FIELD OF THE INVENTION

This invention relates to rocaglate (flavagline) derivatives. More particularly, the invention is directed to rocaglate compositions, their syntheses, and uses.

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 14, 2020, is named 701586-095300USPT_SL.txt and is 9,733 bytes in size.

BACKGROUND

Translation is an essential step in the gene expression pathway that enables cells to make rapid and spatiotemporal alterations to the proteome. Regulation of translation is critical to a wide variety of biological processes, including cellular growth, survival, differentiation, and development. Accordingly, aberrant translational control is associated with several pathological disorders. Small molecules targeting the translation machinery show considerable promise in the treatment of a variety of human maladies including cancer, viral infection, and neurodegeneration. In particular, there is significant interest towards the development of a family of compounds collectively known as rocaglates (flavaglines), a family of natural products found in plants of the genusAglaia.

AglaiaLour. is a large genus of angiosperm plants containing more than 120 species. In 1982, the first rocaglate was isolated from dried roots and stems ofAglaia elliptifoliaMerr. Since this time, over thirty natural products of the rocaglate family have been discovered sharing a highly substituted cyclopenta[b]benzofuran with five contiguous stereocenters. In the last several decades, numerous chemical syntheses of rocaglates have been reported due to their intriguing structures. These natural products exhibit many interesting biological activities including the inhibition of the eukaryotic translation apparatus. For example, the rocaglate congener silvestrol was found to inhibit the eIF4F complex by interfering with the function of the DEAD box RNA helicase eIF4A (SEQ ID NO: 1). Additionally, silvestrol has antitumor activity in a variety of pre-clinical murine cancer models including hematological and solid tumor types.

Chemical syntheses of cyclopenta[b]benzofuran natural products and analogues have revealed structure-activity relationships (SAR) for antineoplastic activity in cancer cell lines leading to improved activity. In particular, the C8a tertiary hydroxyl has been shown to be critical which appears to be related to its role as a hydrogen bond (H-bond) donor; alkylation of this tertiary hydroxyl completely eliminates cytotoxicity. Recently, Iwasaki and coworkers determined the co-crystal structure of rocaglamide bound to a human eIF4A-polypurine RNA complex which, among the interactions identified, was hydrogen bonding between the C8a tertiary hydroxyl of rocaglamide and N7 of a purine RNA base. Replacement of the tertiary hydroxyl with other substituents is an approach expressed in the literature for furthering SAR studies but has been frustrated by the difficulty in achieving chemical modification of this scaffold position.

In order to allow for broader evaluation of rocaglates as therapeutic agents, new methods for their preparation are urgently needed. In addition, expansion of SAR studies requires procurement of novel compounds. Accordingly, there is a continuing need for development of new rocaglates as therapeutic agents and synthetic methods needed to prepare these new compounds.

SUMMARY

In general, the inventions described herein relate to rocaglate compositions, methods for making rocaglates, as well as their usage as therapeutic agents. For example, the preparation and structures of rocaglates that can be used for treatments of eIF4A-dependent conditions such as cancer and other conditions are described.

A first aspect according to the description is a compound having the structure of Formula (A):


