Substituted pyrimidine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-9567318-B2
Application number	US-201013391148-A
Country	US
Kind code	B2
Filing date	Aug 17, 2010
Priority date	Aug 17, 2009
Publication date	Feb 14, 2017
Grant date	Feb 14, 2017

Abstract

The present subject matter relates to a compound represented by the general formula (I) or (I′) or a pharmacologically acceptable salt thereof; pharmaceutical compositions containing at least one of these compounds; methods of making at least one of these compounds; methods of using at least one of these compounds for treating and/or preventing various cancers and/or proliferation disorders; methods of using at least one of these compounds for monitoring the effectiveness of an anticancer therapy against various cancers. In one embodiment, the subject matter relates to compounds that bind with a level of specificity to heat shock protein 70 (Hsp70). In another embodiment, the subject matter relates to compounds that bind with a level of specificity to inhibit both heat shock protein 70 (Hsp70) and heat shock cognate protein 70 (Hsc70).

First claim

We claim:

1. A compound of formula 2a

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein,
X 5 -X 9 are independently selected from CH, substituted C, and N;
Y is S, SO, SO 2 , CH 2 , CHR, CRR, or CO, wherein R is a lower alkyl chain;
Z is selected from the group consisting of alkenyl, alkynyl, aryl, saturated heterocycle, halogen, nitro, aryloxy, alkoxy, alkenyloxy, hydroxyalkyl, dialkylamino, cycloalkylamino, arylamino, diarylamino, acylamino, carbamyl, substituted and unsubstituted amido, alkylamido, alkylsulfonamido, sulfonamido, —NHSO 2 alkenyl, —NHCOalkenyl, —NHCOalkynyl, —COalkenyl, —COalkynyl, trihalocarbon, thioalkyl, SO 2 -alkyl, —COO-alkyl, —COalkyl, and alkyl-CN;
W 1 and W 2 independently at each occurrence are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycle, halogen, nitro, cyano, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, dialkylamino, cycloalkylamino, arylamino, diarylamino, carbamyl, substituted and unsubstituted amido, alkylamido, alkylsulfonamido, sulfonamido, —NHSO 2 alkenyl —NHCOalkenyl, —NHCOalkynyl, —COalkenyl, —COalkynyl, trihalocarbon, thioalkyl, SO 2 -alkyl, —COO-alkyl, —COalkyl, and alkyl-CN; and
W 3 and W 4 independently at each occurrence are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycle, halogen, hydroxyl, nitro, cyano, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, diarylamino, acylamino, carbamyl, substituted and unsubstituted amido, alkylamido, alkylsulfonamido, sulfonamido, —NHSO 2 alkenyl, —NHCOalkenyl, —NHCOalkynyl, —COalkenyl, —COalkynyl, trihalocarbon, thioalkyl, SO 2 -alkyl, —COO-alkyl, —COalkyl, and alkyl-CN.

2. A compound of formula 2a′

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein,
wherein:
each X and Y is independently selected from the group consisting of optionally substituted straight or branched alkyl, alkenyl, or alkynyl; an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl group; halo; an optionally substituted C 2-22 acyl group; a —NR 4 R 5 group; a —C(O)R 6 group; an -(ethoxy) n -R 6 group, wherein n is 1-12; an optionally substituted alkoxycarbonyl group; an optionally substituted alkyloxy group; an optionally substituted amino group; a nitro group; and a carboxyl group;
R 4 and R 5 are each independently selected from the group consisting of H; optionally substituted straight or branched alkyl, alkenyl, or alkynyl; and —C(O)R 6 ; and
each R 6 is independently selected from the group consisting of an optionally substituted straight or branched alkyl, alkenyl, or alkynyl; an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl group; an optionally substituted alkyloxy group; and an alkylacrylate group.

3. A compound of formula 2a″

or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is independently selected from the group consisting of H; optionally substituted straight or branched alkyl, alkenyl, or alkynyl; an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl group; halo; an optionally substituted C 2-22 acyl group; a —C(O)R 6 group; and an -(ethoxy) n -R 6 group, wherein n is 1-12;
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of H; optionally substituted straight or branched alkyl, alkenyl, or alkynyl; an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl group; an optionally substituted C 2-22 acyl group; a —C(O)R 6 group; and an optionally substituted alkoxycarbonyl group; and
X is selected from the group consisting of optionally substituted straight or branched alkyl, alkenyl, or alkynyl; an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl group; halo; an optionally substituted C 2-22 acyl group; a —NR 4 R 5 group; a —C(O)R 6 group; an -(ethoxy) n -R 6 group, wherein n is 1-12; an optionally substituted alkoxycarbonyl group; an optionally substituted alkyloxy group; an optionally substituted amino group; a nitro group; and a carboxyl group; and
each R 6 is independently selected from the group consisting of an optionally substituted straight or branched alkyl, alkenyl, or alkynyl; an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl group; an optionally substituted alkyloxy group; and an alkylacrylate group;
provided that X does not comprise a bridged ring structure.

4. A compound of formula 3a

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
X 5 -X 9 are independently selected from CH, substituted C, and substituted N;
Y is S, SO, SO 2 , CH 2 , CHR, CRR, CO, O, NH, or NR, wherein R is a lower alkyl or alkoxyl chain;
Z is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycle, halogen, hydroxyl, nitro, cyano, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, diarylamino, acylamino, carbamyl, substituted and unsubstituted amido, alkylamido, alkylsulfonamido, sulfonamido, —NHSO 2 alkenyl, —NHCOalkenyl, —NHCOalkynyl, —COalkenyl, —COalkynyl, trihalocarbon, thioalkyl, SO 2 -alkyl, —COO-alkyl, —COalkyl, and alkyl-CN;
W 1 and W 2 independently at each occurrence are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycle, halogen, hydroxyl, nitro, cyano, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, diarylamino, acylamino, carbamyl, substituted and unsubstituted amido, alkylamido, alkylsulfonamido, sulfonamido, —NHSO 2 alkenyl, —NHCOalkenyl, —NHCOalkynyl, —COalkenyl, —COalkynyl, trihalocarbon, thioalkyl, SO 2 -alkyl, —COO-alkyl, —COalkyl, and alkyl-CN; and
W 3 and W 4 independently at each occurrence are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycle, halogen, hydroxyl, nitro, cyano, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, diarylamino, acylamino, carbamyl, substituted and unsubstituted amido, alkylamido, alkylsulfonamido, sulfonamido, —NHSO 2 alkenyl, —NHCOalkenyl, —NHCOalkynyl, —COalkenyl, —COalkynyl, trihalocarbon, thioalkyl, SO 2 -alkyl, —COO-alkyl, —COalkyl, and alkyl-CN; or W 3 and W 4 may be joined together via a linker, so as to form a fused 5- or 6-membered ring.

5. A compound of formula 2b

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
X 10 and X 11 are independently selected from CH, CH 2 , NH, NR′, O, and S such that aromaticity is maintained, wherein R′ is an alkyl or substituted alkyl chain;
Y is S, SO, SO 2 , CH 2 , CHR, CRR, CO, O, NH, or NR, wherein R is a lower alkyl or alkoxyl chain;
Z is selected from the

Assignees

• Chiosis Gabriela
• Taldone Tony
• Rodina Anna
• Patel Pallav
• Kang Yanlong
• Memorial Sloan Kettering Cancer Center

Inventors

• Chiosis Gabriela
• Taldone Tony
• Rodina Anna
• Patel Pallav
• Kang Yanlong

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D239/60

  Three or more oxygen or sulfur atoms · CPC title

• A61K31/513 Primary

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title