Quinazolinone inhibitors of dynein
AssigneeThe Board of Trustees of the Leland Stanford Junior University
InventorsJames K. Chen, Tarun M. Kapoor, Ari J. Firestone, Joshua S. Weinger
Life of this patent
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Abstract
Compounds of formula (I) in which R3 is chosen from hydrogen, cyano, nitro, acetyl and C(═O)NH2, and Ar is optionally substituted monocyclic or bicyclic aryl or heteroaryl, are useful as antitumor agents.
Claims17
A compound of formula
- wherein
- R1 and R2 are independently chosen from hydrogen, halogen, (C1-C10)hydrocarbon, —O—(C1-C6)alkyl, fluoro(C1-C6)alkyl, —O—(C1-C6)fluoroalkyl, hydroxy, methylenedioxy, ethylenedioxy, —CN, —S—(C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)acyl, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)acylamino and -A-R10, wherein A is a (C1-C6)hydrocarbon and R10 is chosen from —O—(C1-C6)alkyl, fluoro(C1-C6)alkyl, —O—(C1-C6)fluoroalkyl, hydroxy, —CN, nitro, —S—(C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)acyl, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino and (C1-C6)acylamino;
- R3 is chosen from cyano, nitro, acetyl and —C(═O)NH2;
- R4 and R5 are independently chosen from hydrogen and methyl;
- Y is O or NR8;
- R8 is chosen from hydrogen and (C1-C7)hydrocarbon and
- Ar is chosen from;
- a. phenyl substituted with from one to three substituents independently chosen from halogen, (C1-C10)hydrocarbon, fluoro(C1-C6)alkyl, —O(C1-C6)fluoroalkyl, —CN, nitro, (C1-C6)alkoxycarbonyl and (C1-C6)acyl;
- b. naphthyl, thiophenyl, furanyl, pyrrolyl, and pyridinyl, any of which may be optionally substituted with from one to three substituents independently chosen from halogen, (C1-C10)hydrocarbon, fluoro(C1-C6)alkyl, —O(C1-C6)fluoroalkyl, —CN, nitro, (C1-C6)alkoxycarbonyl and (C1-C6)acyl;
- and
- c. optionally substituted bicyclic aryl or heteroaryl;
- with the proviso that, when Y is O, Ar is 2,4-dichlorophenyl and R1, R2, R4 and R5 are hydrogen, R3 is not cyano.
A method of inhibiting a dynein comprising bringing said dynein into contact with a compound of formula
- wherein
- R1a is hydrogen or halogen;
- and
- R6 and R7 are halogen.
A method of inhibiting retrograde cilial transport comprising bringing a cell having at least one cilium into contact with a compound of formula
- wherein
- R1a is hydrogen or halogen;
- and
- R6 and R7 are halogen.
A method of inhibiting the growth of a solid tumor comprising bringing said solid tumor into contact with a compound of formula
- wherein
- R1 and R2 are independently chosen from hydrogen, halogen, (C1-C10)hydrocarbon, —O—(C1-C6)alkyl, fluoro(C1-C6)alkyl, —O—(C1-C6)fluoroalkyl, hydroxy, methylenedioxy, ethylenedioxy, —CN, nitro, —S—(C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)acyl, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)acylamino and -A-R10, wherein A is a (C1-C6)hydrocarbon and R10 is chosen from —O—(C1-C6)alkyl, fluoro(C1-C6)alkyl, —O—(C1-C6)fluoroalkyl, hydroxy, —CN, nitro, —S—(C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)acyl, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino and (C1-C6)acylamino;
- R3 is chosen from hydrogen, cyano, nitro, acetyl and —C(═O)NH2;
- R4 and R5 are independently chosen from hydrogen and methyl;
- Y is O or NR8;
- R8 is chosen from hydrogen and (C1-C7)hydrocarbon and Ar is optionally substituted monocyclic or bicyclic aryl or heteroaryl;
- with the proviso that, when Y is O, Ar is 2,4-dichlorophenyl and R1, R2, R4 and R5 are hydrogen, R3 is not cyano.
Dependencies are inferred from the claim text.