Animal and human anti-malarial agents

Patent metadata

Field	Value
Publication number	US-10420771-B2
Application number	US-201816000968-A
Country	US
Kind code	B2
Filing date	Jun 6, 2018
Priority date	Jun 2, 2016
Publication date	Sep 24, 2019
Grant date	Sep 24, 2019

Abstract

Provided herein are Purine Compounds of Formula (I)

or pharmaceutically acceptable salts, tautomers, isotopologs, or stereoisomers thereof, wherein R 1 , R 2 , and R 3 are as defined herein, compositions comprising an effective amount of a Purine Compound, and methods for treating or preventing malaria comprising the administration of an effective amount of a Purine Compound.

First claim

What is claimed is:

1. A method of treating malaria, comprising administering to a subject having malaria an effective amount of a compound of formula (I),

or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, wherein
R 1 is CR 1a R 1b R 1c , wherein R 1a and R 1b are (C 1-4 )alkyl and R 1c is H or (C 1-4 )alkyl; or R 1a and R 1b form a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, and R 1c is H or (C 1-4 )alkyl;
R 2 is L-R 2a or L-R 2b ,

L is a bond or (C 1-2 alkyl);
R 2a is 3-6 membered N-containing heterocyclyl or heteroaryl, each optionally substituted with one or more (C 1-4 )alkyl, or (C 1-4 )alkyl-NR 2 ;
R 2b is (C 1-4 branched or unbranched alkyl)-NR 2 ,
R 3 is phenyl or pyridyl, substituted with at least one halogen, CN, (C 1-4 )alkyl, or O(C 1-4 )alkyl, wherein the alkyl is optionally fluorinated; and
R is H or (C 1-4 ) alkyl.

2. The method of claim 1 , wherein R 1 is CR 1a R 1b R 1c , wherein R 1a and R 1b are (C 1-2 )alkyl and R 1c is H or (C 1-4 )alkyl.

3. The method of claim 2 , wherein R 1 is isopropyl or t-butyl.

4. The method of claim 1 , wherein R 1 is CR 1a R 1b R 1c , and R 1a and R 1b form a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, and R 1c is H or (C 1-2 )alkyl.

5. The method of claim 4 , wherein R 1a and R 1b form a cyclopropyl, cyclobutyl, cyclopentyl or tetrahydropyranyl.

6. The method of claim 4 , wherein R 1c is H or CH 3 .

7. The method of claim 4 , wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl, 1-methyl-cyclopropyl, 1-methyl-cyclobutyl, 1-methyl-cylopentyl, 1-methyl-tetrahydropyranyl or 4-methyl-tetrahydropyranyl.

8. The method of claim 1 , wherein R 2 is L-R 2a and R 2a is selected from azetidyl, pyrolidinyl, piperidyl, piperazinyl, imidazolyl, octahydrocyclopenta[c]pyrrolyl, or octahydro-1H-isoindolyl.

9. The method of claim 8 , wherein L is a bond, —CH 2 — or —CH 2 CH 2 —.

10. The method of claim 8 , wherein R 2 is substituted with CH 3 , CH 2 CH 3 , or CH 2 CH 2 NH 2 .

11. The method of claim 8 , wherein R 2 is azetidyl, piperidyl, pyrrolidyl, octahydrocyclopenta[c]pyrrolyl, octahydro-1H-isoindolyl, CH 2 -pyrrolidyl, CH 2 CH 2 -pyrrolidyl, CH 2 -piperidyl, CH 2 CH 2 -piperidyl, CH 2 CH 2 -imidazolyl, or CH 2 CH 2 -piperazinyl.

12. The method of claim 1 , wherein R 2 is L-R 2b and R 2b is CH 2 NR 2 , CH 2 CH 2 NR 2 , CH(CH 3 )NR 2 , or C(CH 3 ) 2 NR 2 .

13. The method of claim 12 , wherein L is a bond, —CH 2 — or —CH 2 CH 2 —.

14. The method of claim 12 , wherein R 2 is CH 2 CH 2 NH 2 , CH 2 CH 2 NH(CH 3 ), CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH(CH 3 )NH 2 , or CH 2 C(CH 3 ) 2 NH 2 .

