with water (10 ml), then was extracted with EtOAc (3 x 10 ml)Leydig 51588243and dried over anhydrous Na2SO4. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with PE / EtOAc (3: 1) to afford methyl (2S,3R,4R,5S,6R)-10-[(tert-butoxycarbonyl)amino]-2,3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-l l-azatricyclo[6.4.0.0A{2.6}]dodeca-l(12).8.10-triene-4-carboxylate (45 mg, 42.65%) as a off-white solid. LCMS (ES, m / z): 549 [M+H]+.

[0151] Step 10. methyl (5aR,6S,7R,8R,8aS)-3-amino-8,8a-dihydroxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate

[0152] A solution of methyl (2S,3R,4R,5S,6R)-10-[(tert-butoxycarbonyl)amino]-2,3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-l 1 -azatri cyclo[6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-4-carboxylate (45 mg, 0.08 mmol) in TFA (0.4 mL) and DCM (2 mL) was stirred for 2h at 25°C. The reaction mixture was diluted with water (5 ml), then was extracted with EtOAc (3 x 5 ml) and dried over anhydrous NazSC. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford methyl (2S,3R,4R,5S,6R)-10-amino-2,3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-l 1-azatricyclo[6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-4-carboxylate (60 mg, 163.10%) as a yellow oil. LCMS (ES, m / z): 449 [M+H]L

[0153] Step 11. methyl (5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxylate

[0154] A solution of methyl (2S,3R,4R,5S,6R)-10-amino-2,3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-l l-azatricyclo[6.4.0.0A{2.6}]dodeca-l(12).8.10-triene-4-carboxylate (45 mg, 0.10 mmol) and TEA (2 mg, 0.02 mmol) in MeOH (1 mL) and chloroacetaldehyde (1 mL) was stirred for Ih at 90°C. The reaction mixture was diluted with water (5 ml), then was extracted with EtOAc (3 x 5 ml) and dried over anhydrous Na2SO4. The reaction mixture were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1: 1- HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 30; Wavelength: 254 / 220nmnm; RTl(min): 5.552; RT2(min): 6.941; Sample Solvent: EtOH--HPLC; Injection Volume: 0.9 mL; Number Of Runs: 2. The first eluting isomer(RT 5.552min) was concentrated and lyophilized to afford 1-2 (2.6 mg, 6.96%) as a white solid. LCMS (ES, m / z): 393Leydig 51588244[M+H] '. The second eluting isomer (RT 6.941 min) was concentrated and lyophilized to afford 1-1 (16.1 mg, 33.96%) as a white solid. 1-1: ‘H-NMR (DMSO-rfc, 400 MHz) 5 (ppm): 8.37(s, 1H), 7.89(s, 1H), 7.47(s, 1H), 7.45(s, 1H), 7.40(d, J=L2 HZ, 1H), 7.37(s, 1H), 7.35(s, 1H), 7.31-7.27(m, 2H), 7.23-7.19(m, 2H), 6.97(s, 1H), 6.94(s, 1H), 6.88(s, 1H), 5.64(s, 1H), 5.57(d, J=6.8 HZ, 1H), 4.37-4.32(m, 1H), 3.77-3.32(m, 6H), 3.02-2.96(m, 1H). LCMS (ES, m / z): 393[M+H]+. 1-2: 'H-NMR (DMSO-A, 400 MHz) 5 (ppm):7.89(s, 1H), 7.47(s, 1H), 7.45(s, 1H), 7.40(d, J=1.2 HZ, 1H), 7.37(s, 1H), 7.35(s, 1H), 7.31-7.27(m, 2H), 7.23-7.19(m, 2H), 6.97(s, 1H), 6.94(s, 1H), 6.88(s, 1H), 5.64(s, 1H), 5.57(d, J=6.8 HZ, 1H), 4.37-4.32(m, 1H), 3.77-3.32(m, 6H), 3.02-2.96(m, 1H). LCMS (ES, m / z): 393[M+H]+.SYNTHESIS EXAMPLE 2

[0155] Methyl (10S, HR, 12R,13S,14R)- 10, ll-dihydroxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-3,6-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,4,6,8-tetraene- 12-carboxylate (1-3, Racemic)Mel, K2CO31DMF NaOH, H2O, EtOH 60 °C, 2 h 80 °C, 4 h step 2 step 12 38 9Leydig 51588245

[0156] Step 1. methyl 2-chloro-5-methoxyisonicotinate

[0157] A mixture of 2-chloro-5-hydroxypyridine-4-carboxylic acid (5 g, 28.81 mmol, 1 equiv), K2CO3 (15.9 g, 115.24 mmol, 4 equiv) and Mel (12.3 g, 86.43 mmol, 3 equiv) in DMF (150 mL) was stirred for overnight at 60 °C. Desired product could be detected by LCMS. The resulting mixture was extracted with CH2CI2 (3x100 mL). The combined organic layers were washed with deionized water (3x100 mL), dried over anhydrous NazSOi. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 2-chloro-5-methoxyisonicotinate (5.3 g, 88.5%) as a while solid. LCMS (ESI, m / z): 211 [M+H]+

[0158] Step 2. 2-chloro-5-methoxyisonicotinic acid

[0159] A mixture of methyl 2-chloro-5-methoxypyridine-4-carboxylate (5 g, 24.80 mmol, 1 equiv) and NaOH (9.9 g, 248.00 mmol, 10 equiv) in EtOH (100 mL) and H2O (100 mL) was stirred for overnight at 80 °C. Desired product could be detected by LCMS. The resulting mixture was extracted with CH2CI2 (3x100 mL). The combined organic layers were washed with deionized water (3x100 mL), dried over anhydrous NazSCh. After filtration, the filtrateLeydig 51588246was concentrated under reduced pressure to afford 2-chloro-5-methoxy isonicotinic acid (4.5 g, 94.8%) as a white solid. LCMS (ESI, m / z): 188 [M+H]+

[0160] Step 3. 2-chloro-N,5-dimethoxy-N-methylpyridine-4-carboxamide

[0161] A mixture of 2-chloro-5-methoxypyridine-4-carboxylic acid (4.8 g, 24.05 mmol, 1 equiv, 94%), HATU (13.7 g. 36.08 mmol. 1.5 equiv), DIEA (6.2 g, 48.11 mmol, 2 equiv) and methoxy(methyl)amine hydrochloride (3.5 g, 36.08 mmol, 1.5 equiv) in DMF (100 mL) was stirred for 2 h at room temperature. Desired product could be detected by LCMS. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-chloro-N,5-dimethoxy-N-methylpyridine-4-carboxamide (4.8 g, 80.46%) as a colorless oil. LCMS (ESI, m / z): 231 [M+H]+

[0162] Step 4. l-(2-chloro-5-methoxypyridin-4-yl)ethenone

[0163] To a stirred solution of 2-chloro-N,5-dimethoxy-N-methylpyridine-4-carboxamide (4.8 g, 19.35 mmol, 1 equiv, 93%) in THF (100 mL) was added MeMgBr (12.9 mL, 38.71 mmol, 2 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was quenched with sat. NFLCl and extracted with EtOAc (3x100 mL). The combined organic layers were washed with deionized water (3x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford l-(2-chloro-5-methoxypyridin-4-yl)ethanone (3.5 g, 93.53%) as a white solid. LCMS (ESI, m / z): 186 [M+H]+

[0164] Step 5. l-(2-chloro-5-hydroxypyridin-4-yl)ethenone

[0165] To a stirred solution of l-(2-chloro-5 -methoxy pyridin-4-yl)ethanone (3.0 g, 15.52 mmol, 1 equiv. 96%) in DCM (60 mL) was added BBrs (31.0 mL, 31.03 mmol, 2 equiv) dropwise at 0 °C. The resulting mixture was stirred for overnight at room temperature.Desired product could be detected by LCMS. The resulting mixture w as quenched with sat. NELCl and extracted with EtOAc (3x100 mL). The combined organic layers were washed with deionized water (3x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate w as concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford l-(2-chl oro-5 -hy droxypyridin-4-yl)ethanone (550 mg, 19.83%) as a yellow' solid. LCMS (ESI, m / z): 172 [M+H]*

[0166] Step 6. (2E)-l-(2-chloro-5-hydroxypyridin-4-yl)-3-(4-methoxyphenyl)prop-2-en-I-oneLeydig 51588247

[0167] A mixture of l-(2-chloro-5-hydroxypyridin-4-yl)ethanone (550 mg. 3.21 mmol, 1 equiv), NaOH (641 mg, 16.030mmol, 5 equiv) and anisaldehyde (1309 mg, 9.62 mmol, 3 equiv) in MeOH (10 mL) was stirred for overnight at 70 °C. Desired product could be detected by LCMS. The mixture was acidified to pH 7 with cone. HC1. The precipitated solids were collected by filtration and washed with MeOH (3x5 mL) to afford (2E)-l-(2-chloro-5-hydroxypyridin-4-yl)-3-(4-methoxyphenyl)prop-2-en-l-one (700 mg, 71.61%) as a yellow solid. LCMS (ESI, m / z): 290 [M+H]+

[0168] Step 7. 6-chloro-3-hydroxy-2-(4-methoxyphenyl)pyrano[2,3-c]pyridin-4-one

[0169] A mixture of (2E)-l-(2-chloro-5-hydroxypyridin-4-yl)-3-(4-methoxyphenyl)prop-2-en-l-one (650 mg, 2.24 mmol. 1 equiv), H2O2 (636 mg, 5.61 mmol, 2.5 equiv. 30%) and NaOH (269 mg, 6.732 mmol, 3 equiv) in MeOH (10 mL) and H2O (3 mL) was stirred for 1 h at room temperature. The mixture / residue was neutralized to pH 7 with cone. HC1. The precipitated solids were collected by filtration and washed with MeOH (3x20 mL) to afford 6-chloro-3-hydroxy-2-(4-methoxyphenyl)pyrano[2,3-c]pyridin-4-one (380 mg. 55.21%) as a yellow solid. LCMS (ESI, m / z): 304 [M+H]+

[0170] Step 8. methyl (lS,10R, HR)-4-chloro-l-hydroxy-9-(4-methoxyphenyl)-12-oxo-10-phenyl-8-oxa-5-azatricyclo [7.2.1.0A{2,7}]dodeca-2,4,6-triene-l 1 -carboxylate

[0171] A mixture of 6-chloro-3-hydroxy-2-(4-methoxyphenyl)pyrano[2,3-c]pyridin-4-one (380 mg, 1.25 mmol, 1 equiv) and methyl cinnamate (2.0 g, 12.52 mmol, 10.00 equiv) in DCM (8 mL), MeOH (4 mL) and MeCN (4 mL) was stirred for 40 min at room temperature under nitrogen atmosphere and 365 UV. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Ch / MeOH (20: 1) to afford methyl(1 S, 1 OR, 11 R)-4-chloro- 1 -hydroxy-9-(4-methoxyphenyl)- 12-oxo- 10-phenyl-8-oxa-5-azatricyclo[7.2.1.0A{2,7}]dodeca-2,4,6-triene-ll-carboxylate (520 mg, 89.20%) as ayellow solid. LCMS (ESI, m / z): 466 [M+H]+

[0172] Step 9. methyl (2R.4R,5S,6R)-1 l-chloro-2-hydroxy-6-(4-methoxyphenyl)-3-oxo-5-phenyl-7-oxa-10-azatricyclo [6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-4-carboxylate

[0173] A mixture of methyl (1 S, 1 OR, 11 R)-4-chloro- 1 -hy droxy-9-(4-methoxyphenyl)- 12-oxo-10-phenyl-8-oxa-5-azatricyclo[7.2.1.0A{2,7)]dodeca-2,4,6-triene-l 1-carboxylate (360 mg, 0.77 mmol, 1 equiv) and MeONa (417 mg, 7.73 mmol, 10 equiv) in MeOH (10 mL) was stirred for 0.5 h at 70 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel columnLeydig 51588248chromatography, eluted with CH2Ch / MeOH (20: 1) to afford methyl (2R.4R.5S,6R)-11-chloro-2-hydroxy-6-(4-methoxyphenyl)-3-oxo-5-phenyl-7-oxa-10-azatricyclo[6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-4-carboxylate (50 mg, 50.00%) as a yellow solid. LCMS (ESI, m / z): 466 [M+H]+

[0174] Step 10. methyl (2S,3R,4R,5S,6R)-ll-chloro-2,3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-10-azatri cyclo [6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-4-carboxylate

[0175] A mixture of methyl (2R,4R,5S,6R)-1 l-chloro-2-hydroxy-6-(4-methoxyphenyl)-3-oxo-5-phenyl-7-oxa-10-azatricyclo[6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-4-carboxylate (200 mg, 0.43 mmol. 1 equiv), AcOH (258 mg, 4.29 mmol, 10 equiv) and STAB (546 mg, 2.57 mmol, 6 equiv) in MeCN (5 mL) was stirred for 0.5 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CELCk / MeOH (20:1) to afford methyl (2S,3R,4R,5S.6R)-ll-chloro-2,3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-10-azatricyclo[6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-4-carboxylate (165 mg, 82.15%) as ayellow solid. LCMS (ESI, m / z): 468 [M+H]+

[0176] Step 11. methyl (2S,3R,4R,5S,6R)-ll-[(tert-butoxycarbonyl)amino]-2,3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-10-azatricyclo[6.4.0.0A{2,6}]dodeca-1 (12), 8, 10-triene-4-carboxylate

[0177] A mixture of methyl (2S,3R,4R,5S,6R)-ll-chloro-2,3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-10-azatricyclo[6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-4-carboxylate (150 mg, 0.22 mmol, 1 equiv), Pd2(dba)s (21 mg, 0.022 mmol, 0.1 equiv), XantPhos (26 mg, 0.045 mmol, 0.2 equiv), CS2CO3 (146 mg, 0.448 mmol, 2 equiv) and BocNEL (53 mg, 0.45 mmol, 2 equiv) in 1,4-dioxane (5 mL) was stirred for 2 h at 100 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CEhCh / MeOH (20:1) to afford methyl (2S,3R,4R,5S,6R)-ll-[(tert-butoxycarbonyl)amino]-2,3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-10-azatri cyclo [6.4.0.0A{2,6}]dode ca-l(12),8,10-triene-4-carboxylate (170 mg, 69.05%) as ayellow solid. LCMS (ESI, m / z): 549 [M+H]+

[0178] Step 12. methyl (2S,3R,4R,5S,6R)-ll-amino-2,3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-10-azatricyclo[6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-4-carboxylateLeydig 51588249

[0179] A mixture of methyl (2S.3R.4R,5S,6R)-l l-[(tert-butoxycarbonyl)amino]-2.3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-10-azatricyclo[6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-4-carboxylate (160 mg, 0.12 mmol, 1 equiv) and TFA (1 mL) in DCM (2 mb) was stirred for 1 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CTbCh / MeOH (20:1) to afford methyl (2S,3R,4R,5S,6R)-1 l-amino-2,3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-10-azatricyclo[6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-4-carboxylate (20 mg, 25.17%) as a yellow solid. LCMS (ESI, m / z): 449 [M+H]+

[0180] Step 13. methyl (10S,l lR,12R.13S,14R)-10,ll-dihydroxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-3,6-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,4,6,8-tetraene-12-carboxylate

[0181] A mixture of methyl (2S,3R,4R,5S,6R)-ll-amino-2.3-dihydroxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-10-azatricyclo[6.4.0.0A{2.6}]dodeca-l(12).8.10-triene-4-carboxylate (13 mg, 0.029 mmol, 1 equiv), Et3N (10 uL, 0.072 mmol, 2.48 equiv) and chloroacetaldehyde (1 mL, 8.28 mmol, 285.65 equiv) in MeOH (1 mL) was stirred for 1 h at 80 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10 nmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min rnL / min;Gradient: 23% B to 53% B in 10 min; Wavelength: 254nm / 220nm nm; RTl(min): 8.45) to afford methyl (10S, 11R, 12R, 13S, 14R)- 10, 11 -dihydroxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-3,6-diazatetracyclo[7.6.0.0A{3,7[.0A{ 10, 14}]pentadeca- 1,4,6, 8-tetraene-12-carboxylate (2.8 mg, 18.89%) as an off-white solid.