or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

In compounds of Formula (A), X10is CRARB, O, S, NRA, C(O), C═CRARB, SO, or SO2; W10is CHR16or C(═Y10) where Y10is O, S, or NRA; Z10is O, S or NR15; Ring A is a heteroaryl or aryl; M10is S(═O)R14R17, C(R14R17), S(O), S(O2) C(O), C═CHR14, or C═NR14; R10is H, halogen, CN, (C1-C8)alkyl, (C1-C8)haloalkyl, (C2-C8)alkenyl), (C2-C8)alkynyl, ORA, NRARB[(C1-C8)alkylene]ORA, [(C1-C8)alkylene]NRA, [(C1-C8)alkylene]NRARB, C(O)RA, C(O)NHRA, C(O)NRARB, C(O)[(C1-C8)alkylene]NHRA, C(O)[(C1-C8)alkylene]NRARB, CO2RA, C(S)NHRA, C(S)NRARB, SRA, S(O)RA, SO2RA, SO2NHRA, SO2NRARB, NHC(O)RA, NRAC(O)RBNHC(O)NHRA, NHC(O)NRARB, NRAC(O)NRB, NRAC(O)NRBRC, P(O)(OH)(ORA), P(O)(ORA)(ORB), aryl, heteroaryl, cycloalkyl or heterocyclyl; R11is H, halogen, NO2, CN, (C1-C8)alkyl, (C1-C8)haloalkyl, (C2-C8)alkenyl), (C2-C8)alkynyl, ORA, NRARB, [(C1-C8)alkylene]ORA, [(C1-C8)alkylene]NHRA, [(C1-C8)alkylene]NRARB, C(O)RA, C(O)NHRA, C(O)NRARB, C(O)[(C1-C8)alkylene]NHRA, C(O)[(C1-C8)alkylene]NRARB, CO2RA, C(S)NHRA, C(S)NRARB, SRA, S(O)RA, SO2RA, SO2NHRA, SO2NRARB, NHC(O)RA, NRAC(O)RB, NHC(O)NHRA, NHC(O)NRARBNRAC(O)NHRB, NRAC(O)NRBRC, P(O)(OH)(ORA), P(O)(ORA)(ORB) aryl, heteroaryl, acyl, ester, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, amido, or —CO2RA; R12, and R13, independently are H, halogen, CN, (C1-C8)alkyl, (C1-C8)haloalkyl, (C2-C8)alkenyl), (C2-C8)alkynyl, ORA, NRARB, [(C1-C8)alkylene]ORA, [(C1-C8)alkylene]NHRA, [(C1-C8)alkylene]NRARB, C(O)RA, C(O)NHRA, C(O)NRARB, C(O)[(C1-C8)alkylene]NHRA, C(O)[(C1-C8)alkylene]NRARB, CO2RA, C(S)NHRA, C(S)NRARB, SRA, S(O)RA, SO2RASO2NHRA, SO2NRARB, NHC(O)RA, NRAC(O)RB, NHC(O)NHRA, NHC(O)NRARB, NRAC(O)NHRB, NRAC(O)NRBRC, P(O)(OH)(ORA), P(O)(ORA)(ORB), aryl, heteroaryl, cycloalkyl or heterocyclyl; or R12and R13together with the carbon atoms they are attached to form a 3-8 membered cycloalkyl, heterocyclyl; R14is H, halogen, (R18R19)R20, CN, C1-C8(alkyl), (C1—C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, ORANRARB, [(C1-C8)alkylene]ORA, [(C1-C8)alkylene]NHRA, [(C1-C8)alkylene]NRARB, C(O)RA, C(O)NHRA, C(O)NRARBC(O)[(C1-C8)alkylene]NHRA, C(O)[(C1-C8)alkylene]NRARB, CO2RA, C(S)NHRA, C(S)NRARB, SRA, S(O)RA, SO2RA, SO3RA, SO2NHRA, SO2NRARB, NHC(O)RA, NRAC(O)RB, NHC(O)NHRA, NHC(O)NRARB, NRAC(O)NHRBNRAC(O)NRBRC, P(O)(OH)(ORA), P(O)(ORA)(ORB) aryl, heteroaryl, cycloalkyl or heterocycly; R15and R15′ independently are