Antimalarial agents

Patent metadata

Field	Value
Publication number	US-12338219-B2
Application number	US-202017776040-A
Country	US
Kind code	B2
Filing date	Nov 16, 2020
Priority date	Nov 19, 2019
Publication date	Jun 24, 2025
Grant date	Jun 24, 2025

Abstract

The present invention provides methods of treating malaria comprising administration of compounds of Formula (I) or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the variables are as defined herein. The invention also provides uses of the compounds of Formula (I), as defined herein, for the possible inhibition of plasmepsin X, plasmepsin IX or plasmepsin X and IX activity, for treating a Plasmodium infection, and for treating malaria. Also provided are methods of treatment further comprising administration of one or more additional anti-malarial compounds.

First claim

What is claimed:

1. A compound having the structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a heterocycloalkyl, C 3 -C 12 cycloalkyl, aryl or C 1 -C 6 alkylaryl, wherein the heterocycloalkyl, C 3 -C 12 cycloalkyl, aryl, C 1 -C 6 alkylaryl is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OH, alkoxy, haloalkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, spiroC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1 -C 6 alkylN(R 7 )(R 8 );
R 2 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH;
R 3 is hydrogen, halogen, CN, OH, C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl;
R 4 is hydrogen, halogen, CN, OH, C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl;
R 5 is hydrogen, halogen, CN, OH, alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 ) or when taken with R 6 forms a C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl;
R 6 is hydrogen, halogen, CN, OH, alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 ) or when taken with R 5 forms a C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl;
R 7 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH;
R 8 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH; and
R 9 is hydrogen, halogen, CN, alkoxy, C 1 -C 6 alkyl, heterocycloalkyl, heteroaryl, C 3 -C 12 cycloalkyl, aryl, COOH, oxo, COOC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, OH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ), wherein the C 1 -C 6 alkyl can be unsubstituted or substituted with one, two or three substituents selected from the group consisting of halogen, CN, OH, alkoxy, heterocycloalkyl, heteroaryl, C 3 -C 12 cycloalkyl, aryl, COOH, oxo, COOC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, OH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ), and wherein the heterocycloalkyl, heteroaryl, C 3 -C 12 cycloalkyl and aryl can be unsubstituted or substituted with one, two or three substituents selected from the group consisting of halogen, CN, OH, alkoxy, C 1 -C 6 alkyl, COOH, oxo, COOC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, OH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ).

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:

wherein R 1 is unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of halogen, CN, OH, alkoxy, haloalkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, spiroC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1 -C 6 alkylN(R 7 )(R 8 );
R 7 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH; and
R 8 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:

wherein R 1 is unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of halogen, CN, OH, alkoxy, haloalkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl and C 1 -C 6 alkylOH.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:

wherein R 1 is unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of halogen, CN, OH, alkoxy, haloalkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, spiroC 3 -C 6 cycloalkyl, and C 1 -C 6 alkylOH.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a chromane or indane moiety.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, halogen or C 1 -C 6 alkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, halogen or C 1 -C 6 alkyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are independently selected from hydrogen or C 1 -C 6 alkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are independently selected from methyl or ethyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen, C 1 -C 6 alkyl, heteroaryl, or aryl, wherein the C 1 -C 6 alkyl, heteroaryl or aryl can be unsubstituted or substituted with one, two or three substituents selected from the group consisting of halogen, CN, OH, alkoxy.

13. A compound selected from the group consisting of:

Assignees

• Merck Sharp & Dohme Llc
• Msd R&D China Co Ltd
• Walter & Eliza Hall Inst Medical Res
• Merch Sharpe & Dohme LLC

Inventors

• Mccauley John A
• De Lera Ruiz Manuel
• Guo Zhuyan
• Hu Bin
• Kelly Iii Michael J
• Lei Zhiyu
• Olsen David B
• Sleebs Brad
• Zhan Dongmei
• Zhao Lianyun

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P33/06

  Antimalarials · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07D239/22 Primary

  with hetero atoms directly attached to ring carbon atoms · CPC title