[0182] LCMS (ESI, m / z): 473 [M+H]+NMR (400 MHz, DMSO-cfc) 5 8.31 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.46 (d, J= 8.8 Hz, 2H), 7.41 (s, 1H), 7.36 (d, J= TA Hz, 2H), 7.29 (t, J= 7.5 Hz. 2H), 7.24 - 7.18 (m, 1H), 6.95 (d, J= 8.8 Hz, 2H), 5.69 (s, 1H), 5.55 (d, J = 6.2 Hz, 1H), 3.77 (s, 3H), 3.73 (d, J= 12.5 Hz, 1H), 3.37 (s, 3H), 3.06 - 2.97 (m, 1H), 2.05 - 1.94 (m, 1H). LCMS (ESI, m / z): 473 [M+H]+.SYNTHESIS EXAMPLE 3Leydig 51588250

[0183] (5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-iiiethoxy-8a-(4-iiiethoxyphenyl)- / V, / V-dimethyl-8-phenyl-5b,7,8,8a-tetrahydro-6H-cycIopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxamide (1-4)_

[0184] 2,6 -dichloro-4-((4-methoxybenzyl)oxy)pyridineLeydig 515882DMF (10V), 0 °C~r.t„ 3 hstep 1 70%

[0185] A solution of 2,4,6-trichloropyridine (500 g, 2764 mmol, 1 equiv) in DMF (5000 mL), NaH (132.6 g, 3317 mmol, 1.2 equiv, 60%) was added in several portions at 0 °C for 30 min under nitrogen atmosphere followed by the addition of anise alcohol (381.7 g, 2764 mmol, 1 equiv) in portions at 0 °C for for 30 min. The resulting mixture was stirred for 3 h at room temperature. The reaction was quenched by the addition of sat. NH4CI (aq.) (6.7 L) at room temperature. The aqueous layer was extracted with EtOAc (3 x 1500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9: 1). This resulted in 2,6-dichloro-4-[(4-methoxyphenyl)methoxy]pyridine (550 g, yield: 70%) as a white solid.

[0186] 2-chloro-6-methoxy-4-((4-methoxybenzyl)oxy)pyridineMeONa (1.22 eq, 30% in MeOH) f toluene (10 V) N Cl 2 100 °C, 6 hstep 2 80%

[0187] A mixture of 2, 6-di chi oro-4- [(4-methoxyphenyl)meth oxy] pyridine (550 g, 1943 mmol, 1 equiv), MeONa (426.7 g, 2371 mmol, 1.22 equiv, 30% in MeOH) in toluene (5500 mL) was stirred for 6 h at 100 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of sat. NH4CI (aq.) (11 L) at room temperature. The aqueous layer was extracted with EtOAc (2 x 2500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9: 1). This resulted in 2-chloro-6-methoxy-4-[(4-methoxyphenyl)methoxy] pyridine (430 g, yield: 80%) as a white solid.

[0188] (E)-N-methoxy-3-(4-methoxyphenyl)-N-methylacrylamideO HCI OH (1.2 eq )"" NHATU ( 1.5 eq ), DIEA ( 2.5 eq ) '’ DMF (10 V), 0 °C- rt,3 hstep 21 90%Leydig 51588252

[0189] A stirred solution of (E)-3-(4-methoxyphenyl)acrylic acid (300 g. 1.684 mol, 1 equiv) in DMF (3000 mL) was cooled to 0 °C. N, O-dimethylhydroxylamine hydrochloride (197 g, 2.02 mol, 1.2 eq) and DIEA (544 g, 4.21 mol, 2.5 eq) were added into the mixture. Then HATU (960 g, 2.526 mol, 1.5 eq) was added in several batches at 0 °C for 30 mins. The resulting mixture was stirred for 3 h at r.t. under N2 atmosphere. The reaction was monitored by LCMS. The reaction was quenched with 18 L ice / water at room temperature. The resulting mixture was extracted with EtOAc (6 L x 3). The combined organic layers were washed with water (5 L x 4), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column with EA / PE (1: 2) to afford (E)-N-methoxy-3-(4-methoxyphenyl)-N-methylacrylamide (330 g, yield: 90%) as a white solid.

[0190] (E)-l-(6-chloro-2-methoxy-4-((4-methoxybenzyl)oxy)pyridin-3-yl)-3-(4- methoxy pheny l)prop-2-en- 1 -one

[0191] To a mixture of 2-chloro-6-methoxy-4-[(4-methoxyphenyl)methoxy]pyridine (430 g, 1540 mmol, 1 equiv) in THF (3440 mL), n-BuLi (825 mL, 1.34 equiv, 2.5 M) was added dropwise at -78 °C for 1 h. The reaction mixture was stirred at -78 °C for 1 h. (E)-N- methoxy-3-(4-methoxyphenyl)-N-methylacrylamide (681 g, 3081 mmol, 2 equiv) in THF (860 V) was added in above mixture and stirred for 1 h at 25 °C. The reaction was quenched by the addition of sat. NH4Q (aq.) (4.3 L) at room temperature, the resulting mixture was extracted with EtOAc (3 x 6000 mL). The combined organic layers were washed with salt water (3 x 6000 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4: 1). This resulted in (E)-l-(6-chloro-2-methoxy-4- ((4-methoxybenzyl)oxy)pyridin-3-yl)-3-(4-methoxyphenyl)prop-2-en-l-one (577 g, yield: 85%) as a yellow solid.

[0192] (E)-l-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)-3-(4-methoxyphenyl)prop-2- en- 1 -oneLeydig 51588253o o 1,3-dimethoxybenzene (0.5 eq) ^PMB TfOH (0.2 eq), DCM (17 V), rt, 1 h Cl O C< step 4 80% Cl OH20 8

[0193] A mixture of (E)-l-(6-chloro-2-methoxy-4-((4-methoxybenzyl)oxy)pyridin-3-yl)-3-(4-methoxyphenyl)prop -2-en-l-one (577 g, 1314 mmol, 1 equiv), 1,3-dimethoxy benzene (90.7 g, 657 mmol. 0.5 eq) in DCM (10 L), TfOH (39.4 g, 263 mmol, 0.2 equiv) was added dropwise at 0-10 °C for 10 min. The mixture was stirred for 1 h at 25 °C. The reaction was monitored by LCMS, the reaction was adjusted pH=7-8 with saturated NaHCO? aq, the resulting mixture was extracted with DCM (3 x 5000 mL). Combined organic phase and washed with salt water (3 x 5000 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford (E)-l-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)-3-(4-methoxyphenyl)prop-2-en-l-one (340 g, yield: 80%) as alight yellow solid.

[0194] 7-chloro-3-hydroxy-5-methoxy-2-(4-methoxyphenyl)-4H-pyrano[3,2-c|pyridin-4-oneKOAc (3 eq) HOAc (10 V), l2(2 eq)C|95 °C, 16 h step 8 35% over 2 steps

[0195] A mixture of (E)-l-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)-3-(4-methoxyphenyl)prop-2-en-l-one (328 g, 1028 mmol, 1 equiv) in MeOH (3280 mL) and 10% KOH in water (1725 ml, 3 eq) was added dropwise at 10 °C, 30% H2O2 (328 mL, 3084 mmol, 3.0 eq) was added dropwise at 10 °C for 15 min; The mixture was stirred at 25 °C for 1 h; LCMS showed the starting material was consumed and desired MS (336 / 338) was found; The mixture was quenched with 2 N HC1 ( PH=6) the solid was collected by filtration, 242 gLeydig 51588254of 8A was obtained. A mixture of 8 A (242 g, 722 mmol, 1 eq) in HOAC (2420 mL, 10 V). KOAc (212.8 g, 2167 mmol, 3 eq), h (367g, 1444 mmol, 2 eq). And the reaction mixture was stirred at 95 °C for 16 h; The mixture was poured into 10% Na2S2Ch in water (726 mL) and stirred for 10 min. The crude product was collected by filtration and slurry with MeOH (10 V), the solid was collected by filtration to afford 7-chloro-3-hydroxy-5-methoxy-2-(4-methoxyphenyl)-4H-pyrano[3,2-c]pyridin-4-one (120 g, yield: 35% over 2 steps) as a light yellow solid.

[0196] (E)-l-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)-3-(4-methoxyphenyl)prop-2-en-l-one

[0197] A mixture of 7-chloro-3-hydroxy-5-methoxy-2-(4-methoxyphenyl)pyrano[3,2-c]pyridin-4-one (20 g, 60 mmol, 1 equiv), methyl cinnamate (50 g, 300 mmol, 5 equiv) in DCM (250 mL), MeOH (125 mL) and ACN (125 mL) was irradiated with 365 nm blue light for 5 h at 30 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (20: 1). This resulted in methyl (3R,4R,5S)-8-chloro-5-hydroxy-6-methoxy-2-(4-methoxyphenyl)-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2,5-methanooxepino[3,2-c]pyridine-4-carboxylate (21.8 g, crude) as a light yellow solid. 128 g of SM9 was used for the reaction and 140 g of crude product was obtained, the crude product was used for next reaction without further purification.

[0198] Methyl (5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-l-methoxy-5a-(4-methoxyphenyl)-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylateLeydig 51588255

[0199] A mixture of methyl (3R,4R,5S)-8-chloro-5-hydroxy-6-methoxy-2-(4-methoxyphenyl)-10-oxo-3-phenyl-2,3,4,5-tetrahydro-2.5-methanooxepino[3.2-c]pyridine-4-carboxylate (130 g, 262.5 mmol, 1 equiv) in MeOH (2600 mL), 30% MeONa (472.6 g, 2625 mmol, 10 equiv) was added to the mixture, the reaction mixture was stirred for 2 h at 60 °C. the reaction mixture was quenched with H2O (10 L), The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with salt water (1 L), dried over anhydrous Na2SO4. This resulted in methyl (5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-l-methoxy-5a-(4-methoxyphenyl)-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate (111 g, yield: 63% over two steps) as an orange solid.

[0200] Methyl (5aR.6S,7R,8R,8aS)-3-chloro-8.8a-dihydroxy-l-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate

[0201] A mixture of methyl (5aR,6S,7R,8aR)-3-chloro-8a-hydroxy-l-methoxy-5a-(4-methoxyphenyl)-8-oxo-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate (110 g, 228.6 mmol, 1 equiv), STAB (290.7 g, 1371 mmol, 6 equiv), HOAc (137.2 g, 2286 mmol. 10 equiv) in ACN (1100 mL) was stirred for 1 h at 60 °C. The reaction mixture was quenched with H2O (1.1 L), The resulting mixture wasLeydig 51588256extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with salt water (1 L), dried over anhydrous NazSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3: 1). This resulted in methyl (5aR,6S,7R,8R,8aS)-3-chloro-8,8a-dihydroxy-l-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4.5]furo[3,2- c]pyridine-7-carboxylate (72 g, yield: 60%) as a light yellow solid.

[0202] Methyl (5aR,6S,7R,8R,8aS)-3-((tert-butoxycarbonyl)amino)-8,8a-dihydroxy-l-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2- c] py ridine-7-carboxy late(f J / ^\ BocNH2(4 eq) f JA Pd2dba3(0.1 eq), xantphos (0.2 eq)ClW CS2CO3(3 eq), dioxane (15 V)BOCHN-^Z^°Y-W'‘''\\ 100 °C, 16 h A\ J- / \N\ HO i X step 12 60%Nty HO Xz13714

[0203] A mixture of methyl (5aR,6S,7R,8R.8aS)-3-chloro-8,8a-dihydroxy-l-methoxy-5a- (4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7- carboxylate (62 g, 124 mmol, 1 equiv), tert-butyl carbamate (58 g, 496 mmol, 4 equiv), Pdz(dba)3 (11.3 g, 12.4 mmol, 0.1 equiv), xantphos (14.26 g, 24.8mmol, 0.2 equiv), CS2CO3 (121.5 g, 372 mmol, 3 equiv) in dioxane (930 ml) was stirred for 16 h at 100 °C. combined use-test batch (10 g) workup, the reaction mixture was quenched with H2O (5 L). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with salt water (1000 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3: l). This resulted in methyl (5aR.6S,7R,8R,8aS)-3- ((tert-butoxycarbonyl)amino)-8,8a-dihydroxy-l-methoxy-5a-(4-methoxyphenyl)-6-phenyl- 5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate (50 g, yield: 60%) as a light yellow solid.

[0204] Methyl (5aR,6S,7R,8R,8aS)-3-amino-8.8a-dihydroxy-l-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7- carboxylateLeydig 51588257

[0205] A mixture of methyl (5aR,6S,7R,8R,8aS)-3-((tert-butoxycarbonyl)amino)-8,8a-dihydroxy-l-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate (45 g, 77 mmol, 1 equiv) in TFA (1.3 L) and DCM (1.3 L) was stirred for 1 h at 30 °C. Combined 5 g (use test bathch) workup, The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / EA (1: 1). This resulted in methyl (5aR,6S,7R,8R,8aS)-3-amino-8,8a-dihydroxy-l-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4.5]furo[3,2-c]pyridine-7-carboxylate (25 g, yield: 60%) as a light yellow solid.

[0206] Methyl (5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxvlatePH-TROT-822-O

[0207] A mixture of methyl (5aR,6S,7R,8R,8aS)-3-amino-8,8a-dihydroxy-l-methoxy-5a-(4-methoxyphenyl)-6-phenyl-5a,7,8.8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate (20 g, 41.6 mmol, 1 equiv), chloroacetaldehyde (119 g. 625 mmol. 15 equiv. 40 wt% in H2O), DIEA (21.4 g, 167 mmol, 4 equiv) in EtOH (2.4 L) was stirred at 100 °C for 2 h. The mixture was concentrated under reduced pressure. Combined 5 g (use test batch) was purified by reverse phase column (0.5% TFA, ACN: 0-50% in 30 min) to afford methyl (5bS.6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b, 7,8,8a-Leydig 51588258tetrahydro-6H-cyclopenta[4.5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxylate (22 g, crude) as a light brown oil.

[0208] (5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl- 5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxylic acid17 ( Q1, active) 17 ( H1, inactive)

[0209] A mixture of methyl (5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxylate (14 g, 27.8 mmol, 1 equiv), Li OH (17.5 g, 437.5 mmol. 16 equiv), H2O (525 mL) in MeOH (1050 mL) was stirred for 1 h at 60 °C. The mixture was neutralized to pH 6 with IN HC1. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase column (10 mMNH4HCOs, ACN: 0-30% in 30 min) to afford 8 g mixture product as alight brown solid. The mixture was separated by SFC-HPLC with the following condition: Column: CHIRALPAK IG 3*25 cm, 5 um; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1%-FA); Flow rate: 85 mL / min; Gradient: isocratic 40% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wavelength: 220 nm; RTl(min): 4.38; RT2(min): 10.92; Sample Solvent: MeOH(FA); Injection Volume: 2 mL. The first eluting isomer (RT 4.38 min) was concentrated to afford (5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxylic acid (13.3 g of 17 used for SFC and 5 g of product was obtained, yield: 19.6% over 3 steps).Leydig 51588259

[0210] (5bS.6R.7R,8S,8aR)-5b.6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-A. A-dimethyl-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxamide (1-4)

[0211] A stirred solution of (5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxylic acid (5 g, 10.235 mmol, 1 equiv) in DMF (50 mL) was cooled to 0 °C. DIEA (2.64 g, 20.47 mmol, 2 eq), dimethylamine (50 mL, 2M in THF, 2.4 eq) was dropwised to the mixture. Then HATU (7.78 g, 20.47 mmol, 2 eq) was batch wised at 0 °C for 5 min. The resulting mixture was stirred for 30 min at 0 °C under N2 atmosphere. The reaction was monitored by LCMS. The reaction was quenched with 200 ml sat. NH4CI (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with water (4 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: AQ-C1850*250, 10 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 10% B to50 % B in 40 min; Wavelength: 254 nm / 220 nm; RRT: 38 min), The collected fraction was extracted with DCM (3*150 ml), The combined organic phase and washed with water (2*100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, Added MeOH (10 mL) and concentrate dry under reduced pressure to afford (5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-N, N-dimethyl-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxamide (2.5 g, yield: 47.37%) as an off-white solid.

