# US 2020/0392147 A1 · Amidino- and amino-rocaglates as novel translation inhibitors and anticancer agents

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- Number: US 2020/0392147 A1
- Document ID: US20200392147A1
- Status: Published application
- Kind: A1
- Application number: 16/898,959
- Filed: 2020-06-11
- Published: 2020-12-17
- Earliest claimed: 2019-06-12
- Assignees: Trustees of Boston University
- Applicants: Trustees of Boston University
- Inventors: John A. Porco, Jr.; Wenhan Zhang; Jerry Pelletier; Jennifer Chu
- Web page: https://patentgrep.com/patent/US20200392147A1

## CPC

- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 491/147: the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
- C07D 513/14: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Herein are described the preparation of a series of synthetic rocaglates, amidino- and amino-rocaglates, which display inhibition of protein translation and tumor cell proliferation (in vitro and in vivo). The methods described herein allow the preparation of libraries of modified rocaglates. This chemical modification of the rocaglate scaffold changes the C8b-hydroxyl of the natural product series to a more optimal hydrogen bond donor/acceptor.

## Claims

### Claim 1

A compound having the structure of Formula (A):
or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof,
wherein:
X10 is CRARB, O, S, NRA, C(O), C═CRARB, SO, or SO2
W10 is CHR16 or C(═Y10);
Y10 is O, S, or NRA;
Z10 is O, S or NR15′;
Ring A is a heteroaryl or aryl;
M10 is S(═O)R14R17, C(R14R17), S(O), S(O2) C(O), C═CHR14, or C═NR14;
R10 is 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, SO2NHRA, 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;
R11 is 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)NRARB, NRAC(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]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)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 R12 and R13 together with the carbon atoms they are attached to form a 3-8 membered cycloalkyl or heterocyclyl;
R14 is H, halogen, C(R18R19)R20, 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)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;
R15 and 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)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)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 R14, and R15 together 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 R15 or R15′ together with R17 forms a second bond between the nitrogen and carbon atoms they are attached to;
R16 is 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)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;
R18, R19 and R20 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, SO2RA, SO3RA, SO2NHRA, 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, optionally provided that at least one of R18, R19 and R20 is not H;
RA, RB and RC independently 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 RA and RB together with the nitrogen atom to which they are attached form a heterocyclyl ring;
wherein any alkyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, or 3 groups selected from OH, CN, SH, SO2NH2, SO2(C1-C4)alkyl, SO2NH(C1-C4)alkyl, halogen, NH2, NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1-C8)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, NH2—C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2—C(O)-lower alkyl, C(O)-lower alkyl, alkylcarbonylaminyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m—(CH2)p—NH2 or CH2-aryl-alkoxy; or wherein any alkyl, cycloalkyl or heterocyclyl is optionally substituted with oxo; and
“m” and “p” are 1, 2, 3, 4, 5 or 6.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is of Formula (A′):

### Claim 3 (depends on 1)

The compound of claim 1, wherein M10 is C(R14R17) and Z10 is NR15′.

### Claim 4 (depends on 3)

The compound of claim 3, wherein one of R15 or R15′ together with R17 forms a second bond between the nitrogen and carbons atoms they are attached to.

### Claim 5 (depends on 3)

The compound of claim 3, wherein the compound is of Formula (I):

### Claim 6 (depends on 3)

The compound of claim 3, wherein the compound is of Formula (II):

### Claim 7 (depends on 1)

The compound of claim 1, wherein R14 is C(R18R19)R20, provided that at least one of R15, R19 and R20 is not H.