H, halogen, CN, C1-C8(alkyl), (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, ORA, NRARB, [(C1-C8)alkylene]ORA, [(C1-C8)alkylene]NHRA, [(C1-C8)alkylene]NRARB, C(O)RA, C(O)NHRA, C(O)NRARBC(O)[(C1-C8)alkylene]NHRA, C(O)[(C1-C8)alkylene]NRARB, CO2RA, C(S)NHRA, C(S)NRARB, SRA, S(O)RA, SO2RA, SO3RA, SO2NHRA, SO2NRARB, NHC(O)RA, NRAC(O)RB, NHC(O)NHRA, NHC(O)NRARB, NRAC(O)NHRBNRAC(O)NRBRC, P(O)(OH)(ORA), P(O)(ORA)(ORB) aryl, heteroaryl, cycloalkyl or heterocyclyl; or R14, and R15together with the carbon or nitrogen they are bound to form a heterocyclyl or heteroaryl, or R14, and R15′ together with the carbon or nitrogen they are bound to form a heterocyclyl or heteroaryl, or one of R15or R15′ together with R17forms a second bond between the nitrogen and carbon atoms they are attached to; R16is H, halogen, CN, C1-C8(alkyl), (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, ORA, NRARB[(C1-C8)alkylene]ORA, [(C1-C8)alkylene]NHRA, [(C1-C8)alkylene]NRARB, C(O)RA, C(O)NHRAC(O)NRARB, C(O)[(C1-C8)alkylene]NHRA, C(O)[(C1-C8)alkylene]NRARB, CO2RA, C(S)NHRA, C(S)NRARB, SRA, S(O)RA, SO2RA, SO3RA, SO2NHRA, SO2NRARB, NHC(O)RA, NRAC(O)RBNHC(O)NHRA, NHC(O)NRARB, NRAC(O)NHRBNRAC(O)NRBRC, P(O)(OH)(ORA), P(O)(ORA)(ORB), aryl, heteroaryl, cycloalkyl or heterocyclyl; R15, R19and R20independently are H, halogen, CN, C1-C8(alkyl), (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, ORA, NRARB[(C1-C8)alkylene]ORA, [(C1-C8)alkylene]NHRA, [(C1-C8)alkylene]NRARB, C(O)RA, C(O)NHRA, C(O)NRARB, C(O)[(C1-C8)alkylene]NHRA, C(O)[(C1-C8)alkylene]NRARB, CO2RA, C(S)NHRA, C(S)NRARB, SRA, S(O)RA, SO2RA, SO3RA, SO2NHRA, SO2NRARB, NHC(O)RA, NRAC(O)RBNHC(O)NHRA, NHC(O)NRARB, NRAC(O)NRARB, NRAC(O)NRBRC, P(O)(OH)(ORA), P(O)(ORA)(ORB), aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally at least one of R15, R19and R20is not H; RA, RBand RCindependently are H, —OH, aryl, (C1-C8)alkyl, [(C1-C8)alkyl]aryl (C1-C8)alkoxy, C(O)O(C1-C8)alkyl, (C1-C8)haloalkyl, cycloalkyl, heterocyclyl, [(C1-C8)alkylene]heterocyclyl, [(C1-C8)alkylene]aryl or heteroaryl; or RAand RBtogether with the nitrogen atom to which they are attached form a heterocyclyl ring. Any alkyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, or 3 groups selected from OH, CN, SH, SO2NH2, SO2(C1-C4)alkyl, SO2NH(C1-C4)alkyl, halogen, NH2, NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1-C8)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, NH2—C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2—C(O)-lower alkyl, C(O)-lower alkyl, alkylcarbonylaminyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m—(CH2)p—NH2or CH2-aryl-alkoxy; or wherein any alkyl, cycloalkyl or heterocyclyl is optionally substituted with oxo. “m” and “p” are 1, 2, 3, 4, 5 or 6.