[0212] LCMS: (ESI, m z): 516 [M+H]+. HNMR-PH-TRO-SDPC-2024-01-799-0A: 1H NMR (DMSO-6 / 6, 300MHZ), 5 (ppm): 7.59 (s. 1H), 7.35 (d, J= 1.2 Hz, 1H), 7.06-7.03 (m,Leydig 515882604H), 6.98-6.90 (m. 3H), 6.71 (s, 1H), 6.59 (s, 1H), 6.56 (s, 1H). 5.84 (s, 1H), 5.36-5.34 (d, J= 5.6 Hz, 1H), 4.56-4.66 (m, 2H), 4.31-4.25 (m, 4H), 3.58 (s, 3H), 3.30 (s, 3H), 2.81 (s, 3H).SYNTHESIS EXAMPLE 4

[0213] (l()S.llR.12R.13S.14R)-l().ll-diliydroxy-14-(4-iiiethoxyphenyl)-\,\-dimethyl-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca- 1.3.5.8- tetraeiie-12-carboxainide (1-5)1-5 A24

[0214] Step 7. (10S,llR,12R,13S,14R)-10,ll-dihydroxy-14-(4-methoxyphenyl)-13-phenyl-I5-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5.8-tetraene-12-carboxvlic acid

[0215] To a stirred solution A38 (racemic, 150 mg, 0.32 mmol, 1 equiv) in THF (6 mL), H2O (2 mL) was added LiOH (22.81 mg, 0.95 mmol, 3 equiv) in portions at 0 °C under air atmosphere. The resulting mixture was stirred for 1 h at room temperature under air atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with H2O (2 mL). The mixture was acidified to pH 5 with HC1 (aq. IM). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase. MeCN in Water (lOmmol / L NH4HCO3), 10% to 50% gradient in 40 min; detector. UV 220 nm. This resulted in (10S, 11 R,12R, 13S,14R)-10, 11 -dihydroxy-14-(4-methoxyphenyl)-l 3-phenyl-l 5-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14]]pentadeca-l,3,5,8-tetraene-12-carboxylic acid (120 mg, 82.45%) as a off-white solid. LCMS (ESI, m / z):459[M+H]+.Leydig 51588261

[0216] Step 8. (10S,l lR.12R,13S.14R)-10,l l-dihydroxy-14-(4-methoxyphenyl)-A, A-dimethyl-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene- 12-carboxamide

[0217] To a stirred solution of(10S, HR,12R,13S,14R)-10,ll-dihydroxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-12-carboxylic acid (105 mg, 0.23 mmol, 1 equiv) in DMF (6 mL) was added DIEA (118.40 mg, 0.92 mmol, 4 equiv), HATU (130.62 mg, 0.34 mmol, 1.5 equiv), dimethylamine (3 mL) at room temperature under air atmosphere. The resulting mixture was stirred for 1 h at room temperature under air atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 10% to 50% gradient in 40 min; detector, UV 254 nm. This resulted in (10S,l lR,12R,13S,14R)-10,ll-dihydroxy-14-(4-methoxypheny 1)-JV, A'-di methyl- 13-phenyl- 15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-12-carboxamide (90.0 mg). The product was purified by CHIRAL-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)— HPLC, Mobile Phase B: MeOH: EtOH=l: 1-HPLC; Flow rate: 20ML / MIN mL / min;Gradient: isocratic 50; Wavelength: 254 / 220nmnm; RTl(min): 3.355; Sample Solvent: EtOH— HPLC; Injection Volume: 1.6 mL; Number Of Runs: 4). The first eluting isomer (RT1 3.355) was concentrated and lyophilized to afford (1 OS, 11R,12R,13S,14R)-1O,11-dihydroxy-14-(4-methoxyphenyl)-N, N-dimethyl-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{ 10,14}]pentadeca-l,3,5,8-tetraene-12-carboxamide (1-5, 44.4 mg, 39.77%) as a as a white solid. The second eluting isomer(RT=7.489min) was concentrated and lyophilized to afford (10R,llS,12S,13R,14S)-10,ll-dihydroxy-14-(4-methoxyphenyl)-N, N-dimethyl-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-12-carboxamide (A-24, 40.1 mg, 36.03%) as a white solid. LCMS (ESI, m / z):486[M+H]+.

[0218] 1-5: 'H-NMR (DMSO-tfc, 400 MHz) 5 (ppm): 8.76 (s,lH), 8.18-8.16 (m, 1H), 7.81-7.78 (m, 1H), 7.39 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.08-7.00 (m, 3H), 7.85 (d, J = 7.2 Hz. 2H), 6.73 (d, J= 8.8 Hz. 2H), 6.02-5.98 (m. 2H), 4.97 (d, J= 4.0 Hz. 1H), 4.26 (d. J = 12.8 Hz, 1H), 4.12-4.07 (m, 1H), 3.67 (s, 3H). 3.21 (s, 3H). 2.74 (s. 3H). LCMS (ESI, m / z): 486[M+H]+.Leydig 51588262

[0219] A24: ‘H-NMR (DMSO-rfe. 400 MHz) 5 (ppm): 8.73 (s,lH). 8.13 (s, 1H), 7.76 (d..7= 2.0 Hz, 1H), 7.35 (s, 1H), 7.13 (d, J= 9.2 Hz, 2H), 7.08-7.00 (m, 3H), 7.85 (d,,7= 6.8 Hz, 2H), 6.72 (d, J= 8.8 Hz, 2H), 5.96 (d, J= 8.8 Hz, 2H), 4.98-4.95 (m, 1H), 4.26 (d, J= 12.4 Hz, 1H), 4.11-4.06 (m, 1H), 3.67 (s, 3H), 3.21 (s, 3H), 2.74 (s, 3H). LCMS (ESI, m / z):486[M+H]+.SYNTHESIS EXAMPLE 5

[0220] (5bS,6R,7S,8S,8aR)-7-((dimethylamino)methyl)-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-6,7,8,8a-tetrahydro-5bH-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-5b,6-diol (A25; A26 and 1-16)BH3-THF THFRacemic, 1-4Chiral separation

[0221] (10S.l lR,12S.13S,14R)-12-[(dimethylamino)methyl]-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo [7.6.0.0A{3,7}.0A{10,14}]pentadeca- 1.3.5.8-tetraene- 10, 11 -diol

[0222] Add (10S,llR,12R,13S,14R)-10,ll-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-N, N-dimethyl-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca- 1.3.5.8-tetraene-12-carboxamide (racemic, 20 mg, 0.04 mmol, lequiv) in BH3-Me2S(10 N, 58.19 uL, 0.58 mmol, 15 equiv) in THF(2 mL). The reaction mixture was stirred for 3h at 40°C under nitrogen atmosphere, after add MeOH (3 mL) was stirred for overnight at 65°C.Leydig 51588263LCMS indicated the reaction was completed. The solvent was removed under reduced pressure. The solid was purified by flash chromatography with the following conditions: (Column: Xselect CSH Prep C18 Column, 30*250 mm, 10pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 2% B to21 % B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 8.5). The collected fraction was lyophilized to afford A25 (5.0 mg, 25.57%) as an off-white solid. LCMS (ESI, m / z):502[M+H]+'H NMR (400 MHz, DMSO-O 5 8.24 (s, 1H), 7.57 (s, 1H), 7.31 (s, 1H), 7.09-6.98 (m, 7H), 6.63 (s, 1H), 6.57 (d, J= 8.8 Hz, 2H), 5.79 (s, 1H), 4.45 (d, J= 3.6 Hz, 1H), 4.35 (s, 3H), 3.86 (d. J= 11.2 Hz, 1H), 3.56 (s, 3H), 3.27-3.21 (m, 1H),3.17(S,1H) 2.73-2.65 (m, 1H), 2.28 (s, 6H), 2.11-2.08 (m, 1H).

[0223] This product was scaled up to aim to separate the enantiomers.

[0224] The racemic product (A25, 26 mg) was separated by prep-CHlRAI. HPIX' with the following conditions (Column: CHIRALPAK IG, 2*25 cm. 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 40; Wave Length: 254 / 220nmnm; RTl(min): 4.606; RT2(min): 6.378; Sample Solvent: EtOH— HPLC; Injection Volume: 1.0 mL; Number Of Runs: 3) The first eluting isomer (RT 4.606 min) was concentrated and lyophilized to 1-16 (2.0 mg, 8.15%). The second eluting isomer (RT 6.378 min) was concentrated and lyophilized to A26 (3.8 mg, 15.05%) as a solid.

[0225] 1-16: LCMS (ESI, m / z): 502[M+H]+ JH NMR (400 MHz, DMSO-6) 5 8.25 (s, 1H), 7.59 (s, 1H), 7.34 (s, 1H), 7.11-7.07 (m, 4H), 7.10-7.01 (m, 3H),6.73 -6.58 (m, 3H), 5.55 (s, 1H), 4.47 (s, 1H). 4.37 (s. 3H), 3.86 (d. J= 13.6 Hz, 1H), 3.58 (s, 3H), 3.33-3.19 (m, 1H), 2.75-2.67 (m, 1H), 2.28 (s, 6H), 2.12-2.09 (m, 1H).

[0226] A26: LCMS (ESI, m / z):502 [M+H]+ 1H NMR (400 MHz, DMSO- e) 57.58 (s, 1H), 7.34 (d, J= 1.2 Hz, 1H), 7.10-6.99 (m, 7H), 6.64 (s, 1H), 6.59-6.57 (m, 2H), 5.78 (s, 1H), 4.44 (d, J= 4.0 Hz, 1H), 4.37 (s, 3H), 3.85 (d, J= 14.0 Hz, 1H), 3.58 (s, 3H), 3.17 (d. J = 3.2 Hz. 1H). 2.67 (d. J= 11.2 Hz. 1H), 2.22 (s, 6H), 2.02-1.99 (m, 1H).SYNTHESIS EXAMPLE 6

[0227] (10S,llR,12S,13S,14R)-12-(hydroxymethyl)-8-methoxy-14-(4-methoxy phenyl)- 13-phenyl- 15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3^,8-tetraene-10,ll-diol (1-15 and A28)Leydig 515882641-15 A28

[0228] To a stirred mixture of methyl (10S,llR,12R,13S,14R)-10,ll-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-12-carboxylate (racemic, 50 mg, 0.099 mmol, 1 equiv) in THF (1 mL) were added LiBITi (500 uL, IN in THF, 0.50 mmol, 5.00 equiv) at 0 °C. The resulting mixture was stirred for 1 h at 50 °C. Desired product could be detected by LCMS. The reaction was quenched with sat. NFUCl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with deionized water (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 40% gradient in 30 min; detector, UV 254 nm. The crude product was purified by Chiral-HPLC with the following conditions (Column: CHIRALPAKIG3; Mobile Phase A: Hex: (EtOH: DCM=l:l)=50:50; Flow rate: ImL / min mL / min; Gradient: isocratic; Injection Volume: I pL mL), The first eluting isomer (Retention time=1.176 min) was concentrated and lyophilized to afford (10S.llR,12S,13S.14R)-12-(hydroxymethyl)-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7[.0A{10,14}]pentadeca-l,3,5,8-tetraene-10,l 1-diol (I-15, 1.8 mg, 3.64%) as a light pink solid. The second eluting isomer (Retention time=2.169 min) was concentrated and lyophilized to afford (10R,llS,12R,13R,14S)-12-(hydroxymethyl)-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-10,ll-diol (A28, 2.0 mg, 4.07%) as a light pink solid.

[0229] A28:1H NMR (400 MHz, DMSO-rL) 57.59 (s, 1H), 7.34 (s, 1H), 7.12 - 6.96 (m, 7H), 6.65 (s, 1H), 6.58 (d, J= 9.0 Hz, 2H), 5.76 (s, 1H), 5.28 (d, J = 5.1 Hz, 1H). 4.57 - 4.48 (m. 2H), 4.38 (s, 3H), 3.86 (d, J= 14.2 Hz, 1H). 3.65 - 3.59 (m, 1H). 3.58 (s. 3H), 3.51 -3.44 (m, 1H), 3.25 - 3.16 (m, 1H). LCMS (ESI, m / z): 475 [M+H]+.Leydig 51588265

[0230] 1-15: 'H NMR (400 MHz, DMSO-d6) 57.59 (s, 1H), 7.34 (s, 1H). 7.11 - 6.98 (m, 7H), 6.65 (s, 1H), 6.58 (d,,7= 9.0 Hz, 2H), 5.77 (s, 1H), 5.28 (d,. / = 5,l Hz, 1H), 4.57 - 4.49 (m, 2H), 4.38 (s, 3H), 3.86 (d, J= 14.1 Hz, 1H), 3.63 - 3.59 (m, 1H), 3.58 (s, 3H), 3.51 -3.44 (m, 1H), 3.24 - 3.16 (m, 1H). LCMS (ESI, m / z): 475 [M+H]+.SYNTHESIS EXAMPLE 7

[0231] (10S,llR42R,13S,14R)-12-(4,4-difluoropiperidine-l-carbonyl)-8-methoxy- 14-(4-methoxyphenyl)- 13-phenyl- 15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-10,ll-diol (1-11)

[0232] To a stirred solution of (10S,llR,12R,13S,14R)-10,ll-dihydroxy-8-methoxy-14-(4-methoxy phenyl)- 13-pheny 1- 15 -oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-12-carboxylic acid (chiral. 25 mg. 0.05 mmol. 1 equiv) and HATU (29 mg. 0.08 mmol, 1.5 equiv) in DMF (1 mL) was added DIEA (26 mg, 0.20 mmol, 4 equiv) dropwise at 0 °C under air atmosphere. The resulting mixture was stirred for 30 min at room temperature under air atmosphere. The reaction was monitored by LCMS. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with CH2CI2 (5 x 3 mL). The combined organic layers were washed with water (5 x 2 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C 18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10nmol / LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 28% B to 58% B in 10 min; Wavelength: 254nm / 220nm nm; RTl(min): 8.38. The collected fraction was lyophilized to afford (10S,llR,l 2R, 13 S, 14R)- 12-(4,4-difluoropiperidine- 1 -carbony l)-8-methoxy- 14-(4-Leydig 51588266methoxyphenyl)- 13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A] 3, 7}.0A{ 10.14 []pentadeca-l,3,5,8-tetraene-10,l 1 -diol (4.3 mg, 13.73%) as a white solid.

[0233] LCMS (ESI, m / z):592[M+H]+. 'H-NMR (DMSO-6, 400 MHz) 5 (ppm): 7.61 (s,lH), 7.37 (s, 1H), 7.09-7.03 (m, 4H), 6.97-6.93 (m, 3H), 6.74 (s, 1H), 6.59 (d, J= 8.8 Hz, 2H), 5.85 (s, 1H), 5.51 (d, J= 5.6 Hz, 1H), 4.62-4.61 (m, 2H), 4.39-4.35 (m, 1H), 4.30 (s, 3H), 3.92 (s, 2H), 3.68-3.62 (m, 1H), 3.60 (s, 3H), 3.52 (s, 1H), 2.22 (s, 2H), 1.91 (s, 2H). LCMS (ESI, m / z):592[M+H]+.SYNTHESIS EXAMPLE 8

[0234] (5bS,6R,7S,8S,8aR)-7-((4,4-difluoropiperi(line)methyl)-5-methoxy-8a-(4-methoxyDlienyl)-8-nheiiyl-6.7.8,8a-tetrahvdro-5bH-cvcloDenta|4.5|fiiro|2,3-d]imidazo[l.,2-a]pyridine-5b.6-diol (1-23)BH3-Me2S(15 eq) THF (10 V) 0-rt, 3 h

[0235] Add (10S, 11R,12R,13S,14R)-1O,1 l-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-4,4-difluoropiperidine -13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]-pentadeca-l,3,5,8-tetraene-12-carboxamide(Chiral, 40 mg, 0.068 mmol, 1 equiv) in BH--Me2S(10 N, 0.1 ml, 1.0 mmol. 15 equiv) in THF(0.5 mL). The reaction mixture was stirred for 3 h at room temperature under nitrogen atmosphere, after add MeOH (3 mL), was stirred overnight at 65 °C. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure. The crude was purified by Prep-HPLC with the following conditions: (Column: AQ-C18 Column, 30*250 mm. 10pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 0% B to 30 % B in 30 min; Wavelength: 254nm / 220nm nm;). The collected fraction was adjusted pH=8 with NaHCOs and extracted with DCM (5*3). The combined organic phase and washed with water (5 mL*2), dried over anhydrous Na2SOr. After filtration, the filtrate was concentratedLeydig 51588267under reduced pressure. Added MeOH (1 mL) and concentrate dry under reduced pressure to afford (5bS,6R,7S,8S,8aR)-7-((4,4-difluoropiperidine)methyl)methyl)-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-6,7,8,8a-tetrahydro-5bH-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-5b,6-diol (11.53 mg, LCAP: 98.65%, yield: 30%) as a white solid.