### Claim 8 (depends on 1)

The compound of claim 1, wherein:
X10 is O, S, NH, N(C18-C19)alkyl, N(aryl), N(heteroaryl), N(cycloalkyl), or N[(C(O)O(C1-C8)alkyl];
R10 is an aryl or heteroaryl;
R11 is NO2, CN, SO2RA, aryl, heteroaryl, C(O)O(C1-C8)alkyl, (C2-C8)alkenyl), C(O)NRARB or —CO2H;
W10 is C(═Y10);
Y10 is O, NH, S, NHOH, or NHOMe;
R12 is H, OH, aryl, heteroaryl, cycloalkyl, C1-C8(alkyl), O(C1-C8)alkyl, N[O(C1-C8)alkyl][(C1-C8)alkyl], NH[(C1-C8)alkyl], N(OMe)(C1-C8)alkyl, NH[(C1-C8)alkyl] or N[(C1-C8)alkyl]2;
R13 is OH, SH, NH2, NH[(C1-C8)alkyl] or N[(C1-C8)alkyl]2;
R14 is H, (C1-C8)alkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, acyl, allyl, CN, NH2, NH[(C1-C8)alkyl], N[(C1-C8)alkyl]2, OMe, SMe, or OH; and
R15 is H, (C1-C8)alkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, acyl, allyl, CN, NH2, NH[(C1-C8)alkyl], N[(C1-C8)alkyl]2, OMe, SMe, SO3RA, OH, or SH.

### Claim 9 (depends on 1)

The compound of claim 1, wherein:
X10 is O, S, C(O), NH, N(C1-C8)alkyl; N(aryl), N(heteroaryl), N(cycloalkyl), N[(C(O)O(C1-C8)alkyl];
R10 is an aryl or heteroaryl;
R11 is NO2, CN, SO2RA, aryl, heteroaryl, C(O)O(C1-C8)alkyl, (C2-C8)alkenyl), C(O)NRDRE or —CO2H;
W10 is CH2;
R12 is H, OH, aryl, heteroaryl, cycloalkyl, C1-C8(alkyl), O(C1-C8)alkyl, N(OMe)(C1-C8)alkyl, NH[((C1-C8)alkyl) or N[(C1-C8)alkyl]2;
R13 is OH, SH, NH2, NH[(C1-C8)alkyl] or N[(C1-C8)alkyl]2,
R14 is H, (C1-C8)alkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, acyl, allyl, CN, NH2, NH[(C1-C8)alkyl], N[(C1-C8)alkyl]2, OMe, SMe, OH; and
R15′ is H, (C1-C8)alkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, acyl, allyl, CN, NH2, NH[(C1-C8)alkyl], N[(C1-C8)alkyl]2, OMe, SMe, SO3RD, OH, or SH.

### Claim 10 (depends on 1)

The compound of claim 1, wherein:
X10 is O, S, NH, N(C1-C8)alkyl; N(aryl), N(heteroaryl), N(cycloalkyl), or N[(C(O)O(C1-C8)alkyl];
R10 is an aryl or heteroaryl;
R11 is NO2, CN, SO2RA, aryl, heteroaryl, C(O)O(C1-C8)alkyl, (C2-C8)alkenyl), C(O)NRDRE or —CO2H;
W10 is Y20;
Y20 is O, NH, S, NHOH, or NHOMe;
R12 is H, OH, aryl, heteroaryl, cycloalkyl, C1-C8(alkyl), O(C1-C8)alkyl, N[(C1-C8)alkyl]2, N[O(C1-C8)alkyl][(C1-C8)alkyl], N(OMe)(C1-C8)alkyl, NH[(C1-C8)alkyl] or N[(C1-C8)alkyl]2;
R13 is OH, SH, NH2, NH[(C1-C8)alkyl] or N[(C1-C8)alkyl]2;
R14 is H, (C1-C8)alkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, acyl, allyl, CN, NH2, NH[(C1-C8)alkyl], N[(C1-C8)alkyl]2, OMe, SMe, OH;
R15′ is H, (C1-C8)alkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, acyl, allyl, CN, NH2, NH[(C1-C8)alkyl], N[(C1-C8)alkyl]2, OMe, SMe, SO3RD, OH, or SH.

### Claim 11 (depends on 1)

The compound of claim 1, wherein the compound is of Formula (IV) or (IV′):
wherein Ring C is heterocyclyl or heteroaryl.