15. The method of claim 1 , wherein R 3 is phenyl substituted with at least one halogen, CN, fluorinated (C 1-2 )alkyl, or O-fluorinated(C 1-2 )alkyl.

16. The method of claim 15 , wherein R 3 is substituted with at least one F, Cl, CN, CHF 2 , CF 3 , or OCF 3 .

17. The method of claim 15 , wherein R 3 is meta-substituted phenyl.

18. The method of claim 1 , wherein R 3 is pyridyl, substituted with at least one halogen, fluorinated (C 1-2 )alkyl, or O-fluorinated(C 1 2)alkyl.

19. The method of claim 18 , wherein R 3 is substituted with at least one Cl, or CF 3 .

20. The method of claim 1 , wherein the compound is:
9-(2-(1H-imidazol-1-yl)ethyl)-N2-tert-butyl-N8-(3-chlorophenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(piperidin-4-yl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(piperidin-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-(1-(2-aminoethyl)piperidin-4-yl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-(1-(2-aminoethyl)piperidin-4-yl)-N2-tert-butyl-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,4-dichlorophenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(4-chlorophenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,4-dichlorophenyl)-9-(pyrrolidin-3-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(pyrrolidin-3-yl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(pyrrolidin-3-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
9-(3-aminopropyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(4-chlorophenyl)-9-(pyrrolidin-3-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(2-(pyrrolidin-1-yl)ethyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
4-(2-(tert-butylamino)-9-(piperidin-4-yl)-9H-purin-8-ylamino)benzonitrile,
N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-(piperidin-4-yl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-(2-(piperidin-1-yl)ethyl)-9H-purine-2,8-diamine,
N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-(2-(pyrrolidin-1-yl)ethyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(2-(pyrrolidin-3-yl)ethyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(2-(pyrrolidin-2-yl)ethyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,5-dichlorophenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(piperidin-4-yl)-N8-(4-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(2-(piperazin-1-yl)ethyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(piperidin-4-ylmethyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(pyrrolidin-3-ylmethyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-(piperidin-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3-chloro-5-fluorophenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3-chloro-5-(trifluoromethyl)phenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,5-difluorophenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(piperidin-4-yl)-N8-(3-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(5-chloropyridin-3-yl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(piperidin-4-yl)-N8-(2-(trifluoromethyl)pyridin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-9-(3-(dimethylamino)propyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3-(difluoromethyl)phenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N2-cyclopropyl-N8-(3,5-dichlorophenyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
9-(1-(2-aminoethyl)piperidin-4-yl)-N2-tert-butyl-N8-(3,5-dichlorophenyl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,4-dichlorophenyl)-9-(1-methylpiperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,4-dichlorophenyl)-9-(1-ethylpiperidin-4-yl)-9H-purine-2,8-diamine,
N2-tert-butyl-N8-(3,5-dichlorophenyl)-9-(pyrrolidin-3-yl)-9H-purine-2,8-diamine,
9-(1-(2-aminoethyl)piperidin-4-yl)-N2-tert-butyl-N8-(3-chloro-5-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,
N8-(3-chloro-5-(trifluoromethyl)phenyl)-N2-cyclopropyl-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N8-(3,5-dichlorophenyl)-N2-(1-methylcyclopropyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N8-(3-chloro-5-(trifluoromethyl)phenyl)-N2-(1-methylcyclopropyl)-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N8-(3,5-dichlorophenyl)-N2-isopropyl-9-(piperidin-4-yl)-9H-purine-2,8-diamine,
N8-(3-chloro-5-(trifluoromethyl)phenyl)-N2-isopropyl-9-(piperidin-4-yl)-9H-purine-2,8-dia

Assignees

• Celgene Corp

Inventors

• Canan Stacie S
• Hawryluk Natalie Anne

Classifications

• A61P43/00

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

• A61P33/06

  Antimalarials · CPC title

• C07C13/06

  with a four-membered ring · CPC title

• G01N33/56905

  Protozoa · CPC title

• A61K31/52 Primary

  Purines, e.g. adenine · CPC title