[0236] LCMS (ESI, m / z): 578[M+H]+'H NMR (400 MHz, DMSO-t / e): 57.588 (t, J = 1.1 Hz, 1H), 7.335 (d, J = 1.4 Hz, 1H), 7.120 - 7.067 (m, 4H), 7.030- 6.971 (m, 3H), 6.654 (s, 1H), 6.593-6.570 (m, 2H), 5.787 (s, 1H), 5.249-5.236 (d, J = 5.2 Hz, 1H), 4.452-4.430 (t, J = 4.4 Hz, 1H), 4.356 (s, 3H), 3.862-3.827 (d, J = 14 Hz, 1H), 3.580 (s, 3H), 3.323 - 3.277 (m, 1H), 2.757-2.700 (m, 3H), 2.504-2.467 (m, 1H), 2.186-2.149 (m, 1H), 1.988-1.957 (br, 4H).SYNTHESIS EXAMPLE 9

[0237] ((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)(morpholino)methanone (1-8 and A29)1-8 A29Asolution of (1 OS, 11R,12R,13S,14R)-10,1 l-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14]]pentadeca-l,3,5,8-tetraene-12-carboxylic acid (racemic, 30 mg, 0.061mmol, lequiv), HATU (35 mg, 0.091mmol, 1.5equiv) in DMF (3 mL) was treated with morpholine (8 mg, 0.12mmol, 2equiv) for 1 min at room temperature under nitrogen atmosphere followed by the addition of DIEA (39 mg, 0.31mmol, 5equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at roomLeydig 51588268temperature under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The aqueous layer was extracted with EtOAc (2x20 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: (Column: Xselect CSH Prep C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 2% B to31 % B in 10 min; Wavelength: 254nm / 220nm nm: RTl(min): 8.5) to afford the racemic title compound (10 mg, 31%) as a yellow solid. This product was submitted to chiral HPLC purification, using the following conditions: Column:CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1: 1— HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 60; Wavelength: 254 / 220nm nm; RTl(min): 5.298; RT2(min): 9.647; Sample Solvent: EtOH— HPLC; Injection Volume: 1.5 mL; Number Of Runs: 1; The first eluting isomer was concentrated and lyophilized to afford ((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)(morpholino)methanone (1-8, 2.2 mg, 9%) as a white solid. The second eluting isomer was concentrated and lyophilized to afford ((5bR,6S,7S,8R,8aS)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)(morpholino)methanone (A29, 2.5 mg, 11.34%) as a white solid.

[0238] 1-8: 'H-NMR (DMSO-tfc, 400 MHz) 5 (ppm): 57.60 (s, 1H), 7.35 (d, J= 1.2 Hz, 1H), 7.06 - 7.02 (m, 4H), 6.94 - 6.92 (m, 3H), 6.73 (s, 1H), 6.59 (d, J= 8.8 Hz, 2H), 5.81 (s, 1H), 5.43 (d, J= 6.0 Hz, 2H), 4.63 - 4.54 (m, 2H), 4.37 - 4.32 (m, 1H), 4.29 (s, 3H). 3.96 -3.94 (m, 1H), 3.81 - 3.59 (m, 5H). 3.58 (s, 3H). 3.53 - 3.44 (m. 2H). LCMS (ES, m / z): 558 [M+H]+

[0239] A29: ‘H-NMR (DMSO-dfc, 400 MHz) 5 (ppm): 57.60 (s, 1H), 7.36 (d, J= 1.2 Hz, 1H), 7.06 - 7.02 (m, 4H), 6.94 - 6.92 (m, 3H), 6.73 (s, 1H), 6.58 (d, J= 8.8 Hz, 2H), 5.80 (s, 1H), 5.43 (d, J= 5.6 Hz, 2H), 4.63 - 4.57 (m, 2H), 4.34 - 4.29 (m, 4H), 4.04 - 3.91 (m, 1H), 3.82 - 3.69 (m, 3H), 3.69 - 3.61 (m, 2H), 3.58 (s, 3H), 3.53 - 3.42(m, 2H). LCMS (ES, m / z): 558 [M+H]+SYNTHESIS EXAMPLE 10Leydig 51588269(5bS,6R,7S.8S,8aR)-7-((Morpholinyl methyl)-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-6,7.,8.,8a-tetrahvdro-5bH-cvclopenta[4,5]furo[2.,3-d]imidazon.,2-a]pyridine-5b,6-diol (Racemic, A35)BH3-Me2S(15 eq)THF (10 V)O-rt, 3 hAdd (10S, HR,12R,13S,14R)-10,l l-dihydroxy-8-methoxy-14-(4-methoxyphenyl)- 4,4-difluoropiperidine -13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]-pentadeca-l,3,5,8-tetraene-12-carboxamide(racemic, 35 mg, 0.06 mmol, 1 equiv) in BH3-Me2S(10 N, 0.1 ml, 1.0 mmol, 15 equiv) in THF(0.5 mL). The reaction mixture was stirred for 3 h at room temperature under nitrogen atmosphere, after adding MeOH (3 mL), was stirred overnight at 65 °C. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure. The crude was purified by Prep-HPLC with the following conditions: (Column: AQ-C18 Column, 30*250 mm. 10pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 0% B to 30 % B in 30 min; Wavelength: 254nm / 220nm run;). The collected fraction was adjusted pH=8 with NaHCCh and extracted with DCM (5*3). The combined organic phase and washed with water (5 mL*2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Added MeOH ( 1 mL) and concentrate dry under reduced pressure to afford (5bS,6R,7S,8S,8aR)-7-((Morpholinyl)methyl)methyl)-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-6,7,8,8a-tetrahydro-5bH-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-5b,6-diol (13.57 mgs. LCAP: 99.1%. yield: 40%) as a white solid (free base).

[0240] LCMS (ESI, m / z): 558[M+H]+'H NMR (400 MHz, DMSO-rfe): 57.588 (s, 1H), 7.335 (s, 1H), 7.109-7.069 (m, 4H), 7.027-6.973 (dd, J=14.4, 7.2 Hz, 3H), 6.654 (s, 1H), 6.590-6.567 (d, J=9.2Hz, 2H), 5.783 (s, 1H), 5.296-5.223 (br, 1H), 4.439 (s, 1H), 4.359 (s, 3H), 3.872-3.837 (d, J = 14.0 Hz, 1H). 3.660-3.578 (m, 7H), 3.323-3.261 (m. 1H), 2.707-2.650 (m, 1H). 2.504 (br, 2H). 2.330 (br, 2H). 2.111-2.086 (m, 1H).SYNTHESIS EXAMPLE 11Leydig 51588270

[0241] ((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)(3-fluoroazetidin-l-yl)methanone (1-6 and A30)

[0242] A solution of(10S,llR,12R,13S,14R)-10,ll-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-12-carboxylic acid (racemic, 30 mg, 0.061mmol, lequiv), HATU (35 mg, 0.091 mmol, 1.5equiv) in DMF (3 mL) was treated with 3 -fluoroazetidine (9 mg, 0.122mmol, 2equiv) for 1 min at room temperature under nitrogen atmosphere followed by the addition of DIEA (40 mg. 0.305mmol, 5equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The aqueous layer was extracted with EtOAc (2x20 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 3% B to33 % B in 10 min; Wavelength: 254nm / 220nm nm; RTl(min): 8.5). The collected fraction was concentrated to afford the racemic title compound (12 mg, 34%) as a yellow solid. LCMS (ES, m / z): 546 [M+H]+This product was submitted to chiral HPLC purification, using the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1: 1— HPLC; Flow rate: 20ML / MIN mL / min; Gradient:Leydig 51588271isocratic 60; Wavelength: 254 / 220nmnm; RTl(min): 4.212; RT2(min): 7.067; Sample Solvent: EtOH— HPLC; Injection Volume: 1.5 mL; Number Of Runs: 1; The first eluting isomer was concentrated and lyophilized to afford ((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)(3-fluoroazetidin-l-yl)methanone (1-6, 4 mg, 11.09%) as a white solid. The second eluting isomer was concentrated and lyophilized to afford ((5bR,6S,7S,8R,8aS)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetr ahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyri din-7-yl)(3-fluoroazeti din-1 -yljmethanone (A30, 2.7 mg, 7.91%) as a white solid.

[0243] 1-6: LCMS (ES, m / z): 546 [M+H]+H-NMR (DMSO- e. 400 MHz) 5 (ppm): 6 7.59 (s, 1H), 7.35 (d, J= 1.2 Hz, 1H), 7.06 - 6.93 (m, 7H), 6.71 (s, 1H), 6.58 (d, J= 1A Hz, 2H), 5.81 (s, 1H), 5.62 - 5.35 (m, 2H), 4.78 - 4.51 (m, 3H), 4.51 - 4.37 (m, 1H), 4.32 (s, 3H), 4.27 - 4.11 (m. 1H), 3.99 - 3.84 (m, 2H), 3.58 (s, 3H).

[0244] A30: ‘H-NMR (DMSO-<*. 400 MHz) 5 (ppm): 67.59 (s, 1H), 7.35 (d, J= 1.2 Hz, 1H), 7.06 - 6.93 (m, 7H), 6.71 (s, 1H), 6.58 (d, J= 7.4 Hz, 2H), 5.81 (s, 1H), 5.59 - 5.38 (m, 2H), 4.74 - 4.51 (m, 3H), 4.51 - 4.37 (m, 1H), 4.32 (s, 3H), 4.19 - 4.14 (m, 1H), 3.99 - 3.83 (m, 2H), 3.58 (s, 3H). LCMS (ES, m / z): 546 [M+H]+SYNTHESIS EXAMPLE 12

[0245] (5bS,6R,7S,8S,8aR)-7-((3-fluoroazetidinyl methyl)-5-methoxy-8a-(4-methoxyphenvD-8-phenyl-6,7,8,8a-tetrahvdro-5bH-cvclopenta[4,51furo[2,3-d]imidazoH,2-a]pyridine-5b,6-diol (1-21)

[0246] Add (1 OS, 11 R, 12R, 13 S, 14R)- 10,11 -dihydroxy-8-methoxy-l 4-(4-methoxyphenyl)- 3-fluoroazetidinyl -13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]-pentadeca-l,3,5,8-tetraene-12-carboxamide(45 mg, 0.08 mmol. 1 equiv) in BH3-Me2S(10 N,Leydig 515882720.12 ml, 1.2 mmol. 15 equiv) in THF(0.5 mL). The reaction mixture was stirred for 3 h at room temperature under nitrogen atmosphere, after adding MeOH (3 mL), was stirred overnight at 65 °C. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure. The crude was purified by Prep-HPLC with the following conditions: (Column: AQ-C18 Column, 30*250 mm, 10pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 0% B to 30 % B in 30 min; Wavelength: 254nm / 220nm nm;). The collected fraction was adjusted pH=8 with NaHCCh and extracted with DCM (5*3). The combined organic phase and washed with water (5 mL*2), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. Added MeOH (1 mL) and concentrate dry under reduced pressure to afford (5bS,6R,7S,8S,8aR)-7-((3-fluoroazetidinyl)methyl)methyl)-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-6.7.8.8a-tetrahydro-5bH-cyclopenta[4.5]furo[2,3-d]imidazo[l,2-a]pyridine-5b,6-diol (11.7 mgs, LCAP: 97.6%, yield: 26%) as a white solid (free base).

[0247] LCMS (ESI, m / z): 532[M+H]+'H NMR (400 MHz, DMSO-rfe): 57.399 (s, 1H), 7.213 - 7.210 (d, J =1.2 Hz, 1H), 7.156 - 7.075 (m, 5H), 6.957 - 6.940 (m, 2H), 6.648 -6.618 (m, 2H), 6.556 (s, 1H), 5.005 - 4.848 (m, 2H), 4.709 - 4.698 (d, J = 4.4 Hz, 1H), 4.485 4.446 (s, 3H), 4.015-3.979 (d, J = 14.4 Hz, 1H), 3.709 - 3.610 (m, 5H). 3.245 - 3.175 (m, 1H), 3.086 - 3.012 (m, 2H), 2.973 - 2.825 (m, 2H).SYNTHESIS EXAMPLE 13

[0248] (3-Methoxyazetidin-l-yl)((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a- (4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)methanone (1-22)DIEA (3 eq.) HOBt (1.5 eq.) EDC (1.5 eq.) DMF (10 V) 0 °C, 16 h

[0249] A solution of(10S, HR,12R,13S,14R)-10,ll-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-Leydig 51588273l,3,5,8-tetraene-12-carboxylic acid (Chiral, 100 mg, 0.18mmol, lequiv), HOBt (36 mg, 0.27mmol, 1.5equiv), EDC (42 mg, 0.27mmol, 1.5equiv) in DMF (30 mL) was treated with 3 -methoxy azetidine (36 mg, 0.36mmol, 2equiv) for 1 min at room temperature under nitrogen atmosphere followed by the addition of DIEA (117 mg, 0.9mmol, 5equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The aqueous layer was extracted with EtOAc (2x50 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xbridge Prep OBD C18 Column, 19*250 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HCO3). Mobile Phase B: ACN; Flow rate: 25mL / min mL / min;Gradient: 20% B to41 % B in 10 min; Wavelength: 254nm / 220nm nm). The collected fraction was lyophilized to afford (3-methoxyazetidin-l-yl)((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)methanone (1-22, 50 mg. 41%) as a white solid.

[0250] 1-22: 1H-NMR (400 MHz, Chloroform-d, ppm): 57.398 - 7.365 (d, J = 13.2 Hz, 1H), 7.263 - 7.0396 (m, 6H), 6.968 -6.926 (t, J = 8 Hz, 2H), 6.669 - 6.637 (dd, J = 9.2, 4 Hz, 2H), 6.602 - 6.564 (d, J = 15.2 Hz, 1H), 4.732 -4.627 (m, 3H), 4.412 - 4.396 (d, J = 6.4 Hz, 3H), 4.352 - 4.259 (m. 2H), 4.109 - 3.978 (m, 1H). 3.867 - 3.740 (dt, J = 13.9, 4.9 Hz, 2H).3.678 - 3.671 (d, J = 2.8 Hz, 3H), 3.400 - 3.348 (s, 3H).SYNTHESIS EXAMPLE 14

[0251] (5bS,6R,7S,8S,8aR)-7-((3-methoxyazetidinyl methyl)-5-methoxy-8a-(4-methoxyphenyI)-8-phenyl-6,7,8,8a-tetrahydro-5bH-cycIopenta[4,5]furo[2,3-d] imidazo [ 1,2-a] pyridine-5b,6-diol (1-20)BH3«Me2S (15 eq.) THF (10 V) O-rt, 3 h1-20O. O.Leydig 51588274

[0252] Add (10S,llR,12R,13S,14R)-10,ll-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-3-methoxyazetidinyl-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]-pentadeca-l,3,5,8-tetraene-12-carboxamide(43.3 mg, 0.078 mmol, 1 equiv) in BH3-Me2S(10 N, 0.12 ml, 1.2 mmol, 15 equiv) in THF(0.5 rnL). The reaction mixture was stirred for 3 h at room temperature under nitrogen atmosphere, after adding MeOH (3 mL), wasstirred overnight at 65 °C. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure. The crude was purified by Prep-HPLC with the following conditions: (Column: AQ-C18 Column, 30*250 mm, 10pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 0% B to 30 % B in 30 min; Wavelength: 254nm / 220nm nm;). The collected fraction was adjusted pH=8 with NaHCCh and extracted with DCM (5*3), The combined organic phase and washed with water (5 mL*2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Added MeOH (1 mL) and concentrate dry under reduced pressure to afford (5bS,6R,7S,8S,8aR)-7-((3-methoxyazetidinyl)methyl)methyl)-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-6,7,8,8a-tetrahydro-5bH-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-5b,6-diol (11.7 mgs, LCAP: 95.2%, yield: 27%) as a white solid (free base).

[0253] LCMS (ESI, m / z): 544[M+H]+'H NMR (400 MHz, DMSO-rfe): 57.442(s.lH), 7.292 (s, 1H), 7.263-7.125 (m, 4H), 7.103-7.063 (m, 1H), 7.045-6.971 (m, 2H), 6.667 (s, 1H), 6.637 (s,lH), 6.615 (s, 1H), 4.720-4.072 (d, J = 14 Hz, 1H), 4.455 (s, 3H), 4.107-4.072 (d, J=14Hz, 1H), 3.873-3.829 (m, 1H), 3.655-3.608 (m, 5H), 3.130 (s, 3H), 3.116-3.023 (m, 2H), 2.994-2.949 (m, 2H), 2.941-2.606 (m, 1H).SYNTHESIS EXAMPLE 15

[0254] ((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)(pyirolidin-l-yl)methanone (1-9 and A31)Leydig 515882751-9 A31

[0255] A solution of(10S. HR,12R.13S,14R)-10.11-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-12-carboxylic acid (racemic, 30 mg, 0.061mmol, lequiv), HATU (35 mg, 0.091mmol, 1.5equiv) in DMF (3 mL) was treated with pyrrolidine (7 mg, 0.12mmol, 2equiv) for 1 min at room temperature under nitrogen atmosphere followed by the addition of DIEA (39 mg, 0.31mmol, 5equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The aqueous layer was extracted with EtOAc (2x20 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to35 % B in 10 min; Wavelength: 254nm / 220nm nm; RTl(min): 8.5) to afford the racemic title compound (10 mg, 30%) as a yellow solid. LCMS (ES, m / z): 542 [M+H]+This product was submitted to chiral HPLC purification, using the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1: 1- HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 60; Wavelength: 254 / 220nm nm; RTl(min): 5.091; RT2(min): 8.999; Sample Solvent: EtOH--HPLC; Injection Volume: 1.5 mL; Number Of Runs: 1; The first eluting isomer was concentrated and lyophilized to afford ((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-Leydig 51588276tetrahydro-6H-cyclopenta[4.5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)(pyrrolidin-l-yl)methanone (1-9, 3.1 mg, 10%) as a white solid. The second eluting isomer was concentrated and lyophilized to afford ((5bR,6S,7S,8R,8aS)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)(pyrrolidin-l-yl)methanone (A31. 3.1 mg, 10%) as a white solid.

