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US 2020/0392147 A1Published application
Amidino- and amino-rocaglates as novel translation inhibitors and anticancer agents
AssigneeTrustees of Boston University
InventorsJohn A. Porco, Jr., Wenhan Zhang, Jerry Pelletier, Jennifer Chu
Life of this patent
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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.
Claims30
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.
20 more elements
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.
13 more elements
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.
1 more element
Dependencies are inferred from the claim text.