Optionally, the compound of Formula (A) is of Formula (I) or Formula (II):



Optionally, the compound of Formula (A) is of Formula (IV) or (IV′):


wherein Ring C is heterocyclyl or heteroaryl.

A second aspect according to the description is a compound having the structure of formula (B):


or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

In compounds of Formula (B), X30is CRGRH, O, S, NRG, C(O), C═CRGRH, SO, or SO2; Z30is O, S, or NRG; Ring A is a heteroaryl or aryl; R30is aryl, heteroaryl, cycloalkyl or heterocyclyl; R31is H, aryl, heteroaryl, acyl, ester, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, amido, or —CO2RG; R32, is H, halogen, CN, (C1-C8)alkyl, (C1-C8)haloalkyl, (C2-C8)alkenyl), (C2-C8)alkynyl, ORG, NRGRH, [(C1-C8)alkylene]ORG, [(C1-C8)alkylene]NHRG, [(C1-C8)alkylene]NRGRH, C(O)RG, C(O)NHRG, C(O)NRGRH, C(O)[(C1-C8)alkylene]NHRG, C(O)[(C1-C8)alkylene]NRGRH, CO2RG, C(S)NHRG, C(S)NRGRH, SRG, S(O)RG, SO2RG, SO2NHRG, SO2NRGRH, NHC(O)RG, NRGC(O)RH, NHC(O)NHRG, NHC(O)NRGRH, NRGC(O)NHRH, NRGC(O)NRHRJ, P(O)(OH)(ORG), P(O)(ORG)(ORH), aryl, heteroaryl, cycloalkyl or heterocyclyl; R33, and R34independently are H, halogen, CN, (C1-C8)alkyl, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, ORG, NRGRH, [(C1-C8)alkylene]ORG, [(C1-C8)alkylene]NHRG, [(C1-C8)alkylene]NRGRH, C(O)RG, C(O)NHRG, C(O)NRGRH, C(O)[(C1-C8)alkylene]NHRG, C(O)[(C1-C8)alkylene]NRGRH, CO2RG, C(S)NHRG, C(S)NRGRH, SRG, S(O)RG, SO2RG, SO2NHRG, SO2NRGRH, NHC(O)RG, NRGC(O)RH, NHC(O)NHRG, NHC(O)NRGRH, NRGC(O)NHRH, NRGC(O)NRHRJ, P(O)(OH)(ORG), P(O)(ORG)(ORH), aryl, heteroaryl, cycloalkyl or heterocyclyl; or R33, and R34together are O, S, or NRG; RG, RH, RIand RJindependently are H, —OH, aryl, (C1-C8)alkyl, [(C1-C8)alkyl]aryl (C1-C8)alkoxy, C(O)O(C1-C8)alkyl, (C1-C8)haloalkyl, cycloalkyl, heterocyclyl, [(C1-C8)alkylene]heterocyclyl, [(C1-C8)alkylene]aryl or heteroaryl; or wherein the RGand RHtogether with the nitrogen atom to which they are attached form a heterocyclyl ring; or R33, and R34together are NRGand RGand R32are connected and form part of a heterocycle; and R35is H, halogen, CN, (C1-C8)alkyl, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, ORG, NRGRH[(C1-C8)alkylene]ORG, [(C1-C8)alkylene]NHRG, [(C1-C8)alkylene]NRGRH, C(O)RG, C(O)NHRG, C(O)NRGRH, C(O)[(C1-C8)alkylene]NHRG, C(O)[(C1-C8)alkylene]NRGRH, CO2RG, C(S)NHRG, C(S)NRGRH, SRG, S(O)RG, SO2RG, SO2NHRG, SO2NRGRH, NHC(O)RG, NRGC(O)RH, NHC(O)NHRG, NHC(O)NRGRH, NRGC(O)NHRH, NRGC(O)NRHRJ, P(O)(OH)(ORG), P(O)(ORG)(ORH), aryl, heteroaryl, cycloalkyl or heterocyclyl. Any alkyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, or 3 groups selected from OH, CN, SH, SO2NH2, SO2(C1-C4)alkyl, SO2NH(C1-C4)alkyl, halogen, NH2, NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1-C8)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, NH2—C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2—C(O)-lower alkyl, C(O)-lower alkyl, alkylcarbonylaminyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m—(CH2)pNH2or CH2-aryl-alkoxy; or wherein any alkyl, cycloalkyl or heterocyclyl is optionally substituted with oxo. “m” and “p” are 1, 2, 3, 4, 5 or 6.

Optionally, the compound of Formula (B) is of Formula (III):



Optionally, in compound of Formula (B) R33, and R34together are NRGand RGand R32are connected and the compound has the structure (B′):