[0256] 1-9: 'H-NMR (DMSO-^6, 400 MHz) 5 (ppm): 57.59 (s, 1H), 7.35 (d, J= 1.2 Hz, 1H), 7.06 - 7.02 (m, 4H), 6.97 - 6.90 (m, 3H), 6.71 (s, 1H), 6.59 (d, J= 9.2 Hz, 2H), 5.81 (s, 1H), 5.29 (d, J = 5.2 Hz, 1H), 4.68 - 4.65 (m, 1H), 4.61 - 4.57 (m, 1H), 4.31 (s, 3H). 4.14 -4.09 (m, 1H), 3.95 - 3.83 (m, 1H). 3.73 - 3.70 (m, 1H). 3.58 (s. 3H), 3.28 - 3.25 (m. 2H), 2.02 - 1.98 (m, 2H), 1.83 - 1.79 (m, 2H). LCMS (ES, m / z): 542 [M+H]+

[0257] A31: ‘H-NMR (DMSO-t / e, 400 MHz) 5 (ppm): 57.59 (s, 1H), 7.35 (d, J= 1.2 Hz, 1H), 7.06 - 7.02 (m, 4H), 6.97 - 6.90 (m, 3H), 6.72 (s, 1H). 6.59 (d, J= 8.8 Hz, 2H). 5.81 (s, 1H), 5.29 (d, J= 5.6 Hz. 1H), 4.68 - 4.65 (m, 1H), 4.61 - 4.57 (m, 1H), 4.31 (s, 3H). 4.14 -4.09 (m, 1H), 3.95 - 3.91 (m, 1H), 3.73 - 3.70 (m, 1H), 3.58 (s, 3H), 3.28 - 3.25 (m, 2H), 2.02 - 1.99 (m, 2H), 1.83 - 1.79 (m, 2H). LCMS (ES, m / z): 542 [M+H]+SYNTHESIS EXAMPLE 16

[0258] Azetidin-l-yl((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyI)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cycIopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)methanone (1-7 and A32)Leydig 515882771-7 A32

[0259] A s olution of ( 10 S, 11 R, 12R, 13 S, 14R)- 10, 11 -dihy droxy -8 -methoxy -14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10.14}]pentadeca-l,3,5,8-tetraene-12-carboxylic acid (racemic, 30 mg, 0.061mmol, lequiv), HATU (35 mg, 0.091mmol, 1.5equiv) in DMF (3 mL) was treated with azetidine (7 mg, 0.122mmol, 2equiv) for 1 min at room temperature under nitrogen atmosphere followed by the addition of DIEA (40 mg. 0.305mmol, 5equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The aqueous layer was extracted with EtOAc (2x20 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 Column, 30*150 mm. 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min rnL / min; Gradient: 3% B to33 % B in 10 min; Wavelength: 254nm / 220nm nm; RTl(min): 8.5) to afford the racemic title compound (11 mg, 31%) as a yellow solid. LCMS (ES, m / z): 528 [M+H]+This product was submitted to chiral HPLC purification, using the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1: 1- HPLC; Flow?rate: 20ML / MIN mL / min; Gradient: isocratic 60; Wavelength: 254 / 220nmnm; RTl(min): 4.468; RT2(min): 7.886; Sample Solvent: EtOH— HPLC; Injection Volume: 1.5Leydig 51588278mL; Number Of Runs: 1; The first eluting isomer was concentrated and lyophilized to afford azetidin-l-yl((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)methanone (1-7, 3.5 mg, 10.13%) as a white solid. The second eluting isomer was concentrated and lyophilized to afford azetidin-l-yl((5bR,6S,7S,8R,8aS)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)methanone (A32, 3.7 mg, 11.34%) as a white solid.

[0260] 1-7: 'H-NMR (DMSO-6, 400 MHz) 5 (ppm): 57.59 (s, 1H), 7.35 (d, J= 1.2 Hz, 1H), 7.08 - 6.92 (m, 7H), 6.71 (s, 1H), 6.58 (d, J= 8.8 Hz, 2H), 5.81 (s, 1H). 5.37 (d, J= 4.8 Hz. 2H), 4.59 - 4.51 (m. 3H), 4.41 - 4.35 (m. 1H), 4.32 (s, 3H), 3.93 - 3.82 (m, 3H). 3.58 (s, 3H), 2.33 - 2.23 (m, 3H). LCMS (ES, m / z): 528 [M+H]+

[0261] A32: 'H-NMR (DMSO-C76, 400 MHz) 5 (ppm): 57.59 (s, 1H), 7.35 (d, J= 1.2 Hz, 1H), 7.08 - 6.92 (m, 7H), 6.71 (s, 1H), 6.58 (d, J= 9.2 Hz, 2H), 5.81 (s, 1H), 5.37 (d, J = 5.2 Hz. 2H), 4.57 - 4.51 (m. 3H), 4.39 - 4.37 (m, 1H), 4.32 (s, 3H), 3.93 - 3.82 (m, 3H). 3.58 (s, 3H), 2.32 - 2.23 (m, 3H). LCMS (ES, m / z): 528 [M+H]+SYNTHESIS EXAMPLE 17

[0262] (3,3-difluoroazetidin-l-yl)((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy- 8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a] pyridin-7 -yl)methanone (1-13)F F HATU, DIEA, DMFrt 1h

[0263] A solution of(10S, HR,12R,13S,14R)-10,ll-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-12-carboxyhc acid (Chiral, 30 mg, 0.061mmol, lequiv), HATU (35 mg, 0.091mmol, 1.5equiv) in DMF (3 mL) was treated with 3,3-difluoroazetidine (12 mg, 0.12mmol, 2equiv) for 1 min at room temperature under nitrogen atmosphere followed byLeydig 51588279the addition of DIEA (39 mg, 0.31mmol, 5equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The aqueous layer was extracted with EtOAc (2x20 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xbridge Prep OBD C18 Column, 19*250 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25mL / min mL / min; Gradient: 20% B to41 % B in 10 min; Wavelength: 254nm / 220nm nm; RTl(min): 8.68). The collected fraction was lyophilized to afford (3.3-difluoroazetidin-l-yl)((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7.8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)methanone (3.2 mg, 11%) as a white solid.

[0264] 1-13: ‘H-NMR (DMSO-i / e, 400 MHz) 5 (ppm): 57.60 (s, 1H), 7.36 (d, J= 0.8 Hz, 1H), 7.07 - 7.00 (m, 4H), 6.97 - 6.94 (m, 3H), 6.72 (s, 1H). 6.58 (d, J= 8.8 Hz, 2H). 5.79 (s, 1H), 5.52 (d, J= 5.2 Hz. 1H), 5.29 - 5.02 (m, 1H), 5.01 - 4.70 (m, 1H), 4.64 (t, J= 5.2 Hz, 1H), 4.56 (d, J= 13.6 Hz, 1H), 4.40 - 4.18 (m, 5H), 4.15 - 3.95 (m, 1H), 3.59 (s, 3H). LCMS (ES, m / z): 564 [M+HfSYNTHESIS EXAMPLE 18

[0265] (10S,llR,12R,13S,14R)-8,10,ll-trihydroxy-14-(4-methoxyphenyl)-N, N-dimethyl-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-1,3,5, 8- tetraene- 12-carb oxamide (I- 10)H2N OH HATU, DIEA, DMF

[0266] To a stirred solution of (IOS. HR,12R.13S,14R)-8, 10.11 -trihydroxy- 14-(4-methoxy phenyl)-! 3-phenyl-l 5-oxa-4,7-diazatetracyclo[7.6.0.0A{3, 7}.0A{ 10,14}]pentadeca-l,3,5,8-tetraene-12-carboxylic acid (Chiral, 50 mg, 0.11 mmol, 1 equiv) and HATU (60 mg, 0.16 mmol, 1.5 equiv) in DMF (2 mL) was added DIEA (54 mg, 0.42 mmol, 4 equiv) and ethanol amine (4.69 mg, 0.076 mmol, 1.5 equiv) dropwise at 0 °C under air atmosphere. TheLeydig 51588280resulting mixture was stirred for 30 min at room temperature under air atmosphere. The reaction was monitored by LCMS. The reaction was quenched with sat. NH4CI (aq.) at room temperature. The resulting mixture was extracted with EtOAc (10 x 3 mL). The combined organic layers were washed with water (10 x 2 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 8% B to 29% B in 7 min; Wavelength: 254nm / 220nm nm; RTl(min): 6.48). The collected fraction was lyophilized to afford( 1 OS, 11 R, 12R, 13 S, 14R)-8, 10, 11 -trihydroxy- 14-(4-methoxyphenyl)-N, N-dimethyl- 13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-12-carboxamide (3.4 mg, 6.11%) as a white solid.

[0267] LCMS (ESI, m / z):502[M+H]+. ’H-NMR (DMSO- s, 400 MHz) 5 (ppm): 8.37-8.36 (m, 1H), 7.60 (s,lH), 7.36 (s, 1H), 7.08-6.98 (m, 7H), 6.71 (s, 1H), 6.60 (d, J= 8.8 Hz, 2H), 5.82 (s, 1H), 5.34 (d, J= 4.0 Hz, 1H), 4.70-4.67 (m, 1H), 4.57-4.48 (m, 2H), 4.35 (s, 3H), 4.05-4.00 (m, 1H), 3.59 (s, 3H), 3.93-3.36 (m, 2H), 3.15-3.13 (m, 2H). LCMS (ESI, m / z):502[M+H]+.SYNTHESIS EXAMPLE 19

[0268] (Methoxyamino)((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4- methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d] imidazo [ 1,2-a] py ridin-7-yl)methanone (1-19)HCI 1.5 eq H2N HATU(2 eq), DIEA(5 eq) DMF (30 V) 0-rt,12 h

[0269] To a stirred solution of(10S. HR,12R.13S,14R)-8,10,l l-trihydroxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-12-carboxylic acid (Racemic, 20 mg, 0.044 mmol, 1 equiv) and HATU (30Leydig 51588281mg, 0.088 mmol. 2.0 equiv) in DMF (1 mL) was added DIEA (27 mg, 0.22 mmol, 5 equiv) and methoxyamine hydrocloride (5.5 mg, 0.066 mmol, 1.5 equiv) dropwise at 0 °C under air atmosphere. The resulting mixture was stirred overnight at room temperature under air atmosphere. The reaction was monitored by LCMS. The reaction was quenched with sat. NH4CI (aq.) at room temperature. The resulting mixture was extracted with EtOAc (10 x 3 mL). The combined organic layers were washed with water (10 x 2 mL), dried over anhydrous Na2SC>4. After fdtration, the fdtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 8% B to 29% B in 7 min;Wavelength: 254nm / 220nm nm). The collected fraction was lyophilized to afford 6 mgs of the racemic title compound (29 %) as a white solid.

[0270] LCMS (ESI, m / z): 518 [M+H]+. 'H-NMR (DMSO- 400 MHz) 5 (ppm): 5 11.289 (s, 1H). 7.592 (t, J = l.l Hz, 1H), 7.349 - 7.346 (d, J = 1.4 Hz, 1H), 7.089 - 7.051 (m, 2H), 7.001 - 6.961 (m, 5H), 6.710 (s, 1H), 6.597 - 6.575 (m, 2H), 5.849 (s, 1H), 5.526-5.522 (br, 1H), 4.560 - 4.508 (m, 2H), 4.337-4.420 (br, 3H), 3.789-3.744 (dd, J = 18 Hz, 1H), 3.579-3.531 (d, J = 19.2 Hz, 6H).SYNTHESIS EXAMPLE 20

[0271] (10S,llR 2S,13S,14R)-8-methoxy-12-[(methoxyimino)methyl]-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}] pentadeca- 1,3,5,8-tetraene- 10,ll-diol (I-17)Leydig 51588282HCI H2N 'O^ EtOH, AcOK, r.t., 3 h step 21-17

[0272] Step 1. (10S,llR,12R,13S,14R)-10,ll-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca- 1.3.5.8-tetraene-12-carbaldehyde

[0273] A mixture of (10S, HR,12S,13S,14R)-12-(hydroxymethyl)-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca- 1.3.5.8-tetraene-10,l 1-diol (racemic, 40 mg, 0.084 mmol, 1 equiv) and DMP (36 mg, 0.084 mmol, 1 equiv) in DCM (1 mL) was stirred for 2 h at room temperature. Desired product could be detected by LCMS. The residue was purified by silica gel column chromatography, eluted with CELCh / MeOH (10:1) to afford (10S,llR,12R,13S,14R)-10,l l-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14]]pentadeca-l,3,5,8-tetraene-12-carbaldehyde (40 mg, 87.87%) as a light yellow solid. LCMS (ESI, m / z): 473 [M+H]+

[0274] Step 2. (10S,llR.12S,13S,14R)-8-methoxy-12-[(methoxyimino)methyl]-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca- 1.3.5.8-tetraene- 10, 11 -diol

[0275] A mixture of (10S, HR,12R,13S,14R)-10,ll-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca- 1.3.5.8-tetraene-12-carbaldehyde (30 mg, 0.063 mmol, 1 equiv) and O-methylhydroxylamine hydrochloride (53 mg, 0.630 mmol, 10 equiv) in MeOH (4 mL) was stirred for overnight atLeydig 51588283room temperature. The resulting mixture was extracted with EtOAc (3x20 mL). The combined organic layers were washed with deionized water (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xbridge Prep OBD C18 Column, 19*250 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 32% B to57 % B in 10 min; Wavelength: 254nm / 220nm nm; RTl(min): 8.68) to afford (1 OS, 1 lR,12S,13S,14R)-8-methoxy- 12- [(methoxyimino)methy 1] - 14-(4-methoxy phenyl)- 13 -phenyl- 15-oxa-4, 7 -diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-10,ll-diol (3.4 mg, 10.68%) as a white solid. The product is racemic and an E / Z mixture.

[0276] LCMS (ESI, m / z): 502 [M+H]+'H NMR (400 MHz, DMSO- e) 57.61 (s, 1H), 7.38 - 7.33 (m, 2H), 7.13 - 7.04 (m, 3H), 7.04 - 6.97 (m, 4H), 6.71 (s, 1H), 6.60 (d, J= 8.9 Hz, 2H), 5.92 (s, 1H), 5.71 (d, J= 5.6 Hz, 1H), 4.47 - 4.43 (m, 1H), 4.38 - 4.31 (m, 4H), 3.92 - 3.83 (m. 1H), 3.72 (s. 3H), 3.59 (s, 3H). LCMS (ESI, m / z): 502 [M+H]+.SYNTHESIS EXAMPLE 21

[0277] (10S,llR,12R,13S,14R)-8,10,ll-trihydroxy-14-(4-methoxyphenyl)-Af, A-dimethyl-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-1,3,5, 8- tetraene- 12-carboxamide (I- 12)Leydig 51588284LiOH, H2O, MeOH1 hr, 60 °CHATU; DIEA; DMF1-12

[0278] (5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxylic acid

[0279] A mixture of methyl (5bS,6R,7R,8S.8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxylate (450 mg, 0.9 mmol, 1 equiv), LiOH (350 mg, 14 mmol, 16 equiv), H2O (5 mL) in MeOH (30 mL) was stirred for Ih at 60°C. The mixture was neutralized to pH 6 with IN HC1. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase column (10 mM NH4HCO3, ACN: 0-30% in 30 min) to afford (5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxylic acid (220 mg, 45%) as a light brown solid and (5bS,6R,7R,8S.8aR)-5,5b,6-trihydroxy-8a-(4-Leydig 51588285methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4.5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxylic acid (racemic, 50 mg, 20%) as a light brown solid. LCMS (EST, m / z): 475 [M+H]+

[0280] (10S, 1 lR,12R,13S,14R)-8, 10,1 l-trihydroxy-14-(4-methoxyphenyl)-A / / V-dimethyl-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3.7}.0A{10.14}]pentadeca-l,3,5,8-tetraene-12-carboxamide (1-12)

[0281] To a stirred solution of (10S,llR,12R,13S,14R)-10,ll-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]-pentadeca-l,3,5,8-tetraene-12-carboxylic acid (racemic. 50 mgs, 0.10 mmol, 1 equiv) and HATU (47 mg, 0.12 mmol, 1.2 equiv) in DMF (1 mL) was added DIEA (26 mg, 0.20 mmol, 2 equiv), dimethylamine (0.5 mL) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 20 min at room temperature under air atmosphere. The reaction was monitored by LCMS. A by-product with MW = 501 could be detected by LCMS. The reaction was quenched with sat. NH4C1 (aq.) at room temperature. The resulting mixture was extracted with EtOAc (10 x 3 mL). The combined organic layers were washed with water (10 x 2 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product w as purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 OBD Column, 30*150 mm. 5pm: Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 8% B to 29% B in 7 min; Wavelength: 254nm / 220nm nm; RTl(min): 6.48). The collected fraction w as lyophilized to afford (10S,llR,12R,13S,14R)-8,10,ll-trihydroxy-14-(4-methoxyphenyl)-N, N-dimethyl-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{ 10,14}]pentadeca-l,3,5,8-tetraene-12-carboxamide (3.4 mg, 6.1 1%) as a white solid.