### Claim 12 (depends on 11)

The compound of claim 11, wherein Ring C is heteroaryl.

### Claim 13 (depends on 11)

The compound of claim 11, wherein Ring C has structure of Formula (XIII):
wherein;
C1 is N, O, S or CR110;
C2 is N, O, S or CR111;
C3 is N, O, S or CR112;
R110, R111 and R112 independently are H, CN, halogen, ORM, SRM, (C1-C8)alkyl, C(O)O(C1-C8)alkyl, C(O)(C1-C8)alkyl, SO2(C1-C8)alkyl, SO2NRMRN, C(O)NRMRN, NRMRN or NRMC(O)RN, and R11 is H or (C1-C8)alkyl;
RM and RN independently 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 RM and RN together with the nitrogen atom to which they are attached of NRMRN or NRMC(O)RN, optionally form a heterocyclyl ring.

### Claim 14 (depends on 1)

The compound of claim 1, wherein Ring A has the structure of Formula (XIV):
wherein;
A1 is N, C(O), NH or CR120;
A2 is N, C(O), NH or CR121;
A3 is N, C(O), NH or CR122;
A4 is N, C(O), NH or CR123; and
R120, R121, R122 and R123 are 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, RP and RQ independently 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 Ro and R together with the nitrogen atom to which they are attached form a heterocyclyl ring.

### Claim 15 (depends on 1)

The compound of claim 1, wherein Ring A has the structure of formula (XV);
wherein;
any two of B1, B2 and B3 are CR130 and N and the remaining ring atom is N(R131) or S, wherein R130 is H, CN, halogen, ORR, SRR, (C1-C8)alkyl, C(O)O(C1-C8)alkyl, C(O)(C1-C8)alkyl, SO2(C1-C8)alkyl, SO2NRRRS, C(O)NRRRS, NRRRS or NRRC(O)RS, and R131 is H or (C1-C8)alkyl;
RR and RS, independently 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 the RR and RS together with the nitrogen atom to which they are attached of NRRRS or NRRC(O)RS, optionally form a heterocyclyl ring.

### Claim 16

A compound having the structure of Formula (B):
or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof,
wherein:
X30 is CRGRH, O, S, NRG, C(O), C═CRGRH, SO, or SO2 Z30 is O, S, or NRG;
A is a heteroaryl or aryl;
R30 is aryl, heteroaryl, cycloalkyl or heterocyclyl;
R31 is 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 R34 independently 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)NHRJ, P(O)(OH)(ORG), P(O)(ORG)(ORH), aryl, heteroaryl, cycloalkyl or heterocyclyl; or R33, and R34 together are O, S, or NRG, or R33, and R34 together are NRG, and RG and R32 are connected and form part of a heterocycle or heteroaryl;
R35 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
RG, RH, RI and RJ independently 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 RG and RH together with the nitrogen atom to which they are attached form a heterocyclyl ring;
wherein any alkyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, or 3 groups selected from OH, CN, SH, SO2NH2, SO2(C1-C4)alkyl, SO2NH(C1-C4)alkyl, halogen, NH2, NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (C1-C8)alkyl, O(C1-C8)alkyl, O(C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, NH2—C(O)-alkylene, NH(Me)-C(O)-alkylene, CH2—C(O)-lower alkyl, C(O)-lower alkyl, alkylcarbonylaminyl, CH2—[CH(OH)]m—(CH2)p—OH, CH2—[CH(OH)]m—(CH2)p—NH2 or CH2-aryl-alkoxy; or wherein any alkyl, cycloalkyl or heterocyclyl is optionally substituted with oxo;
“m” and “p” are 1, 2, 3, 4, 5 or 6.