In compounds of Formula (B′) R200is H, halogen, CN, (C1-C8)alkyl, (C1-C8)haloalkyl, (C2-C8)alkenyl), (C2-C8)alkynyl, ORGNRGRH, [(C1-C8)alkylene]ORG, [(C1-C8)alkylene]NHRG, [(C1-C8)alkylene]NRGRH, C(O)RG, C(O)NHRG, C(O)NRGRH, C(O)[(C1-C8)alkylene]NHRG, C(O)[(C1-C8)alkylene]NRGRH, CO2RG, C(S)NHRG, C(S)NRGRH, SRG, S(O)RG, SO2RG, SO2NHRG, SO2NRGRH, NHC(O)RG, NRGC(O)RH, NHC(O)NHRG, NHC(O)NRGRH, NRGC(O)NHRH, NRGC(O)NRHRJ, P(O)(OH)(ORG), P(O)(ORG)(ORH), aryl, heteroaryl, cycloalkyl or heterocyclyl. RG, RH, and RIindependently are H, —OH, aryl, (C1-C8)alkyl, [(C1-C8)alkyl]aryl (C1-C8)alkoxy, C(O)O(C1-C8)alkyl, (C1-C8)haloalkyl, cycloalkyl, heterocyclyl, [(C1-C8)alkylene]heterocyclyl, [(C1-C8)alkylene]aryl or heteroaryl; or wherein the RGand RHtogether with the nitrogen atom to which they are attached form a heterocyclyl ring; and D1is N, C(O), NH or CR210; D2is N, C(O), NH or CR220; R210and R220are independently are H, halogen, CN, C1-C8(alkyl), (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, ORO, NRORP, [(C1-C8)alkylene]ORO, [(C1-C8)alkylene]NHRA, [(C1-C8)alkylene]NRORP, C(O)RO, C(O)NHRO, C(O)NRORP, C(O)[(C1-C8)alkylene]NHRO, C(O)[(C1-C8)alkylene]NRORP, CO2RO, C(S)NHRO, C(S)NRORP, SRO, S(O)RO, SO2RO, SO2NHRO, SO2NRORP, NHC(O)RO, NROC(O)RP, NHC(O)NHRO, NHC(O)NRORP, NROC(O)NHRP, NROC(O)NRPRQ, P(O)(OH)(ORO), P(O)(ORO)(ORP), tosylate, aryl, heteroaryl, cycloalkyl or heterocyclyl. RO, RPand RQindependently are H, —OH, aryl, (C1-C8)alkyl, [(C1-C8)alkyl]aryl (C1-C8)alkoxy, (C1-C8)haloalkyl, cycloalkyl, heterocyclyl, [(C1-C8)alkylene]heterocyclyl, [(C1-C8)alkylene]aryl or heteroaryl; or ROand RPtogether with the nitrogen atom to which they are attached form a heterocyclyl ring.

Optionally, the compound of Formula (B′) is of Formula (III′),



A third aspect according to the description is a method for preparing a compound having the Formula (A). The method comprises providing a solution of a compound having Formula (V), and reacting the compound (VI), or salts thereof, with a base to provide an intermediate in the solution, and reacting the intermediate with the compound having Formula (VI) or salts thereof. The structures of (V) and (VI) are;


where R26is a (C1-C3)alkyl, CH3, aryl, CF3, alkyl substituted aryl, or methyl aryl.

Optionally, the compound of Formula (V) is of Formula (V′):



A fourth aspect according to the description is a method for preparing a compound having the Formula (B). the method comprises providing a solution of a compound having Formula (IX), and reacting the compound (X) or salts thereof, with a base to provide an intermediate in the solution, and reacting the intermediate with the compound having Formula (IX). The structures of (IX) and (X) are as follows:


where R36is a (C1-C3)alkyl, CH3, aryl, CF3, alkyl substituted aryl, or methyl aryl.

Optionally, the compound of Formula (IX) is of Formula (IX′):



A fifth aspect according to the description is a pharmaceutical composition comprising a compound according to any one of the first, second, third, and fourth aspects and a pharmaceutically acceptable carrier, diluent, or excipient is described.

A sixth aspect according to the description is a method for treating an eIF4A-dependent condition in a subject in need thereof is described. The method comprises administering to the subject a therapeutically effective amount of a compound according to any one of the first, second, third, or fourth aspects.

A seventh aspect according to the description is an antibody-drug conjugate (ADC) is described. The antibody-drug conjugate comprising an antibody covalently attached through a linker to a compound having a structure according the first, second, third, or fourth aspects.

An eighth aspect according to the description is a pharmaceutical composition of the antibody-drug conjugate according to the seventh aspect including a pharmaceutically acceptable carrier, diluent, or excipient is described.

A ninth aspect according to the description is a method for treating an eIF4A-dependent condition in a subject in need thereof is described. The method comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate according to the seventh or eighth aspect.

Rocaglates described herein show high cytotoxicity against cancer cells. The methods for producing modified rocaglates described herein greatly expands the available rocaglates as bioactive agents.