[0282] LCMS (ESI, m / z):502[M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.64 (s, 1H), 7.51 (s 1H), 7.09-7.02 (m, 5H), 6.79-6.71(m, 4H), 6.17 (s, 1H), 5.10 (d, J= 8.8 Hz, 2H), 4.27 (d, J= 12.8 Hz, 1H). 3.86-3.81(m. 1H), 3.68 (s, 3H), 3.17 (s, 3H), 2.71 (S, 3H). LCMS (ESI, m / z): 502 [M+H]+.SYNTHESIS EXAMPLE 22

[0283] (10S,llR,12S,13S,14R)-12-(hydroxymethyl)-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-l,3,5,8-tetraene-8,10,11-triol (A33, racemic)Leydig 51588286LiBH4, THF1 hr, 50 °CA33

[0284] To a stirred mixture of methyl (10S, HR,12R,13S.14R)-10,l l-dihydroxy-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14]]pentadeca-l,3,5,8-tetraene-12-carboxylate (400 mg, 0.80 mmol, 1 equiv) in THF (1 mL) were added LiBH₄ (1.6 mL, IN in THF, 1.60 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred for 1 h at 50 °C. Desired product could be detected by LCMS. The reaction was quenched with sat. NFUCl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with deionized water (3x10 mL), dried over anhydrous Na₂SO₄. After fdtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: Xselect CSH Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 18% B to 48% B in 7 min; Wave Length: 254nm / 220nm nm; RTl(min): 6.37, The collected fraction was lyophilized to afford (1OS,11R,12S,13S,14R)-12-(hydroxymethyl)-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14}]pentadeca-1,3,5,8-tetraene-8,10,l 1 -triol (17.6 mgs, 4.07%) as a light pink solid. LCMS

[0285] A33: NMR (400 MHz, DMSO-rfe) 5 7.64 (s, 1H), 7.47 (s, 1H), 7.09 - 6.99 (m, 5H), 6.82 - 6.63 (m, 5H), 6.07 (s, 1H), 5.05 (s, 1H). 4.90 (d, J= 7.9 Hz, 1H). 3.99 - 3.90 (m, 1H), 3.68 (s, 3H), 3.53 - 3.44 (m, 2H), 3.25 - 3.19 (m, 1H). 2.82 - 2.75 (m, 1H). 2.06 - 1.94 (m, 1H). LCMS (ESI, m / z): 461 [M+H]’.SYNTHESIS EXAMPLE 23

[0286] (10S,llR,13S,14R)-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo[7.6.0.0A{3,7}.0A{10,14[] pentadeca-l,3,5,8-tetraene-10,ll-diol (A34; A35; 1-14, and A37)Leydig 51588287BocNH2Pd2dba3, xantphos, Cs2CO3, dioxane 100 °C, o nstep 316 17DIEA, EtOH, 90 °C, 2 h Chiral separation A34, A35, 1-14, and A37step 5

[0287] Step 1. (2R,5S,6R)-10-chloro-2-hydroxy-12-methoxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa- 11 -azatri cyclo [6.4.0.0A{2,6}]dodeca-l(12),8,10-trien-3-one

[0288] To a stirred solution of methyl (2R,4R,5S,6R)-10-chloro-2-hydroxy-12-methoxy-6-(4-methoxyphenyl)-3-oxo-5-phenyl-7-oxa-l l-azatricyclo[6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-4-carboxylate (racemic, 300 mg, 0.61 mmol, 1 equiv) in DMSO (6 rnL) was added LiCl (51 mg, 1.21 mmol, 2 equiv) in water (1 mL) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 1 h at 100 °C under air atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (2 mL). The resulting mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na2SO. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (2R,5S,6R)-10-chloro-2-hydroxy-12-methoxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-l l-azatricyclo[6.4.0.0A{2,6}]dodeca-l(12),8,10-trien-3-one (250 mg, 90.60%) as ayellow solid. LCMS (ESI, m / z): 438 [M+H]+Leydig 51588288

[0289] Step 2. (2S.3R,5S,6R)-10-chloro-12-methoxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-11 -azatricyclo [6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-2,3-diol

[0290] To a stirred mixture of (2R,5S,6R)-10-chloro-2-hydroxy-12-methoxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-Il-azatricyclo[6.4.0.0A{2,6}]dodeca-I(I2),8,10-trien-3-one (250 mg, 0.57 mmol, 1 equiv) in THF (10 mL) were added LiBHi (3.1 mL, 0.63 mmol, 1.1 equiv) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. Desired product could be detected by LCMS. The reaction was quenched with sat. NH4CI (aq.) at room temperature. The aqueous layer was extracted with EtOAc (3x30 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford (2S,3R,5S,6R)-10-chloro-12-methoxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-ll-azatricyclo[6.4.0.0A{2,6}]dodeca-l(12),8,10-triene-2,3-diol (200 mg, 75.65%) as a colorless oil. LCMS (ESI, m / z): 440 [M+H]+

[0291] Step 3. tert-butyl N-[(2S,3R,5S,6R)-2,3-dihydroxy-12-methoxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-l l-azatricyclo[6.4.0.0A{2.6}]dodeca-l(12).8.10-trien-10-yl] carbamate

[0292] A mixture of (2S,3R,5S,6R)-10-chloro-l 2-methoxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-ll-azatricyclo[6.4.0.0A{2,6}] dodeca-l(12),8,10-triene-2,3-diol (200 mg, 0.46 mmol, 1 equiv), Pd2(dba)3 (83 mg. 0.091 mmol. 0.2 equiv), XantPhos (105 mg, 0.18 mmol, 0.4 equiv), CS2CO3 (296 mg. 0.91 mmol, 2 equiv) and tert-butyl carbamate (107 mg, 0.91 mmol, 2 equiv) in dioxane (1 mL) was stirred for 3 h at 100 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The residue was purified by silica gel column chromatography, eluted with CLLCh / MeOH (20:1) to afford tert-butyl N-[(2S,3R,5S,6R)-2,3-dihydroxy-12-methoxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-l 1-azatricyclo[6.4.0.0A{2,6}] dodeca-l(12),8,10-trien-10-yl]carbamate (180 mg, 76.05%) as a yellow oil. There are two sets of racemic compounds in the mixture. LCMS (ESI, m / z): 521 [M+H]+

[0293] Step 4. (2S.3R,5S,6R)-10-amino-12-methoxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-ll-azatricyclo[6.4.0.0A{2,6}] dodeca-l(12),8,10-triene-2,3-diol

[0294] A mixture of tert-butyl N-[(2S,3R,5S,6R)-2,3-dihydroxy-12-methoxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-Il-azatricyclo[6.4.0.0A{2,6}]dodeca-I(I2),8,10-trien-10-yl]carbamate (170 mg, 0.33 mmol, 1 equiv) and TFA (2 mL) in DCM (2 mL) was stirred for I h at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was neutralized to pH 7 with saturatedLeydig 51588289NaHCCh (aq.). The aqueous layer was extracted with EtOAc (3x20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CTECh / MeOH (10: 1) to afford (2S,3R,5S,6R)-10-amino- 12-methoxy-6-(4-methoxyphenyl)-5-phenyl-7 -oxa-11 -azatricyclo[6.4.0.0A{2.6}]dodeca-l(12).8,10-triene-2.3-diol (150 mg. 87.40%) as ayellow oil. LCMS (ESI, m / z): 421 [M+H]+

[0295] Step 5. (10S,l lR,13S,14R)-8-methoxy-14-(4-methoxyphenyl)-13-phenyl-15-oxa-4,7-diazatetracyclo [7.6.0.0A{3,7).0A{10,14}]pentadeca-l,3,5,8-tetraene-10,ll-diol

[0296] A mixture of (2S,3R,5S,6R)-10-amino-12-methoxy-6-(4-methoxyphenyl)-5-phenyl-7-oxa-ll-azatricyclo[6.4.0.0A{2.6}] dodeca-l(12),8,10-triene-2,3-diol (440 mg, 1.048 mmol, 1 equiv), DIEA (272 mg, 2.096 mmol, 2 equiv) and chloroacetaldehyde (164 mg, 2.096 mmol, 2 equiv) in EtOH (10 mL) was stirred for 2 h at 90 °C. The residue was purified by silica gel column chromatography, eluted with CEECh / MeOH (12:1) to afford a crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: CHIRAL ARTCelluloseSZ; Mobile Phase A: Hex(0.1%DEA): (IP A:DCM=1: l)=70:30; Flow rate: 1 mL / min; Gradient: isocratic; Injection Volume: 0.6pl mL. Four eluents were collected as C / D / E / F, each as a white solid. LCMS (ESI, m / z): 445 [M+H]+

[0297] Isomer C (A34, 4.8 mg, 0.98%): 'H NMR (400 MHz, DMSO-t / e) 57.74 (s, 1H), 7.43 (s, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.11 - 7.03 (m, 3H), 6.89 - 6.82 (m, 3H), 6.71 (d, J = 8.9 Hz, 2H), 6.07 (s, 1H), 5.48 (s, 1H), 4.77 (t, J= 7.4 Hz, 1H), 4.26 (s, 3H), 3.67 (s, 3H), 3.33 - 3.26 (m. 2H), 2.27 - 2.16 (m, 1H). LCMS (ESI, m / z): 445 [M+H]~.

[0298] Isomer D (A35, 5.2 mg, 1.07%): 'H NMR (400 MHz, DMSO-t*) 57.74 (s, 1H), 7.43 (s, 1H), 7.18 (d,.7= 8.7 Hz, 2H), 7.13 - 7.02 (m, 3H), 6.91 - 6.81 (m, 3H), 6.71 (d,.7 = 8.7 Hz, 2H), 6.05 (s, 1H), 5.47 (s, 1H), 4.77 (t, J= 7.4 Hz, 1H), 4.26 (s, 3H), 3.67 (s, 3H), 3.34 - 3.26 (m, 2H), 2.27 - 2.15 (m, 1H). LCMS (ESI, m / z): 445 [M+H]~.

[0299] Isomer E (1-14, 1.2 mg, 0.95%): 'H NMR (400 MHz, DMSO-t*) 57.61 (s, 1H).7.37 (d, J= 1.3 Hz, 1H), 7.15 - 7.09 (m, 2H), 7.08 - 7.00 (m, 5H), 6.70 (s, 1H), 6.61 (d, J = 8.9 Hz, 2H), 5.59 (s, 1H), 5.25 (s, 1H), 4.47 (s, 1H), 4.37 (s, 3H), 4.25 - 4.14 (m, 1H), 3.60 (s, 3H), 2.84 (t, J= 13.7 Hz, 1H), 2.28 - 2.16 (m, 1H). LCMS (ESI, m / z): 445 [M+H]+.

[0300] Isomer F (A37, 1.5 mg, 0.31%): 'H NMR (400 MHz, DMSO-r / e) 57.60 (s, 1H).7.35 (s, 1H), 7.15 - 7.08 (m. 2H), 7.08 - 6.99 (m. 5H), 6.69 (s, 1H), 6.61 (d, J= 8.8 Hz, 2H),Leydig 515882905.58 (s. 1H), 5.24 (s. 1H), 4.49 - 4.44 (m, 1H), 4.37 (s, 3H), 4.24 - 4.15 (m, 1H). 3.60 (s, 3H), 2.88 - 2.78 (m, 1H), 2.26 - 2.17 (m, 1H). LCMS (EST, m / z): 445 [M+H]+.

[0301] Based on biological data, isomers D (1-14) and F (A37) are active, while isomers C and E are inactive.EXAMPLES

[0302] The following examples illustrate various properties of the compounds provided herein. Structures of the compounds identified in the examples are provided in Appendix I.EXAMPLE 1

[0303] This example illustrates the effect of compounds of Formula I on mRNA translation. The Cell-based Nanoluciferase Reporter Assay for Translation Inhibition examined translation of mRNA encoding nLUC luciferase reporter transfected into HEK cells in the presence of compounds of Formula I. mRNA were modified with either an AGA rich leader sequence, or a CAA rich leader sequence (FIG. 1). Compounds of Formula I (1-4, 1-11, and 1-16) were tested along with RocA and Zotatifin as comparative compounds. The AGA nanoluciferase reporter construct has been previously described (Ernst J. T. et al., J. Med. Chem, 2020, 63, 11, 5879-5955). RNA was made from this reporter construct template, using the NEB HiScribe® T7 ARC A mRNA kit following the manufacturer’s recommendations. HEK-293T cells were transiently transfected with the RNA using TransIT-mRNA and mRNA Boost reagents following manufacturer’s recommendations. Briefly, each well of a 384 well plate had 5000 cells, 2 ng RNA, 0.004 ul TransIT-mRNA, and 0004 ul Boost reagent. Cells and transfection complex were incubated in a 37 °C incubator for 30 minutes. Relevant compounds dissolved in DMSO were serially diluted 2-fold from stock solutions and added to wells using a Bravo Automated Liquid Handling platform (Agilent); the highest drug concentration was 50 pM and that of DMSO was 1%. The compound treated cells were incubated in a 37 °C incubator for 4 hours. Nano-Gio luciferase reagent (Promega) was prepared by diluting NanoGio substrate 1:50 into NanoGio buffer and 20 ul detection reagent was dispended to each well and incubated at room temperature for at least 3 minutes. The luminescence signal was read using a PHERAStar plate reader, translation inhibition was calculated as a percentage of DMSO-treated controls. IC50 values were calculated using Genedata.Leydig 51588291

[0304] The results are presented Table 1 (all compounds) and in Fig. 1A and Fig. IB (showing only Zotatifin and 1-4).Table 1Compound AGA nLUC CAA nLUC CAA / AGA RatioIC50 IC50RocA 6.1 62 10Zotatifin 2.45 44 181-5 34 10000 2941-11 30 6800 2261-16 58 37000 637

[0305] As demonstrated by the results, the compounds of Formula I inhibited translation of mRNA with AGA-rich leader sequences, but did not significantly inhibit translation of mRNA with CAA-rich leader sequences. The comparative compounds did not exhibit the same selectivity.EXAMPLE 2

[0100] This example illustrates the binding kinetics of compounds of Formula I with respect to mRNA containing an AGA leader sequence. The assay used m6A-capped RNA with an AGA-rich leader sequence immobilized on a sensor surface to detect EIF4A1 binding when exposed to solutions containing EIF4A1 and DMSO, EIF4A1 and Zotatifin, or EIF4A and a compound of Formula I (A24, 1-4, or 1-11). Briefly, Recombinant eIF4Al was purchased from Active Motif (Cat # 81216). Biotinylated AGA RNA (5’-AGAGAGAGAGAGAGAGAG-3’Bi) (lug / mL) was immobilized on SA chips. The protein with or without compounds at increasing concentrations were injected in buffer containing 14.4 mM HEPES pH 7.4, 108 mM NaCl, 1 mM MgC12, 0.36 mM TCEP, 1 mM ATP, and 1% DMSO, using a Biacore 8k system (Cytiva). The measured response units (RU) are proportional to the amount of protein bound to the chip. The equilibrium dissociation constant (KD) was calculated from the steady state binding using the bivalent analyte kinetics model.