### Claim 17 (depends on 15)

The compound of claim 15, wherein the compound is of Formula (III):

### Claim 18 (depends on 16)

The compound of claim 16, wherein:
X30 is O, S, CH2, NH, N(C1-C8)alkyl; N(aryl), N(heteroaryl), N(cycloalkyl), N[(C(O)O(C1-C8)alkyl];
R30 is aryl or heteroaryl;
R31 is aryl, heteroaryl, C(O)O(C1-C8)alkyl, (C2-C8)alkenyl), C(O)NRGRH or —CO2H;
R32 is OH, CON[(C1-C8)alkyl]2, CON(OMe)[(C1-C8)alkyl], CO[O(C1-C8)alkyl], CH2[O(C1-C8)alkyl], CH2OH, or (C1-C8)alkyl;
R33 is H;
R34 is OH, SH, NH2, NH(C1-C8)alkyl or N[C1-C8)alkyl]2;
Z is O, S or NH
R35 is H, (C1-C8)alkyl, aryl, heteroaryl, cyclalkyl, C(O)O(C1-C8)alkyl, NMe2 or OMe.

### Claim 19 (depends on 16)

The compound of claim 16, wherein the compound is of Formula (B′):
wherein:
R200 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;
RG, RH, RI and RI independently 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 RG and RHtogether with the nitrogen atom to which they are attached form a heterocyclyl ring; and
D1 is N, C(O), NH or CR210;
D2 is N, C(O), NH or CR220;
R210 and R220 are 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, SO2NR, 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, RP and RQ independently 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 Ro and R together with the nitrogen atom to which they are attached form a heterocyclyl ring.

### Claim 20 (depends on 19)

The compound of claim 19, wherein the compound is of Formula (III′):

### Claim 21

A method for preparing a compound having the Formula (A), the method comprising:
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;
wherein the structures of (V) and (VI) are:
wherein R26 is a (C1-C3)alkyl, CH3, aryl, CF3, alkyl substituted aryl, or methyl aryl.

### Claim 22 (depends on 1)

A method for treating a eIF4A dependent condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound claim 1.

### Claim 23 (depends on 22)

The method of claim 22, wherein the eIF4A dependent condition is a disease of uncontrolled cell growth, proliferation and/or survival, a disease of inappropriate cellular inflammatory responses, a disease caused by a parasite or a neurodegenerative disease requiring neuroprotection.

### Claim 24 (depends on 23)

The method of claim 23, wherein the parasite is a fungus or a virus.

### Claim 25 (depends on 23)

The method of claim 23, wherein the eIF4A dependent condition is cancer.

### Claim 26 (depends on 23)

The method of claim 23, wherein the eIF4A dependent condition is a solid tumor, colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, malignant glioma, fibrotic diseases, glioblastoma, hepatocellular cancers, thyroid cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, melanoma, multiple melanoma, myeloma, pancreatic cancer, pancreatic carcinoma, renal cell carcinoma, renal cancer, cervical cancer, urothelial cancer, prostate cancer, castration-resistant prostate cancer, ovarian cancer, breast cancer, triple-negative breast cancer, leukemia, acute myeloid leukemia, Hodgkins lymphoma, non-Hodgkins lymphoma, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, multiple myeloma, myelodysplastic syndrome, Alzheimer's, Parkinson's, Fragile X Syndrome and autism disorders.

### Claim 27 (depends on 23)

The method of claim 23, wherein the eIF4A dependent condition is diffuse large B-cell lymphoma, hepatocellular cancers, acute myeloid leukemia, breast cancer, colorectal cancer, small cell lung cancer, metastasis of tumors and non-small cell lung cancer.

### Claim 28 (depends on 23)

The method of claim 23, further comprising administering one or more additional therapy.

### Claim 29 (depends on 28)

The method of claim 28, wherein the one or more additional or combination therapy is an antiviral agent.

### Claim 30 (depends on 29)

The method of claim 29, wherein the antiviral compound is one or more of ribavirin, daclatasvir, sofosbuvir, velpatasvir, ledipasvir/sofosbuvir, telaprevir, interferon aphacon-1, interferon alpha-2b, glecaprevir and pibrentasvir, simeprevir, pegylated interferon, pegylated interferon alpha-2b, interferon alpha-2a, elbasvir, and grazoprevir.