[0101] The results are presented in FIG. 2B along with a graphic depiction of the assay in FIG. 2A. Dissociation characteristics calculated from the data are presented in Table 2A.Leydig 51588292Table 2ATest Compound koff Half-Life KDDMSO 0.028 24.6 3.53E'06A24 0.026 26.5 8. O5E-06Zotatifm 0.007 98.6 6.56E'071-4 0.012 57.5 8.21E'071-11 0.011 62.7 6.84E’07

[0102] The results show that the compounds of Formula I have a larger (faster) koff as compared to Zotatifm, wherein kOff, is the dissociation constant (the proportion of ligandreceptor complex that dissociates in unit time) in the absence of free ligand.

[0103] Additional selectivity studies were conducted with Zotatifm and Compound 1-4 measuring binding of AGA RNA to EIF4A2 and EIF4A1. EIF4A2 protein was obtained from Viva Biotech. These studies were run using the conditions described above for EIF4A1. The affinity (KD) for Zotatifm and compound 1-4 between EIF4A1 and its paralogue EIF4A2 are shown in Table 2B.Table 2BeIF4A Paralog Compound KD (nM)eIF4Al Compound 1-4 1.09E-07eIF4A2 Compound 1-4 1.31E-06eIF4Al Zotatifm 8.4E-08eIF4A2 Zotatifm 4.29E-07

[0104] The results show that Zotatifm has a 5-fold preferential affinity for EIF4A1 over EIF4A2, while Compound 1-4 favors eIF4Al inhibition by 12-fold over eIF4A2. This suggests a greater selectivity profile for Compound 1-4 as compared to Zotatifm.EXAMPLE 3Leydig 51588293

[0306] This example illustrates the ATP dependent helicase activity of eIF4Al. Trapping is measured by increased hydrolase activity to convert ATP to ADP. Under normal cellular function there is a dynamic state where eIF4Al goes from inactive to active state as needed to initiate mRNA translation. In the presence of Zotatifin, the ATP consumption keeps going up as reflected by the increase in luminescence signal in the assay, suggesting that Zotatifin is keeping the eIF4Al trapped to the mRNA, whereas compounds 1-4, 1-11 and 1-9 do not show this feature (FIGs. 3 A, 3B, and 3C). This suggests that compounds of Formula I do not trap eIF4Al to its target mRNA.EXAMPLE 4

[0307] This example illustrates the effect that compounds provided herein have on populations of lymphocytes using Fluorescence-activated cell sorting (FACS) and analysis.

[0308] Frozen PBMCs (AllCells) were cultured in AIM-V media (Gibco) supplemented with 10% heat-inactivated FBS (Gibco). Cells were thawed, washed, counted, and seeded at a concentration of 2M / mL into stimulation cocktail in base media including 50uM 2-Mercaptoethanol, 0.5 ug / mL CD40L multimer (Miltenyi), 15 ng / mL IL-4 (PeproTech), and 25 ng / mL IL-21 (PeproTech). PBMCs were incubated at 37°C with 5% CO2 for 3 days. Then, stimulated PBMCs were treated with compound: DMSO, 7 nM Bortezomib, 25 nM Zotatifin or 175 nM 1-4 in technical duplicate. Cells were incubated for another 3 days prior to antibody staining. Each sample was harvested and washed with ice cold PBS and then blocked with 4 uL of FcR Blocking Reagent (Miltenyi) at 4°C for 20 min. Samples were then stained with L1VE / DEAD Fixable Near IR (780) Viability Kit (Invitrogen) at room temperature for 30 min in the dark. Samples were washed once in Stain Buffer (BD) and then labeled with 5 uL of each antibody: BV421 Mouse Anti -Human CD 19 (BD), PE Mouse Antihuman CD38 (Biolegend), and BB515 Mouse Anti-Human CD27 (BD). Samples were incubated for 30 min at 4°C in the dark. Samples were washed twice with Stain Buffer prior to fixing in 2.7% paraformaldehyde for 15 min a room temperature. Samples were resuspended in Stain Buffer and kept in the dark at 4°C until analysis. Fluorescence Minus One (FMO) control samples were stained with all fluorophores in the panel using extra DMSO control wells. Beads were used for compensation. Samples were run on a CytoFLEX and analyzed using Flow Jo.Leydig 51588294

[0309] The results are presented in Figs. 4A-4C, and show that 1-4 selectively reduced plasma B cell populations while sparing other lymphocytes. By contrast, bortezomib and zotatifin reduced all lymphocytes to a greater extent.EXAMPLE 5

[0310] This example illustrates the effect of compounds of Formula I in a rat efficacy model.

[0311] The experiment examined the ability of compounds of Formula I to reduce IgG production in rats challenged with KLH antigen dissolved in PBS and immunized by intraperitoneal injection to 8-9 weeks old female Sprague Dawley rats. Test compound 1-4 was administered orally to rats at 5 different daily dosages. Vehicle without test compound served as a control. On days 7, 14 and 21 blood was collected form all rats in the study under anesthesia with 1-4% isoflurane. The serum was separated by centrifugation for 15 min at 3,000 rpm and stored at -80°C until assay. Serum levels of anti-KLH IgM (days 7, 14, and 21), anti-KLH IgG (days 14 and 21) and total IgG (day 21) were measured by ELISA.

[0312] The results are presented in FIGs. 5A-5C. The results show that oral 1-4 has greater activity to reduce anti-KLH IgG titers by 92-69% at the doses tested (FIG. 5A). 1-4 showed less activity in reducing total IgG (FIG. 5B). Furthermore, 1-4 did not significantly reduce anti-KLH IgM titers (FIG. 5C).EXAMPLE 6

[0313] This example illustrates the effect of compounds of Formula I in a range of in vitro functional assays. These assays are:

[0314] Plasma B cell IgG Secretion Assay. Total frozen PBMCs (AllCells) were thawed and washed twice with culture media, AIM-V (Gibco) supplemented with 10% heat-inactivated FBS (Gibco). Cells were counted and 25 uL was seeded into 384-well roundbottom plates at a concentration of 2M cell / mL. Compounds were dispensed using a Tecan D300e digital dispenser in 8-pt dose response starting at 10 uM with 3-fold dilution steps. Compounds were incubated for Ih prior to PBMC stimulation. To stimulate B cells, CD40L was mixed with crosslinking antibody in equal volumes for 30 minutes at room temperature. Then, the control cocktail was made at 2X containing 100 uM 2-Mercaptoethanol in culture media. Stimulation cocktail was made at 2X containing 100 uM 2-Mercaptoethanol, 1 ug / mL CD40L multimer (Miltenyi), 30 ng / mL IL-4 (PeproTech), 50 ng / mL IL-21 (PeproTech). 25Leydig 51588295uL of 2X control or stimulation cocktail was added to the appropriate control and test wells and cells were incubated at 37°C with 5% CO2 for 4 days. Supernatants were collected and HTRF was run for IgG according to manufacturer’s instructions (Revvity). IgG concentrations were interpolated from the standard curve and IC50 values were calculated using Genedata.

[0315] Cell Viability Assay: Fresh PBMCs (iXCells), HepG2 (ATCC), THP-1 (ATCC), NITI (ATCC), or RPMI8226 (ATCC) cells were seeded into white-walled 384-well plates at a concentration of 20K, 50K, 300K, 250K, or 300K cells / well, respectively. PBMCs, THP-1 and RPMI8226 cells were cultured in RPMI 1640 + 10% heat-inactivated FBS (Gibco). HepG2 cells were cultured in DMEM + 10% FBS (Gibco) and NITI cells were cultured in DMEM / F12 + GlutaMAX + 10% FBS (Gibco). Compounds were dispensed using aTecan D300e digital dispenser in 11 pt dose-response starting at 25 uM with 2-fold dilution steps. Cells were incubated for 48h at 37°C with 5% CO2 prior to running Cell Titer Gio (Promega) according to manufacturer’s instructions. IC50 values were calculated using Genedata.

[0316] Insulin secretion assay. NIT-1 insulinoma beta cells were cultured in DMEM / F12 media supplemented with GlutaMAX and 10% heat inactivated FBS. Cells were seeded 20 ul media containing 10.000 cells / well in a 384 well plate on day 0. On day 1, 17.5 ul media was removed from each well and 20 ul fresh media was added. Cells were treated with relevant compounds serially diluted from DMSO stock solutions using a D300e digital dispenser (Tecan), the highest drug concentration was 20 gM and that of DMSO was 1%. The compound treated cells were incubated in a 37 °C incubator overnight. On day 2. 17.5 ul media was removed from each well and 20 ul fresh media was added. Compound treatment was repeated similarly to day 1. The compound treated cells were incubated in a 37 °C incubator overnight. On day 3, media from each well was diluted 1:3 by adding 5 ul cell media to 10 ul fresh media before subjecting to an HTRF assay using the HTRF Insulin High Range Detection Kit (Revvity) following the supplier's recommended protocol. Insulin concentrations from each well were interpolated from the standard curve and IC50 values were calculated using Genedata.

[0317] Monocyte TNF-a and IL-6 secretion assay: Human fresh PBMC were obtained from iXCells Biotechnologies. Upon receipt, monocytes were isolated from fresh PBMC using the Classical Monocyte Isolation Kit (Miltenyi Biotec) following the supplier’s recommendations. Cells were counted and diluted to 500,000 cells / ml complete media containing RPMI media supplemented with 10% heat inactivated FBS. 45 ul cell suspensionLeydig 51588296was seeded per well in a 384 well plate. Cells were incubated in a 37 °C incubator for 30 minutes before being treated with relevant compounds serially diluted from DMSO stock solutions using a D300e digital dispenser (Tecan). Compound treated monocytes were incubated in a 37 °C incubator for another 30 minutes. Monocytes were activated by adding 5 ul of R848 to final concentration of 10 ug / ml, 5 ug / ml, and 2.5 ug / ml and the cell plate was incubated in a 37 °C incubator overnight. The next day, cell media was used to measure TNF-a and IL-6 concentrations, using the HTRF human TNF-a and IL-6 kits (Revvity), following the manufacturer’s protocols. TNF-a and IL-6 concentrations from each well were interpolated from the standard curve and IC50 values were calculated using Genedata.

[0318] T cell IFN-y secretion assay. On day 0, frozen PBMCs were thawed, washed and resuspended in Aim-V media supplemented with 10% heat inactivated FBS. Cells were counted and diluted to 1 million cells / ml media. For a 384 w'ell plate, 45 ul cell suspension was added to each well. Cells were incubated with compounds serially diluted from DMSO stock solutions using a D300e digital dispenser (Tecan) for 30 minutes in a 37 °C incubator. Cells ere then activated by adding 5 ul Dynabeads™ Human T-Activator CD3 / CD28 for T Cell Expansion and Activation (Thermo Fisher) to final bead:cell ratio 1:1 and returned to the incubator. On day 2, cell media was used to measure IFN-y concentration, using the HTRF human IFN-y detection kit (Revvity), following the manufacturer’s protocol. IFN-y concentrations from wells were interpolated from the standard curve and IC50 values were calculated using Genedata.

[0319] The results are presented in Tables 7A-7E below', and the structures of the compounds identified in these tables are provided in Appendix I. The results show that compounds provided herein show high level of specificity towards eIF4Al (Nluc) and plasma cells (Plasma cell IgG secretion and RPMI8226 killing). While all the compounds have low activity in all the other assays tested. This further reinforces the functional specificity' of compounds in Formula I to Plasma cell biology.Table 3A1-1 1-2 1-3 1-4 1-5 A24 1-6 A30 Assay (nM)Nluc 135.8 ± 81.8 7270 50000 31.5 ±6.5 209 ± 8.32 50000 36 23000 Plasma B 365 ± 152 41.7 ± 221 ± 122 21.4 10000 cell IgG 21.2RPMI-8226 3940 ± 3090 123.8 ± 2555 ± 813 35.838.7Leydig 51588297THP-1 5310 9555 ± 50.313467PBMCCVS 18500 ± 5894 12663 ± 22400 ± 41611841 3677NIT-1 CVS 21100 ±6690 11200 ± 25000 24.49690Insulin 23700 11006 ± 25000 4220 secretion 7192HepG2 23500 ± 25000 25000 15000CVS 2620Caco2 498CD 14 3840 ±TNFalpha 4074CD14 IL6IFN- 258 ±93.3gammaTable 3B1-7 A32 1-8 A29 1-9 A31 1-10 1-11 1-12 Assay (nM)Nluc 31.7 25000 71.7 7470 29 13300 704 34.9 ±3.5 346 Plasma B cell 21.2 10000 18.1 941 16.4 8330 50.7 18.6 ±9.3 29.7 IgGRPMI-8226 50.3 59.9 1980 54.4 11900 191 103 ±12.7 90.8 THP-1 72.7 124 14400 127 25000 217 134 189 PBMCCVS 377 378 21200 437 25000 1410 5370 ± 6864455 NIT-1 CVS 401 5360 20800 884 22600 11500 3040 7390 Insulin 4930 6650 25000 4675 ± 25000 17500 3600 ± 9300 secretion 5169 3309 HepG2 CVS 25000 25000 25000 25000 25000 25000 17080 ± 2500011200 Caco2CD14 1988 ± 3416 ± TNFalpha 1216 2151 CD14 IL6 5105 ± 5168 ±6922 6833 IFN-gamma 297 ± 565 ±432.7203Table 3C1-13 A34 A35 1-14 1-15 A28 A37 A26 Assay (nM)Nluc 17.8 2780 ± 16500 56.9 ± 64.3 19200 103 ± 665300 17.3 59Leydig 51588298Plasma B cell 12.1 1600 56.2 34.8 93.8 408 IgGRPMI-8226 51 6060 2720 881 5510 1690 THP-1 46.4 2490 9530 25000 25000 12300 PBMC CVS 280 25000 25000 25000 25000 10800 NIT-1 CVS 1150 25000 17000 25000 25000 6970 Insulin 7390 25000 8200 15300 4060 secretionHepG2 CVS 25000 12500 7610 25000 25000 25000 Caco2CD14TNFalpha 10000 10000 10000 CD14 IL6 10000IFN-gamma 2500 1350 10000Table 3D1-16 A33 1-17 1-18 1-19 1-20Assay (nM)Nluc 49.6 ± 61.9 58.8 92.4 136 18.34.38Plasma B cell 56.7 ± 17.7 84.9 235 40 55IgG 35.5RPMI-8226 307 62.2 200THP-1 25000 25000PBMC CVS 19400 3160NIT-1 CVS 16200 25000Insulin 5760 228secretionHepG2 CVS 25000 25000 25000Caco2CD14TNFalpha 452CD14 IL6IFN-gamma 4140Table 3E1-21 1-22 1-23Assay (nM)Nluc 20 19.6 49.4Plasma B cell 84.6 14.6 106IgGRPMI-8226 277 52.4 649THP-1PBMC CVS 1160NIT-1 CVSLeydig 51588299InsulinsecretionHepG2 CVS 13000 25000 6700Caco2CD14TNFalphaCD14 IL6IFN-gammaEXAMPLE 7

[0320] Enhanced crosslinking and immunoprecipitation (eCLIP) RNA sequencing studies were conducted to identify how compound treatment modulated EIF4A binding to RNA in different cell types.

[0321] The technical details for eCLIP sequencing have been previously described (Blue S. M. et al., Nat Protoc. 2002 Mar 23;17(5): 1223-1265). In brief, a compound-insensitive liver-derived cell line (HepG2), and a compound-sensitive plasma cell derived cell line (RPMI8226) were treated for 1 hour with (a) DMSO or (c) 10 uM Compound 1-4. Cells were UV-crosslinked, followed by cell lysis and RNA fragmentation. EIF4A-mRNA complexes were immunoprecipitated using an antibody specific to eIF4Al (Abeam, catalog #ab31217). The mRNAs pulled down by immunoprecipitation were isolated for library preparation, which included the addition of adapter sequences for sequencing. The library was then sequenced and analysis of EIF4A1 immunoprecipitation was compared to size-matched input control). Binding site identification was performed using the bioinformatics pipeline Skipper (Boyle, Evan A. et al., Cell Genomics. 2023 Jun 14; 3(6); 100317).

[0322] Gene Ontology (GO) analysis of eCLIP-seq in RPMI8226 cell line, comparing DMSO 10 uM compound 1-4, shows that compound treatment highly enriched for several pathways over DMSO including response to endoplasmic reticulum stress, protein folding, proteolysis involved in protein catabolic process, and regulation of RNA splicing.

[0323] eCLIP-seq analysis of XBP1 / RNA interaction with EIF4A1 protein in RPMI8226 cells was performed (data not shown). The analysis showed significant enrichment, particularly in the 5’UTR of the transcript. The enrichment suggests that XBP1 translation will be inhibited at the protein level when compounds bind to the EIF4A1 / RNA interface.

[0324] Western blot analysis of RPMI8226 cells treated with DMSO or compound 14 (FIG. 6A) supports eCLIP-seq on the protein level. The analysis shows that XBP1 is reduced in a dose-dependent manner with compound 1-4 treatment. Other relevant transcription factors show varying degrees of sensitivity to compound treatment. Similar expressionLeydig 515882100patterns are observed in primary PBMC cultures that drive plasma cell differentiation (FIG.6B). The data provided in Figs. 6A and 6B are representative of two independent experiments for the RPMI8226 cell line and PBMC cultures.

[0325] Taken together, these mechanisms of action studies identify XBP-1 as a key transcription factor in plasma cell biology where EIF4A1 inhibition leads to reduction of XBP-1 expression.Leydig 515882101Appendix I: Compounds used in Examples 1-7Compound Structure Stereochemistry1-1 chiralchiral1-3 racemicLeydig 515882Leydig 515882103A-30 ChiralN1-7 chiralA32 chiralHO1-8 chiralHOLeydig 515882104A29 chiral1-9 chiralA31 chiral1-10 chiralLeydig 5158821051-111-121-13A34Leydig 515882106A35 chiralHO01-14 chiral1-15 chiralHO0" A28 chiral OHHOOLeydig 515882107A37 chiralA26 chiral1-16 chiralA33 chiralLeydig 5158821081-17 Racemic; a mixture of cis or trans1-18 racemic1-19 racemic1-20 chiralLeydig 5158821091-21 chiral1-22 chiralHO1-23 chiralHO HOLeydig 515882110

[0105] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0106] The use of the terms “a” and '‘an’’ and '‘the” and “at least one’’ and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to.”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0107] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possibleLeydig 515882I l lvariations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

1. Leydig 515882112CLAIMS:or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:n is 1 or 2;X is O, S. NH, CRnR12, N(Ci-C8)alkyl, C(O). CH-CHRnR12. NC(O)R15. S(O) or S(O)2;each instance of Y is independently CR8, N, NR8, O, or S;each instance of Z is independently CR9or N;R1is H. halogen, Ci-Cs alkyl, Ci-Cs haloalkyl. C(O)O(Ci- C8)alkyl. C(O)(Ci- C8)alkyl, SO2(Ci-Cs)alkyl, C2-Cs alkenyl, C2-C8alkynyl, OR14, NHR14, NR14R14, CN, [Ci-Cs alkylene] OR14, [Ci-Cs alkylene]NHR14, [Ci-C8alkylene]NR14R14, C(O)R15, C(O)NHR14, C(O)NR14R14, C(O)[CI-C8alkylene]NHR14, C(O)[Ci-C8alkylene]NR14R14, CO2R14, C(S)NHR14, C(S)NR14R14. SR14. S(O)R14, SO2R14, SO2N(H)(R14), SO2NR14R14, NHC(O)R15, NR14C(O)R15, NHC(O)NHR14, NHC(O)NR14R14. NR14C(O)NHR14, NR14C(O)NR14R14, P(O)(OH)(OR14), P(O)(OR14) (OR14), aryl, heteroaryl, cycloalkyl, or heterocyclyl;R2is H, halogen, hydroxyl, CN, N3, SR14, Ci-C8alkyl, Ci-Cs haloalkyl, O-(Ci- C8)alkyl, O-(Ci- C8)haloalkyl, C2-C8alkynyl, NHC(O)(Ci-Cs)alkyl or heteroaryl;R3, R3a. R4. and R4aindependently areH, halogen, CN, Ci-Cs alkyl, Ci-Cs haloalky l, C2-C8alkenyl, C2-C8alkynyl, OR14, NHR14, NR14R14, [Ci-Cs alkylene]OR14, [Ci- C8alkylene]NHR14, [Ci-C8alkylene]NR14R14, C(O)R15, C(O)NHR14, C(O)NR14R14, C(O)[Ci- C8alkylene]NHR14, C(O)[Ci-C8alkylene]NR14R14, CO2R14, C(S)NHR14, C(NR14)R14, C(S)NR14R14, SR14, S(O)R4, SO2R14, SO2NHR14, SO2NR14R14, NHC(O)R15, NR14C(O)R15, NHC(O)NHR14, NHC(O)NR14R14, NR14C(O)NHR14, NR14C(O)NR14R14, P(O)(OH)(OR14), P(O)(OR14) (OR14), aryl, heteroaryl, cycloalkyl or heterocyclyl; or R3and R3a, or R4andLeydig 515882113R4atogether form oxo or alkenyl; or R3and R4. R3aand R4a, or R3aand R2together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;R5and R6are each independently aryl, heterocyclyl, heteroaryl, or cycloalkyl;R7is H. halogen, Ci-Cs alkyl, Ci-Cs haloalkyl, C(O)O(Ci- Cs)alkyl, C(O)(Ci-Cs alkyl), SO2(Ci-C8 alkyl). C2-Cs alkenyl, C2-Cs alkynyl, OR14. NHR14, NR14R14, CN, [Ci-Cs alkylene]OR14, [Ci-Cs alkylene]NHR14, [Ci-Cs alkylene]NR14R14, C(O)R15, C(O)NHR14, C(O)NR14R4, C(O)[Ci-Cs alkylene]NHR4, C(O)[Ci-Cs alkylene]NR14R14, CO2R14, C(NR14)R14, C(S)NHR14, C(S)NR14R14, SR14, S(O)R14, SO2R14, SO2N(H)(R14), SO2NR14R14, NHC(O)R15, NR14C(O)R15, NHC(O)NHR14, NHC(O)NR14R14, NR14C(O)NHR14, NR14C(O)NR14R14, P(O)(OH)(OR14), P(O)(OR14) (OR14), aryl, heteroaryl, cycloalkyl, or heterocyclyl;each R8and each R9are each independently a hydrogen, hydroxyl, halogen, CN, SR10, Ci-Cs alkyl, Ci-Cs alkoxy, Ci-Cs haloalkyl, Ci-Cs heteroalkyl, C2-Cs alkenyl, C2-Cs alkynyl, aryl, heterocyclyl or heteroaryl;R10is hydrogen, halogen, Ci-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, Ci-Cs haloalkyl, Ci-Cs heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;R11and R12Independently are H, CN, halogen, OR13, SR13, Ci-Cs alkyl, NH(R13) or NR13R13;each R13is independently H, Ci-Cs alkyl, Ci-Cs haloalkyl, cycloalkyl, heterocyclyl, [Ci-Cs alkylene] heterocyclyl, aryl, [Ci-Cs alkylene] aryl, heteroaryl, or [Ci-Cs alkylene] heteroaryl;each R14is independently H, Ci-Cs alkyl, Ci-Cs haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, [Ci-Cs alkylene] cycloalkyl, [Ci-Cs alkylene] heterocyclyl, [Ci-Cs alkylene] aryl, [Ci-Cs alkylene] heteroaryl, [Ci-Cs alkylene]-OR15, O(Ci-Cs)alkyl, O(Ci-Cs)haloalkyl, O(cycloalkyl), O(heterocyclyl), O(aryl). or O(heteroaryl); or wherein two R14groups together with a nitrogen atom to which they are both attached (e.g., NR14R14, [Ci-Cs alkylene]NR14R14, C(O)NR14R14, C(O)[Ci-Cs alkylene]NR14R14, C(S)NR14R14. SO2NR14R14, NHC(O)NR14R14or NR14C(O)NR14R14) optionally form a heterocyclyl ring;each R13is independently H, (Ci-Cs)alkyl, (Ci-Cs)haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl O(Ci-Cs)alkyl, O(Ci-Cs)haloalkyl, O(cycloalkyl), O(heterocyclyl), O(aryl), or O(heteroaryl);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(Ci-C4)alkyl,Leydig 515882114SO2NH(Ci-C4)alkyl. halogen, NH2, NH(Ci-C4)alkyl, N[(Ci-C4)alkyl]2. C(O)NH2, COOH, COOMe, acetyl, (Ci-Cs)alkyl, O(Ci-Cs)alkyl, O(Ci-Cs)haloalkyL (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, NH2-C(O)-alkylene. NH(Me)-C(O)-alkylene, CH2-C(O)-(Ci-C6)alkyl, C(O)-(Ci-C6)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; wherein "m" and"p" are 1, 2, 3, 4, 5 or 6.

2. The compound of claim 1, wherein X is O, N, S, S(O), or S(O)2.

3. The compound of claim 1, wherein X is O or N.

4. The compound of claim 1, wherein X is O.

5. The compound of any of claims 1-4, wherein R1is hydroxyl or C1-C3 alkoxy, optionally a methoxy.

6. The compound of any one of claims 1-5, wherein R2is hydroxyl.

7. The compound of any one of claims 1-6, wherein R3ais H.

8. The compound of any one of claims 1-7, wherein R3is hydroxyl.

9. The compound of any one of claims 1-8. wherein R4ais H.

10. The compound of any one of claims 1-8, wherein R4is hydrogen; an alkyl, optionally substituted with a hydroxyl; C(O)OH; C(O)NR14R14, CO2R14, C(NR14)R14, or CH2NR14R14.

11. The compound of any one of claims 1-8, wherein R4is:Leydig 51588211512. The compound of any one of claims 1-8, wherein both R4and R4aare H.

13. The compound of any one of claims 1-12, wherein R5is aryl, optionally substituted with 1, 2, or 3 groups selected from OH, CN, halogen, (Ci-Cs)alkyl, O(Ci-C8)alkyl, or O(Ci-C8)haloalkyl.

14. The compound of any one of claims 1-12, wherein R5is phenyl, optionally substituted with 1, 2. or 3 groups selected from OH. CN, halogen, (Ci-Cs)alkyl, O(Ci-Cs)alkyl, or O(Ci-C8)haloalkyl.

15. The compound of any one of claims 1-12, wherein R5is phenyl, optionally substituted with CN or halogen.

16. The compound of any one of claims 1-12, wherein R5is phenyl.

17. The compound of any one of claims 1-12, wherein R5is phenyl substituted with fluorine.

18. The compound of any one of claims 1-17, wherein R6is aryl, optionally substituted with 1, 2, or 3 groups selected from OH, CN, halogen, (Ci-C8)alkyl, O(Ci-C8)alkyl, or O(Ci-Cs)haloalkyl.

19. The compound of any one of claims 1-16, wherein R6is phenyl, optionally substituted with 1, 2, or 3 groups selected from OH, CN, halogen, (Ci-Cs)alkyl, O(Ci-Cs)alkyl, or O(Ci-C8)haloalkyl.

20. The compound of any one of claims 1-16, wherein R6is phenyl, optionally substituted with CN, halogen, or O(Ci-C8)alkyl.

21. The compound of any one of claims 1-16, wherein R6is phenyl substituted with CN.

22. The compound of any one of claims 1-16, wherein R6is phenyl substituted with O(Ci-C8)alkyl, optionally methoxy.

23. The compound of any one of claims 1-16, wherein R6is phenyl substituted with halogen, optionally bromine.

24. The compound of any one of claims 1-12, wherein R5is phenyl and R6is methoxyphenyl.

25. The compound of any one of claims 1-24, wherein R7is H.

26. The compound of any one of claims 1-25, wherein each R8is H.

27. The compound of any one of claims 1-25, wherein each R8is halogen, Ci-Cs alkyl, or Ci-Cs alkoxy.Leydig 51588211628. The compound of any one of claims 1-26, wherein each R9is H.

29. The compound of any one of claims 1 -26, wherein R8is halogen, Ci-Cs alkyl, or Ci-Cs alkoxy.

30. The compound of any one of claims 1-29, wherein each instance of Y is independently CR8or N. optionally wherein each instance of R8is hydrogen, halogen, or methyl.

31. The compound of any one of claims 1-30, wherein each instance ofZ is independently CH or N.

32. The compound of any one of claims 1-31, wherein the compound of Formula I is a compound of Formula IA:or pharmaceutically acceptable salt thereof.

33. The compound of any one of claims 1-31, wherein the compound of Formula I is a compound of Formula II or Formula II A:Leydig 51588211734. The compound of any one of claims 1-12 or 25-31, wherein the compound of Formula I is a compound of Formula III or IIIA:Leydig 515882118wherein R16is C1-C3 alkoxy or CN.

35. The compound of any one of claims 1-12 or 25-31, wherein the compound of Formula I is a compound of Formula IV or IVA:Leydig 51588236. The compound of claim 1, wherein the compound is any one of compounds I-1 to 1-43.

37. The compound of claim 1, wherein the compound is:(5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-N, N-dimethyl-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxamide;Leydig 515882((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)(pyrrolidin-l-yl)methanone;azetidin-l-yl((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)- 8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)methanone;Leydig 515882121((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl- 5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)(3-fluoroazetidin- 1 -yl)methanone;((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl- 5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)(morpholino)methanone;Leydig 515882122(5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-N-(2-hydroxyethyl)-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a] py ridine-7-carboxamide;(4,4-difluoropiperidin-l-yl)((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)methanone;Leydig 515882(5bS,6R,7R,8S,8aR)-5,5b,6-trihydroxy-8a-(4-methoxyphenyl)-N, N-dimethyl-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxamide;(3,3-difluoroazelidin-l-yl)((5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-melhoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4.5]furo[2,3-d]imidazo[l,2-a]pyridin-7-yl)methanone;Leydig 515882124(5bS,6R,8S,8aR)-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-6,7,8,8a-tetrahydro- 5bH-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-5b,6-diol;(5bS,6R,7S,8S,8aR)-5-methoxy-8a-(4-methoxyphenyl)-7-(morpholinomethyl)-8-phenyl-6,7,8,8a-tetrahydro-5bH-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-5b,6-diol;Leydig 515882(5bS,6R,7S,8S,8aR)-7-((4,4-difluoropiperidin-l-yl)methyl)-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-6.7.8.8a-tetrahydro-5bH-cyclopenta[4.5]furo[2,3-d]imidazo[l,2-a]pyridine-5b,6-diol;(E)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro- 6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carbaldehyde O-methyl oxime;Leydig 515882(5bS,6R,7R,8S,8aR)-5b,6-dihydroxy-5-methoxy-8a-(4-methoxyphenyl)-8-phenyl-5b,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[2,3-d]imidazo[l,2-a]pyridine-7-carboxylic acid;or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

38. A compound that binds eIF4A with a koff of 0.01 to 0.02; optionally wherein the compound is a compound of any of claims 1-37.

39. A method of preparing a compound according to any of claims 1-37 having the structure of Formula (VI), the method comprising combining a compound of Formula (V) with a compound of Formula (VII):HNLeydig 515882127wherein, in Formula (V), (VII), and (VI), R1, R2, R3, R3a, R5, R6, R7, R8, R9, and R14, are as defined in any of the preceding claims.

40. The method of claim 39, wherein the method comprises combining a compound of Formula (V-A) with a compound of Formula (VII) to provide a compound of Formula (VII-A):Leydig 515882128wherein, in Formula (V-A), (VII), and (VII-A), R1, R2, R3, R3a, R5, R6, R7, R8, R9, and R14, are as defined in any of the preceding claims.

41. The method of claim 28, further comprising reducing the compound of Formula (VII-A) to provide a compound of Formula (VIII):Leydig 51588242. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-38 and a pharmaceutically acceptable excipient.

43. A compound of any one of claims 1-38 or pharmaceutical composition of claim 42 for use to treat a disease.

44. The compound or composition of claim 43, wherein the disease is mediated by eIF4a activity.

45. The compound or composition of claim 43 or 44, wherein the disease is an autoimmune or inflammatory' disease.

46. The compound or composition of claim 45, wherein the disease is an antibody-mediated autoimmune or inflammatory disease.Leydig 51588213047. The compound or composition of claim 43 or 44, wherein the disease is cancer.

48. The compound or composition of any of claims 43-46, wherein the compound reduces IgG expression.

49. The compound or composition any of claims 43-47, wherein the method selectively reduces the number or concentration of plasma B cells compared to the reduction in the number of other B cells or total lymphocytes.

50. A method of inhibiting eIF4a activity or treating a disease in a subject comprising administering to the subject a therapeutically effective amount of compound of any one of claims 1-37 or the pharmaceutical composition of claim 42.

51. The method of claim 50, wherein the disease is mediated by eIF4a activity.

52. The method of claim 51, wherein the disease is an autoimmune or inflammatory disease.

53. The method of claim 52, wherein the disease is an antibody-mediated autoimmune or inflammatory disease.

54. The method of claim 50 or 51, wherein the disease is cancer.

55. The method of any one of claims 50-54, wherein the method reduces IgG expression.

56. The method of any one of claims 50-55, wherein the method selectively reduces the number or concentration of plasma B cells compared to the reduction in the number of other B cells or total lymphocytes.

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